AEPA
United States
Environmental Protection
Agency
EPA/690/R-21/002F | July 2021 | FINAL
Provisional Peer-Reviewed Toxicity Values for
Pentaerythritol Tetranitrate (PETN)
(CASRN 78-11-5)
U.S. EPA Office of Research and Development
Center for Public Health and Environmental Assessment
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Environmental Protection
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EPA/690/R-21/002F
July 2021
https://www.epa.gov/pprtv
Provisional Peer-Reviewed Toxicity Values for
Pentaerythritol Tetranitrate (PETN)
(CASRN 78-11-5)
Center for Public Health and 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
Daniel D. Petersen, MS, PhD, DABT, ATS, ERT
Center for Public Health and Environmental Assessment, Cincinnati, OH
CONTRIBUTOR
Jeffrey Swartout, MS
Center for Public Health and Environmental Assessment, Cincinnati, OH
DRAFT DOCUMENT PREPARED BY
SRC, Inc.
7502 Round Pond Road
North Syracuse, NY 13212
PRIMARY INTERNAL REVIEWERS
Elizabeth Owens, PhD
Center for Public Health and Environmental Assessment, Cincinnati, OH
Q. Jay Zhao, PhD, MPH, DABT
Center for Public Health and Environmental Assessment, Cincinnati, OH
ADDITIONAL INTERNAL REVIEWERS
John C. Lipscomb, PhD, DABT, Fellow ATS
Center for Environmental Solutions and Emergency Response, Cincinnati, OH
Jeffrey Swartout, MS
Center for Public Health and Environmental Assessment, Cincinnati, OH
PRIMARY EXTERNAL REVIEW
Eastern Research Group, Inc.
110 Hartwell Avenue
Lexington, MA 02421-3136
PPRTV PROGRAM MANAGEMENT
Teresa L. Shannon
Center for Public Health and Environmental Assessment, Cincinnati, OH
J. Phillip Kaiser, PhD, DABT
Center for Public Health and Environmental Assessment, Cincinnati, OH
Questions regarding the content of this PPRTV assessment should be directed to the U.S. EPA
Office of Research and Development (ORD) Center for Public Health and Environmental
Assessment (CPHEA) website at https://ecomments.epa.gov/pprtv.
in
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TABLE OF CONTENTS
COMMONLY USED ABBREVIATIONS AND ACRONYMS v
BACKGROUND 1
QUALITY ASSURANCE 1
DISCLAIMERS 2
QUESTIONS REGARDING PPRTVs 2
1. INTRODUCTION 3
2. REVIEW OF POTENTIALLY RELEVANT DATA (NONCANCER AND CANCER) 7
2.1. HUMAN STUDIES 22
2.1.1. Oral Exposures 22
2.1.2. Single-Dose (Acute) Studies 24
2.1.3. Continuous Exposure Studies 24
2.1.4. Inhalation Exposures 25
2.2. ANIMAL STUDIES 25
2.2.1. Oral Exposures 25
2.2.2. Inhalation Exposures 30
2.3. OTHER DATA (SHORT-TERM TESTS, OTHER EXAMINATIONS) 30
2.3.1. Genotoxi city 30
2.3.2. Additional Animal Studies 33
2.3.3. Metabolism/Toxicokinetic Studies 34
2.3.4. Mode-of-Action/Mechanistic Studies 36
3. DERIVATION 01 PROVISIONAL VALUES 38
3.1. DERIVATION OF ORAL REFERENCE DOSES 38
3.1.1. Derivation of a Subchronic Provisional Reference Dose 38
3.1.2. Derivation of a Chronic Provisional Reference Dose 42
3.2. DERIVATION OF INHALATION REFERENCE CONCENTRATIONS 44
3.3. SUMMARY OF NONCANCER PROVISIONAL REFERENCE VALUES 44
3.4. CANCER WEIGHT-OF-EVIDENCE DESCRIPTOR 45
3.5. MODE-OF -ACTION DISCUSSION 46
3.6. DERIVATION OF PROVISIONAL CANCER RISK ESTIMATES 47
3.6.1. Derivation of a Provisional Oral Slope Factor 47
3.6.2. Derivation of a Provisional Inhalation Unit Risk 47
3.6.3. Summary of Cancer Risk Estimates 47
APPENDIX A. SCREENING PROVISIONAL VALUES 48
APPENDIX B. DATA TABLES 51
APPENDIX C. BENCHMARK DOSE MODELING RESULTS 56
APPENDIX D. REFERENCES 69
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COMMONLY USED ABBREVIATIONS AND ACRONYMS
a2u-g
alpha 2u-globulin
IVF
in vitro fertilization
ACGIH
American Conference of Governmental
LC50
median lethal concentration
Industrial Hygienists
LD50
median lethal dose
AIC
Akaike's information criterion
LOAEL
lowest-observed-adverse-effect level
ALD
approximate lethal dosage
MN
micronuclei
ALT
alanine aminotransferase
MNPCE
micronucleated polychromatic
AR
androgen receptor
erythrocyte
AST
aspartate aminotransferase
MOA
mode of action
atm
atmosphere
MTD
maximum tolerated dose
ATSDR
Agency for Toxic Substances and
NAG
N-acetyl-P-D-glucosaminidase
Disease Registry
NCI
National Cancer Institute
BMC
benchmark concentration
NOAEL
no-observed-adverse-effect level
BMCL
benchmark concentration lower
NTP
National Toxicology Program
confidence limit
NZW
New Zealand White (rabbit breed)
BMD
benchmark dose
OCT
ornithine carbamoyl transferase
BMDL
benchmark dose lower confidence limit
ORD
Office of Research and Development
BMDS
Benchmark Dose Software
PBPK
physiologically based pharmacokinetic
BMR
benchmark response
PCNA
proliferating cell nuclear antigen
BUN
blood urea nitrogen
PND
postnatal day
BW
body weight
POD
point of departure
CA
chromosomal aberration
PODadj
duration-adjusted POD
CAS
Chemical Abstracts Service
QSAR
quantitative structure-activity
CASRN
Chemical Abstracts Service registry
relationship
number
RBC
red blood cell
CBI
covalent binding index
RDS
replicative DNA synthesis
CHO
Chinese hamster ovary (cell line cells)
RfC
inhalation reference concentration
CL
confidence limit
RfD
oral reference dose
CNS
central nervous system
RGDR
regional gas dose ratio
CPHEA
Center for Public Health and
RNA
ribonucleic acid
Environmental Assessment
SAR
structure activity relationship
CPN
chronic progressive nephropathy
SCE
sister chromatid exchange
CYP450
cytochrome P450
SD
standard deviation
DAF
dosimetric adjustment factor
SDH
sorbitol dehydrogenase
DEN
diethylnitrosamine
SE
standard error
DMSO
dimethylsulfoxide
SGOT
serum glutamic oxaloacetic
DNA
deoxyribonucleic acid
transaminase, also known as AST
EPA
Environmental Protection Agency
SGPT
serum glutamic pyruvic transaminase,
ER
estrogen receptor
also known as ALT
FDA
Food and Drug Administration
SSD
systemic scleroderma
FEVi
forced expiratory volume of 1 second
TCA
trichloroacetic acid
GD
gestation day
TCE
trichloroethylene
GDH
glutamate dehydrogenase
TWA
time-weighted average
GGT
y-glutamyl transferase
UF
uncertainty factor
GSH
glutathione
UFa
interspecies uncertainty factor
GST
glutathione-S'-transfcrase
UFC
composite uncertainty factor
Hb/g-A
animal blood-gas partition coefficient
UFd
database uncertainty factor
Hb/g-H
human blood-gas partition coefficient
UFh
intraspecies uncertainty factor
HEC
human equivalent concentration
UFl
LOAEL-to-NOAEL uncertainty factor
HED
human equivalent dose
UFS
subchronic-to-chronic uncertainty factor
i.p.
intraperitoneal
U.S.
United States of America
IRIS
Integrated Risk Information System
WBC
white blood cell
Abbreviations and acronyms not listed on this page are defined upon first use in the
PPRTV document.
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PROVISIONAL PEER-REVIEWED TOXICITY VALUES FOR
PENTAERYTHRITOL TETRINITRATE (CASRN 78-11-5)
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 U.S. Environmental Protection Agency (U.S. EPA)
guidance on human health toxicity value derivations.
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.
Currently available PPRTV assessments can be accessed on the U.S. EPA's PPRTV
website at https://www.epa.gov/pprtv. PPRTV assessments are eligible to be updated on a 5-year
cycle and revised as appropriate to incorporate new data or methodologies that might impact the
toxicity values or affect the characterization of the chemical's potential for causing adverse
human-health effects. Questions regarding nomination of chemicals for update can be sent to the
appropriate U.S. EPA Superfund and Technology Liaison (https://www.epa.gov/research/fact-
sliects-regional-science).
QUALITY ASSURANCE
This work was conducted under the U.S. EPA Quality Assurance (QA) program to ensure
data are of known and acceptable quality to support their intended use. Surveillance of the work
by the assessment managers and programmatic scientific leads ensured adherence to QA
processes and criteria, as well as quick and effective resolution of any problems. The QA
manager, assessment managers, and programmatic scientific leads have determined under the
QA program that this work meets all U.S. EPA quality requirements. This PPRTV was written
with guidance from the CPHEA Program Quality Assurance Project Plan (PQAPP), the QAPP
titled Program Quality Assurance Project Plan (PQAPP) for the Provisional Peer-Reviewed
Toxicity Values (PPRTVs) and Related Assessments/Documents (L-CPAD-0032718-QP), and the
PPRTV development contractor QAPP titled Quality Assurance Project Plan—Preparation of
Provisional Toxicity Value (PTV) Documents (L-CPAD-0031971-QP). As part of the QA
system, a quality product review is done prior to management clearance. A Technical Systems
Audit may be performed at the discretion of the QA staff.
All PPRTV assessments receive internal peer review by at least two Center for Public
Health and Environmental Assessment (CPHEA) scientists and an independent external peer
review by at least three scientific experts. The reviews focus on whether all studies have been
correctly selected, interpreted, and adequately described for the purposes of deriving a
provisional reference value. The reviews also cover quantitative and qualitative aspects of the
provisional value development and address whether uncertainties associated with the assessment
have been adequately characterized.
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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
U.S. EPA Office of Research and Development (ORD) CPHEA website at
https://ecomments.epa.gov/pprtv.
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1. INTRODUCTION
Pentaerythritol tetranitrate (PETN), CASRN 78-11-5, belongs to the class of compounds
known as organic nitrates. It is used mainly as a demolition explosive and in the manufacture of
detonating fuses and blasting caps (O'Neil. 2013; Lewis. 2007). Commercial PETN is usually
mixed with plasticized nitrocellulose or synthetic rubber because PETN in its pure form is too
sensitive to friction and impact (NCBI, 2021). PETN is one of the most powerful explosives
known, and along with cyclotrimethylenetrinitramine (RDX), it is the main ingredient in Semtex,
a plastic explosive. Additionally, PETN is one of a number of organic nitrates (e.g., nitroglycerin
[NTG]) used therapeutically as coronary vasodilators in the treatment of cardiovascular
conditions (angina pectoris, acute myocardial infarction, congestive heart failure). However,
PETN was removed from most markets as a treatment option in the early 1990s, with the notable
exception of Eastern Europe, because clear evidence of its efficacy was lacking [for recent
reviews, see Daiber and Miinzel (2015); Miinzel et al. (2013); Miinzel and Gori (2013); O'Neil
(2013); Rutherford and St rut hers (2013); Daiber et al. (2012); Daiber and Miinzel (2010); Daiber
et al. (2009); Gori and Daiber (2009); Kosmicki (2009); Bode-Boger and Koida (2005)1. Its use
(or consideration of use) in western countries has re-emerged, and clinical studies continue to
re-evaluate its efficacy as a treatment for certain cardiovascular disease conditions (Daiber and
Miinzel 2015; Rutherford and Struthcrs. 2013; Kalidindi et al.. 2012; Gori and Daiber. 2009;
Bode-Boger and Koida. 2005). PETN is listed on U.S. EPA's Toxic Substances Control Act's
(TSCA) public inventory (U.S. EPA. 2020b). and it is registered with Europe's Registration,
Evaluation, Authorisation and Restriction of Chemicals (REACH) program (ECHA. 2018).
PETN is subject to the Section 4 Test Rule (U.S. EPA. 2018b) and Section 12(b) Export
Notifications (U.S. EPA. 2016) under TSCA. It is also listed on the 2015 Comprehensive
Environmental Response, Compensation, and Liability Act (CERCLA) Substance Priority List
(ATSDR. 2016).
Commercial PETN is produced by the continuous nitration of pentaerythritol. In this
process, pentaerythritol and nitric acid are fed into a reaction where PETN precipitates, and is
then isolated by dilution with water and filtration (NCBI. 2021). The empirical formula for
PETN is C5H8N4O12, and its structure is shown in Figure 1. Table 1 summarizes its
physicochemical properties. PETN is a white crystalline solid at room temperature and is
extremely explosive, especially when dry, detonating at around 210°C (NOAA. 2016). PETN's
low vapor pressure and Henry's law constant indicate that it is not expected to volatilize from
either dry or moist surfaces. If PETN did partition to the atmosphere, its vapor pressure indicates
that it would exist there in both the vapor and particulate phases. The estimated half-life of
vapor-phase PETN in air by reaction with photochemically produced hydroxyl radicals is
6.6 days. The low water solubility and high soil adsorption coefficient for PETN indicate that it
will have low mobility in soil and is not expected to leach to groundwater or undergo runoff after
a rain event. Based on tests using microbial cultures isolated from river water and sewage sludge,
PETN may undergo some degree of biodegradation in the environment (NCBI. 2021).
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O
Figure 1. Pentaerythritol Tetranitrate (CASRN 78-11-5) Structure
Table 1. Physicochemical Properties of PETN (CASRN 78-11-5)
Property (unit)
Value3
Physical state
Solid
Boiling point (°C)
205-215 (explodes)b
Melting point (°C)
141
Density (g/cm3 at 25°C)
1.73 (predicted average)
Vapor pressure (mm Hg at 25°C)
5.45 x 10-9
pH (unitless)
NA
pKa (unitless)
NA
Solubility in water (mol/L at 25°C)
1.36 x 10-4
Octanol-water partition coefficient (log Kow)
3.03 (predicted average)
Henry's law constant (atm-m3/mol at 25°C)
8.43 x 10 (predicted average)
Soil adsorption coefficient Koc (L/kg)
120 (predicted average)
Atmospheric OH rate constant (cm3/molecule-sec at 25°C)
5.69 x 10-13 (predicted average)
Atmospheric half-life (d)
6.6 (estimated)0
Relative vapor density (air = 1)
NA
Molecular weight (g/mol)
316
Flash point (°C)
170 (predicted average)
aData were extracted from the U.S. EPA CompTox Chemicals Dashboard (PETN, CASRN 78-11-5.
https://comDtox.epa.gov/dashboard/dsstoxdb/resiilts7searclFDTXSID202343Q. Accessed May 4, 2021). All values
are experimental averages unless otherwise noted.
bNC6I (202D.
CU.S. EPA (2012b).
NA = not applicable; PETN = pentaerythritol tetranitrate.
A previous 2010 PPRTV assessment, which this document supersedes, was available for
PETN from the U.S. EPA; no toxicity values are available from other agencies/organizations
(see Table 2).
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Table 2. Summary of Available Toxicity Values for PETN (CASRN 78-11-5)
Source
(parameter)3'b
Value
Notes
Reference0
Noncancer
PPRTV (p-RfD)
2 x 10 3 mg/kg-d
Value is for both the
subchronic and chronic p-RfDs
U.S. EPA (2010) (archived in 2021)
IRIS
NV
NA
U.S. EPA (2020a)
HEAST
NV
NA
U.S. EPA (2011b)
DWSHA
NV
NA
U.S. EPA (2018a)
ATSDR
NV
NA
ATSDR (2018)
IPCS
NV
NA
IPCS (2020)
CalFPA
NV
NA
CalEPA (2019)
OSHA
NV
NA
OSHA (2020a): OSHA (2020b)
NIOSH
NV
NA
NIOSH (2021)
ACGIH
NV
NA
ACGIH (2020)d
Cancer
PPRTV (p-OSF)
4 x 10 3 (mg/kg-d) 1
Screening p-OSF
U.S. EPA (2010) (archived in 2021)
IRIS
NV
NA
U.S. EPA (2020a)
HEAST
NV
NA
U.S. EPA (2011b)
DWSHA
NV
NA
U.S. EPA (2018a)
NTP
NV
NA
NTP (2016)
IARC
NV
NA
IARC (2018)
CalEPA
NV
NA
CalEPA (2019)
ACGIH
NV
NA
ACGIH (2020)
aSources: ACGIH = American Conference of Governmental Industrial Hygienists; ATSDR = Agency for Toxic
Substances and Disease Registry; CalEPA = 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;
PPRTV = provisional peer-reviewed toxicity value.
Parameters: p-OSF = provisional oral slope factor; p-RfD = provisional reference dose.
°Reference date is the publication date for the database and not the date the source was accessed.
dAn ACGIH value for pentaerythritol is available; however, the tetranitrate form (PETN) is expected to have
sufficiently different solubility (and other ADME parameters) making the applicability of this value unclear.
ADME = absorption, distribution, metabolism, excretion; NA = not applicable; NV = not available;
PETN = pentaerythritol tetranitrate.
Literature searches were conducted in January 2016 and updated most recently in
April 2021 for studies relevant to the derivation of provisional toxicity values for PETN
(CASRN 78-11-5). 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: American Conference of
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Governmental Industrial Hygienists (ACGIH), Agency for Toxic Substances and Disease
Registry (ATSDR), California Environmental Protection Agency (CalEPA), Defense Technical
Information Center (DTIC), European Centre for Ecotoxicology and Toxicology of Chemicals
(ECETOC), European Chemicals Agency (ECHA), U.S. EPA Chemical Data Access Tool
(CDAT), U.S. EPA ChemView, U.S. EPA Integrated Risk Information System (IRIS), U.S. EPA
Health Effects Assessment Summary Tables (HEAST), U.S. EPA Office of Water (OW),
International Agency for Research on Cancer (IARC), U.S. EPA TSCATS2/TSCATS8e,
U.S. EPA High Production Volume (HPV), Chemicals via IPCS INCHEM, European Centre for
Ecotoxicology and Toxicology of Chemicals (ECETOC), Japan Existing Chemical Data Base
(JECDB), European Chemicals Agency (ECHA), Organisation for Economic Cooperation and
Development (OECD) Screening Information Data Sets (SIDS), OECD International Uniform
Chemical Information Database (IUCLID), OECD HPV, National Institute for Occupational
Safety and Health (NIOSH), National Toxicology Program (NTP), Occupational Safety and
Health Administration (OSHA), and World Health Organization (WHO).
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2. REVIEW OF POTENTIALLY RELEVANT DATA
(NONCANCER AND CANCER)
Tables 3A and 3B provide overviews of the relevant noncancer and cancer evidence
bases, respectively, for PETN and include all potentially relevant acute and repeated-dose
short-term, subchronic, and chronic studies as well as reproductive and developmental toxicity
studies. Principal studies used in the PPRTV assessment for derivation of provisional toxicity
values are identified in bold. The phrase "statistical significance" and the term "significant,"
used throughout the document, indicate ap-value of < 0.05 unless otherwise specified.
Single-dose studies are not time averaged over 24 hours, as the effects of PETN are related more
to peak exposure levels than longer-term averages as the half-life is much less than 24 hours.
Thus single-dose study dosimetry is expressed as mg/kg rather than mg/kg-day.
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Table 3A. Summary of Potentially Relevant Noncancer Data for PETN (CASRN 78-11-5)
Category3
Number of Male/Female,
Strain, Species, Study
Type, Study Duration,
Reported Doses
Adjusted Dosimetryb
Critical Effects
NOAELb
LOAELb
Reference
(comments)
Notes0
Human
1. Oral (mg/kg-d)
Acute
37 healthy adult male
volunteers (10 placebo,
9 PETN, 18 other nitrates).
Single dose 80-mg tablet.
Once; 0, 1.1 mg/kg
5.7% decrease in systolic
blood pressure; no
toxicologically relevant side
effects reported.
NDr
1.1
Draeoni et al. (2007)
PR
(Double-blind clinical
trial with random
allocation.)
Acute
10 M, 2 F (12 total) heart
failure patients: 8 of the
subjects received both
placebo and PETN
treatment, 4 PETN only.
Time between treatment
administration was
determined by
"return-to-baseline"
hemodynamics. Single dose
40-mg tablet.
Once; 0, 0.57 mg/kg
7-14% decrease in systemic
arterial pressure 20-240 min
after administration; no
toxicologically relevant side
effects reported.
NDr
0.57
Amsterdam et al.
(1980)
(Double-blind clinical
trial, crossover design
[pre- and
post-treatment
comparison].)
PR
Acute
14 M, 5 F (19 total) heart
failure patients. Single dose
80-mg tablet.
Once; 1.1 mg/kg
8-10% decrease in systemic
arterial pressure 1-5 h after
administration, compared with
pretreatment values; no
toxicologically relevant side
effects reported.
NDr
1.1
Shah et al. (1980):
Shellock et al. (1980)
PR
(Clinical trial [pre- and
post-treatment
comparison].)
Acute
15 M angina patients: all
patients received each
treatment at random over a
5-d period (1 treatment/d,
2 treatment d, 3 placebo d).
Single dose 20-, 40-mg
tablets.
Once; 0, 0.29,
0.57 mg/kg
5-10% decrease in systolic
blood pressure in supine or
standing position 90 min after
low- or high-dose
administration, compared with
the placebo; no toxicologically
relevant side effects reported.
NDr
0.29
Daeenais et al. (1969)
PR
(Double-blind clinical
trial, crossover design.)
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Table 3A. Summary of Potentially Relevant Noncancer Data for PETN (CASRN 78-11-5)
Category3
Number of Male/Female,
Strain, Species, Study
Type, Study Duration,
Reported Doses
Adjusted Dosimetryb
Critical Effects
NOAELb
LOAELb
Reference
(comments)
Notes0
Acute
10 M angina patients: each
subject received both
placebo and PETN
treatment; 7-d interval
between different
treatments. Single dose
40-mg tablet.
Once; 0, 0.57 mg/kg
Increased time to exercise-
induced angina (implicit
vasodilation); no effect on
blood pressure; the study
authors did not report whether
any toxicologically relevant
side effects occurred during the
trial.
NDr
0.57
Giles etal. C198D
(Double-blind clinical
trial [pre- and
post-treatment
comparison].)
PR
Acute
10 M healthy adult
volunteers: each subject
received both placebo and
PETN treatment; 7-d
interval between different
treatments. Single dose
2 x 80-mg tablets.
Once; 0, 2.3 mg/kg
Suppression of serum cGMP
increase (vasodilation
precursor); blood pressure
reduced; the study authors did
not report whether any
toxicologically relevant side
effects occurred during the
trial.
NDr
2.3
Henstridee et al.
PR
(2009)
(Double-blind clinical
trial [pre- and
post-treatment
comparison].)
Acute
6 M, 6 F (12 total) healthy
adult volunteers: all patients
received each treatment at
random; 7-d interval
between different
treatments. Single dose 25-,
50-, or 80-mg tablets.
Once; 0, 0.36,0.71,
1.1 mg/kg
Implicit vasodilation
(reduction in plasma viscosity
and capillary erythrocyte
velocity); 7% reduction in
blood pressure at 1.1 mg/kg-d;
the study authors did not report
whether any toxicologically
relevant side effects occurred
during the trial.
0.36
0.71
Bohm and Haustein
(1998)
(Single-blind clinical
trial, crossover design
[pre- and
post-treatment
comparison].)
PR
Short term
5 M healthy and 5 M
coronary artery disease
patients per group; 3 d.
Short-term dose
2 x 150-mg tablets/d.
0, 4.3 mg/kg-d
Suppression of endothelin-1
secretion (suggestive of
vasodilation); no effect on
blood pressure; the study
authors reported no "severe"
side effects.
4.3
NDr
Predel et al. (1995)
(Double-blind clinical
trial.)
PR
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Table 3A. Summary of Potentially Relevant Noncancer Data for PETN (CASRN 78-11-5)
Category3
Number of Male/Female,
Strain, Species, Study
Type, Study Duration,
Reported Doses
Adjusted Dosimetryb
Critical Effects
NOAELb
LOAELb
Reference
(comments)
Notes0
Short term
42 angina patients (40 M,
2 F). 30-mg
extended-release tablets,
either 2 or 4/d. 14 d.
0, 0.86, 1.7 mg/kg-d
6/42 had headache or flushing
side effects, 2/42 had itching
side effect. Reduction in
angina attacks, reduction in
chest pain, reduction in NTG
use. It was not reported which
effects occurred at which dose.
