United States
Environmental Protection
1=1 m m Agency
EPA/690/R-10/021F
Final
9-30-2010
Provisional Peer Reviewed Toxicity Values for
Pentaerythritol tetranitrate (PETN)
(CASRN 78-11-5)
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National Center for Environmental Assessment
Office of Research and Development
U.S. Environmental Protection Agency
Cincinnati, OH 45268

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AUTHORS, CONTRIBUTORS, AND REVIEWERS
CHEMICAL MANAGER
Alan J. Weinrich, CIH, CAE
National Center for Environmental Assessment, Cincinnati, OH
DRAFT DOCUMENT PREPARED BY
SRC, Inc.
7502 Round Pond Road
North Syracuse, NY 13212
PRIMARY INTERNAL REVIEWERS
Harlal Choudhury, DVM, Ph.D., DABT
National Center for Environmental Assessment, Cincinnati, OH
Maureen R. Gwinn, Ph.D., DABT
National Center for Environmental Assessment, Washington, DC
This document was externally peer reviewed under contract to
Eastern Research Group, Inc.
110 Hartwell Avenue
Lexington, MA 02421-3136
Questions regarding the contents of this document may be directed to the U.S. EPA Office of
Research and Development's National Center for Environmental Assessment, Superfund Health
Risk Technical Support Center (513-569-7300)

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TABLE OF CONTENTS
COMMONLY USED ABBREVIATIONS	ii
BACKGROUND	1
HISTORY	1
DISCLAIMERS	1
QUESTIONS REGARDING PPRTVS	2
INTRODUCTION	2
REVIEW 01 PERTINENT DATA	2
HUMAN STUDIES	3
ANIMAL STUDIES	4
Oral Exposure	4
Inhalation Exposure	8
OTHER STUDIES	8
DERIVATION OF PROVISIONAL SUBCHRONIC AND CHRONIC ORAL RfD VALUES
FOR PENTAERYTHRITOL TETRANITRATE	8
Subchronic p-RfD	8
Chronic p-RfD	10
FEASIBILITY OF DERIVING PROVISIONAL SUBCHRONIC AND CHRONIC
INHALATION RfC VALUES FOR PENTAERYTHRITOL TETRANITRATE	11
PROVISIONAL CARCINOGENICITY ASSESSMENT FOR PENT AERYTHRIT OL
TETRANITRATE	11
WEIGHT-OF -EVIDENCE DESCRIPTOR	 11
QUANTITATIVE ESTIMATES OF CARCINOGENIC RISK	12
REFERENCES	13
APPENDIX A. DERIVATION OF A SCREENING ORAL SLOPE FACTOR FOR
PENT AERYTHRIT OL TETRANITRATE (PETN)	17
i	Pentaerythritol tetranitrate (PETN)