NDr
0.86
Roberts (1958)
(Double-blind, placebo
controlled clinical trial.
Both doses grouped
together for effects)
PR
Short term
Ill pregnant women with
abnormal uterine blood
flow: 57 placebo, 54 PETN.
12-wk duration, 80 mg
2 times/d.
0, 2.3 mg/kg-d
Vasodilation with potential for
reduced blood pressure
(implicit from therapeutic
efficacy). No significant
increase in toxicologically
relevant side effects observed.
NDr
2.3
Schleussner et al.
(2014)
(Double-blind,
placebo-controlled
clinical trial with
random allocation.)
PR; the
2.3-mg/kg-d
dose is
considered a
NO A F.I, for
side effects.
Short term
71 M, 9 F (80 total)
coronary artery disease
patients, 40 placebo,
40 PETN (80 mg
3 times/d). 8-wk duration.
0, 3.4 mg/kg-d
Vasodilation measured by
brachial arterial blood flow;
the study authors did not report
whether any toxicologically
relevant side effects occurred
during the trial.
NDr
3.4
Schnorbus et al. (2010)
(Double-blind, placebo
controlled clinical trial
with random
allocation. Side effects
recorded in subject
diaries, but not
reported.)
PR
10
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Table 3A. Summary of Potentially Relevant Noncancer Data for PETN (CASRN 78-11-5)
Category3
Number of Male/Female,
Strain, Species, Study
Type, Study Duration,
Reported Doses
Adjusted Dosimetryb
Critical Effects
NOAELb
LOAELb
Reference
(comments)
Notes0
Short term
19 M, 2 F (21 total)
subjects completed the
study. Each subject
(alternating) took PETN,
30-mg tablets 4 times/d or
placebo, 4 wk on, 4 wk off.
12-wk duration.
0, 1.7 mg/kg-d
Vasodilation with potential for
reduced blood pressure
(implicit from therapeutic
efficacy); the study authors
reported no "detectable
differences" in incidence of
toxicologically relevant side
effects between PETN and
placebo treatment. Incidence of
side effects similar in both
control and treated groups. No
significant variations in blood
pressure.
NDr
1.7
Aubert et al. (1970)
(Double-blind
placebo-controlled
clinical trial, crossover
design.)
PR; the
1.7-mg/kg-d
dose is
considered a
I.OAF.I. for
vasodilatory
effects and a
NO A F.I, for
side effects.
Short term
10 M, 6 F (16 total)
coronary artery disease
patients and 5 healthy
volunteer controls (sex not
specified); time-release
formulation (Duotrate),
either 30-mg tablets
2 times/d or 45-mg tablets
2 times/d. Various
durations up to 8 wk.
0, 0.86, 1.3 mg/kg-d
Vasodilation with potential for
reduced blood pressure
(implicit from therapeutic
efficacy); 15/16 vs. 8/12 for
the placebo group; side effects
were not elevated compared
with placebo.
NDr
0.86
Cass and Cohen (1961)
(Clinical trial,
placebo -controlled,
blinding not reported.
Extended-release
formulation;
concurrent NTG
treatment.)
PR
11
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Table 3A. Summary of Potentially Relevant Noncancer Data for PETN (CASRN 78-11-5)
Category3
Number of Male/Female,
Strain, Species, Study
Type, Study Duration,
Reported Doses
Adjusted Dosimetryb
Critical Effects
NOAELb
LOAELb
Reference
(comments)
Notes0
Short term
45 M, 27 F (72 total)
coronary heart disease
patients.
Weeks 1-2: placebo
Weeks 3-4: 0.86
Weeks 5-6: placebo
Weeks 7-8: 0.86, or 1.7
Note: 11 subjects
increased to 1.7 mg/kg-d
during second 2-wk
period due to no
improvement in angina
symptoms during
Weeks 3-4.
Dosing 2 x or 4 x 30-mg
extended-release tablets
every 12 h)
0,0.86,1.7 mg/kg-d
Vasodilation with potential
for reduced blood pressure
(implicit from therapeutic
efficacy); 3/72 patients
removed due to side effects at
0.86 mg/kg-d during PETN
treatment (2 with headaches,
other not specified). No
reporting of toxicologically
relevant side effects in
remaining 69 patients during
PETN or placebo treatment.
Side effects not considered
significant.
NDr
0.86
Hedges and Gordon
(1965)
(Single-blind placebo-
controlled clinical
trial, crossover
design.)
PR, PS;
the
0.86-mg/kg-d
dose is
considered a
NOAEL for
side effects.
12
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Table 3A. Summary of Potentially Relevant Noncancer Data for PETN (CASRN 78-11-5)
Category3
Number of Male/Female,
Strain, Species, Study
Type, Study Duration,
Reported Doses
Adjusted Dosimetryb
Critical Effects
NOAELb
LOAELb
Reference
(comments)
Notes0
Short term
493 M, 162 F, stable angina
patients (655 total). 248 M,
79 F placebo (327 total),
245 M, 83 F PETN
(328 total). 12-wk duration;
80 mg, 2 times/d.
0, 2.3 mg/kg-d
Vasodilation with potential for
reduced blood pressure
(implicit from therapeutic
efficacy); 10/328 PETN and
7/327 placebo subjects were
removed from the study for
reasons not well characterized
by the study authors. Some
toxicologically relevant side
effects, similar in number in
the PETN group to the placebo
group, were reported but
otherwise uncharacterized.
Thus, the LOAEL applies to
the vasodilatation elfect, not
the side effects.
NDr
2.3
Oelze et al. (2014)
(Double-blind,
multicenter, clinical
trial with placebo
control and random
allocation. Most
subjects were on
several other drugs,
including
beta-blockers,
antithrombotics,
statins, and ACE
inhibitors.)
PR
Short term
50 angina patients, sex not
reported; 30 mg 2 or
3 times/d; various durations
up to 12 wk.
0, 0.86, 1.3 mg/kg-d;
45 patients received
0.86 mg/kg-d,
5 received
1.3 mg/kg-d. Both
time-release (Duotrate)
and standard
formulation PETN
used.
Vasodilation with potential for
reduced blood pressure
(implicit from therapeutic
efficacy), toxicologically
relevant side effects: giddiness,
light-headedness, vertigo, and
palpations reported in 10/50,
persistent in 1/50, leading to
withdrawal from study.
NDr
0.86
Plot/ (1960)
(Clinical trial,
placebo -controlled,
crossover design,
blinding not reported.
Extended-release
formulation of PETN;
concurrent NTG
treatment. The study
authors did not report
which side effects
occurred at which
dose.)
PR; the
0.86-mg/kg
dose is
considered a
NO A F.I, for
side effects.
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Table 3A. Summary of Potentially Relevant Noncancer Data for PETN (CASRN 78-11-5)
Category3
Number of Male/Female,
Strain, Species, Study
Type, Study Duration,
Reported Doses
Adjusted Dosimetryb
Critical Effects
NOAELb
LOAELb
Reference
(comments)
Notes0
Short term
19 M, IF, angina patients.
Each subject received
placebo and both dose
levels of PETN. Various
durations up to 6 mo.
2 x 10-mg tablets 4 times/d
for Dose 1; 3 x 10-mg
tablets 4 times/d for Dose 2.
0, 1.1, 1.7 mg/kg-d
Vasodilation with potential for
reduced blood pressure
(implicit from therapeutic
efficacy). 6/20 patients
experienced improved
condition at the low dose.
Other effects including
toxicologically relevant side
effects of headaches,
drowsiness, and nausea at the
high dose (absent when
high-dose group reverted to
low dose).
1.1
(but see
comment
about
0.86-mg/kg-
d dose)
1.7
Rosenberg and
PR; the
1.1-mg/kg-d
dose was
considered a
NO A F.I, for
side effects
and the
1.7-mg/kg-d
dose was
considered a
LOAEL for
side effects.
Michelson (1955)
(Double-blind,
placebo-controlled
clinical trial, crossover
design; concurrent
treatment with NTG;
study authors reported
no anginal pain
reduction at
0.86 mg/kg-d for
5 individuals in a
previous trial [i.e., lack
of therapeutic effect].)
Short term
14 M, 6 F, coronary artery
disease patients
(12 placebo, 8 PETN)
Note: Prior to double-blind
study, all subjects had 1 wk
titration with PETN to
determine personal optimal
dose, followed by 1 wk
washout with the placebo,
then 4 wk with PETN or
placebo. PETN doses were
40, 60, or 80 mg, 4 times/d.
0, 2.3, 3.4, 4.6 mg/kg-d
Vasodilation with potential for
reduced blood pressure
(implicit from therapeutic
efficacy);
headache, first 2 wk:
6/8 PETN, 3/12 placebo;
headache, second 2 wk:
5/8 PETN, 2/12 placebo.
NDr
2.3
Shrivastava et al.
(1983)
(Double-blind
placebo-controlled
clinical trial. Actual
doses for each subject
not reported.)
PR
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Table 3A. Summary of Potentially Relevant Noncancer Data for PETN (CASRN 78-11-5)
Category3
Number of Male/Female,
Strain, Species, Study
Type, Study Duration,
Reported Doses
Adjusted Dosimetryb
Critical Effects
NOAELb
LOAELb
Reference
(comments)
Notes0
Short term
22 M, 14 F, angina patients.
4-wk duration; 10-mg
tablet, 8 times/d.
1.1 mg/kg-d
Vasodilation with potential for
reduced blood pressure
(implicit from therapeutic
efficacy); toxicologically
relevant side effects were:
5 headache, 5 nausea,
3 dizziness, 1 insomnia,
1 drowsiness. 2 withdrew due
to side effects (1 dizziness and
palpitation, 1 anorexia and
constipation).
NDr
1.1
Edson et al. (1961)
(Double-blind clinical
trial, no placebo
control group.)
PR; the
LOAEL
applies to
both the
vasodilatation
effect and side
effects.
Short term
37 healthy and
27 cardiovascular disease
patients, sex not reported.
Various durations up to
30 wk, 30-160 mg/d. Doses
were increased
incrementally for some
subjects; others received
high dose throughout.
0.43,0.86, 1.1, 1.4,
1.7, 2.0, 2.3 mg/kg-d;
doses linked to effects
primarily as averages
for specific treatment
groups within a range:
average (range) =
100 (30-140),
101 (30-160),
112 (30-140),
125 (100-160) mg/d,
corresponding to 1.4,
1.6, 1.8 mg/kg-d.
Vasodilation with potential for
reduced blood pressure
(implicit from therapeutic
efficacy); 7/10 patients showed
partial relief of symptoms at
the 100-101-mg/d dose,
indicating therapeutic efficacy;
decreased systolic blood
pressure in 7/21 hypertensive
subjects (dose not specified);
1/64 subjects in the 2.0-mg/kg
dose group complained of
worsening headaches and did
not complete the study. No
control group data reported.
NDr
NDr
Perlman (1952)
(Clinical trial, no
placebo control group.
Poor reporting of
cardiovascular
outcomes; cannot
determine exact doses
or any endpoint.)
PR
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Table 3A. Summary of Potentially Relevant Noncancer Data for PETN (CASRN 78-11-5)
Category3
Number of Male/Female,
Strain, Species, Study
Type, Study Duration,
Reported Doses
Adjusted Dosimetryb
Critical Effects
NOAELb
LOAELb
Reference
(comments)
Notes0
Short term to
subchronic
21 M, 8 F, arteriosclerosis
patients. 7-14 mo
durations. 28 subjects,
10-mg tablets, 4/d;
1 subject 10 mg, 3 times/d;
8 subjects increased to
20 mg, 4 times/d.
0.42-0.57, 1.1 mg/kg-d
in 8 subjects; no
control group.
Vasodilation with potential for
reduced blood pressure
(implicit from therapeutic
efficacy); therapeutic effects
for 23/29 patients at
0.57 mg/kg-d were categorized
as fair (2), good (18), or
excellent (3), based on
decreased number of angina
attacks and decreased need for
NTG; 1/29 had slight nausea at
0.57 mg/kg-d, 1/29 had nausea
and headache at 0.57 mg/kg-d.
NDr
0.57
PhilliDS (1953)
(Clinical case series.
No control [placebo]
group; concurrent
treatment with NTG.)
PR; the
0.57-mg/kg-d
dose is
considered a
LOAEL for
vasodilatory
effects and a
NO A F.I, for
side effects.
Short term
6 M, 4 F, inpatients with
diseases other than
coronary artery disease or
other heart conditions. 4-wk
duration; 10-mg tablet,
4 times/d, Weeks 1-2;
20 mg, 3 times/d,
Weeks 3-4.
2 wk at 0.57 mg/kg-d,
2 wk at 0.86 mg/kg-d
Decreased response to NTG
challenge, suggestive of
development of cross-nitrate
tolerance, toxicological
significance uncertain but
doubtful. Headaches reported
in some individuals but always
associated with NTG
challenge.
NDr
NDr
Schelling and Lasaena
PR
(1967)
(Clinical trial [pre- and
post-treatment]. No
endpoints of
toxicological
significance for PETN
treatment; cannot
establish LOAEL or
NOAEL because of
comorbidities and lack
of placebo group.)
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Table 3A. Summary of Potentially Relevant Noncancer Data for PETN (CASRN 78-11-5)
Category3
Number of Male/Female,
Strain, Species, Study
Type, Study Duration,
Reported Doses
Adjusted Dosimetryb
Critical Effects
NOAELb
LOAELb
Reference
(comments)
Notes0
Short term
10 healthy volunteers per
group (60 mg, 3 times/d),
7 d.
0, 2.6 mg/kg-d
6% decrease in systolic blood
pressure and 18% increase in
heart rate following PETN
administration, compared with
pretreatment. No
toxicologically relevant side
effects reported.
NDr
2.6
J tin et al. (2001)
(Double-blind clinical
trial with random
allocation [pre- and
post-treatment
comparison with
NTG].)
PR; the
2.6-mg/kg-d
dose is
considered a
LOAEL for
vasodilatory
effects and a
NO A F.I, for
side effects.
Short term
28 M healthy volunteers:
80 mg 3 times/d for 6 d
3.4 mg/kg-d (subjects
were their own
controls)
6% decrease in systolic blood
pressure, 7% decrease in
diastolic blood pressure, and
increased blood flow in
forearm following PETN
therapy (compared with
pretreatment). The study
authors did not report whether
any toxicologically relevant
side effects occurred during the
trial.
NDr
3.4
Gori et al. (2003)
(Double-blind clinical
trial with random
allocation [pre- and
post-treatment
comparison with
NTG].)
PR; the
3.4-mg/kg-d
dose is
considered a
LOAEL for
vasodilatory
effects and a
NO A F.I, for
side effects.
Short term
111 pregnant women
(54 PETN, 57 placebo) at
mid-gestation (average
gestational age at
start = 21.5 wk). 0 or 80 mg
2 times/d for 88-90 d
0, 2.1 mg/kg-d;
assuming an average
body weight of 75 kg
for pregnant women
[see Table 8-29 in U.S.
EPA (201 la)l
Vasodilation with potential for
reduced blood pressure
(implicit from the therapeutic
effect of increased
uteroplacental and
fetoplacental perfusion).
NDr
2.1
Bowkalow et al. (2018)
(Double-blind clinical
trial with random
allocation.)
PR; side
effects not
reported.
2. Inhalation (mg/m3)
ND
17
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Table 3A. Summary of Potentially Relevant Noncancer Data for PETN (CASRN 78-11-5)
Category3
Number of Male/Female,
Strain, Species, Study
Type, Study Duration,
Reported Doses
Adjusted Dosimetryb
Critical Effects
NOAELb
LOAELb
Reference
(comments)
Notes0
Animal
1. Oral (mg/kg-d)
Short term
5 M/5 F, F344/N rat, diet,
7 d/wk, 14 d;
0, 620, 1,240, 2,500, 5,000,
or 10,000 ppm.
M: 0, 65.7, 129.0,
347.8, 674, 1,110;
F: 0, 79.0, 168.0,
355.7, 635, 1,310
No compound-related
toxicologically relevant effects
on mortality, clinical signs,
body weight, or gross
necropsy.
1,310 (F)
NDr
Bucher et al. (1990);
NTP (1989)
PR
Short term
5 M/5 F, B6C3F1 mouse,
diet, 7 d/wk, 14 d;
0, 620, 1,240, 2,500, 5,000,
or 10,000 ppm.
M: 0, 173, 308.7,
539.7, 1,380, 2,600;
F: 0, 187,556.9, 703.1,
1,800, 2,530
58-85% decrease in
body-weight gain in females;
13% decrease in terminal body
weight at >1,800 mg/kg-d.
703.1 (F)
1,800 (F)
Bucher et al. (1990);
NTP (1989)
PR
Short term
6 (sex not specified),
mongrel dog, gavage,
7 d/wk, 3 wk;
30 mg/d.
1.3
Coronary effects of uncertain
biological significance
(increased coronary vascular
resistance and mechanical
efficiency; reduced coronary
blood flow, left ventricular
oxygen consumption, and left
ventricular work).
NDr
NDr
Bender et al. (1963)
(Cannot determine
toxicological relevance
or lack thereof because
effects are opposite of
expected biological
action [vasodilation].)
PR
Subchronic
10 M/10 F, F344/N rat,
diet, 7 d/wk, 14 wk;
0, 620, 1,240, 2,500, 5,000,
or 10,000 ppm.
M: 0, 39.1, 88.04,
190.0, 330, 630;
F: 0, 42.8, 85.56,
200.0, 370, 830
Significant changes in
body-weight gain and relative
brain weight at concentration
>200 mg/kg-d.
85.56 (F)
200.0 (F)
Bucher et al. (1990);
NTP (1989)
PR
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Table 3A. Summary of Potentially Relevant Noncancer Data for PETN (CASRN 78-11-5)
Category3
Number of Male/Female,
Strain, Species, Study
Type, Study Duration,
Reported Doses
Adjusted Dosimetryb
Critical Effects
NOAELb
LOAELb
Reference
(comments)
Notes0
Subchronic
10 M/10 F, B6C3F1 mouse,
diet, 7 d/wk, 13 wk;
0, 620, 1,240, 2,500, 5,000,
or 10,000 ppm.
M: 0, 109, 302.6,
362.5, 925, 2,140;
F: 0, 172, 306.3, 632.5,
1,340, 3,120
No observed noncancer effects.
A hepatocellular adenoma was
observed in 1 female mouse at
3,120 mg/kg-d.
3,120 (F)
NDr
Bucher et al. (1990);
NTP (1989)
PR
Chronic
50 M/50 F, F344/N rat,
diet, 7 d/wk, 2 yr;
M: 0, 5,000, or 10,000 ppm;
F: 0, 1,240, or 2,500 ppm.
M: 0, 240, 490;
F: 0, 80, 165
No observed effects.
490 (M)
NDr
Bucher etal. (1990);
NTP (1989)
PR
Chronic
50 M/50 F, B6C3F1 mouse,
diet, 7 d/wk, 2 yr;
0, 5,000, or 10,000 ppm.
M: 0, 810, 1,620;
F: 0, 1,020, 1,936
No observed effects.
1,936 (F)
NDr
Bucher et al. (1990);
NTP (1989)
PR
Chronic
45 M + F (sex ratio not
reported), albino rat, diet,
7 d/wk, 1 yr;
0 or 2 mg/kg-d.
0,2
No observed effects.
NDr
NDr
Donahue (1944)
(Confidence in study is
low due to 50%
mortality from
parasitic infection in
the colony.)
PR
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Table 3A. Summary of Potentially Relevant Noncancer Data for PETN (CASRN 78-11-5)
Category3
Number of Male/Female,
Strain, Species, Study
Type, Study Duration,
Reported Doses
Adjusted Dosimetryb
Critical Effects
NOAELb
LOAELb
Reference
(comments)
Notes0
Reproductive/
Developmental
10 M/10 F, Sprague
Dawley rat, gavage in corn
oil, 7 d/wk, 28 d in males
(premating through
mating), up to 56 d in
females (premating through
PND 3);
0, 100, 500, or
1,000 mg/kg-d.
0, 100, 500, 1,000
No observed effects.
1,000
NDr
Onitin et al. (2009)
PR
(Study did not report
mating/fertility
indices.)
2. Inhalation (mg/m3)
ND
aDuration categories are defined as follows: Acute = exposure for <24 hours; short term = repeated exposure for >24 hours to <30 days; long term
(subchronic) = repeated exposure for >30 days <10% lifespan for humans (>30 days up to approximately 90 days in typically used laboratory animal species); and
chronic = repeated exposure for >10% lifespan for humans (>~90 days to 2 years in typically used laboratory animal species) (U.S. EPA. 2002).
bDosimetry: Doses are presented as ADDs (mg/kg-day), except single-dose studies where mg/kg doses are presented. Where applicable, reported body-weight data were
used if available; if not. reference body-weight values for rodents reported by U.S. EPA (1988) were used; for humans, a default value of 70 kg was used, except for
pregnant women, where 75 kg was used.
°Notes: PR = peer reviewed; PS = principal study.
ACE = angiotensin-converting enzyme; ADD = adjusted daily dose; cGMP = cyclic guanosine monophosphate; F = female(s); LOAEL = lowest-observed-adverse-effect
level; M = male(s); ND = no data; NDr = not determined; NOAEL = no-observed-adverse-effect level; NTG = nitroglycerin; PETN = pentaerythritol tetranitrate;
PND = postnatal day.
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Table 3B. Summary of Potentially Relevant Cancer Data for PETN (CASRN 78-11-5)
Category
Number of Male/Female, Strain, Species, Study
Type, Reported Doses, Study Duration
Dosimetry3
Critical Effects
Reference
Notesb
Human
1. Oral (mg/kg-d)
ND
2. Inhalation (mg/m3)
ND
Animal
1. Oral (mg/kg-d)
Carcinogenicity
50 M/50 F, F344/N rat, diet (0,5,000,
10,000 ppm M: 0,1,240,2,500 ppm F); 2 yr
M: 0,67.2,137;
F: 0,20,41.3
Increases in Zymbal and thyroid gland
tumors (dose related in females)
Bucher et al. (1990):
NTP (1989)
PR, PS
Carcinogenicity
50 M/50 F, B6C3F1 mouse, diet (0, 5,000,
10,000 ppm); 2 yr
M: 0, 122, 243;
F: 0, 153, 290.4
No exposure-related neoplastic lesions
Bucher et al. (1990):
NTP (1989)
PR
2. Inhalation (mg/m3)
ND
'Dosimetry: The units for oral exposures are expressed as HEDs (mg/kg-day); HED = adjusted daily animal dose (mg/kg-day) x (BWa ^ BWh)14 (U.S. EPA. 2005).
using study-specific TWAs (for the control, low-, and high-dose groups, respectively) of 0.433, 0.419, and 0.413 kg for male rats; 0.289, 0.276, and 0.284 kg for female
rats; 0.0371, 0.0354, and 0.0369 kg for male mice; 0.0363, 0.0332, and 0.0368 kg for female mice; and 70 kg for humans (U.S. EPA. 2011c).
bNotes: PR = peer reviewed; PS = principal study.
BW = body weight; F = female(s); HED = human equivalent dose; M = male(s); ND = no data; PETN = pentaerythritol tetranitrate; TWA = time-weighted average.
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2.1. HUMAN STUDIES
2.1.1. Oral Exposures
Data regarding oral PETN exposure in humans are available from numerous clinical
studies. The therapeutic effects of oral PETN administration are similar to other nitrovasodilators
that increase coronary blood supply to the heart and decrease myocardial oxygen demands
through preferential dilation of large veins and arteries via smooth muscle relaxation (Kiemenska
and Beresewicz. 2009; Kosmicki. 2009; Daibcr et al.. 2008; Murad, 1990). Historically, the
typical oral dosage of PETN used to treat angina pectoris has been 10-80 mg as a tablet up to
4 times daily or 30-80 mg as a sustained release capsule every 12 hours fMurad (1990);
PDR (1987) as cited in NTP (1989)1. with a total daily dose ranging from 30-320 mg/day
(0.43-4.6 mg/kg-day for a 70-kg adult). Daibcr and Miinzel (2015) reported a usage of
50-80 mg per dose (therapeutic action of 8-12 hours), and recent clinical trials have evaluated
daily doses of 160-240 mg/day (2.3-3.4 mg/kg-day for a 70-kg adult) (Miinzel et al.. 2014;
Schleussner et al .. 2014; Schnorbus et al .. 2010). As noted in the "Mode of Action" section
below, the therapeutic vasodilatory action of organic nitrates, including PETN, are attributed to
their active intermediate, nitric oxide (NO) [reviewed by Daibcr and Miinzel (2015); Miinzel et
al. (2013); Kosmicki (2009); Daibcr et al. (2008); Bode-Boger and Koida (2005); Murad (1990)1.
As discussed in the "Metabolism" section below, NO is released during PETN metabolism.
Most of the clinical studies in the PETN literature were designed to test the effectiveness
of a generally continuous intake of the drug in alleviating angina pectoris. Dosing protocols
consisted of administering 3 or 4 immediate-release tablets 3 or 4 times per day or
2 delayed/sustained-release tablets every 12 hours for durations ranging from 3 days to
30 weeks. Given the half-life of PETN for humans in the range of 4-8 hours (Weber et al.. 1995)
and a therapeutic action duration of 8-12 hours (Daibcr and Miinzel 2015). the typical dosing
protocols should result in a relatively constant effective internal concentration. Presentation of
study results was almost always focused on symptomology rather than on explicit measures of
specific endpoints, such as vasodilation or blood pressure. Therefore, the effectiveness of PETN
in eliciting the primary therapeutic effect—vasodilation—is largely implicit in these studies for
findings of efficacy in alleviating clinical symptoms. The effect (or lack of effect) on blood
pressure, the endpoint of greatest concern for environmental exposures to the general population,
was infrequently mentioned. Several acute-exposure studies, however, were designed to study
vasodilation and blood pressure effects (Henstridge et al.. 2009; Dragoni et al.. 2007; Bohm and
Haustein. 1998; Amsterdam et al.. 1980; Sh el lock et al.. 1980; Dagenais et al.. 1969). In all those
studies, blood pressure reductions were observed; see Table 3A.
The studies using multiple daily treatment protocols ("continuous-exposure" studies)
generally reported efficacy of PETN in alleviating angina symptoms at the lowest treatment
levels, which are designated as LOAELs in the general population for the critical effect of
vasodilation, with the potential for reduced blood pressure. Referring to Table 3A, short-term to
subchronic exposure-duration LOAELs for vasodilation in the range of 0.57-3.4 mg/kg-day
(assuming a 70 kg adult) have been established (Oel/e et al.. 2014; Schleussner et al.. 2014;
Schnorbus et al.. 2010; Shrivastava et al.. 1983; Aubcrt et al.. 1970; Hedges and Gordon. 1965;
Cass and Cohen. 1961; Edson et al.. 1961; Plot/. 1960; Rosenberg and Michel son. 1955;
Phillips. 1953). In all but one of these studies, vasodilation was implicit (based on therapeutic
efficacy). The one exception is the study of Schnorbus et al. (2010). which determined
vasodilation by an increase in brachial artery blood flow at a dose level of 3.4 mg/kg-day. Two
of the continuous-exposure studies established LOAELs for decreased blood pressure of
2.6 mg/kg-day (Jurt et al.. 2001) and 3.4 mg/kg-day (Gori et al.. 2003). LOAELs for two other
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continuous-exposure studies could not be established because either the treatment levels
associated with the reported effects were not specified (Perlman. 1952) or the toxicological
relevance of the reported effects could not be determined (Schelling and Lasagna. 1967). In the
former case (Perlman. 1952). the therapeutic efficacy was evident (implicit vasodilation) and
reduced blood pressure in 7/21 hypertensive subjects was reported, but the exact doses were not
specified among several dose levels used, ranging from 30 mg/day to 160 mg/day. In the latter
case (Schelling and Lasagna. 1967). the toxicological significance of the reported endpoint
(decreased response to NTG challenge) could not be determined (see Table 3 A). No NOAELs
were identified in any of the continuous-exposure studies, although a NOAEL of 0.86 mg/kg-day
was implied by Rosenberg and Michel son (1955). who reported no anginal pain reduction at
0.86 mg/kg-day for five individuals in a previous trial. A confounding factor in several of the
studies was concurrent treatment with NTG or other drugs affecting cardiovascular activity
(Oelze et at.. 2014; Cass and Cohen. 1961; Plot/. 1960; Rosenberg and Michel son. 1955;
Phillips. 1953). Thus, determining the exact contribution of PETN to the efficacy of the
treatment in these studies is problematic. Notably, the lowest apparent LOAEL of
0.57 mg/kg-day was determined from the Phillips (1953) study, with concurrent NTG treatment,
which excludes this value for consideration as a POD.
Side Effects
The term "side effect" is used in the document to largely include toxicologically relevant
symptoms expressed by patients, including headache, nausea, dizziness, etc. This is distinct from
hemodynamic signs, including blood pressure, heart rate, blood flow, etc., measured in patients.
Side effects associated with therapeutic use of organic nitrates (including PETN) are well
characterized and virtually all are considered to be secondary to the primary action of
vasodilation [reviewed by Daiber et al. (2008); Bode-Boger and Koida (2005); Murad (1990)1. In
double-blind, placebo-controlled, randomized clinical trials following oral PETN administration,
study participants exhibited side effects such as headaches (see also Table B-l) at NOAEL doses
as low as 1.1 mg/kg-day (Rosenberg and Michelson. 1955). Other evidence from
non-placebo-controlled studies, or inadequately reported studies, show increases in side effects at
doses >2.3 mg/kg-day (Schelling and Lasagna. 1967). Evidence from the placebo-controlled
studies of greater than 4 weeks showed NOAELs for side effects ranging from
0.86-2.3 mg/kg-day (Schleussner et al.. 2014; Aubert et al.. 1970; Hedges and Gordon, 1965).
Additional data from studies lacking a placebo control or inadequately reported studies show
putative NOAELs for side effects in the same range (0.57-2.3 mg/kg-day) [e.g., Phillips (1953);
Perlman (1952)1. Headaches, sometimes severe, and nausea due to cerebral vasodilation are the
most common side effects. Side effects generally occurred at doses higher than those associated
with the therapeutic effect of vasodilation, though the NOAELs for side effects overlap the
NOAELs and LOAELs for the primary vasodilation effect, and in Edson et al. (1961), the
LOAEL for side effects was the same as the LOAEL for vasodilatation.
Blood Pressure Effects
Of particular interest is the potential for a reduction in blood pressure, which, although
perhaps a beneficial effect for some cardiac patients, is a detrimental effect in the general
population, particularly for those individuals susceptible to hypotension. The latter would
include pregnant women, infants, the elderly, those with diabetes, and men on erectile
dysfunction medication, among others. Blood pressure, however, is rarely measured in rodent
studies. There are other studies in the database supporting this effect including the work of
Bender et al. (1963) who reported mean arterial pressure in dogs, and the work with
spontaneously hypertensive rats (Commarato et al.. 1973) and related studies, see below.
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2.1.2. Single-Dose (Acute) Studies
The human clinical studies reporting decreases in blood pressure have largely been
single-dose administrations designed to study the acute hemodynamic activity of PETN, rather
than as treatment for angina pectoris. The studies have been conducted with cardiac patients
(Giles et al.. 1981; Amsterdam et al.. 1980; Shel lock et al.. 1980; Dagenais ct al.. 1969).
pregnant women (Henstridge et al.. 2009). and healthy volunteers (Henstridge et al.. 2009;
Dragoni et al.. 2007; Bohm and Haustein. 1998) alike. Because of uncertainties of the effective
half-life of PETN, the dosimetry here is shown as actual dose. Five of the seven single-dose
studies reported reduced systolic (or "systemic") blood pressure in the range of 5-14% at doses
ranging from 20-80 mg. In one double-blind study, Dagenais et al. (1969). reported a 5-10%
reduction in blood pressure for 15 angina patients following a single dose of 20 mg PETN.1
Another study showing acute effects of PETN on hemodynamic parameters is Amsterdam et al.
(1980). who reported a 7—14% reduction in blood pressure for 12 healthy volunteers given a
single dose of 40 mg (also a double-blind design). In addition, Bohm and Haustein (1998)
reported a 7% reduction in blood pressure at a dose of 80 mg for 12 healthy volunteers, but no
effects at doses of 25 or 50 mg. In a study in pregnant women, significant reductions in blood
pressure and compensatory increase in heart rate occurred within 15 minutes of treatment of
160 mg (Henstridge et al .. 2009). Conversely, one of the single-dose studies reported no effect
on blood pressure at doses of 40 mg in 10 angina patients (Giles ct al.. 1981). These effects on
hemodynamic parameters represent the proximal effects of PETN, and because they appear in
acute as well as longer term studies, indicate less of an effect for duration of exposure on the
severity of the effect than is typically the case.
2.1.3. Continuous Exposure Studies
Only 3 (Gori et al.. 2003; Jurt et al.. 2001; Perl man. 1952) of the 16 multiple-daily-dose
studies reported reductions in blood pressure. Two of the studies (Gori et al .. 2003; Jurt et al ..
2001) were designed to evaluate PETN for development of tolerance and potential for oxidative
stress, relative to NTG, rather than to evaluate the clinical efficacy of PETN for treatment of
angina. The two studies were conducted in the same laboratory with healthy volunteer subjects
and used double-blind protocols (Gori et al.. 2003; Jurt et al.. 2001). Although Jurt et al. (2001)
used a separate control group, the subjects in the Gori et al. (2003) study were their own controls
(before and after measurements). Gori et al. (2003) found that both PETN and NTG increased
forearm blood flow, but that, unlike NTG, repeated PETN treatment was not associated with the
development of tolerance or presence of oxidative stress markers. Jurt et al. (2001) reported an
average 6% reduction in systolic blood pressure associated with PETN treatment at
2.6 mg/kg-day (60 mg, 3 times daily for 7 days). Gori et al. (2003) confirmed the vasodilatory
action and lack of development of tolerance for PETN and reported a 6—7% reduction in both
systolic and diastolic blood pressure for 28 healthy male volunteers administered PETN at
3.4 mg/kg-day (80 mg, 3 times daily for 6 days). Both sets of investigators reported no side
effects. The third multiple-daily-dose study reporting blood pressure effects was a clinical trial
investigating the efficacy of PETN for 27 cardiovascular patients and the potential for side
effects in 37 healthy volunteers (Perlman. 1952) at dose levels from 0.43-2.3 mg/kg-day, with
treatment durations up to 30 weeks. Perl man (1952) reported that systolic blood pressure was
reduced in 7 of 21 hypertensive subjects, presumably from the cardiovascular patient group (but
not specified as such); neither the magnitude of the decrease nor the effective dose level(s) was
reported. Of the other 13 multiple-daily-dose studies, only 2 specifically reported that blood
1 Single doses of 20 or 40 mg or placebo (randomized) were administered daily over a 5-day period (two treatment
days, three placebo days), but blood pressure measurements were taken immediately after each dose.
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pressure was not affected (Schleussner et al.. 2014; Predel et al.. 1995). There was no mention of
blood pressure endpoints in the remaining 11 studies.
2.1.4. Inhalation Exposures
No human studies following inhalation exposure to PETN have been identified.
2.2. ANIMAL STUDIES
2.2.1. Oral Exposures
Short-Term Studies
Bucher et al (1990); NTP (1989) (Rat Study)
F344/N rats (five/sex/dose) were fed diets containing 0, 3,100, 6,200, 12,500, 25,000, or
50,000 ppm of National Formulary (NF) Grade PETN (PETN NF), a 1:4 formulation of PETN
(purity >99%) and D-lactose monohydrate, typically used in human therapeutics, for 14 days.
Equivalent PETN concentrations were 0, 620, 1,240, 2,500, 5,000, or 10,000 ppm, respectively.
Based on the average of the reported initial and final body weights and food-consumption data
from Day 7, the average daily consumption of PETN calculated for this review was 65.7, 129.0,
347.8, 674, or 1,110 mg/kg-day, respectively, in males and 79.0, 168.0, 355.7, 635, or
1,310 mg/kg-day, respectively, in females. The animals were observed twice daily for mortality
and clinical signs of toxicity. Body weight was measured weekly and food consumption
monitored throughout the study. Gross necropsy was performed on all animals at sacrifice.
Terminal body weights were within 5% of control in all treated groups (see Table B-2).
The study authors indicated that there were "no clinical signs or toxic lesions" related to
exposure. No further details were provided.
The NOAEL of 1,310 mg/kg-day in females is identified based on a lack of reported
effects.
Bucher et al. (1990); NTP (1989) (Mouse Study)
B6C3F1 mice (five/sex/dose) were fed diets containing 0, 3,100, 6,200, 12,500, 25,000,
or 50,000 ppm PETNNF (0, 620, 1,240, 2,500, 5,000, or 10,000 ppm PETN) for 14 days. Based
on the average of the reported initial and final body weights and food-consumption data from
Day 7, the average daily consumption of PETN calculated for this review was 173, 308.7, 539.7,
1,380, or 2,600 mg/kg-day, respectively, in males and 187, 556.9, 703.1, 1,800, or
2,530 mg/kg-day, respectively, in females. The animals were observed twice daily for mortality
and clinical signs of toxicity. Body weight was measured weekly and food consumption
monitored throughout the study. Gross necropsy was performed on all animals at sacrifice.
Microscopic histopathology was limited to the kidney from the control and the two highest dose
groups.
All mice survived until sacrifice. No clinical signs of toxicity were reported. Terminal
body weight was significantly decreased by 13% in the highest dosed females, compared with
control; body-weight gain significantly decreased by 58—85% in females at >1,800 mg/kg-day
(statistics performed for this review; see Table B-2). The study authors indicated that no
exposure-related gross or microscopic lesions were observed.
A NOAEL of 703.1 mg/kg-day and a LOAEL of 1,800 mg/kg-day are identified based on
a statistically significant 58% decrease in terminal body-weight gain in female mice.
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Bender et al (1963)
Six mongrel dogs (sex not specified) were administered PETN at a dose of 30 mg via
gavage daily for 3 weeks (vehicle and purity not reported). Based on the average reported body
weights (15.0-30.5 kg), the estimated daily dose is 1.3 mg/kg-day. Body weight, respiratory rate
and ventilator volume, blood oxygen content, and various cardiovascular endpoints (coronary
blood flow, cardiac output, oxygen consumption, left ventricular work, mean arterial pressure,
mean pulmonary artery pressure, mean coronary sinus pressure, and mechanical efficiency) were
determined before the daily PETN administration and after the final PETN administration on
Day 21.
A statistically significant 2.3% decrease in body weight was observed following PETN
exposure, compared with pre-exposure values. No significant changes were observed in
respiratory rate, ventilator volume, or blood oxygen content. The observed decrease in body
weight is not considered biologically relevant because the effect was small (<10%). No
significant changes were observed in systemic blood pressure values. Significant increases were
observed in local cardiac effects including coronary vascular resistance and mechanical
efficiency, while significant reductions were observed in other local cardiovascular indicators
including coronary blood flow, left ventricular oxygen consumption, and left ventricular work.
The coronary fractional flow (coronary blood flow/cardiac output) was significantly decreased
by 37%. Because the coronary effects are in the opposite direction of the expected action of
PETN (vasodilation), the biological significance of the observed cardiac effects is not clear.
Because of the uncertainty in the biological significance of the cardiac effects, a NOAEL
or LOAEL cannot be identified for this study.
Subchronic Studies
Bucher et al (1990); NTP (1989) (Rat Study)
F344/N rats (10/sex/dose) were fed diets containing 0, 3,100, 6,200, 12,500, 25,000, or
50,000 ppm of PETN NF (0, 620, 1,240, 2,500, 5,000, or 10,000 ppm PETN) for 14 weeks.
Based on the reported daily food consumption per kilogram of body weight at Week 7, the
average daily consumption of PETN calculated for this review was 39.1, 88.04, 190, 330, or
630 mg/kg-day, respectively, in males and 42.8, 85.56, 200, 370, or 830 mg/kg-day, respectively,
in females. The animals were observed twice daily for clinical signs of toxicity. Body weights
were recorded at study initiation, once per week during the study, and at necropsy. Feed
consumption was measured 2-3 days per week. At necropsy, blood was collected for
whole-blood methemoglobin (MetHb) concentration. All animals were grossly examined, and
the brain, heart, right kidney, liver, lungs, and thymus were removed and weighed.
Comprehensive histological examinations were conducted in the control and highest dose groups
of both sexes; evaluations at lower doses were limited to the Zymbal gland in females at
370 mg/kg-day.
No mortalities or clinical signs of toxicity were reported. A statistically significant
6-7%) decrease in terminal body weight was observed in females at >370 mg/kg-day, and a
statistically significant decrease in total body-weight gain was observed in females at
>200 mg/kg-day (12%> at 200 mg/kg-day, 17%> at 370 mg/kg-day, and 18%> at 830 mg/kg-day),
compared with controls (statistics performed for this review; see Table B-3). No body-weight
effects were observed in males (see Table B-3). MetHb levels were <1%> in all control and
exposed groups. In females, relative brain weights were increased significantly by 6-8%> at
>200.0 mg/kg-day, compared with controls, and relative kidney weights were significantly
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increased by 6% at 830 mg/kg-day, compared with controls (see Table B-3); absolute organ
weights were not reported. No additional organ-weight effects were noted in females, and no
dose-related organ-weight effects were observed in males (see Table B-3). No exposure-related
non-neoplastic gross or histopathological lesions were observed. An adenoma of the Zymbal
gland was observed in one female rat at 830 mg/kg-day.
The decreases in body weight for females did not exceed 10% and are not considered to
be biologically significant. The increases in relative kidney weights for females are also not
considered toxicologically relevant because they were less than 10%. The increases in relative
brain weight and the 12% decrease in body-weight gain are considered to be toxicologically
relevant. The NOAEL of 85.56 and LOAEL of 200 mg/kg-day are identified based on increased
relative brain weight and decreased body-weight gain in female rats.
Bucher et al (1990); NTP (1989) (Mouse Study)
B6C3F1 mice (10/sex/dose) were fed diets containing 0, 3,100, 6,200, 12,500, 25,000, or
50,000 ppm PETNNF (0, 620, 1,240, 2,500, 5,000, or 10,000 ppm PETN) for 13 weeks. Based
on the average of the daily feed-consumption data for Weeks 7 and 13, the average daily
consumption of PETN calculated for this review was 109, 302.6, 362.5, 925, or
2,140 mg/kg-day, respectively, for males and 172, 306.3, 632.5, 1,340, or 3,120 mg/kg-day,
respectively, for females. Clinical signs, body weights, feed consumption, and whole-blood
MetHb concentrations were evaluated as reported above for rats. Necropsies and measurements
of brain, heart, right kidney, liver, lungs, and thymus weights were performed on all animals.
Comprehensive histological examinations were conducted in the control and highest dose groups
of both sexes; histological evaluations at lower doses were limited to the liver in females at
1,340 mg/kg-day.
No mortalities, clinical signs of toxicity, or body-weight effects were reported. MetHb
levels were <1% in all control and exposed groups. In highest dosed females, relative liver and
kidney weights were slightly, but significantly, increased by 7—8%, compared with controls
(see Table B-4); absolute organ weights were not reported. No additional organ-weight effects
were noted (see Table B-4). No exposure-related gross or histopathological lesions were
observed. A hepatocellular adenoma was observed in one female mouse at 3,120 mg/kg-day.
The highest dose used is a NOAEL of 3,120 mg/kg-day in females, identified for the lack
of dose-related toxicologically relevant effects. The minor increases in relative liver and kidney
weights in females are not considered toxicologically relevant effects due to their small
magnitude (< 10%).
Chronic/Carcinogenicity Studies
Bucher et al (1990); NTP (1989) (Rat Study)
F344/N rats (50/sex/dose) were fed diets containing PETN NF for 2 years. Males were
fed dietary concentrations of 0, 25,000, or 50,000 ppm PETN NF (0, 5,000, or 10,000 ppm
PETN) and females were fed dietary concentrations of 0, 6,200, or 12,500 ppm (0, 1,240, or
2,500 ppm PETN). The lower dietary concentrations of PETN NF were selected for the female
rats because higher concentrations caused 12—18% decreases in body-weight gains in the
14-week study summarized above. Bucher et al. (1990) reported an average daily PETN
consumption of approximately 240 or 490 mg/kg-day in males and 80 or 165 mg/kg-day in
females, respectively. Clinical signs, body weights, and feed consumption were evaluated
throughout the study. Necropsies were performed on each rat. Comprehensive histological
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examinations were performed on low-dose rats that died before Month 21 and on all control and
high-dose rats. Histological examinations in the remaining low-dose rats were limited to the
liver, kidneys, and gross lesions in both sexes; the brain, pancreas, and testes in males; and the
esophagus, lungs, thyroid, and uterus in females.
No exposure-related changes were observed in survival, clinical signs, or feed
consumption. Mean body weights were 2-9% lower in high-dose males throughout the study,
compared with controls; terminal body weights were 7% lower than controls (statistics not
reported; data reporting was inadequate for independent statistical review). Mean body weights
for the low-dose males and all dosed females remained within 5% of control values throughout
the study. No exposure-related non-neoplastic lesions were observed in either sex.
Adenomas or carcinomas of the Zymbal gland occurred in all chronically treated groups
of male and female rats, but the incidences were low and did not demonstrate statistical
significance when compared with controls. However, females had a significant dose-related
trend in adenomas or carcinomas (see Table B-5). The incidences of Zymbal gland neoplasms
exceeded the mean historical incidences for each sex, (see Table B-5). There were no increases
in hyperplasia to suggest an increase of proliferative lesions of the Zymbal gland. Based on the
occurrence of 9% Zymbal gland neoplasms in the high-dose female rats compared with none in
controls, a statistically significant trend in females, (p = 0.028), and the occurrence of a Zymbal
gland tumor in one high-dose female rat, (1/10 compared with 0/10 in controls) in the 14-week
study summarized above, the study authors concluded that the results of the chronic study
suggested a possible PETN-related effect.
Thyroid gland follicular cell adenomas or carcinomas (combined) were observed only in
high-dose female rats (3/50). Although this incidence was not significantly increased compared
with controls (0/50), there was a statistically significant dose-related trend in females and it
exceeded historical control incidences (see Table B-5). Because there were no indications of
increased follicular cell adenomas or carcinomas, or increased follicular cell hyperplasia in
males, the NTP study authors did not consider the marginal increase in follicular cell tumors in
females to be related to PETN. However, for the purposes of this PPRTV assessment, the
U.S. EPA considers these thyroid tumors to be treatment related.
Other neoplastic findings included mononuclear leukemia in male rats that occurred with
a negative trend due to an incidence in the high-dose group that was significantly lower than in
controls.
A NOAEL of 10,000 ppm (490 mg/kg-day) is identified in male rats based on a lack of
exposure-related noncancer effects. The body-weight decreases observed in high-dose males are
not considered toxicologically relevant due to the small magnitude of effect (<10%). NTP
concluded that there was "Equivocal Evidence of Carcinogenic Activity" of PETN in both male
and female rats based on the increase in neoplasms of the Zymbal gland exceeding historical
controls.
Bucher et al (1990); NTP (1989) (Mouse Study)
B6C3F1 mice (50/sex/dose) were fed diets containing 0, 25,000, or 50,000 ppm
PETN NF (0, 5,000, or 10,000 ppm PETN) for 2 years. Bucher et al. (1990) reported an average
daily PETN consumption of approximately 810 or 1,620 mg/kg-day in males and 1,020 or
1,936 mg/kg-day in females. Clinical signs, body weights, and feed consumption were evaluated
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throughout the study. Necropsy was performed on each mouse. Comprehensive histological
examinations were performed on low-dose mice that died before Month 21 and on all control and
high-dose mice. Histological examinations in the remaining low-dose mice were limited to the
stomach and gross lesions in both sexes, and the liver and spleen in females.
There were no exposure-related decreases in survival, clinical signs, effects on body
weight or food consumption, or increases in non-neoplastic or neoplastic lesions. Combined
tumors of the subcutaneous tissues (primarily fibromas and fibrosarcomas) occurred with a
negative dose-related trend in male mice; incidences in both dosed groups were significantly
lower than in controls. Skin tumors in the male mice control group occurred at a rate nearly five
times higher than in historical controls, but the study authors did not provide a rationale for this
discrepancy.
For non-neoplastic effects, a NOAEL of 1,936 mg/kg-day in female mice is identified
based on a lack of exposure-related effects. There was no evidence of carcinogenicity in male or
female mice under the conditions of this bioassay.
Donahue (1944)
Male and female albino rats (45/group; sex ratio not reported) were fed PETN at dietary
doses of 0 or 2 mg/kg-day for 1 year. Body weights were recorded weekly. Blood was collected
monthly from 20 rats/group for hematology (erythrocyte count, hemoglobin [Hb] concentration
total, and differential leukocyte counts). After the exposure period, the surviving animals were
sacrificed. The liver, kidneys, spleen, heart with lungs, brain, and testes were removed, and the
weight, volume, and density (ratio of weight to volume) were recorded. Histopathological
examinations were performed on the liver, kidneys, spleen, heart, lungs, brain, and femur; the
study authors noted that particular attention was paid to histological changes in the vascular
walls of these tissues. Organs from animals that died before the scheduled sacrifice do not seem
to have been examined.
High mortality (46.6% in the control group and 20% in the exposed group) was attributed
to an infestation of parasitic tapeworm larvae observed in the livers of a large number of
surviving rats (11/24 surviving controls, 12/36 surviving exposed). However, no data were
provided regarding the presence or absence of parasitic infection in animals that died before the
scheduled sacrifice. Body weights and growth curves were comparable between groups
throughout the study. Erythrocyte and Hb values fluctuated throughout the study but remained
within normal ranges for both control and exposed rats. Leukocyte values were abnormally high
in both groups; the study authors attributed this finding to the observed parasitic infection. There
were no exposure-related changes in organ weights, volumes, or density. No exposure-related
histopathological lesions were observed.
A NOAEL or LOAEL are not identified from this study because confidence in this study
is low due to the observed parasitic infestation and high mortality in both the control and
exposure groups.
Reproductive/Developmental Studies
Quinnetal. (2009)
Groups of Sprague Dawley rats (10/sex/group) were administered PETN (purity >98%)
at daily doses of 0, 100, 500, or 1,000 mg/kg-day via gavage in corn oil for up to 56 days.
Dosing began 2 weeks prior to mating and continued in both sexes during mating. After mating,
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dosing of males continued until a total dosing period of 28 days was completed, whereupon they
were sacrificed. Female exposure continued through gestation until Postnatal Day (PND) 3;
dams with offspring were sacrificed on PND 4. During the exposure period, the animals were
observed daily for mortality and clinical signs of toxicity. Parental body weights were recorded
weekly. During premating, pregnancy, and lactation, food consumption was measured weekly.
During the mating period, pregnancy was indicated by presence of a sperm plug. Dams were
allowed to deliver, and the litters were examined for the number and sex of pups, number of live
and dead pups, number of runts, and presence of gross abnormalities. Live pups were counted
and sexed, and litter weights were recorded on PNDs 1 and 4. At sacrifice, all parental animals
and offspring were examined grossly. The testes and epididymides of all male parental animals
were removed and weighed. The ovaries, testes, epididymides, and all organs showing
macroscopic lesions from parental animals were examined microscopically.
No exposure-related mortalities were observed; four animals died during the exposure
period due to gavage error (esophageal perforation). No clinical signs of toxicity were observed.
Male body weights and food consumption were comparable between the exposure and control
groups throughout the study. Body weights were significantly elevated by 3-9% in females
exposed to 100 or 500 mg/kg-day on Day 20 of exposure (approximately the end of the mating
period) and at necropsy, compared with control; female body weights were comparable to
control at the high dose throughout the study. Increased body weights in females at 100 and
500 mg/kg-day were accompanied by significant 43-57% increases in food consumption during
premating and pregnancy.
The study authors did not report mating or fertility indices, and the total number of
pregnant females and litters produced per group was not reported. No changes in gestation
duration, number of pups, or pup sex ratio were observed. On PND 1, male pup body weights
were significantly elevated by 6% at 500 mg/kg-day; however, body weights were comparable to
control at 100 and 1,000 mg/kg-day on PND 1 and in all dose groups on PND 4. No
exposure-related changes were observed in female pup body weights. No exposure-related gross
deformities or lesions were observed in offspring, but traditional microscopic developmental
outcome analyses in pups were not performed.
In parental animals, there were no exposure-related changes in relative testes,
epididymides, or ovary weights (absolute weights not reported). No gross lesions were observed
in adult males or females at necropsy, and no exposure-related histological lesions were observed
in the testes, epididymides, or ovaries. The numbers of corpora lutea and implants were
comparable between control and exposed females.
A NOAEL of 1,000 mg/kg-day is identified based on a lack of toxicologically relevant
effects in reproductive organs in parental animals, litter parameters, or neonatal pup body weight,
survival, or gross morphology.
2.2.2. Inhalation Exposures
No repeated-exposure inhalation studies have been identified.
2.3. OTHER DATA (SHORT-TERM TESTS, OTHER EXAMINATIONS)
2.3.1. Genotoxicity
Table 4 provides an overview of genotoxicity studies of PETN. "Military-grade" PETN
solutions in dimethylsulfoxide (DMSO) did not induce reverse mutations in Salmonella
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typhimurium when tested without metabolic activation in a spot test, or with metabolic activation
in a plate incorporation assay (Whong et al.. 1980). Similarly, the pharmaceutical-grade
1:4 PETN-lactose mixture used in the NTP toxicity and carcinogenicity studies (PETN NF) was
not mutagenic in S. typhimurium when tested with or without metabolic activation in a
preincubation assay (NTP. 1989; Mortelmans et al.. 1986).
PETNNF induced a 17-31% increase in sister chromatid exchanges (SCEs) in cultured
Chinese hamster ovary (CHO) cells in the presence and absence of metabolic activation;
however, the response was not dose related and cell cycle delay was not induced (NTP. 1989).
The lack of a dose-response may have been due to precipitation of the test compound at mid- and
high-dose levels (NTP. 1989). PETN NF did not induce chromosomal aberrations (CAs) in CHO
cells when tested with or without metabolic activation (NTP. 1989).
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Table 4. Summary of PETN Genotoxicity
Endpoint
Test System
Doses/Concentrations
Tested
Results
without
Activation3
Results
with
Activation3
Comments
References
Genotoxicity studies in prokaryotic organisms
Mutagenicity
Salmonella typhimurium
strains TA98, TA100,
TA1535, TA1537,
TA1538
0, 0.625, 1.25 mg/spot
ND
Spot test; test substance was military-grade
PETN.
Who tie et al. (1980)
Mutagenicity
S. typhimurium strains
TA98, TA100, TA1535,
TA1537, TA1538
Up to 2.5 mg/plate
ND
Plate incorporation assay; test substance was
military-grade PETN.
Who tie et al. (1980)
Mutagenicity
S. typhimurium strains
TA98, TA100, TA1535,
TA1537
0, 100, 333, 1,000,
3,333, 10,000 ng/plate
Preincubation assay; test substance was
pharmaceutical-grade PETN NF
(1:4 PETN-lactose mixture); precipitate was
noted at 10,000 |ig/plate.
NTP (1989);
Mortelttiatts et al. (1986)
Genotoxicity studies in mammalian cells—in vitro
SCE
CHO cells
0, 160, 500, 1,600,
2,500 ng/mL
+
+
Test substance was pharmaceutical-grade
PETN NF (1:4 PETN-lactose mixture). All
concentrations induced a 17-31% increase
in SCEs with and without metabolic
activation, compared with controls;
however, the response was not dose related
and cell cycle delay was not induced.
Precipitate was noted at >500 ng/plate.
NTP (1989)
CA
CHO cells
0, 1,000, 1,600,
2,500 ng/mL
Test substance was pharmaceutical-grade
PETN NF (1:4 PETN-lactose mixture). CAs
were not induced in the presence or absence
of S9 activation.
NTP (1989)
a+ = positive; - = negative; ND = no data.
CA = chromosomal aberration; CHO = Chinese hamster ovary (cell line cells); PETN = pentaerythritol tetranitrate; PETN NF = National Formulary (NF) Grade PETN;
SCE = sister chromatid exchange.
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2.3.2. Additional Animal Studies
Acute Toxicity Studies
Several acute animal studies have evaluated cardiovascular endpoints following exposure
to PETN. Statistically significant coronary artery dilation was observed in dogs following acute
oral exposure to 9-12 mg/kg. Daily administration for 5 days did not result in nitrate tolerance
(Fink and Bassenge. 1997; Bassenge et al.. 1996). Observed effects in dogs exposed to lower
doses (-0.4-0.8 mg/kg) included decreased coronary blood flow and reduced cardiac work load
(Sullivan et al.. 1964). Transient decreases in systemic blood pressure were also observed in
most studies in rabbits, cats, and dogs following single oral exposures to 0.4-50 mg/kg
(Mullenlicim et al.. 2001; Commarato et al.. 1973; Baneriee et al.. 1970; Sullivan et al.. 1964;
von Oettingen and Donahue. 1944); however, mean arterial pressure was not significantly
decreased in dogs following exposure to 12 mg/kg (Bassenge et al.. 1996). Decreased pulmonary
arterial pressure, as well as bronchodilation, has also been reported in dogs following inhalation
of low aerosol levels ranging from 11-225 |ig; however, systemic cardiovascular changes
(e.g., decreased heart rate, decreased systemic blood pressure) were not observed (Aviado et al..
1969).
Acute studies evaluating endpoints other than cardiovascular are limited to a single case
study in a dog that ingested an unknown quantity of PETN while training to detect explosives
(Potocniak et al.. 2008). The dog presented with central nervous system (CNS) depression,
including bradycardia, swaying gait and broad-based stance, proprioceptive deficits in hind
limbs, ataxia, inability to stand, and disorientation. Clinical tests showed transient mild anemia,
increased urinary bilirubin, and increased serum levels of aspartate aminotransferase (AST),
alanine aminotransferase (ALT), alkaline phosphatase (ALP), and gamma glutamyl transferase
(GGT). The dog fully recovered after 1 week.
Studies Evaluating Actions of PETN in Animal Models of Cardiovascular Disease
Additional actions of PETN on the cardiovascular system have been studied using animal
models of cardiovascular disease, including atherosclerosis (in cholesterol-fed rabbits) and
hypertension (in N omega-nitro-L-arginine methyl ester [l-NAME] spontaneously hypertensive
rats).
Studies in atherosclerotic rabbit models have suggested that PETN treatment may slow or
prevent the formation of atherosclerotic lesions. In cholesterol-fed rabbits, dietary exposure to
6 mg/kg-day PETN for 15 weeks protected against the development of aortic atherosclerosis and
endothelial dysfunction without affecting the vasodilatory potency of PETN in aortic rings
(Koida and Noack. 1995; Koida et al.. 1995). The results of a subsequent study in cholesterol-fed
rabbits indicated that dietary exposure to 6 mg/kg-day PETN for 16 weeks reduced the
progression of aortic lesion formation, endothelial dysfunction, and low-density lipoprotein
(LDL) oxidation in established atherosclerosis (Hacker et al.. 2001). Koida et al. (1998)
proposed that the observed reductions in vascular superoxide production following exposure to
6 mg/kg-day PETN for 16 weeks contributes to the observed protective effects of PETN in
experimental atherosclerosis.
Evidence for therapeutic benefits of PETN treatment in hypertensive rat models are
inconsistent. In spontaneously hypertensive rats, acute exposure to 30 mg/kg resulted in a
statistically significant decrease in systolic blood pressure 15 minutes after administration, with
blood pressure values returning to near-control levels by 30 minutes after administration
(Commarato et al.. 1973). Similarly, studies in hypertensive Wistar rats found that exposure to
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PETN at twice daily doses of 50 mg/kg for 6 weeks resulted in a statistically significant
5% decrease in systolic blood pressure (Torok and Kristek. 2002; Kristek, 2000). Significant
alterations in cardiovascular system parameters by PETN included reduced wall thickness of the
thoracic aorta, carotid artery, and septal branch of the left descending coronary artery; reduced
cross-sectional area of the carotid artery; increased inner diameter of the thoracic artery; and
decreased wall: diameter ratio in the thoracic and carotid arteries. In contrast, subchronic studies
in spontaneously hypertensive rats did not find any changes in general cardiovascular system
parameters (including blood pressure or the geometry of conduit arteries, including inner
diameter, wall thickness, or cross-sectional area of the thoracic aorta, carotid artery, and
coronary artery) following exposure to PETN at once or twice daily doses of 100 mg/kg via
gavage for 6 weeks (Dovinova et al.. 2009; Gerova et al.. 2005). However, Kristek et al. (2003)
reported increased blood platelet cyclic guanosine 3c,5c-monophosphate (cGMP) content and
decreased aortic nitric oxide synthase (NOS) activity.
While evidence for reduced blood pressure in hypertensive rats following PETN
exposure is inconsistent, limited evidence suggests that pre- and postnatal exposure to PETN
may have lasting effects on blood pressure and endothelial function. Following maternal
exposure to 50 mg/kg-day during pregnancy and lactation, female offspring of spontaneously
hypertensive rats show a persistent reduction in blood pressure in adulthood along with enhanced
NO-mediated vasodilation in response to acetylcholine (Wu et al.. 2015). No changes in blood
pressure were observed in dams or male offspring.
2.3.3. Metabolism/Toxicokinetic Studies
Absorption and Distribution
In humans, oral absorption of PETN is relatively rapid. Davidson et al. (1970) and
Davidson et al. (1971) identified radioactivity in the blood within 15 minutes of oral
administration of radiolabeled PETN in humans, with peak blood radioactivity between
2-8 hours. Blood levels declined to about 40 and 10% of the peak level at 24 and 48 hours,
respectively, with half-lives estimated in the range of 7.1-8.3 hours (Davidson et al., 1971). In
another study, peak blood levels were achieved between 2 and 3 hours, with a plasma
elimination half-life of 4-5 hours (Weber et al.. 1995). Based on data in ligated rats, PETN is
absorbed very slowly in the stomach, with increased rate of absorption in the intestines (DiCarlo
et al .. 1967). Initially (within 2 hours of administration), absorption is more rapid in the small
intestine than the large intestine; however, the rate and extent of absorption in the large intestine
increases between 2 and 4 hours. This shift in absorption is attributed to the extensive
degradation of PETN into denitrated metabolites by bacterial flora in the large intestine; very
little breakdown of PETN was observed in the stomach and small intestine (DiCarlo et al.. 1967).
Consistent with human data, maximal levels of radioactivity in the blood occur in rodents within
4 hours of oral administration of radiolabeled PETN [reviewed by Litchfield (1971)1. After
absorption, PETN binds to both plasma proteins and erythrocytes, and is rapidly distributed
throughout the body, with organ radioactivity levels greater than blood levels after 1 hour
[reviewed by N I P (1989); Litchfield (1971)1. Absorption and distribution data are consistent
with observed therapeutic effects, with peak vasodilatory effects of organic nitrates occurring
60-90 minutes following oral administration, with a duration of action of 3-6 hours [reviewed
by Murad (1990)1.
Metabolism
The metabolism of PETN has been extensively studied; a summary of available data is
presented below based on the following reviews: Daiber et al. (2008). Daiber et al. (2004).
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Daiber and Miinzel (2015). Gori and Daiber (2009). Miinzel et al. (2013). Klemenska and
Beresewicz (2009). NTP (1989). Litchfield (1971). Murad (1990). and Miinzel and Gori (2013).
PETN is sequentially denitrated to form pentaerythritol trinitrate (PETriN, CASRN 1607-17-6),
pentaerythritol dinitrate (PEDN, CASRN 1607-01-8), pentaerythritol mononitrate (PEMN,
CASRN 1607-00-7), and pentaerythritol (PE, CASRN 115-77-5), releasing a molecule of
inorganic nitrite at each denitration step. In humans, PEDN and PEMN are the primary
compounds detected in blood following oral administration, with only trace amounts of PETriN;
the parent compound has not been quantified in the blood. This may be due, in part, to the
breakdown of PETN and PETriN by intestinal microorganisms before absorption. In vitro, PETN
metabolism has been shown to occur in the blood (primarily in red blood cells [RBCs]), in
subcellular fractions of the heart, by liver parenchymal and reticuloendothelial cells, and in
isolated aortas. At low concentrations (<1 |iM), PETN is sequentially denitrated by
mitochondrial aldehyde dehydrogenase 2 (ALDH-2), and the nitrite molecules released during
metabolism are reduced to NO in the mitochondria via various pathways. At higher
concentrations, PETN and its denitrated metabolites can also be metabolized by cytochrome
P450 (CYP450) in the smooth endoplasmic reticulum, leading to the generation of NO.
Denitrated metabolites can be glucuronidated before excretion, and evidence from biliary
cannulated rats indicated that glucuroni dated metabolites can undergo enterohepatic circulation
via reabsorption from the intestines after removal of glucuronic acid.
Excretion
Excretion is primarily via urine and feces, with negligible excretion of breakdown
products via the lungs (Davidson et al.. 1971; Litchfield. 1971; Davidson et al.. 1970). In humans
given a single 20-mg dose, mean urinary excretion was 53.1% of the administered dose after
24 hours and 60.3% after 48 hours, and mean fecal excretion was 31.5% of the administered
dose after 48-72 hours (Davidson et al.. 1970). Similar proportions were observed following a
single 40-mg dose (49.8% of administered dose in urine after 48 hours and 41.2% of
administered dose in feces after 72 hours) (Davidson et al.. 1971). The primary compounds
identified in urine were PEMN and PE, while PETN and PE were the primary compounds in
feces (see Table 5) (Davidson et al.. 1971. 1970). The presence of PETN in feces was attributed
to unabsorbed and unmetabolized parent compound and/or excretion of PETN via enterohepatic
circulation, while PE was attributed to metabolic breakdown of PETN by intestinal flora and/or
excretion of PETN via enterohepatic circulation (Davidson et al.. 1971. 1970). The renal
excretion of primary metabolites PEMN and PE in humans was first order, with half-lives of
7.1 hours following a 20-mg dose and 8.3 hours following a 40-mg dose (Davidson et al.. 1971).
In rats or mice, 36% of the administered oral dose was excreted within 24 hours in the urine,
with 60% of the administered dose recovered after 4 days; 10% of the administered dose was
recovered in rat feces (Litchfield, 1971). The primary urinary metabolites were PEMN and PE in
rats and PE in mice, and the primary fecal metabolite was PE (NTP. 1989; Litchfield. 1971). In
dogs, 88%) of the administered oral dose was excreted in urine, primarily as PEMN and PE, and
10%) was excreted in feces, primarily as PE (DiCarlo et al.. 1969).
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Table 5. Excretion of PETN and Metabolites in Humans Following a Single
Oral Exposure
Compound Excreted
20 mga
40 mgb
Urine
Feces
Urine
Feces
Percent of administered dose recovered (as radioactivity)
within 48 h (urine) or 48-72 h (feces)
60.3 ±3.6
31.5 ± 4.8
49.8
41.2
Relative quantities (%) of parent compound and metabolites:
PETN
PETriN
PEDN
PEMN
PE
None to trace0
None
0.6 ±0.4
51.4 ± 10.3
48.1 ± 10.4
26.7 ± 13.4
0.4 ±0.8
0.9 ± 1.5
5.9 ±3.5
66.3 ± 14.6
None
None
1
74
25
45
None
2
2
51
''Davidson et al. (1970): data presented as mean ± SD. as reported by the study authors (percent excreted in urine
and feces) or as calculated for this review based on individual subject data (relative quantities).
bDavidson et al. (1971): data presented as mean, as reported by the study authors (percent of administered dose
recovered in urine and feces) or approximate mean (relative percent quantities of parent compound and
metabolites; estimated from graphically presented data).
°PETN detected in trace amounts in the urine of one subject.
PE = pentaerythritol; PEDN = pentaerythritol dinitrate; PEMN = pentaerythritol mononitrate;
PETN = pentaerythritol tetranitrate; PETriN = pentaerythritol trinitrate; SD = standard deviation.
2.3.4. Mode-of-Action/Mechanistic Studies
The therapeutic vasodilatory action of organic nitrates, including PETN, are attributed to
their active intermediate, NO [reviewed by Daiber and Miinzel (2015); Miinzel et al. (2013);
Kosmicki (2009); Daiber et al. (2008); Bode-Boger and Koida (2005); Murad (1990)1. As
discussed in the "Metabolism" section above, NO is released during PETN metabolism. Free NO
is transported into the nucleus of vascular smooth muscle cells where it initiates the NO/cGMP
intracellular signaling pathway, ultimately leading to smooth muscle relaxation [reviewed by
Daiber and Miinzel (2015); Miinzel et al. (2013); Miinzel and Gori (2013); Klemenska and
Beresewicz (2009); Daiber et al. (2008); Murad (1990)1. However, the mechanisms underlying
cerebral vasodilation (leading to the primary toxicologically relevant side effect of headaches)
seem to be different from those identified for coronary vasodilation (therapeutic goal). As
reviewed by Bode-Boger and Koida (2005), the 100-fold decrease in the degree of vasodilation
in cerebral arteries versus coronary arteries, in response to organic nitrate therapy, along with the
cessation of headache after the first few days of therapy, supports the hypothesis that cerebral
vasodilation occurs via a different pathway than coronary vasodilation. Evidence suggests that
cerebral arteries may lack enzymes required for bioactivation of nitrates to NO. One proposed
alternate mechanism for cerebral vasodilation in the absence of metabolism-generated NO is
activation of the NO/cGMP pathway subsequent to direct activation of sensory nerve fibers by
organic nitrates, triggering a release of calcitonin gene-related peptide.
Long-term organic nitrate use is generally associated with nitrate tolerance, endothelial
dysfunction, sympathetic activation, and a potential increase in risk for ischemic episodes.
PETN, however, is unique among the long-acting nitrovasodilators because chronic use is not
associated with these effects. Long-acting in this instance refers to the action of the drug
compared with NTG, not to the extended-release formulation of PETN, which is a separate issue.
The mechanisms of nitrate tolerance have been extensively researched, and a summary of
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available data is presented below based on the following reviews: Bai et al. (2018); Opelt et al.
(2018); Steven et al. (2017); Daiber and Miinzel (2015); Miinzel et al. (2013); Miinzel and Gori
(2013); Rutherford and St rut hers (2013); Daiber et al. (2012); Daiber and Miinzel (2010); Daiber
et al. (2009); Klemenska and Beresewicz (2009); Kosmicki (2009); Daiber et al. (2008); Daiber
et al. (2004). There are several potential mechanisms for nitrate tolerance and endothelial
dysfunction following extended nitrate therapy, such as with NTG. Release of NO from PETN
by ALDH-2 results in oxidation of the enzyme at the reactive cysteine C302, which requires an
endogenous reductant for reactivation, which can be depleted, leading to the formation of
reactive oxygen species (ROS). ROS generation and the subsequent formation of superoxide or
peroxynitrite, can lead to reversible or irreversible inactivation of ALDH-2, resulting in reduced
NO generation and a decreased therapeutic effect following nitrate administration. Additionally,
peroxynitrite can cause uncoupling of endothelial NOS, leading to endothelial dysfunction. An
additional mechanism of endothelial dysfunction and nitrate resistance may be through
interaction of nitrates with the expression of prostaglandin 12 (PGI2) synthase. Nitrate donors
induce the expression of miR-199 (a micro-RNA), which targets the PGI2 synthase messenger
RNA (mRNA), lowering PG12 levels and blocking vasodilation through that mechanism (Bai et
al.. 2018). However, neither PETN nor its metabolite PETriN affects the nitrate esterase activity
of ALDH-2 or elicits ROS formation in isolated arteries or mitochondria. Furthermore, PETN
exhibits intrinsic antioxidant properties due to the redox potential of its dinitrate metabolite and
induction of protective genes, both in vitro and in vivo, including heme-oxygenase (HO-1) and
ferritin (HO-1 mediates the conversion of heme into bilirubin, one of the strongest antioxidants
in the body, and ferritin chelates iron, which suppresses hydroxyl radical formation). These
antioxidant actions of PETN may explain the lack of nitrate tolerance or endothelial dysfunction
following PETN therapy.
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3. DERIVATION OF PROVISIONAL VALUES
3.1. DERIVATION OF ORAL REFERENCE DOSES
3.1.1. Derivation of a Subchronic Provisional Reference Dose
The database of potentially relevant studies for deriving a subchronic provisional
reference dose (p-RfD) for PETN includes numerous clinical studies evaluating the compound's
therapeutic use as a venous dilator at doses ranging from 0.57-4.6 mg/kg-day for the long-term
treatment of cardiovascular diseases (see Table 3A). In addition, several acute studies have
established a single-exposure effective dose for reduced blood pressure as low as 0.29 mg/kg
(Dagenais et at.. 1969). The available animal studies are considered less relevant for deriving the
subchronic p-RfD due to the extent of the human database and the much higher doses
(39.1-3,120 mg/kg-day) evaluated in animal studies, including a subchronic-duration dietary
study in mice and rats (Buchcr et al.. 1990; N I P. 1989) and a reproductive/developmental (R/D)
gavage study in rats (Ouinn et al .. 2009). Effects associated with the therapeutic use of organic
nitrates are well characterized and generally secondary to actions on the cardiovascular system,
including hypotension, headache, and dizziness due to cerebral vasodilation, along with other
subjective complaints [reviewed by Dai her et al. (2008); Bode-Boger and Koida (2005); Murad
(1990)1. As discussed in the "Human Studies" section and shown in Table 3 A, several of the
available clinical trials reported an increase in toxicologically relevant side effects following
exposure to PETN.
The designation of the POD for the subchronic p-RfD for PETN is focused on identifying
the lowest therapeutic dose because the primary effect of vasodilation is considered to be
toxicologically relevant in the general population, particularly in chronically exposed individuals
with pre-existing hypotension or susceptible to hypotension; such people include pregnant
women, infants, the elderly suffering from dehydration or malnutrition, diabetics, and those
taking certain medications (diuretics, antidepressants, erectile dysfunction drugs). The lowest
dose of PETN associated with a vasodilatory effect in the continuous-exposure clinical trials is
0.57 mg/kg-day in the Phillips (1953) study. This study, however, involved intermittent
concurrent treatment with NTG, which elicits the same effects as PETN, thereby making the
determination of the specific effective dose of PETN difficult. Because PETN and NTG act in
the same way, though NTG has a shorter half-life, the combined therapeutically effective dose
will be higher than for either drug alone. This study, and several others with concurrent NTG
treatment (Cass and Cohen. 1961; Plot/. 1960; Rosenberg and Michel son. 1955) were not
considered further as the basis for the POD. Of the remaining PETN-only, continuous-exposure
studies, the lowest effective vasodilatory dose of PETN was 0.86 mg/kg-day (Hedges and
Gordon, 1965). Note that the most of the studies mentioned above with concurrent NTG
treatment (Cass and Cohen. 1961; Plot/. 1960; Rosenberg and Michel son. 1955) also showed the
same lowest effective dose at 0.86 mg/kg-day. In those studies, NTG treatment was episodic, and
thus may not have consistently influenced the effective dose of PETN. Those studies are thus
supportive of using the 0.86 mg/kg-day LOAEL as a potential POD. Vasodilation was implicit in
Hedges and Gordon (1965). and in most of the other clinical trials, and was judged to be present
based on the observed therapeutic efficacy at the treatment dose. Other clinical studies reported
effective continuous treatment results at doses ranging from 50 mg (Bohm and Haustein. 1998)
to 80 mg (Edson et al.. 1961) and higher (Schleussner et al.. 2014; Schnorbus et al.. 2010; Jurt et
al.. 2001; Shrivastava et al.. 1983; Aubert et al .. 1970). The effective therapeutic dose for all
these studies was the lowest (or only) administered treatment level. No clear NOAELs for
therapeutic efficacy were reported in the continuous-exposure studies. Rosenberg and Michel son
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(1955) briefly mentioned a lack of therapeutic efficacy at a dose of 0.86 mg/kg-day for five
patients in a preliminary trial to their main study. This study, however, was discounted because
the study was confounded by concurrent treatment with NTG.
NOAELs for side effects in the continuous-exposure clinical studies have been
established in placebo-controlled studies, without concurrent NTG treatment, at doses as low as
0.86 mg/kg-day in the relevant (not confounded by NTG treatment) continuous exposure studies
for headaches in 3/72 patients (Hedges and Gordon. 1965). Evidence from the piacebo-control 1 ed
studies of greater than 4 weeks showed NOAELs for side effects ranging from
0.57-2.3 mg/kg-day (Hedges and Gordon. 1965; Plotz. 1960; Rosenberg and Michelson. 1955;
Phillips. 1953).
Several acute-exposure (single-dose) studies reported effective doses of PETN; these
doses ranged from 0.29-1.1 mg/kg (Dragoni et at.. 2007; Bohm and Haustein. 1998; Giles et at..
1981; Amsterdam et at.. 1980; Shettock et ai. 1980; Dagenais et at.. 1969). The lowest effective
dose from a single exposure (0.29 mg/kg) was reported by Dagenais et at. (1969) to be associated
with a 5-10% reduction in systolic blood pressure in 15 angina patients; this result by itself,
would seem to define the most sensitive effect, which, in this case, was an overt reduction in
blood pressure, rather than vasodilation.
Conclusion
Environmental exposures to PETN, as outlined previously, could lead to toxicologically
relevant vasodilatory effects in the general healthy population, but particularly in chronically
exposed individuals with pre-existing hypotension or those susceptible to hypotension, such as
pregnant women, infants, the elderly suffering from dehydration or malnutrition, those with
diabetes, and those taking certain medications (diuretics, antidepressants, erectile dysfunction
drugs). Thus, the level of potential concern for the general population would be the lowest
effective therapeutic dose.
Approach for Deriving the Subchronic p-RfD
The lowest LOAEL applicable to continuous exposure of PETN is (0.86 mg/kg-day)
from the continuous-exposure clinical study of Hedges and Gordon (1965). Some single-dose
studies had lower effect levels between 0.29-0.71 mg/kg (Bohm and Haustein. 1998; Giles et at..
1981; Amsterdam et at.. 1980; Dagenais et at.. 1969). However, given the uncertainties in
extrapolating an acute exposure to an equivalent continuous exposure, effect levels derived from
the repeat-exposure clinical studies are judged to be much more representative of continuous
daily human exposures. Therefore, the single-dose acute studies are not considered further as the
basis for the subchronic p-RfD.
A LOAEL of 0.86 mg/kg-day is selected as the POD for deriving the subchronic p-RfD
based on implicit vasodilation, given the therapeutic efficacy of PETN at that average daily dose
(ADD) administered to coronary heart disease patients (Hedges and Gordon. 1965). Angina was
reduced by more than two-thirds by patients taking PETN compared with control. Some patients
also left the study because of side effects of lowered blood pressure, again indicating therapeutic
efficacy. The ADD was estimated from the treatment schedule of one 30-mg extended-release
tablet every 12 hours, assuming a 70 kg adult body weight. The 0.86-mg/kg-day dose level was
the lowest treatment dose; a NOAEL was not established in this study. Although the treatment
protocol included a 2-week placebo administration phase intervening between the two 2-week
PETN treatment phases, averaging the effective PETN dose over the entire 6 weeks was judged
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to be inappropriate. The latter decision is based on the reported efficacy of treatment during the
first 2 weeks of PETN administration (Hedges and Gordon. 1965) and immediate biological
action reported following single doses of 20-40 mg PETN (Amsterdam et al.. 1980; Dagenais et
al.. 1969). These observations are consistent with the short half-life and duration of efficacy for
PETN, both on the order of a few hours (Weber et al .. 1995). In addition, the LOAEL of
0.86 mg/kg-day may be near a threshold, given the observations of no effect of PETN in a
preliminary study (Rosenberg and Michel son. 1955). but with effects at the same dose in
additional placebo-control 1 ed continuous studies 4 weeks in duration or longer (Cass and Cohen.
1961; Plotz. 1960; Roberts. 1958). Thus, there is evidence across the database that NOAELs and
LOAELs are overlapping. All these considerations indicate that the biological activity of PETN
depends more on the immediate (peak) internal concentration than on a longer-term average.
Therefore, although the LOAEL POD is based on a relatively short exposure duration,
the effects are expected to be due to the acute vasodilatory effects of PETN, and longer-term
exposure would not be required to evaluate efficacy. In those studies that used the
extended-release formulation, the internal exposure would be somewhat continuous. As for the
potential for increased toxicity with longer exposures, few side effects were evident at exposures
up to 30 weeks. The side effects were generally mild, consisting of headaches, dizziness, and
nausea, all attributable to the primary effect of vasodilation. Furthermore, significantly higher
doses in sub chronic-duration animal studies reveal no toxicologically relevant effects with a
LOAEL of 200 mg/kg-day in rats, and a NOAEL of 3,120 mg/kg-day in mice (Buchcr et al..
1990; N I P. 1989). Therefore, the lowest effective therapeutic dose in evidence from the large
clinical study database is deemed appropriate as the basis for a LOAEL in the general human
population and to serve as a POD for the subchronic p-RfD. The subchronic p-RfD for PETN,
based on the LOAEL of 0.86 mg/kg-day (Hedges and Gordon. 1965). is supported by two
additional studies (Cass and Cohen. 1961; Plotz. I960); however, these two studies were
partially confounded by concurrent treatment with NTG. Thus, the subchronic p-RfD is derived
as follows:
Subchronic p-RfD = LOAEL UFc
= 0.86 mg/kg-day -M00
= 9 x 10"3 mg/kg-day
Table 6 summarizes the uncertainty factors for the subchronic p-RfD for PETN.
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Table 6. Uncertainty Factors for the Subchronic p-RfD for PETN
UF
Value
Justification
UFa
1
A UFa of 1 is applied because the assessment is based on clinical data from humans.
UFd
3
A UFd of 3 (100 5) is applied. The database contains numerous clinical oral studies, including several
recent, medium to large, well-designed, placebo-controlled, double-blind, randomized studies of
4-30 wk in duration, that identify NOAELs or LOAELs in cardiovascular disease patients treated
with PETN to induce coronary vasodilation at doses up to 4.6 mg/kg-d. The database also includes
short-term-, subchronic-, and chronic-duration oral studies in rats and mice that found either no
effects or onlv mild nonspecific effects on bodv weisht at hieh doses (>200 nm/ku-d) (Bucher et al.
1990; NIP. 19891 as well as an oral R/D toxicity screening study in rats that found no effects at
doses ud to 1.000 me/ke-d (Quitin et al.. 2009). However, a multiseneration reproductive toxicity
study or a developmental teratology study have not been conducted.
UFh
10
A UFh of 10 is applied for intraspecies variability to account for human-to-human variability in
susceptibility (including hypotensive individuals) in the absence of quantitative information to assess
the toxicokinetics and toxicodynamics of PETN in humans.
UFl
3
A UFl of 3 (10°5) is applied because of overlapping NOAEL and LOAEL values likely near the
threshold response, for example. Rosenberg and Michelson (1955).
UFS
1
UFS is not applicable to the subchronic p-RfD because the principal study was 8 wk in duration and
because the very short half-life of NO causes dosing to be episodic, not cumulative, and thus the
effects would not be dependent on duration.
UFC
100
Composite UF = UFA x UFD x UFH x UFL x UFS.
LOAEL = lowest-observed-adverse-effect level; NO = nitric oxide; NOAEL = no-observed-adverse-effect level;
PETN = pentaerythritol tetranitrate; p-RfD = provisional reference dose; R/D = reproductive/developmental;
UF = uncertainty factor; UFA = interspecies uncertainty factor; UFC = composite uncertainty factor; UFD = database
uncertainty factor; UFH = intraspecies variability uncertainty factor; UFL = LOAEL-to-NOAEL uncertainty factor;
UFS = subchronic-to-chronic uncertainty factor.
Confidence in the subchronic p-RfD for PETN is medium as explained in Table 7.
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Table 7. Confidence Descriptors for the Subchronic p-RfD for PETN
Confidence Categories
Designation
Discussion
Confidence in principal
study
M
Confidence in the orincioal studv (Hedges and Gordon, 1965) is
medium. The study appears to be of high quality, with a single-blind
randomized crossover design, 72 subjects, and clear, well-reported
results. However, a NOAEL was not identified because effects were
seen at both doses in the study.
Confidence in database
M
Confidence in the database is medium. The database comprises
multiple well-conducted and well-reported clinical trials that
demonstrate the effects of PETN in cardiac patients and healthy
volunteers at exposure levels near the POD. The database also contains
short-term-, subchronic-, and chronic-duration oral studies in rats and
mice that found either no effects or only mild nonspecific effects on
bodv weight at high doses (>200 mg/kg-d) (Bucher et al.. 1990; NTP.
1989). as well as an oral R/D toxicity screening studv in rats that found
no effects at doses ud to 1.000 mg/kg-d (Quitin et al.. 2009). However,
neither a multigenerational reproductive study nor a developmental
teratology study has been done.
Confidence in subchronic
p-RfDa
M
Overall confidence in the subchronic p-RfD is medium.
aThe overall confidence cannot be greater than lowest entry in table (medium).
M = medium; NOAEL = no-observed-adverse-effect level; PETN = pentaerythritol tetranitrate; POD = point of
departure; p-RfD = provisional reference dose; R/D = reproductive/developmental.
3.1.2. Derivation of a Chronic Provisional Reference Dose
As discussed for the derivation of the subchronic p-RfD, the database of potentially
relevant studies for deriving a chronic reference dose value for PETN includes numerous clinical
studies evaluating the compound's therapeutic use as a venous dilator for the long-term treatment
of cardiovascular diseases using therapeutic doses ranging from 0.57-4.6 mg/kg-day
(see Table 3A). Due to the extent of the human database, the available animal studies evaluating
much higher doses (39.1-3,120 mg/kg-day), including a chronic-duration dietary study in mice
and rats (Bucher et al.. 1990; N I P. 1989) and an R/D gavage study in rats (Quinn et al.. 2009).
were not considered as principal studies for deriving the chronic p-RfD. While no
chronic-duration clinical studies were identified, any potential toxicologically relevant effects of
PETN are expected to be due to acute vasodilatory effects of PETN and transient in nature.
Further, the results of the chronic-duration animal studies revealed no additional noncancer
hazards. Therefore, short-term-duration clinical studies are considered appropriate for deriving
the chronic p-RfD.
Approach for Deriving the Chronic p-RfD
The basis for the chronic p-RfD is the same as for the subchronic p-RfD, with the lowest
effective therapeutic dose serving as a LOAEL and vasodilation as the critical effect. The
LOAEL is 0.86 mg/kg-day for vasodilation, with potential for reduced blood pressure,
established in the clinical study of Hedges and Gordon (1965). The chronic p-RfD for PETN is
derived as follows:
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Chronic p-RfD = NOAEL UFc
= 0.86 mg/kg-day -MOO
= 9 x 10"3 mg/kg-day
Table 8 summarizes the uncertainty factors for the chronic p-RfD for PETN.
Table 8. Uncertainty Factors for the Chronic p-RfD for PETN
UF
Value
Justification
UFa
1
A UFa of 1 is applied because the assessment is based on clinical data from humans.
UFd
3
A UFd of 3 (100 5) is applied. The database contains numerous clinical oral studies, including several
recent, medium to large, well-designed, placebo-controlled, double-blind, randomized studies of
4-30 wk in duration that identity NOAELs or LOAELs in cardiovascular disease patients treated with
PETN to induce coronary vasodilation at doses up to 4.6 mg/kg-d. The database also includes
short-term-, subchronic-, and chronic-duration oral studies in rats and mice that found either no
effects or onlv mild nonspecific effects on bodv weisht at hieh doses (>200 nm/ku-d) (Bucher et al.
1990; NIP. 19891 as well as an oral R/D toxicity screening study in rats that found no effects at
doses ud to 1.000 me/ke-d (Quitin et al.. 2009). However, a multieeneration reproductive toxicity
study or a developmental teratology study have not been conducted.
UFh
10
A UFh of 10 is applied to account for human-to-human variability in susceptibility (including
hypotensive individuals) in the absence of quantitative information to assess the toxicokinetics and
toxicodynamics of PETN in humans.
UFl
3
A UFl of 3 (10°5) is applied because of overlapping NOEAL and LOAEL values likely near the
threshold of response. For example. Rosenberg and Michelson (1955).
UFS
1
A UFS of 1 is applied. Although the assessment is based on relatively short 8-30-wk clinical trials in
humans, any potential toxicologically relevant effects of PETN are expected to be due to the acute
vasodilatory effects of PETN and transient in nature. Furthermore, the database included 2-yr studies
in rats and mice that assessed systemic toxicity at doses much higher than the human clinical doses
and reported no effects. Therefore, increased risk is not expected following longer duration exposure.
UFC
100
Composite UF = UFA x UFD x UFH x UFL x UFS.
LOAEL = lowest-observed-adverse-effect level; NOAEL = no-observed-adverse-effect level;
PETN = pentaerythritol tetranitrate; p-RfD = provisional reference dose; R/D = reproductive/developmental;
UF = uncertainty factor; UFA = interspecies uncertainty factor; UFC = composite uncertainty factor;
UFd = database uncertainty factor; UFH = intraspecies variability uncertainty factor; UFL = LOAEL-to-NOAEL
uncertainty factor; UFS = subchronic-to-chronic uncertainty factor.
The confidence of the chronic p-RfD for PETN is medium as explained in Table 9.
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Table 9. Confidence Descriptors for the Chronic p-RfD for PETN
Confidence Categories
Designation
Discussion
Confidence in the
principal study
M
Confidence in the orincioal studv (Hedges and Gordoa 1965) is
medium. The study appears to be of high quality, with a single-blind
randomized crossover design, 72 subjects, and clear, well-reported
results. However, a NOAEL was not identified, because effects were
observed at both doses used in the study.
Confidence in database
M
Confidence in the database is medium. The database comprises
multiple well-conducted and well-reported clinical trials that
demonstrate the effects of PETN in cardiac patients and healthy
volunteers at exposure levels near the POD. The database also contains
short-term-, subchronic-, and chronic-duration oral studies in rats and
mice that found either no effects or only mild nonspecific effects on
bodv weight at high doses (>200 me/ke-dl (Bucher et al. 1990; NTP.
1989). as well as an oral R/D toxicity screening studv in rats that found
no effects at doses ud to 1.000 mg/kg-d (Quitin et al.. 2009). However,
neither a multigenerational reproductive study nor a developmental
teratology study has been done.
Confidence in chronic
p-RfDa
M
Overall confidence in the subchronic p-RfD is medium.
aThe overall confidence cannot be greater than lowest entry in table (medium).
M = medium; NOAEL = no-observed-adverse-effect level; PETN = pentaerythritol tetranitrate; POD = point of
departure; p-RfD = provisional reference dose; R/D = reproductive/developmental.
3.2. DERIVATION OF INHALATION REFERENCE CONCENTRATIONS
No information was available on the subchronic or chronic inhalation toxicity of PETN,
thus precluding the derivation of provisional reference concentration (p-RfC) values for PETN.
3.3. SUMMARY OF NONCANCER PROVISIONAL REFERENCE VALUES
A summary of the noncancer provisional reference values is shown in Table 10.
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Table 10. Summary of Noncancer Reference Values for PETN
(CASRN 78-11-5)
Toxicity Type
(units)
Species/
Sex
Critical Effect
p-Reference
Value
POD
Method
POD (HED)
UFc
Principal
Study
Subchronic p-RfD
(mg/kg-d)
Human/
both
Vasodilation
9 x 1(T3
LOAEL
0.86
100
Hedges and
Gordon (1965V
Chronic p-RfD
(mg/kg-d)
Human/
both
Vasodilation
9 x 1(T3
LOAEL
0.86
100
Hedges and
Gordon (1965V
Subchronic p-RfC
(mg/m3)
NDr
Chronic p-RfC
(mg/m3)
NDr
aSee Table 3A.
HED = human equivalent dose; LOAEL = lowest-observed-adverse-effect level; NDr = not determined;
PETN = pentaerythritol tetranitrate; POD = point of departure; p-RfC = provisional reference concentration;
p-RfD = provisional reference dose; UFC = composite uncertainty factor.
3.4. CANCER WEIGHT-OF-EVIDENCE DESCRIPTOR
The cancer weight-of-evidence (WOE) descriptor for PETN is "Suggestive Evidence of
Carcinogenic Potential" following oral exposure and "Inadequate Information to Assess
Carcinogenic Potential" following inhalation exposure; see the details below and in Table 11.
Table 11. Cancer WOE Descriptors for PETN
Possible WOE
Descriptor
Designation
Route of Entry
(oral, inhalation,
or both)
Comments
"Carcinogenic to Humans"
NS
NA
No human data are available.
"Likely to Be Carcinogenic
to Humans "
NS
NA
The available data do not support this descriptor.
"Suggestive Evidence of
Carcinogenic Potential"
Selected
Oral
There is suggestive evidence of Zymbal gland
tumors in M and F rats and thyroid tumors in
F rats in a 2-vr oral bioassav (Bucher et al.,
1990; NTP, 1989). There is no evidence of
carcinogenicity in M or F mice in a 2-yr oral
bioassav (Bucher et al., 1990; NTP, 1989)
(see Appendix A).
"Inadequate Information
to Assess Carcinogenic
Potential"
Selected
Inhalation
No carcinogenicity studies are available that
evaluated inhalation exposure.
"Not Likely to Be
Carcinogenic to Humans"
NS
NA
The available data do not support this descriptor.
F = female(s); M = male(s); NA = not applicable; NS = not selected; PETN = pentaerythritol tetranitrate;
WOE = weight of evidence.
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Following U.S. EPA (2005) Guidelines for Carcinogen Risk Assessment, the database for
exposure to PETN provides evidence leading to a WOE descriptor of "Suggestive Evidence of
Carcinogenic Potential" following oral exposure, in that both rare (normal incidence 1% or less)
Zymbal gland and thyroid gland tumors were identified. In a 2-year bioassay in rats, incidences
of rare Zymbal gland carcinomas or adenomas were observed in all treated groups of both sexes
(see Table B-5). The incidences did not reach statistical significance (p < 0.05) when compared
with control group incidences. However, they are rare tumors (both concurrent control and
historical control incidence is less than 1%) that did exceed mean historical incidences for each
sex, and there was a statistically significant trend in females (p < 0.028) (see Table B-5). Site
concordance between males and females and a dose-response in females also adds to the WOE.
Considering the overall occurrence of rare Zymbal gland tumors in 3 of 35 (9%) of dosed female
rats compared with none in the controls in the chronic study, and a Zymbal gland tumor in one
high-dose female rat in the subchronic-duration 14-week study, NTP (1989) concluded that the
Zymbal gland tumors were possibly related to PETN exposure. Additional neoplastic findings in
the rats included thyroid gland follicular cell adenomas or carcinomas in a small number of
high-dose females (see Table B-5). The high-dose incidence was not statistically significantly
higher than that in controls, but the incidence exceeded historical control incidences and showed
a statistically significant dose-related trend (Cochran-Armitage trend test, p = 0.016;
see Table B-5). For the purposes of this PPRTV assessment, the U.S. EPA considers these
thyroid tumors to be treatment related. Because there were no indications of increased thyroid
follicular cell adenomas, carcinomas, or hyperplasia in chronically exposed males, the small
increase in follicular cell tumors in females was not considered PETN-related by NTP; however,
based on the increase in neoplasms of the Zymbal gland, the NTP study authors concluded that
this study provided "Equivocal Evidence of Carcinogenic Activity" of PETN for male and
female F344/N rats.
In this assessment, the study results show a rare tumor type (Zymbal gland tumors) with a
statistically significant dose-response in females, but not males (Bucher et al.. 1990; NTP. 1989).
This tumor type also appears in a high-dose female in the subchronic (14-week) assay. There is
also evidence of thyroid tumors, with a statistically significant trend in females. NTP designated
the carcinogenic potential "Equivocal." U.S. EPA finds that the observation of rare Zymbal
gland tumors in both female and male rats and thyroid tumors in female rats constitute sufficient
evidence for the identification of a hazard, but not strong enough to warrant a descriptor of
"Likely to Be Carcinogenic to Humans. " Thus, for this assessment, the cancer descriptor for
PETN is determined to be "Suggestive Evidence of Carcinogenic Potential. "
3.5. MODE-OF-ACTION DISCUSSION
The Guidelines for Carcinogenic Risk Assessment (U.S. EPA. 2005) defines mode of
action (MO A) ".. .as a sequence of key events and processes, starting with interaction of an agent
with a cell, proceeding through operational and anatomical changes, and resulting in cancer
formation." Examples of possible modes of carcinogenic action for any given chemical include
"mutagenicity, mitogenesis, programmed cell death, cytotoxicity with reparative cell
proliferation, and immune suppression."
A limited amount of information is available on the genotoxicity and mutagenicity of
PETN. Available in vitro data indicate that PETN and its metabolites are not mutagenic in
bacterial systems (NTP. 1989; Mortelmans et al.. 1986; Whong et al.. 1980). Limited in vitro
data indicate that PETN has the potential to induce clastogenic effects in mammalian cells (NTP.
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1989). No additional data regarding potential mechanisms of carcinogenicity are available. Thus,
a detailed MOA discussion for PETN is precluded.
3.6. DERIVATION OF PROVISIONAL CANCER RISK ESTIMATES
3.6.1. Derivation of a Provisional Oral Slope Factor
Although there is sufficient data to derive a provisional oral slope factor (p-OSF), the
U.S. EPA cancer guidelines (U.S. EPA. 2005) state that a quantitative assessment is not usually
conducted when the cancer descriptor is "Suggestive Evidence of Carcinogenic Potential. "
However, they go on to say that, if a quantitative assessment is useful for a specific purpose, it
may be conducted. Therefore, for purposes of this provisional value assessment, a screening
p-OSF is presented in Appendix A.
3.6.2. Derivation of a Provisional Inhalation Unit Risk
The lack of data on the carcinogenicity of PETN following inhalation exposure precludes
deriving a quantitatively estimated provisional inhalation unit risk (p-IUR).
3.6.3. Summary of Cancer Risk Estimates
A summary of the cancer risk estimates is shown in Table 12.
Table 12. Summary of Cancer Risk Estimates for PETN (CASRN 78-11-5)
Toxicity Type
(units)
Species/Sex
Tumor Type
Cancer Risk
Estimate
Principal Study
Screening p-OSF
(nig/kg-d)"1
F344/N rat, F
Combined Zymbal gland and
thyroid (see Appendix A)
4.3 x 1(T3
Bucher et al. (1990); NTP
(1989)
p-IUR (lng/in3) 1
NDr
F = female(s); NDr = not determined; PETN = pentaerytMtol tetranitrate; p-IUR = provisional inhalation unit risk;
p-OSF = provisional oral slope factor.
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APPENDIX A. SCREENING PROVISIONAL VALUES
For the reasons noted in the main Provisional Peer-Reviewed Toxicity Value (PPRTV)
document, it is inappropriate to derive provisional cancer toxicity values for pentaerythritol
tetranitrate (PETN). 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 Center for Public Health and Environmental
Assessment (CPHEA) 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 provisional reference values 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 could be more uncertainty associated with deriving 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
CPHEA.
A National Toxicology Program (NTP) 2-year bioassay in rats and mice is available for
developing a screening provisional oral slope factor (p-OSF) (Bucher et al.. 1990; NTP. 1989).
In the rat study, "Equivocal Evidence of Carcinogenicity" was observed in female and male rats
based on marginal increases in combined incidence of rare Zymbal gland adenomas and
carcinomas. There was also a marginal increase in the combined incidence of thyroid gland
follicular cell adenomas and carcinomas in female rats. Although the NTP (1989) concluded that
thyroid gland tumors were not related to PETN because there were no statistical indications of
increased follicular cell adenomas or carcinomas, or increased follicular cell hyperplasia in
males, the U.S. EPA considers suggestive evidence from a single sex to be informative. In the
mouse study, there was no evidence of carcinogenicity.
Benchmark dose (BMD) modeling was performed for Zymbal gland tumors in female
rats (see Table A-l; additional BMD details in Appendix C). Rationale for modeling marginal
increases for Zymbal gland tumors include a significant dose-related trend in females
(see Table B-5) and evidence for potential biological relevance based on their presence in every
group of chronically treated rats and one high-dose female in the companion subchronic study
(Bucher et al.. 1990; NTP. 1989). Thyroid gland tumors in females were also BMD modeled
because there was a significant dose-related trend in these tumors.
Before modeling, all doses were converted to human equivalent doses (HEDs) using
3/4 body-weight (BW3/4) scaling (U.S. EPA, 2005), according to the equation below:
HED = dose x (BWa - BWh)14
where
Dose = average daily animal dose (ADD)
BWa = study-specific, time-weighted, body weight
averages (TWA) for rat (see Table 3B footnote)
BWh = human body weight [70 kg; U.S. EPA (201 lc)1
The animal doses, calculated HED values, and associated Zymbal gland tumor and
thyroid tumor incidences are provided in Table A-l.
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Table A-l. Animal Doses, HEDs, and Zymbal and Thyroid Gland Adenoma
or Carcinoma Incidences in Female Rats Exposed Orally to PETNa
Animal Dose
mg/kg-d
HED
mg/kg-d
Zymbal Gland Adenoma or
Carcinoma Incidence
Thyroid Gland Adenoma or
Carcinoma Incidence
0
0
0/36
0/50
80
20
1/37
0/48
165
41.3
3/35
3/50
aBucher et al. (1990): NTP (1989).
HED = human equivalent dose; PETN = pentaerytliritol tetranitrate.
BMD modeling of the data on incidences of Zymbal and thyroid gland adenomas or
carcinomas in female rats (Bucher et al.. 1990; NTP. 1989) yielded the 10% benchmark dose
lower confidence limit (BMDLio) (HED) values shown in Table A-2. Modeling procedures and
results are described in detail in Appendix C.
Table A-2. BMD Model Results for Zymbal and Thyroid Gland Tumors in
Female Ratsa
Reference
Tumor Endpoint
Model Type
Goodness-of-
Fit /7-Value
BMD io (HED)
mg/kg-d
BMDLio (HED)
mg/kg-d
p-OSF
(mg/kg-d)1
Bucher et
al. (1990):
NTP (1989)
Zymbal gland adenoma
or carcinoma in female
rats
Multistage-
Cancer-
1st degree
0.9224
56
27
3.7 x 10~3
Bucher et
al. (1990):
NTP (1989)
Thyroid gland
adenoma or carcinoma
in female rats
Multistage-
Cancer-
2nd degree
0.7050
60
40
2.5 x 10~3
Bucher et
al. (1990):
NTP (1989)
Combined Zymbal
adenoma or
carcinoma, or thyroid
adenoma or
carcinoma
MS-Combo
NA
36
23
4.3 x 10"3
aBucher et al. (1990): NTP (1989).
BMD = benchmark dose; BMDL = benchmark dose lower confidence limit (subscripts denote BMR:
i.e., 10 = exposure concentration associated with 10% extra risk); BMR = benchmark response; HED = human
equivalent dose; NA = not applicable; p-OSF = provisional oral slope factor.
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The BMDL 10 (HED) of 23 mg/kg-day for the combined incidence of thyroid and Zymbal
gland tumors was used as the point of departure (POD) for calculating the screening p-OSF as it
was the lowest POD, compared with either of the individual tumor types. Because the study
(Bucher et al .. 1990; N I P. 1989) was conducted for the full lifetime of the rats (2 years), no
adjustment for less-than-lifetime observation was necessary. The mode of action (MOA) by
which PETN might induce Zymbal or thyroid gland tumors is not known; in the absence of
definitive information, a linear approach was used to obtain the slope from the POD. The
screening p-OSF of 4.3 x 10 3 (mg/kg-day) 1 was derived as follows:
Screening p-OSF = BMR BMDLio (HED)
= 0.1 ^ 23 mg/kg-day
= 4.3 x 10"3 (mg/kg-day)"1
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APPENDIX B. DATA TABLES
Table B-l. Acute Clinical Studies Evaluating Subjective Complaints
Following PETN Administration
Study/Type
Subjects
Duration and Dose"
Results
Fife et al. (1958)
Double-blind
clinical trial,
crossover design
Trial 1: 75 angina patients;
53 M/2 F;
Trial 2: 42 angina patients,
subset of Trial 1, sex not
reported.
Each subject received both
placebo and PETN treatment
(2 wk on, 2 wk off, with half
receiving treatment each
2-wk period).
2 wk;
Trial 1: 0, 2.6 mg/kg-d;
Trial 2: 0,
1.3-2.6 mg/kg-d PETN,
dose was 1.3 mg/kg-d for
first week and
2.6 mg/kg-d for second
week of the second trial,
if tolerated.
"Mild" side effects (headache,
giddiness, palpitation, insomnia, GI
symptoms):
Trial 1: 14/75 PETN, 12/75 placebo;
p > 0.1;b
Trial 2: 7/42 PETN, 6/42 placebo;
p > 0.1
"Moderate to severe" side effects
(headache/nausea):
Trial 1: 8/75 PETN, 2/75 placebo;
p = 0.1;
Trial 2: 5/42 PETN, 0/42 placebo;
p = 0.06
Roberts (1958)
Double-blind
clinical trial,
crossover design
42 angina patients,
40 M/2 F.
Both standard PETN and
time-release were used.
Each subject received a
placebo and PETN treatment
during the study period at
2-wk intervals; neither
doctor nor patient knew what
treatment was supplied at
bimonthly visits.
2-wk intervals over
experimental period (up
to 9 mo.); 0, 0.86,
1.7 mg/kg-d
Transient effects were reported in some
subjects and disappeared after a few
days; effects included headache or
flushing (6/42), itching (2/42), and
exacerbation of existing eczema (2/42).
Incidence of side effects was not
reported for the placebo period.
Amsterdam et
al. (1980)
Double-blind
clinical trial,
crossover design
12 (10 M/2 F) heart failure
patients
8 of the subjects received
both placebo and PETN
treatment; time between
treatment administration was
determined by "return to
baseline" hemodynamics.
Once; 0, 0.57 mg/kg
Qualitative: Side effects were evaluated
but not reported.
Predel et al.
(1995)
Double-blind
clinical trial
5 healthy and 5 coronary
artery disease (20 M/0 F)
patients per group.
3 d; 0, 4.3 mg/kg-d
Qualitative: No side effects reported.
aDoses in mg/kg-day were calculated using reported body-weight means (if available) or a reference human body
weight of 70 kg (U.S. EPA. 2011c).
bAll statistics in this table were performed for this review (two-tailed Fisher's exact test).
F = female(s); GI = gastrointestinal; M = male(s); PETN = pentaerythritol tetranitrate.
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Table B-2. Body Weight for F344/N Rats and B6C3F1 Mice Exposed to
PETN in the Diet for 14 Days3
Parameterb
Exposure, ppm PETN (mg/kg-d)c
Male rats
0
620 (65.7)
1,240 (129.0)
2,500 (347.8)
5,000 (674)
10,000 (1,110)
Terminal body weight (g)
208 ±7
207 ±5
(-0)
213 ±5
(+2)
213 ±7
(+2)
209 + 5
(+0)
209 + 7
(+0)
Body-weight gain (g)
69 ±8
74 ±2
(+7)
80 ± 1
(+16)
81 + 4
(+17)
77 + 2
(+12)
77 + 3
(+12)
Female rats
0
620 (79.0)
1,240 (168.0)
2,500 (355.7)
5,000 (635)
10,000 (1,310)
Terminal body weight (g)
145 ±3
144 ±2
(-1)
145 ±2
(0)
147+1
(+1)
145 + 2
(0)
138+1
("5)
Body-weight gain (g)
41 ±2
37 ± 1
(-10)
39 ±2
("5)
41 + 1
(0)
38+1
("7)
31+ ld
(-24)
Male mice
0
620 (173)
1,240 (308.7)
2,500 (539.7)
5,000 (1,380)
10,000 (2,600)
Terminal body weight (g)
25.6 ± 1
25.1 ± 1.1
("2)
25.6 ±0.8
(0)
26.1 + 1
(+2)
27.1 + 1
(+6)
25.9 + 0.8
(+1)
Body-weight gain (g)
2.7 ±0.3
2.2 ±0.4
(-19)
3 ±0.3
(+11)
3.1+0.5
(+15)
4.3+0.3
(+59)
3.3+0.2
(+22)
Female mice
0
620 (187)
1,240 (556.9)
2,500 (703.1)
5,000 (1,800)
10,000 (2,530)
Terminal body weight (g)
20.6 ±0.4
20.2 ±0.5
("2)
20.1±0.4
("2)
20.1 + 0.2
("2)
19.7 + 0.4
(-4)
18 + 0.9d
(-13)
Body-weight gain (g)
2.6 ±0.1
2 ±0.3
("23)
1.9 ±0.2
(-27)
1.8 + 0.4
(-31)
1.1 +0.4d
(-58)
0.4 + 0.7d
(-85)
aBucher et al. (1990): NTP (1989).
bData reported as mean ± SEM (% change compared with control) for 5 mice; % change control = [(treatment
mean - control mean) + control mean] x 100.
Daily doses in mg/kg-day were calculated for this review based on reported body-weight and food-consumption
data.
Significantly different from control (p < 0.05), as calculated for this review (Student's /-test).
PETN = pentaerythritol tetranitrate; SEM = standard error of the mean.
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Table B-3. Body Weight and Relative Organ Weights in F344/N Rats
Exposed to PETN in the Diet for 14 Weeks3
Parameterb
Exposure, ppm PETN (mg/kg-d)c
Male
0
620 (39.1)
1,240 (88.04)
2,500 (190)
5,000 (330)
10,000 (630)
Terminal body weight (g)
339 ±9
331 ±8
("2)
335 ±7
(-1)
351 ± 6
(+4)
336 ±8
(-1)
336 ±6
(-1)
Body-weight gain (g)
156 ±6
147 ± 10
(-6)
152 ±6
("3)
168 ±6
(+8)
153 ±5
("2)
153 ±5
("2)
Brain (mg/g BW)
5.2 ±0.15
[n = 6]
5.5 ±0.11
(+6) [n = 6]
5.5 ±0.12
(+6) [n = 6]
5.1 ±0.49
("2) [n = 6]
5.4 ±0.53
(+4) [n = 6]
5.6 ±0.12
(+8) [n = 6]
Liver (mg/g BW)
37 ±0.88
30.6 ±0.98**
(-17)
32.5 ± 1.24*
(-12)
32.9 ± 1.61
(-11)
33.1 ± 0.9
(-11)
32.7 ± 1.52
(-12)
Right kidney (mg/g BW)
4.6 ±0.55
4.5 ±0.6
("2)
4.4 ±0.54
(-4)
4.6 ±0.61
(0)
4.5 ±0.52
("2)
4.6 ±0.55
(0)
Thymus (mg/g BW)
1 ± 0.16
1 ±0.29
(0)
0.8 ±0.1
("20)
1 ± 0.16
(0)
0.7 ±0.02
(-30)
0.8 ±0.12
("20)
Heart (mg/g BW)
2.7 ±0.06
2.7 ±0.08
(0)
2.7 ±0.08
(0)
2.9 ±0.25
(+7)
2.7 ±0.08
(0)
2.6 ±0.07
(-4)
Lung (mg/g BW)
4.1 ±0.12
In = 5]
3.7 ±0.1
(-10) [n = 6]
3.9 ±0.2
("5) [n = 6]
3.8 ± 0.18
(-7) [n = 6]
3.7 ±0.1
(-10) [n = 5]
3.9 ±0.09
(-5) [n = 6]
Female
0
620 (42.8)
1,240 (85.56)
2,500 (200)
5,000 (370)
10,000 (830)
Terminal body weight (g)
215 ± 2
210 ±3
("2)
211 ±3
("2)
206 ±4
(-4)
203 ± 4d
(-6)
201 ± 4d
("7)
Body-weight gain (g)
76 ±3
70 ±2
("8)
72 ± 1
("5)
67 ± 2d
(-12)
63 ± 2d
(-17)
62 ± 2d
(-18)
Brain (mg/g BW)
8.3 ±0.09
8.6 ±0.15
(+4)
8.7 ±0.12
(+5)
8.8 ±0.13*
(+6)
9 ± 0.13**
(+8)
9 ±0.19**
(+8)
Liver (mg/g BW)
32.9 ±0.41
32.5 ±0.63
(-1)
31.1 ± 0.7
("5)
32.3 ±0.74
("2)
31.9 ±0.85
("3)
33.1 ±0.78
(+1)
Right kidney (mg/g BW)
3.1 ±0.05
3.1 ±0.05
(0)
3.1 ±0.05
(0)
3.2 ±0.06
(+3)
3.2 ±0.05
(+3)
3.3 ±0.06*
(+6)
Thymus (mg/g BW)
1.1 ±0.1
1 ±0.03
(-9)
1.1 ±0.02
(0)
1 ± 0.04
(-9)
1 ± 0.04
(-9)
0.9 ±0.05
(-18)
Heart (mg/g BW)
2.8 ±0.04
2.8 ±0.05
(0)
2.8 ±0.08
(0)
2.9 ±0.06
(+4)
2.9 ±0.07
(+4)
3 ± 0.06
(+7)
Lung (mg/g BW)
4.8 ± 0.11
4.6 ±0.08
(-4)
4.7 ±0.1
("2)
4.8 ±0.08
(0)
4.8 ±0.11
(0)
4.7 ±0.12
("2)
aBucher et al. (1990): NTP (1989).
bData reported as mean ± SEM (percent change compared with control) for 10 rats, unless otherwise noted; percent
change control = [(treatment mean - control mean) control mean] x 100.
Daily doses in mg/kg-day were calculated for this review based on daily food intake (in g/kg B W) reported by the
study authors.
Statistically significantly different from control (p < 0.05), as calculated for this review (Student's /-test).
* Statistically significantly different from control (p < 0.05), as reported by the study authors.
**Statistically significantly different from control (p < 0.01), as reported by the study authors.
BW = body weight; PETN = pentaerythritol tetranitrate; SEM = standard error of the mean.
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Table B-4. Body Weight and Relative Organ Weights in B6C3F1 Mice
Exposed to PETN in the Diet for 13 Weeks3
Parameterb
Exposure, ppm PETN (mg/kg-d)c
Male
0
620 (109)
1,240 (302.6)
2,500 (362.5)
5,000 (925)
10,000 (2,140)
Terminal body weight (g)
30.9 ±0.3
32 ±0.6
(+4)
30 ±0.8
("3)
32.7 ±0.8
(+6)
31.6 ±0.6
(+2)
31.1 ± 0.6
(+1)
Brain (mg/g BW)
14.6 ±0.34
14.5 ±0.56
(-1)
14.3 ±0.4
("2)
14.1 ±0.37
("3)
14.8 ±0.34
(+1)
15.2 ±0.34
(+4)
Liver (mg/g BW)
52.9 ± 1.01
55.1 ±0.97
(+4)
56.3 ± 1.13
(+6)
53.7 ± 1.49
(+2)
55.4 ±2.13
(+5)
52.3 ± 1.34
(-1)
Right kidney (mg/g BW)
8.8 ±0.27
8.9 ±0.25
(+1)
8.8 ±0.38
(0)
8.7 ±0.21
(-1)
8.4 ±0.16
("5)
9.1 ±0.21
(+3)
Thymus (mg/g BW)
1.3 ± 0.13
1.2 ± 0.11
("8)
1.3 ±0.26
(0)
1.2 ±0.17
("8)
1.2 ± 0.11
("8)
1.3 ±0.24
(0)
Heart (mg/g BW)
4.8 ±0.15
4.8 ± 0.11
(0) [n = 9]
4.8 ±0.14
(0)
4.5 ±0.12
(-6)
4.7 ±0.15
("2)
4.8 ±0.11
(0)
Lung (mg/g BW)
5.9 ± 0.19
6.2 ±0.3
(+5)
6 ±0.33
(+2)
6 ±0.38
(+2)
6.1 ±0.23
(+3)
6.3 ±0.25
(+7)
Female
0
620 (172)
1,240 (306.3)
2,500 (632.5)
5,000 (1,340)
10,000 (3,120)
Terminal body weight (g)
27.3 ±0.6
29 ±0.7
(+6)
29.1 ±0.7
(+7)
27.4 ±0.6
(+0.4)
28.3 ±0.7
(+4)
27.7 ±0.8
(+1)
Brain (mg/g BW)
17.9 ±0.35
17.4 ±0.5
("3)
17.4 ±0.41
("3)
17.7 ±0.46
(-1)
17.4 ±0.46
("3)
18 ±0.41
(+1)
Liver (mg/g BW)
50.2 ±0.71
51.7 ± 1.16
(+3)
49.8 ±0.94
(-1)
51.7 ±0.75
(+3)
52.5 ± 1.1
(+5)
53.8 ±0.71*
(+7)
Right kidney (mg/g BW)
6.4 ±0.1
6.8 ±0.21
(+6)
6.3 ±0.14
("2)
6.6 ± 0.11
(+3)
6.7 ±0.15
(+5)
6.9 ±0.12*
(+8)
Thymus (mg/g BW)
1.8 ± 0.16
1.6 ±0.12
(-11)
1.8 ± 0.19
(0)
1.8 ±0.21
(0)
1.8 ± 0.15
(0)
2 ±0.14
(+11)
Heart (mg/g BW)
4.5 ±0.13
4.3 ±0.1
("4)
4.1 ±0.1
(-9)
4.4 ±0.17
("2)
4.4 ±0.15
("2)
4.5 ±0.1
(0)
Lung (mg/g BW)
7.2 ±0.27
6.9 ±0.24
("4)
6.3 ±0.33
(-13)
6.5 ±0.31
(-10)
6.6 ±0.32
("8)
6.8±0.28
(-6)
aBucher et al. (1990): NTP (1989).
bData reported as mean ± SEM (percent change compared with control) for 10 mice, unless otherwise noted;
percent change control = [(treatment mean - control mean) + control mean] x 100.
Daily doses in mg/kg-day were calculated for this review based on daily food intake (in g/kg B W) reported by the
study authors.
*The p-valuc was statistically significant at < 0.05.
BW = body weight; PETN = pentaerythritol tetranitrate; SEM = standard error of the mean.
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Table B-5. Incidences of Zymbal Gland and Thyroid Gland Tumors in
F344/N Rats Exposed to PETN in the Diet for 2 Years3
Exposure, ppm PETN (mg/kg-d)b
Male
0
5,000 (240)
10,000 (490)
Zymbal gland
Hyperplasia
0/49 (0%)
1/45 (2%)
0/41 (0%)
Adenoma
0/49 (0%)
1/45 (2%)
0/41 (0%)
Carcinoma
0/49 (0%)
2/45 (4%)
2/41 (5%)
Adenoma or carcinoma0
0/49 (0%)
3/45 (7%)
2/41 (5%)
Logistic regression tests'1
p = 0.135
p = 0.108
p = 0.219
Cochran-Armitage testd
p = 0.157
NA
NA
Fisher's exact testd
NA
p = 0.106
p = 0.205
Female
0
1,240 (80)
2,500 (165)
Zymbal gland
Hyperplasia
1/36 (3%)
0/37 (0%)
0/35 (0%)
Adenoma
0/36 (0%)
0/37 (0%)
2/35 (6%)
Carcinoma
0/36 (0%)
1/37 (3%)
1/35 (3%)
Adenoma or carcinoma6
0/36 (0%)
1/37 (3%)
3/35 (9%)
Logistic regression tests'1
p = 0.055
p = 0.492
p = 0.116
Cochran-Armitage testd
p = 0.028
NA
NA
Fisher's exact testd
NA
p = 0.507
p = 0.115
Thyroid gland
Hyperplasia
1/50 (2%)
0/48 (0%)
1/50 (2%)
Follicular cell adenoma or carcinomaf
0/50 (0%)
0/48 (0%)
3/50 (6%)
Logistic regression trend testd
p = 0.033
NR
p = 0.110
Cochran-Armitage trend testd
p = 0.016
NA
NA
Fisher's exact testd
NA
NR
p = 0.121
aBucher et al. (1990): NTP (1989).
' Daily doses in mg/kg-day were calculated by Bucheretal. (1990).
historical incidence at the study laboratory (mean± SD): 4/599 (0.7 ± 1.0%); historical incidence in NTP studies:
19/1,936 (1.0 ± 1.7%, range 0-8%).
dThe /^-values in the control incidence are for the trend test for combined tumor incidence. The /^-values in the
exposure group incidence columns are for pairwise comparisons between that dose group and the controls for
combined incidence of adenoma or carcinoma. The logistic regression test regards tumors in animals dying before
terminal kill as nonfatal. The Cochran-Armitage and Fisher's exact tests directly compare the overall incidence
rates.
"Historical incidence at the study laboratory (mean± SD): 1/649 (0.2 ± 0.6%); historical incidence in NTP studies:
11/1,983 (0.6 ± 1.3%, range 0-6%).
historical incidence at the study laboratory (mean± SD): 5/627 (0.8 ± 1.3%); historical incidence in NTP studies:
19/1,938 (1.0 ± 1.2%, range 0-4%).
NA = not applicable; NR = not reported; NTP = National Toxicology Program; PETN = pentaerythritol tetranitrate;
SD = standard deviation.
55
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APPENDIX C. BENCHMARK DOSE MODELING RESULTS
MODEL-FITTING PROCEDURE FOR CANCER INCIDENCE DATA
The model-fitting procedure for dichotomous cancer incidence is as follows. The
Multistage-Cancer model in the U.S. EPA's Benchmark Dose Software (BMDS, Version 2.6) is
fit to the incidence data using the extra risk option. The Multistage-Cancer model is run for all
polynomial degrees up to n - 1 (where n is the number of dose groups including control). An
adequate model fit is judged by three criteria: (1) goodness-of-fit p-walue (p > 0.05), (2) visual
inspection of the dose-response curve, and (3) scaled residual at the data point (except the
control) closest to the predefined benchmark response (BMR). Among all of the models
providing adequate fit to the data, the benchmark dose lower confidence limit/benchmark
concentration lower confidence limit (BMDL/BMCL) for the model with the lowest Akaike's
information criterion (AIC) is selected as the point of departure (POD). In accordance with U.S.
EPA (2012a) guidance, benchmark dose/benchmark concentration (BMD/BMC) and
BMDL/BMCL values associated with an extra risk of 10% are calculated. A combined tumor
analysis using the MS-Combo model is run for each tumor type individually and then combined.
A combined tumor analysis is appropriate when tumors of different clonal origin are indicated.
BMD MODELING OF CANCER ENDPOINTS
The incidence data for Zymbal gland tumors and thyroid gland tumors in female rats
were modeled separately and those results are shown in Tables C-l and C-2 and Figures C-l and
C-2. The incidence data for Zymbal gland adenoma or carcinoma in female rats exposed to
dietary pentaerythritol tetranitrate (PETN) for 2 years were combined with thyroid gland
adenoma or carcinoma (Bucher et al.. 1990; N I P. 1989) and used for BMD modeling using an
MS-Combo model.
Increased Incidence of Zymbal Gland Adenoma or Carcinoma in Female Rats Exposed to
PETN for 2 Years
The procedure outlined above was applied to the data for increased combined incidence
of Zymbal gland adenoma or carcinoma in female rats exposed to dietary PETN for 2 years
(Bucher et al.. 1990; N I P. 1989) (see Table C-l). Table C-2 summarizes the BMD modeling
results. All models provided adequate fit to the data, so the model with the lowest AIC was
selected (Multistage-Cancer lst-degree). Thus, the BMDLio (human equivalent dose [HED]) of
27 mg/kg-day from this model is selected for this endpoint (see Figure C-l).
Increased Incidence of Thyroid Gland Adenoma or Carcinoma in Female Rats Exposed to
PETN for 2 Years
The procedure outlined above was applied to the data for increased incidence of thyroid
gland adenoma or carcinoma in female rats exposed to dietary PETN for 2 years (Bucher et al..
1990; N I P. 1989) (see Table C-1). Table C-2 summarizes the BMD modeling results. All
models provided adequate fit to the data, so the model with the lowest AIC was selected
(Multistage-Cancer 2nd-degree). Thus, the BMDLio (HED) of 40 mg/kg-day from this model is
selected for this endpoint (see Figure C-2).
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Table C-l. Combined Incidence of Zymbal Gland and Thyroid Gland
Tumors in Female F344/N Rats Administered Dietary PETN for 2 Years3
HED, mg/kg-db
0
20
41.3
Sample size0
36/50
37/48
35/50
Zymbal gland incidence
0
1
3
Thyroid gland incidence
0
0
3
aBucher et al. (1990): NTP (1989).
'Estimated daily animal doses were converted into HEDs based on the animal :human BW"4 ratio (U.S. EPA. 2005)
using study-specific TWA BWs for rats and 70 kg for humans (U.S. EPA. 2011c).
°Note that sample sizes in the Zymbal gland and thyroid gland tumor analyses are different (see Table A-l).
BW = body weight; HED = human equivalent dose; PETN = pentaerythritol tetranitrate; TWA = time-weighted
average.
Model Predictions for Zymbal Gland and Thyroid Gland Adenomas or Carcinomas in
Female Rats Administered Dietary PETN for 2 Years
The procedure outlined above was applied to the data for incidence of Zymbal gland and
thyroid gland adenomas or carcinomas in female rats (see Table C-l). The software converged
on the Multistage-Cancer lst-degree model for the Zymbal gland tumors and the
Multistage-Cancer 2nd-degree model for thyroid tumors, which provided adequate fit (p > 0.05);
thus, these were selected as the best-fitting models (see Table C-2). The BMDLio (HED) values
from these models are 27.0 and 39.7 mg/kg-day, respectively. Figures C-l and C-2 show the
model fit to the data. The MS-Combo model yields a BMDLio (HED) value of 23 mg/kg-day,
and the model output for the combined tumor analysis is shown in Table C-2.
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Table C-2. BMD Model Results for Zymbal and Thyroid Gland Adenoma and Carcinoma in Female Rats
Administered Dietary PETN for 2 Years3
Model
df
X2 Goodness-of-Fit
/>-Valucb
Scaled Residual:
Dose Nearest BMDC
Scaled Residual:
Control BMDC
AIC
BMDio
mg/kg-d
BMDLio
mg/kg-d
Zymbal Gland Multistage-Cancer
(lst-degree)d
2
0.9224
0.236
0
31.84
55.6481
26.9849
Zymbal Gland Multistage-Cancer
(2nd-degree)
1
1
0
0
33.67
45.3659
27.5424
Thyroid Gland Multistage-Cancer
(lst-degree)
2
0.4859
0.679
0
27.0466
104.048
45.8064
Thyroid Gland Multistage-Cancer
(2nd-degree)d
2
0.7050
0.361
0
25.9494
59.8238
39.6929
Multitumor (MS-Combo)d
NA
NA
NA
NA
NA
35.76216
22.59085
aBucher et al. (1990): NTP (1989).
bValues <0.1 fail to meet conventional goodness-of-fit criteria.
°Scaled residuals for dose group near BMD.
dSelected model. All models provided adequate fit to the data. BMDLs for models providing adequate fit were nearly identical, so the model with the lowest AIC was
selected.
AIC = Akaike's information criterion; BMD = benchmark dose; BMDio = 10% benchmark dose; BMDL = benchmark dose lower confidence limit (subscripts denote
BMR: i.e., 10 = exposure concentration associated with 10% extra risk); df= degree(s) of freedom; NA = not applicable; PETN = pentaerythritol tetranitrate.
58
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BMDL
Multistage Cancer Model, with BMR of 10% Extra Risk for the BMD and 0.95 Lower Confidence Limit for t
30
dose
12:19 09/13 2017
Multistage Cancer
Linear extrapolation
Figure C-l. Multistage (1-Degree) Model for Incidence of Zymbal Gland Adenoma or
Carcinoma in Female F344/N Rats Administered Dietary PETN for 2 Years
(Bucher et al.. 1990: NTP. 1989)
Text Output for Figure C-l:
Multistage Cancer Model. (Version: 1.10; Date: 02/28/2013)
Input Data File:
C:/Users/JKaiser/Desktop/BMDS240/Data/msc_zym_petn_Mscl-BMR10.(d)
Gnuplot Plotting File:
C:/Users/JKaiser/Desktop/BMDS240/Data/msc_zym_petn_Mscl-BMR10.pit
Wed Sep 13 12:19:57 2017
BMDS Model Run
The form of the probability function is:
P[response] = background + (1-background)*[1-EXP(
-betal*doseAl) ]
The parameter betas are restricted to be positive
Dependent variable = Effect
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Independent variable = Dose
Total number of observations = 3
Total number of records with missing values = 0
Total number of parameters in model = 2
Total number of specified parameters = 0
Degree of polynomial = 1
Maximum number of iterations = 5 00
Relative Function Convergence has been set to: le-008
Parameter Convergence has been set to: le-008
Default Initial Parameter Values
Background = 0
Beta(1) = 0.00217791
Asymptotic Correlation Matrix of Parameter Estimates
( *** The model parameter(s) -Background
have been estimated at a boundary point, or have been specified by
the user,
and do not appear in the correlation matrix )
Beta(1)
Beta (1) 1
Parameter Estimates
95.0% Wald Confidence
Interval
Variable Estimate Std. Err. Lower Conf. Limit Upper Conf.
Limit
Background 0 * * *
Beta(1) 0.00189334 * * *
* - Indicates that this value is not calculated.
Analysis of Deviance Table
Model
Full model
Fitted model
Reduced model
Log(likelihood)
-14.8351
-14.9202
-17.1083
# Param's
3
1
1
Deviance Test d.f.
0.170198
4 .54653
P-value
0.9184
0.103
AIC:
31.8404
Dose
Goodness of Fit
Est._Prob. Expected Observed Size
Scaled
Residual
0.0000
20.0000
41.3000
Chi^2 = 0.16
0.0000
0.0372
0. 0752
d.f. = 2
0.000 0.000 36
1.375 1.000 37
2.633 3.000 35
P-value = 0.9224
0. 000
-0.326
0.236
60
Pentaerythritol tetranitrate
-------
EPA/690/R-21/002F
Benchmark Dose Computation
Specified effect = 0.1
Risk Type = Extra risk
Confidence level = 0.95
BMD = 55.64 81
BMDL = 2 6.9849
BMDU = 2 05.925
Taken together, (26.9849, 205.925) is a 90 % two-sided confidence
interval for the BMD
Multistage Cancer Slope Factor = 0.00370577
Multistage Cancer Model, with BMR of 10% Extra Risk for the BMD and 0.95 Lower Confidence Limit for t
dose
12:32 09/13 2017
Figure C-2. Multistage (2-Degree) Model for Incidence of Thyroid Gland Adenoma or
Carcinoma in Female F344/N Rats Administered Dietary PETN for 2 Years
(Bucher et al.. 1990: NTP. 1989)
61
Pentaerythritol tetranitrate
-------
EPA/690/R-21/002F
Text Output for Figure C-2:
Multistage Model. (Version: 3.4; Date: 05/02/2014)
Input Data File: //AA. AD.EPA.GOV/ORD/CIN/USERS/MAIN/A-E/DPETERSE/Net
MyDocuments/BMDS/BMDS2704/msc_PETN Thyroid Female_Opt.(d)
Gnuplot Plotting File: //AA.AD.EPA.GOV/ORD/CIN/USERS/MAIN/A-E/DPETERSE/Net
MyDocuments/BMDS/BMDS2704/msc_PETN Thyroid Female_Opt.pit
Wed Sep 04 15:32:35 2019
BMDS Model Run
The form of the probability function is:
P[response] = background + (1-background)*[1-EXP(
-betal*dose/sl-beta2*dose/s2) ]
The parameter betas are restricted to be positive
Dependent variable = Effect
Independent variable = Dose
Total number of observations = 3
Total number of records with missing values = 0
Total number of parameters in model = 3
Total number of specified parameters = 0
Degree of polynomial = 2
Maximum number of iterations = 5 00
Relative Function Convergence has been set to: le-008
Parameter Convergence has been set to: le-008
Default Initial Parameter Values
Background = 0
Beta(l) = 0
Beta(2) = 3.90286e-005
Asymptotic Correlation Matrix of Parameter Estimates
( *** The model parameter(s) -Background -Beta(l)
have been estimated at a boundary point, or have been specified by
the user,
and do not appear in the correlation matrix )
Beta(2)
Beta (2) 1
Parameter Estimates
95.0% Wald Confidence
Interval
Variable Estimate Std. Err. Lower Conf. Limit Upper Conf.
Limit
Background 0 NA
Beta(1) 0 NA
62
Pentaerythritol tetranitrate
-------
EPA/690/R-21/002F
Beta(2) 2.94395e-005 1.69987e-005 -3.87732e-006 6.27563e-
005
NA - Indicates that this parameter has hit a bound
implied by some inequality constraint and thus
has no standard error.
Analysis of Deviance Table
Model
Full model
Fitted model
Reduced model
Log(likelihood)
-11.3484
-11.9747
-14.6652
# Param's
3
1
1
Deviance Test d.f.
1.25261
6.63362
P-value
0.5346
0.03627
AIC:
25.9494
Dose
Goodness of Fit
Est._Prob. Expected Observed Size
Scaled
Residual
0.0000
20.0000
41.3000
Chi^2 = 0.70
0.0000
0.0117
0.0490
d.f. = 2
0.000 0.000 50.000
0.562 0.000 48.000
2.449 3.000 50.000
P-value = 0.7050
0. 000
-0.754
0.361
Benchmark Dose Computation
Specified effect = 0.1
Risk Type = Extra risk
Confidence level = 0.95
BMD = 59.8238
BMDL = 39.6929
BMDU = 2 43.165
Taken together, (39.6929, 243.165) is a 90 % two-sided confidence
interval for the BMD
Cancer Slope Factor = 0.00251934
63 Pentaerythritol tetranitrate
-------
EPA/690/R-21/002F
Text Output for MS-Combo Model for Combined Incidence of Zymbal Gland Adenoma or
Carcinoma and Thyroid Gland Adenoma or Carcinoma in Female F344/N Rats
Administered Dietary PETN for 2 Years (Bucher et at, 1990; NTP, 1989):
MS_COMBO. (Version: 1.10; Date: 01/29/2017)
Input Data File: C:\Users\dpeterse\OneDrive - Environmental
Protection Agency (EPA)\Profile\Desktop\test.(d)
Gnuplot Plotting File: C:\Users\dpeterse\OneDrive - Environmental
Protection Agency (EPA)\Profile\Desktop\test.pit
Wed Sep 04 17:17:51 2019
BMDS Model Run
The form of the probability function is:
P[response] = background + (1-background)*[1-EXP(
-betal*doseAl)]
The parameter betas are restricted to be positive
Dependent variable = Effect
Independent variable = Dose
Data file name = PETNZybmalFemale.dax
Total number of observations = 3
Total number of records with missing values = 0
Total number of parameters in model = 2
Total number of specified parameters = 0
Degree of polynomial = 1
Maximum number of iterations = 50 0
Relative Function Convergence has been set to: le-008
Parameter Convergence has been set to: le-008
Default Initial Parameter Values
Background = 0
Beta(1) = 0.00217791
Asymptotic Correlation Matrix of Parameter Estimates
( *** The model parameter(s) -Background
have been estimated at a boundary point, or have been
specified by the user,
and do not appear in the correlation matrix )
Beta(1)
Beta (1) 1
64
Pentaerythritol tetranitrate
-------
EPA/690/R-21/002F
Confidence Interval
Variable
Upper Conf. Limit
Background
¦k
Beta(1)
Parameter Estimates
95.0% Wald
Estimate Std. Err. Lower Conf. Limit
0 * *
0.00189334 * *
* - Indicates that this value is not calculated.
Model
value
Full model
Fitted model
0.9184
Reduced model
0 .103
AIC :
Analysis of Deviance Table
Log(likelihood) # Param's Deviance Test d.f.
-14 .8351
-14 . 9202
-17 .1083
31.8404
Log-likelihood Constant
0.170198
4.54653
12 .397374590988454
Dose
Est. Prob.
Goodness of Fit
Expected Observed Size
Scaled
Residual
0.0000
20.0000
41.3000
ChiA2 = 0.16
0 .0000
0.0372
0.0752
d.f. = 2
0.000 0.000 36.000
1.375 1.000 37.000
2.633 3.000 35.000
P-value = 0.9224
0 .000
-0 .326
0 .236
Benchmark Dose Computation
Specified effect = 0.1
Risk Type = Extra risk
Confidence level = 0.95
BMD = 55.6481
BMDL = 2 6.9849
65
Pentaerythritol tetranitrate
-------
EPA/690/R-21/002F
BMDU
205.925
Taken together, (26.9849, 205.925) is a 90
interval for the BMD
O.
O
two-sided confidence
Multistage Cancer Slope Factor
0 .00370577
MS_COMBO. (Version: 1.10; Date: 01/29/2017)
Input Data File: C:\Users\dpeterse\OneDrive - Environmental
Protection Agency (EPA)\Profile\Desktop\test.(d)
Gnuplot Plotting File: C:\Users\dpeterse\OneDrive - Environmental
Protection Agency (EPA)\Profile\Desktop\test.pit
Wed Sep 04 17:17:51 2019
BMDS Model Run
The form of the probability function is:
P[response] = background + (1-background)*[1-EXP(
The parameter betas are restricted to be positive
Dependent variable = Effect
Independent variable = Dose
Data file name = PETNThyroidFemale.dax
Total number of observations = 3
Total number of records with missing values = 0
Total number of parameters in model = 3
Total number of specified parameters = 0
Degree of polynomial = 2
Maximum number of iterations = 50 0
Relative Function Convergence has been set to: le-008
Parameter Convergence has been set to: le-008
-betal*doseAl-beta2*doseA2)]
Default Initial Parameter Values
Background
Beta(1)
Beta(2)
0
0
3 . 9028 6e-005
Asymptotic Correlation Matrix of Parameter Estimates
( *** The model parameter(s) -Background -Beta(l)
have been estimated at a boundary point, or have been
specified by the user
66
Pentaerythritol tetranitrate
-------
EPA/690/R-21/002F
Beta (2)
and do not appear in the correlation matrix )
Beta(2)
1
Confidence Interval
Variable
Upper Conf. Limit
Background
¦k
Beta(1)
¦k
Beta(2)
Estimate
0
0
2.94395e-005
Parameter Estimates
Std. Err.
95.0% Wald
Lower Conf. Limit
* - Indicates that this value is not calculated.
Model
value
Full model
Fitted model
0 . 5346
Reduced model
0.03627
AIC :
Analysis of Deviance Table
Log(likelihood) # Param's Deviance Test d.f.
-11.3484
-11. 9747
-14 . 6652
25 . 9494
Log-likelihood Constant
1. 25261
6.63362
9 .8832848452188156
P-
Dose
Goodness of Fit
Est._Prob. Expected Observed
Size
Scaled
Residual
0.0000
20.0000
41.3000
ChiA2 = 0.70
0 .0000
0.0117
0.0490
d.f. = 2
0.000 0.000 50.000
0.562 0.000 48.000
2.449 3.000 50.000
P-value = 0.7050
0 .000
-0.754
0 .361
Benchmark Dose Computation
Specified effect = 0.1
Risk Type = Extra risk
67
Pentaerythritol tetranitrate
-------
EPA/690/R-21/002F
Confidence level = 0.95
BMD = 59.8 23 8
BMDL = 39.6929
BMDU = 243.165
Taken together, (39.6929, 243.165) is a 90 % two-sided confidence
interval for the BMD
Multistage Cancer Slope Factor = 0.00251934
**** Start of combined BMD and BMDL Calculations.****
Combined Log-Likelihood -26.894855234855342
Combined Log-likelihood Constant 22.2 8 0 65943 62 07 2 69
Benchmark Dose Computation
Specified effect = 0.1
Risk Type = Extra risk
Confidence level = 0.95
BMD = 35.7621
BMDL = 22.5 90 8
BMDU = 61.8 096
Multistage Cancer Slope Factor = 0.00442657
68
Pentaerythritol tetranitrate
-------
EPA/690/R-21/002F
APPENDIX D. REFERENCES
ACGIH (American Conference of Governmental Industrial Hygienists). (2020). 2020 TLVs and
BEIs: Based on the documentation of the threshold limit values for chemical substances
and physical agents & biological exposure indices. Cincinnati, OH.
Amsterdam. EA; Lee. G; A wan. NA; Low. R; Mason. DT. (1980). Effects of oral pentaerythritol
tetranitrate in cardiac failure and angina pectoris. Assessment by hemodynamic
measurement and exercise capacity. La Nouvelle presse medicale 9: 2443-2446.
AT SDR (Agency for Toxic Substances and Disease Registry). (2016). The priority list of
hazardous substances that will be the subject of toxicological profiles [ATSDR Tox
Profile], Atlanta, GA: U.S. Department of Health and Human Services, Agency for Toxic
Substances and Disease Registry, https://www.atsdr.cdc.gov/spl/
ATSDR (Agency for Toxic Substances and Disease Registry). (2018). Minimal risk levels
(MRLs). June 2018. Atlanta, GA: Agency for Toxic Substances and Disease Registry
(ATSDR).
Aubcrt. A; Nvberg. G; Slaastad. R; Tieldflaat L. (1970). Prophylactic treatment of angina
pectoris. A double-blind cross-over comparison of alprenolol and pentanitrol. Br Med J 1:
203-206. http://dx.doi.org/10.1136/bmi. 1.5690.203
Aviado. DM; Kishimoto. T; Kneidinger. HI. (1969). Bronchopulmonary effects of
pentaerythrityl tetranitrate and isoproterenol. J Pharmacol Exp Ther 165: 274-285.
Bai. YP; Zhang. JX; Sun. Q; Zhou. IP; Luo. JM; He. LF; Lin. XC; Zhu. LP; Wu. WZ; Wang.
ZY; Zhang. GG. (2018). Induction of microRNA-199 by nitric oxide in endothelial cells
is required for nitrovasodilator resistance via targeting of prostaglandin 12 synthase.
Circulation 138: 397-41 1. http://dx.doi.Org/10.l 161/CIRCULATIONAHA.l 17.029206
Bancriec- S; Mukheriee. AK; Haider. AK. (1970). Pentaerythritol tetranitrate sustained-release
tablets: Relation of in vitro release of the drug to blood pressure changes after
administration of anesthetized cats. J Pharm Sci 59: 273-274.
http://dx.doi.org/10.1002/ips.260059Q233
Bassenge. E; Stalleicken. D; Fink. B. (1996). Non-intermittent long-term administration of
pentaerithrityl-tetranitrate results in unexpected, tolerance-devoid coronary- and
venodilation. In S Moncada; J Stamler; S Gross; EAHiggs (Eds.), Biology of Nitric
Oxide, Part 5 (pp. 193-193). London, UK: Portland Press.
Bender. AD; Sullivan. FJ; Horvath. SM. (1963). Effects of continued pentaerythritol tetranitrate
administration on myocardial circulation and metabolism. Experientia 19: 254-256.
Bode-Boger. SM; Koida. G. (2005). Organic nitrates in cardiovascular disease [Review], Cell
Mol Biol (Noisy-le-grand) 51: 307-320. http://dx.doi.Org/10.l 170/T632
Bohm. C; Haustein. KO. (1998). Effect of pentaerithrityl tetranitrate on parameters of the
microcirculation. Int J Clin Pharmacol Ther 36: 398-402.
Bowkalow. S; Schleussner. E; Kahier. C; Schneider. U; Lehmann. T; Groten. T. (2018).
Pentaerythrityltetranitrate (PETN) improves utero- and feto-placental Doppler parameters
in pregnancies with impaired utero-placental perfusion in mid-gestation - a secondary
analysis of the PETN-pilot trial. J Perinat Med 46: 1004-1009.
http://dx.doi. org/10.1515/i pm-2017-023 8
Bucher. JR; Huff. J; Haseman. JK; Eustis. SL; I .ilia. HS; Murthv. AS. (1990). No evidence of
toxicity or carcinogenicity of pentaerythritol tetranitrate given in the diet to F344 rats and
B6C3F1 mice for up to two years. J Appl Toxicol 10: 353-357.
http://dx.doi.org/10.1002/iat.25501005Q8
69
Pentaerythritol tetranitrate
-------
EPA/690/R-21/002F
CalEPA (California Environmental Protection Agency). (2019). Consolidated table of
OEHHA/ARB approved risk assessment health values (September 19, 2019 ed.).
Sacramento, CA: California Air Resources Board.
https://www.arb.ca.gov/toxics/healthval/contable.pdf
Cass. LJ; Cohen. JD. (1961). The correlation of pain relief with blood nitrate levels in angina
pectoris when treated with pentaerythritol tetranitrate. Curr Ther Res 3: 23-27.
Commarato- MA; Winburv. MM; Kaplan. HR. (1973). Glyceryl trinitrate and pentrinitrol
(pentaerythritol trinitrate): Comparative cardiovascular effects in dog, cat and rat by
different routes of administration. J Pharmacol Exp Ther 187: 300-307.
Dagenais. GR; Mason. RE; Friesinger. GC; Wender. ('; Ross. RS. (1969). Exercise tolerance in
patients with angina pectoris: Daily variation and effect of pentaerythritol tetranitrate.
Johns Hopkins Med J 125: 301-311.
Daibcr. A; Miinzel. T. (2010). Characterization of the antioxidant properties of pentaerithrityl
tetranitrate (PETN)-induction of the intrinsic antioxidative system heme oxygenase-1
(HO-1). In Advanced protocols in oxidative stress II, methods in molecular biology. New
York, NY: Humana Press. http://dx.doi.org/10.1007/978-l-6Q761-411-1 22
Daibcr. A; Miinzel. T. (2015). Organic nitrate therapy, nitrate tolerance, and nitrate-induced
endothelial dysfunction: Emphasis on redox biology and oxidative stress. Antioxid Redox
Signal 23: 899-942. http://dx.doi.org/10.1089/ars.2Q15.6376
Daibcr. A; Oclzc. M; Coldewev. M; Bachschmid. M; Wen/el. P; Svdow. K; Wendt. M;
Kleschvov. AL; Stalleickcn. D; Ullrich. V; Miitsch. A; Miinzel. T. (2004). Oxidative
stress and mitochondrial aldehyde dehydrogenase activity: A comparison of
pentaerythritol tetranitrate with other organic nitrates. Mol Pharmacol 66: 1372-1382.
http://dx.doi.Org/10.l 124/mol. 104.002600
Daiber. A; Oelze. M; Wenzel. P; Bollmann. F; Pautz. A; Kleinert. H. (2012). Heme oxygenase-1
induction and organic nitrate therapy: Beneficial effects on endothelial dysfunction,
nitrate tolerance, and vascular oxidative stress. Int J Hypertens 2012: 842632.
http://dx.doi.org/10.1155/2012/842632
Daiber, A; Oelze, M; Wenzel, P; Wickramanayake, JM; Schuhmacher, S; Jansen, T; Lackner,
KJ; Torzewski, M; Miinzel, T. (2009). Nitrate tolerance as a model of vascular
dysfunction: Roles for mitochondrial aldehyde dehydrogenase and mitochondrial
oxidative stress [Review], Pharmacol Rep 61: 33-48. http://dx.doi.org/10.lQ16/S1734-
1140(09)70005-2
Daiber, A; Wenzel, P; Oelze, M; Miinzel, T. (2008). New insights into bioactivation of organic
nitrates, nitrate tolerance and cross-tolerance [Review], Clin Res Cardiol 97: 12-20.
http://dx.doi.org/10.1007/s00392-007-Q588-7
Davidson, IW; Miller, HS; DiCarlo, FJ. (1970). Absorption, excretion and metabolism of
pentaerythritol tetranitrate by humans. J Pharmacol Exp Ther 175: 42-50.
Davidson, IW; Miller, HS; DiCarlo, FJ. (1971). Pharmacodynamics and biotransformation of
pentaerythritol tetranitrate in man. J Pharm Sci 60: 274-277.
http://dx.doi.org/10.1002/ips.260060Q226
DiCarlo, FJ; Coutinho, CB; Crew, MC. (1967). Sites of absorption of pentaerythritol tetranitrate.
Arch Int Pharmacodyn Ther 167: 163-170.
DiCarlo, FJ; Melgar, MP; Havnes, LJ; Gala, RL; Crew, MC. (1969). Metabolism of
pentaerythritol trinitrate and pentaerythritol by dogs. J Pharmacol Exp Ther 168: 235-
239.
70
Pentaerythritol tetranitrate
-------
EPA/690/R-21/002F
Donahue. DP. (1944). Chronic toxic manifestations of PETN (pp. 30-39). (U.S. Public Health
Bulletin No. 282). Washington, DC: Federal Security Agency, U.S. Public Health
Service.
Dovinova. I; Cacanviova. S; Faberova, V; Kristck. F. (2009). The effect of an NO donor,
pentaerythrityl tetranitrate, on biochemical, functional, and morphological attributes of
cardiovascular system of spontaneously hypertensive rats. Gen Physiol Biophys 28: 86-
93. http://dx.doi.org/10.4149/gpb 2009 01 86
Dragoni. S; Gori. T; Li si. M; Di Stolfo. G; Pautz. A; Kleinert. H; Parker. JD. (2007).
Pentaerythrityl tetranitrate and nitroglycerin, but not isosorbide mononitrate, prevent
endothelial dysfunction induced by ischemia and reperfusion. Arterioscler Thromb Vase
Biol 27: 1955-1959. http://dx.doi.org/10.1161/ATVBAHA.107.149278
ECHA (European Chemicals Agency). (2018). Registered Substances: Helsinki, Finland.
Retrieved from http://echa.europa.eu/web/guest/information-on-chemicais/registered-
sub stances
Edson. IN; Younger. D; Dipitto. F; Hoffman. I; Yarvis. M. (1961). A comparison of the
effectiveness of pentaerythritol tetranitrate with pentaerythritol tetranitrate and
meprobamate in angina pectoris. Am J Med Sci 241: 83-88.
Fife. R; Howitt. G; Stevenson. J. (1958). Trial of drugs for angina of effort: The oral use of
pentaerythritol tetranitrate, including a comparison with aminophylline and
dihydroxypropyltheophylline. Scott Med J 3: 15-20.
http://dx.doi. org/10.1177/003693305800300102
Fink. B; Bassenge. E. (1997). Unexpected, tolerance-devoid vasomotor and platelet actions of
pentaerythrityl tetranitrate. J Cardiovasc Pharmacol 30: 831-836.
http://dx.doi.org/10.1097/00005344-199712000-0002Q
Gerova. M; Kristek. F; Cacanviova. S; Cebova. M. (2005). Acetylcholine and bradykinin
enhance hypotension and affect the function of remodeled conduit arteries in SHR and
SHR treated with nitric oxide donors. Braz J Med Biol Res 38: 959-966.
http://dx.doi.org/10.1590/S0100-879X2005000600Q19
Giles, TP; Iteld, BJ; Quiroz, AC; Mautner, RK. (1981). The prolonged effect of pentaerythritol
tetranitrate on exercise capacity in stable effort angina pectoris. Chest 80: 142-145.
http://dx.doi.Org/10.1378/chest.80.2.142
Gori. T; At-Hesaven. A; Jottiffe. C; Parker. JP. (2003). Comparison of the effects of
pentaerythritol tetranitrate and nitroglycerin on endothelium-dependent vasorelaxation in
humans. Eur Heart J 24: 318-318.
Gori, T; Paiber, A. (2009). Non-hemodynamic effects of organic nitrates and the distinctive
characteristics of pentaerithrityl tetranitrate [Review], Am J Cardiovasc Drugs 9: 7-15.
http://dx.doi.org/10.1007/BF03256591
Hacker, A; Mutter, S; Mever, W; Koida, G. (2001). The nitric oxide donor pentaerythritol
tetranitrate can preserve endothelial function in established atherosclerosis. Br J
Pharmacol 132: 1707-1714. http://dx.doi.org/10.1038/si.bip.0704021
Hedges, RN, Jr.; Gordon, WZ. (1965). A spectral analysis of coronary heart disease. Correlation
of results of therapy using a long-acting nitrate compound. Angiology 16: 728-738.
http://dx.doi.org/10.1177/0003319765016012Q2
Henstridge. PC; Puffy, SJ; Formosa, MF; Ahimastos, AA; Thompson, BR; Kingwett, BA.
(2009). Oral nitrate therapy does not affect glucose metabolism in healthy men. Clin Exp
Pharmacol Physiol 36: 1086-1092. http://dx.doi.Org/10.l 111/i. 1440-1681.2009.05195.x
71
Pentaerythritol tetranitrate
-------
EPA/690/R-21/002F
IARC (International Agency for Research on Cancer). (2018). I ARC monographs on the
evaluation of carcinogenic risk to humans.
http://monographs.iarc.fr/ENG/Monographs/PDFs/index.php
IPCS (International Programme on Chemical Safety). (2020). INCHEM: Chemical safety
information from intergovernmental organizations [Database], Geneva, Switzerland:
World Health Organization, Canadian Centre for Occupational Health and Safety. Inter-
Organization Programme for the Sound Management of Chemicals. Retrieved from
http://www.inchem.org/
Jurt. U; Gori. T; Ravandi. A; Babaci. S; Zeman. P; Parker. ID. (2001). Differential effects of
pentaerythritol tetranitrate and nitroglycerin on the development of tolerance and
evidence of lipid peroxidation: A human in vivo study. J Am Coll Cardiol 38: 854-859.
http://dx.doi.org/10.1016/SQ735-1097f0n01414-0
Kalidindi. M; Yclauthar. L; Khan. K; Aciuilina. J. (2012). The role of nitrates in the prevention of
preeclampsia: An update [Review], Curr Opin Obstet Gynecol 24: 361-367.
http://dx.doi.org/10.1097/GCQ.0b013e32835a31de
Klemenska. E; Beresewicz. A. (2009). Bioactivation of organic nitrates and the mechanism of
nitrate tolerance [Review], Cardiol J 16: 11-19.
Koida. G; Hacker. A; Noack. E. (1998). Effects of nonintermittent treatment of rabbits with
pentaerythritol tetranitrate on vascular reactivity and superoxide production. Eur J
Pharmacol 355: 23-31. http://dx.doi.org/10.1016/S0014-2999(98)00460-9
Koida. G; Noack. E. (1995). Effects of pentaerythrityl-tetranitrate and isosorbide-5-mononitrate
in experimental atherosclerosis. In K Schror; CR Pace-Asciak (Eds.), Mediators in the
cardiovascular system : regional ischemia (pp. 201-206). Boston. MA: Birkhauser
Verlag.
Koida. G; Stein. D; Kottenberg. E; Schnaith. EM; Noack. E. (1995). In vivo effects of
pentaerythrityl-tetranitrate and isosorbide-5-mononitrate on the development of
atherosclerosis and endothelial dysfunction in cholesterol-fed rabbits. J Cardiovasc
Pharmacol 25: 763-773. http://dx.doi.org/10.1097/00005344-199505000-00Q12
Kosmicki, MA. (2009). Long-term use of short- and long-acting nitrates in stable angina pectoris
[Review], Curr Clin Pharmacol 4: 132-141.
http://dx.doi.org/10.2174/157488409788185016
Kristek. F. (2000). Pentaerythrityl tetranitrate attenuates structural changes in conduit arteries
evoked by long-term NO-synthase inhibition. Br J Pharmacol 130: 450-456.
http://dx.doi.org/10.1038/si.bip.07033Q7
Kristek, F; Faberova, V; Varga, I. (2003). Long-term effect of molsidomine and pentaerythrityl
tetranitrate on cardiovascular system of spontaneously hypertensive rats. Physiol Res 52:
709-717.
Lewis. R. (2007). Pentaerythritol tetranitrate (PETN). In Hawley's condensed chemical
dictionary. New York, NY: John Wiley & Sons. http://dx.doi.org/10.1021/ipQ617930
Litchfield. Mil. (1971). Aspects of nitrate ester metabolism [Review], J Pharm Sci 60: 1599-
1607.
Mortelmans. K; Haworth. S; Lawlor. T; Speck. W; Tainer. B; Zeiger. E. (1986). Salmonella
mutagenicity tests: II. Results from the testing of 270 chemicals. Environ Mutagen 8: 1-
119. http://dx.doi.org/10.1002/em.28600807Q2
Mullenheim. J; Muller. S; Laber. U; Thamer. V; Mever. W; Bassenge. E; Fink. B; Koida. G.
(2001). The effect of high-dose pentaerythritol tetranitrate on the development of nitrate
tolerance in rabbits. Naunyn-Schmiedebergs Arch Pharmacol 364: 269-275.
http://dx.doi.org/10.1007/s00210010Q464
72
Pentaerythritol tetranitrate
-------
EPA/690/R-21/002F
Miinzei, T; Daiber, A; Gori, T. (2013). More answers to the still unresolved question of nitrate
tolerance [Review], Eur Heart J 34: 2666-2673.
http://dx.doi.org/10.1093/eurhearti/eht249
Miinzei T; Gori. T. (2013). Nitrate therapy and nitrate tolerance in patients with coronary artery
disease. Curr Opin Pharmacol 13: 251-259. http://dx.doi.Org/10.1016/i.coph.2012.12.008
Miinzei. T; Meinertz. T; Tebbe. U; Schneider. HT; Stalleicken. D; Wargenau, M; Gori. T;
Klingmann. I. (2014). Efficacy of the long-acting nitro vasodilator pentaerithrityl
tetranitrate in patients with chronic stable angina pectoris receiving anti-anginal
background therapy with beta-blockers: A 12-week, randomized, double-blind, placebo-
controlled trial. Eur Heart J 35: 895-902. http://dx.doi.org/10.1093 eurhcarti/eht384
Murad. F. (1990). Drugs used for the treatment of angina: Organic nitrates, calcium-channel
blockers, and P-adrenergic antagonists. In AG Gilman; TH Rail; AS Nies; P Taylor
(Eds.), The pharmacological basis of therapeutics (8th ed., pp. 764-783). New York, NY:
Pergamon Press.
NCBI (National Center for Biotechnology Information). (2021). PubChem annotation record for
pentaerythritol tetranitrate, source: Hazardous Substances Data Bank (HSDB)
[Database]: PubChem. Retrieved from
https://pubchem.ncbi.nlm.nih.gov/source/hsdb/6313
NIOSH (National Institute for Occupational Safety and Health). (202 1). NIOSH pocket guide to
chemical hazards: Index of chemical abstracts service registry numbers (CAS No.).
Available online at http://www.cdc.gov/niosh/npg/npgdcas.html
NO A A (National Oceanic and Atmospheric Administration). (2016). Cameo Chemicals. Version
2.4.2. Pentaerythritol tetranitrate. CAS number 78-11-5 (Version 2.6). Silver Spring, MD.
Retrieved from https://cameochemicals.noaa.gov/chemical 12283
NTP (National Toxicology Program). (1989). Toxicology and carcinogenesis studies of
pentaerythritol tetranitrate with 80% D-lactose monohydrate (PETN, NF) in F344/N rats
and B6C3F1 mice (feed studies). (NTP TR 365). 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 rptsZtr365.pdf
NTP (National Toxicology Program). (2016). 14th Report on carcinogens. Research Triangle
Park, NC. https://ntp niehs.nih.gov/pubhealth/roc index-1.html
O'NeiL MJ. (2013). Pentaerythritol tetranitrate. In MJ O'Neill; PE Heckelman; PH Dobbelaar; KJ
Roman; CM Kenney; LS Karaffa (Eds.), The Merck index (15th ed., pp. 94). Cambridge,
UK: Royal Society of Chemistry.
Oelze, M; Kroiler-Schon, S; Steven, S; Lubos, E; Doppler, C; Hausding, M; Tobias, S;
Brochhausen, C; Li, H; Torzewski, M; Wenzel, P; Bachschmid, M; Lackner, KJ; Schulz,
E; Miinzei, T; Daiber, A. (2014). Glutathione peroxidase-1 deficiency potentiates
dysregulatory modifications of endothelial nitric oxide synthase and vascular dysfunction
in aging. Hypertension 63: 390-396.
http://dx.doi.org/10.1161/HYPERTEN SIONAHA. 113.01602
Opelt. M; Wolkart, G; Eroglu, E; Waldeck-Weiermair, M; Matti, R; Graier, WF; Kottau, A;
Fassett, IT; Schrammel, A; Maver, B; Gorren, ACF. (2018). Sustained formation of
nitroglycerin-derived nitric oxide by aldehyde dehydrogenase-2 in vascular smooth
muscle without added reductants: Implications for the development of nitrate tolerance.
Mol Pharmacol 93: 335-343. http://dx.doi.org/10.1124/mol. 117.110783
73
Pentaerythritol tetranitrate
-------
EPA/690/R-21/002F
OSHA (Occupational Safety & Health Administration). (2020a). Air contaminants: Occupational
safety and health standards for shipyard employment, subpart Z, toxic and hazardous
substances. (OSHA Standard 1915.1000). Washington, DC.
https://www.osha.gov/pls/oshaweb/owadisp.show document?p table STANDARDS&p
id10286
OSHA (Occupational Safety & Health Administration). (2020b). Table Z-l: Limits for air
contaminants. Occupational safety and health standards, subpart Z, toxic and hazardous
substances. Available online at
http://www.osha.gov/pls/oshaweb/owadisp.show document?p table STANDARDS&p
id=9992
Perlman. A. (1952). A study of the therapeutic action and toxicity of pentaerythritol tetranitrate.
Angiology 3: 16-19. http://dx.doi.Org/10.l 177/000331975200300102
Phillips. E. (1953). A comparison of peritrate and other organic nitrates in the treatment of
angina pectoris. Ariz Med 10: 171-174.
Plot/. M. (1960). The treatment of angina pectoris with a new prolonged action pentaerythritol
tetranitrate. Am J Med Sci 239: 194-197.
Potocniak. D; Baric-Rat'ai. R; l.emo. N; Matiiatko. V; Kis. I; Mrliak. V; Harapin. I. (2008).
Poisoning of a dog with the explosive pentaerythrityl tetranitrate. J Small Anim Pract 49:
314-318. http://dx.doi.org/10.1111/i. 1748-5827.2008.00549.X
Predet. HG; Knigge. H; Prinz. U; Kramer. HI; Stalleicken. D; Rost. RE. (1995). Exercise
increases endothelin-1 plasma concentrations in patients with coronary artery disease:
Modulatory role of LDL cholesterol and of pentaerithrityltetranitrate. J Cardiovasc
Pharmacol 26 Suppl 3: S497-S501.
Quinn. MJ. Jr.; Crouse. LC; McFarland. CA; LaFiandra. EM; Johnson. MS. (2009).
Reproductive and developmental effects and physical and chemical properties of
pentaerythritol tetranitrate (PETN) in the rat. Birth Defects Res B Dev Reprod Toxicol
86: 65-71. http://dx.doi.org/10.1002/bdrb.20184
Roberts. JT. (1958). Continuous twenty-four hour vasodilation in the treatment of angina
pectoris; time-disintegration capsules containing pentaerythritol tetranitrate reduced the
severity and frequency of angina pectoris attacks. Conn Med 22: 813-815.
Rosenberg. UN; Michelson. AL. (1955). The use of pentaerythritol tetranitrate in chronic
coronary insufficiency. Am J Med Sci 230: 254-258.
Rutherford. E; St rut hers. AD. (2013). Pentaerythrityl tetranitrate (PETN): A better nitrate?
[Comment], Eur Heart J 40: e23-e25. http://dx.doi.org/10.1093 eurhcarti/eht403
Schetting, JL; Lasagna, L. (1967). A study of cross-tolerance to circulatory effects of organic
nitrates. Clin Pharmacol Ther 8: 256-260. http://dx.doi.org/10.1002/cptl96782256
Schleussner. E; Lehmann. T; Kahler. C; Schneider. U; Schlembach. D; Groten. T. (2014). Impact
of the nitric oxide-donor pentaerythrityl-tetranitrate on perinatal outcome in risk
pregnancies: A prospective, randomized, double-blinded trial. J Perinat Med 42: 507-514.
http://dx.doi. org/10.1515/i pm-2013 -0212
Schnorbus, B; Schiewe, R; Ostad, MA; Medler, C; Wachtlin, D; Wenzel, P; Daiber, A; Miinzel,
T; Warnholtz. A. (2010). Effects of pentaerythritol tetranitrate on endothelial function in
coronary artery disease: Results of the PENTA study. Clin Res Cardiol 99: 115-124.
http://dx.doi.org/10.1007/s00392-009-0Q96-z
Shah. PK; Shettock. FG; Berman. DS; Rubin. SA; Singh. BN; Swan. HJ. (1980). Sustained
beneficial effects of oral pentaerythritol tetranitrate on ventricular function in chronic
congestive heart failure. LaNouvelle presse medicale 9: 2447-2450.
74
Pentaerythritol tetranitrate
-------
EPA/690/R-21/002F
Sheiiock. FG; Shah. PK; Bcrrnan. DS; Rubin. SA; Singh. BN; Swan. HI. (1980). Sustained
benefits or oral pentaerythritol tetranitrate on ventricular function in chronic congestive
heart failure. Clin Pharmacol Ther 28: 436-440. http://dx.doi.org/10.1038/clpt.198Q.185
Shrivastava. RK; Tatturv. VK; Davican. G; Shah. BK. (1983). Pentaerythritol tetranitrate
(Peritrate) efficacy trial in patients with angina-pectoris. Curr Ther Res 33: 841-847.
Steven. S; Oelze. M; Brandt M; Ullmann. E; Kroller-Schon. S; Heeren. T; Tran. LP; Daub. S;
Dib. M; Stalleicken. D; Wenzel. P; Miinzel. T; Daiber. A. (2017). Pentaerythritol
tetranitrate in vivo treatment improves oxidative stress and vascular dysfunction by
suppression of endothelin-1 signaling in monocrotaline-induced pulmonary hypertension.
Oxid Med Cell Longev 2017: 4353462. http://dx.doi.Org/10.l 155/2017/4353462
Sullivan. FJ; Bender. AD; Horvath. SM. (1964). Acute effects of pentaerythritol tetranitrate on
various myocardial hemodynamic and metabolic parameters in the normal anesthetized
dog. Arch Int Pharmacodyn Ther 147: 229-235.
Torok. J; Kristek. F. (2002). Beneficial effect of pentaerythrityl tetranitrate on functional and
morphological changes in the rat thoracic aorta evoked by long-term nitric oxide synthase
inhibition. Vascul Pharmacol 38: 177-182. http://dx.doi.org/10.lQ16/S1537-
1891(02)00193-3
U.S. EPA (U.S. Environmental Protection Agency). (1988). Recommendations for and
documentation of biological values for use in risk assessment [EPA Report], (EPA/600/6-
87/008). Cincinnati, OH. http://cfpub.epa. gov/ncea/cfm/recordisplav.cfm?deid=34855
U.S. EPA (U.S. Environmental Protection Agency). (2002). A review of the reference dose and
reference concentration processes. (EPA/630/P-02/002F). Washington, DC.
https://www.epa.gov/sites/production/files/2014-12/documents/rfd-final.pdf
U.S. EPA (U.S. Environmental Protection Agency). (2005). Guidelines for carcinogen risk
assessment [EPA Report], (EPA/630/P-03/001F). Washington, DC.
https://www.epa.gov/sites/production/fiies/2013-
09/documents/cancer guidelines final 3-25-05.pdf
U.S. EPA (U.S. Environmental Protection Agency). (2010). Provisional Peer Reviewed Toxicity
Values for pentaerythritol tetranitrate (PETN) (CASRN 78-11-5) [EPA Report],
Cincinnati, OH.
U.S. EPA (U.S. Environmental Protection Agency). (201 la). Exposure factors handbook: 201 1
edition [EPA Report], (EPA/600/R-090/052F). Washington, DC: U.S. Environmental
Protection Agency, Office of Research and Development, National Center for
Environmental Assessment.
http://cfpub.epa.gov/ncea/cfm/recordisplav.cfm?deid=236252
U.S. EPA (U.S. Environmental Protection Agency). (201 lb). Health effects assessment summary
tables (HEAST) for superfund. Available online at https://epa-heast.ornl.gov/heast.php
U.S. EPA (U.S. Environmental Protection Agency). (201 lc). Recommended use of body weight
3/4 as the default method in derivation of the oral reference dose. (EPA/100/R-11/0001).
Washington, DC. https://www.epa.gov/sites/production/files/2013-
09/documents rccommcndcd-usc-ot'-bw34.pdf
U.S. EPA (U.S. Environmental Protection Agency). (2012a). Benchmark dose technical
guidance. (EPA/100/R-12/001). Washington, DC: U.S. Environmental Protection
Agency, Risk Assessment Forum, https://www.epa.gov/risk/benchmark-dose-technical-
gui dance
75
Pentaerythritol tetranitrate
-------
EPA/690/R-21/002F
U.S. EPA (U.S. Environmental Protection Agency). (2012b). Estimation Programs Interface
Suite™ for Microsoft® Windows, v 4.11 [Computer Program], Washington, DC.
Retrieved from https://www.epa.gov/tsca-screening-toois/epi-suitetm-estimation-
program-interface
U.S. EPA (U.S. Environmental Protection Agency). (2016). Chemicals subject to TSCA Section
12(b) export notification requirements (current as of May 27, 2016) [EPA Report],
https://www.epa.gov/tsca-import-export-requirements/tsca-requirements-exporting-
chcmicals
U.S. EPA (U.S. Environmental Protection Agency). (2018a). 2018 Edition of the drinking water
standards and health advisories [EPA Report], (EPA/822/F-18/001). Washington, DC:
U.S. Environmental Protection Agency, Office of Water.
https://www.epa.gov/sites/production/files/2018-03/documents/dwtable2018.pdf
U.S. EPA (U.S. Environmental Protection Agency). (2018b). Sunset dates of chemicals subject
to final TSCA section 4: Test requirements and related section 12(b) actions [Database],
Retrieved from https://www.epa.gov/assessing-and-managing-chemicals-under-
tsca. sunset-dates-chemicals-subiect-final-tsca-section-4-test
U.S. EPA (U.S. Environmental Protection Agency). (2020a). Integrated risk information system.
IRIS assessments [Database], Washington, DC. Retrieved from http://www.epa.gov/iris/
U.S. EPA (U.S. Environmental Protection Agency). (2020b). The Toxic Substances Control
Act's public inventory (TSCA inventory). Updated June 2020 [Database], Washington,
DC: U.S. Environmental Protection Agency, Office of Chemical Safety and Pollution
Prevention. Retrieved from https://www.epa.gov/tsca-inventorv/how-access-tsca-
inventory#download
von Oettingen. WF; Donahue. DP. (1944). Acute toxic manifestations of PETN. In Toxicity and
potential dangers of penta-erythritol-tetranitrate (PETN). (U.S. Public Health Bulletin
No. 282). Washington, DC: Federal Security Agency, U.S. Public Health Service.
Weber. W; Michaclis. K; Luckow. V; Kuntze. U; Stalleickcn. D. (1995). Pharmacokinetics and
bioavailability of pentaerithrityl tetranitrate and two of its metabolites.
Arzneimittelforschung 45: 781-784.
Whong. WZ; Speciner. ND; Edwards. GS. (1980). Mutagenic activity of tetryl, a nitroaromatic
explosive, in three microbial test systems. Toxicol Lett 5: 11-17.
http://dx.doi.org/10.1016/03 78-4274(80)90142-3
Wu. Z; Siuda. D; Xia. N; Reifenberg. G; Daiber. A; Miinzel. T; Forstermann. U; Li. H. (2015).
Maternal treatment of spontaneously hypertensive rats with pentaerythritol tetranitrate
reduces blood pressure in female offspring. Hypertension 65: 232-237.
http://dx.doi.org/10.1161/HYPERTEN SIONAHA. 114.04416
76
Pentaerythritol tetranitrate
------- |