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COMMONLY USED ABBREVIATIONS
BMC
benchmark concentration
BMD
benchmark dose
BMCL
benchmark concentration lower bound 95% confidence interval
BMDL
benchmark dose lower bound 95% confidence interval
HEC
human equivalent concentration
HED
human equivalent dose
IUR
inhalation unit risk
LOAEL
lowest-observed-adverse-effect level
LOAELadj
LOAEL adjusted to continuous exposure duration
LOAELhec
LOAEL adjusted for dosimetric differences across species to a human
NOAEL
no-ob served-adverse-effect level
NOAELadj
NOAEL adjusted to continuous exposure duration
NOAELhec
NOAEL adjusted for dosimetric differences across species to a human
NOEL
no-ob served-effect level
OSF
oral slope factor
p-IUR
provisional inhalation unit risk
p-OSF
provisional oral slope factor
p-RfC
provisional reference concentration (inhalation)
p-RfD
provisional reference dose (oral)
POD
point of departure
RfC
reference concentration (inhalation)
RfD
reference dose (oral)
UF
uncertainty factor
UFa
animal-to-human uncertainty factor
UFC
composite uncertainty factor
UFd
incomplete-to-complete database uncertainty factor
UFh
interhuman uncertainty factor
UFl
LOAEL-to-NOAEL uncertainty factor
UFS
subchronic-to-chronic uncertainty factor
WOE
weight of evidence
11
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PROVISIONAL PEER-REVIEWED TOXICITY VALUES FOR
PENTAERYTHRITOL TETRANITRATE (PETN, CASRN 78-11-5)
BACKGROUND
HISTORY
On December 5, 2003, the U.S. Environmental Protection Agency's (EPA) Office of
Superfund Remediation and Technology Innovation (OSRTI) revised its hierarchy of human
health toxicity values for Superfund risk assessments, establishing the following three tiers as the
new hierarchy:
1)	EPA's Integrated Risk Information System (IRIS)
2)	Provisional Peer-Reviewed Toxicity Values (PPRTVs) used in EPA's Superfund
Program
3)	Other (peer-reviewed) toxicity values, including
~	Minimal Risk Levels produced by the Agency for Toxic Substances and Disease
Registry (ATSDR);
~	California Environmental Protection Agency (CalEPA) values; and
~	EPA Health Effects Assessment Summary Table (HEAST) values.
A PPRTV is defined as a toxicity value derived for use in the Superfund Program when
such a value is not available in EPA's IRIS. PPRTVs are developed according to a Standard
Operating Procedure (SOP) and are derived after a review of the relevant scientific literature
using the same methods, sources of data, and Agency guidance for value derivation generally
used by the EPA IRIS Program. All provisional toxicity values receive internal review by a
panel of six EPA scientists and external peer review by three independently selected scientific
experts. PPRTVs differ from IRIS values in that PPRTVs do not receive the multiprogram
consensus review provided for IRIS values. This is because IRIS values are generally intended
to be used in all EPA programs, while PPRTVs are developed specifically for the Superfund
Program.
Because new information becomes available and scientific methods improve over time,
PPRTVs are reviewed on a 5-year basis and updated into the active database. Once an IRIS
value for a specific chemical becomes available for Agency review, the analogous PPRTV for
that same chemical is retired. It should also be noted that some PPRTV documents conclude that
a PPRTV cannot be derived based on inadequate data.
DISCLAIMERS
Users of this document should first check to see if any IRIS values exist for the chemical
of concern before proceeding to use a PPRTV. If no IRIS value is available, staff in the regional
Superfund and Resource Conservation and Recovery Act (RCRA) program offices are advised to
carefully review the information provided in this document to ensure that the PPRTVs used are
appropriate for the types of exposures and circumstances at the Superfund site or RCRA facility
in question. PPRTVs are periodically updated; therefore, users should ensure that the values
contained in the PPRTV are current at the time of use.
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It is important to remember that a provisional value alone tells very little about the
adverse effects of a chemical or the quality of evidence on which the value is based. Therefore,
users are strongly encouraged to read the entire PPRTV document and understand the strengths
and limitations of the derived provisional values. PPRTVs are developed by the EPA Office of
Research and Development's National Center for Environmental Assessment, Superfund Health
Risk Technical Support Center for OSRTI. Other EPA programs or external parties who may
choose of their own initiative to use these PPRTVs are advised that Superfund resources will not
generally be used to respond to challenges of PPRTVs used in a context outside of the Superfund
Program.
QUESTIONS REGARDING PPRTVS
Questions regarding the contents of the PPRTVs and their appropriate use (e.g., on
chemicals not covered, or whether chemicals have pending IRIS toxicity values) may be directed
to the EPA Office of Research and Development's National Center for Environmental
Assessment, Superfund Health Risk Technical Support Center (513-569-7300), or OSRTI.
INTRODUCTION
No RfD, RfC, or carcinogenicity assessments for pentaerythritol tetranitrate (PETN) were
available on IRIS (U.S. EPA, 2008), in the Health Effects Assessment Summary Tables
(HEAST; U.S. EPA, 1997), or in the Drinking Water Standards and Health Advisories list
(U.S. EPA, 2006). The Chemical Assessments and Related Activities (CARA) list (U.S. EPA,
1991, 1994) did not include any relevant EPA documents. The Agency for Toxic Substances
and Disease Registry (ATSDR, 2008) and the World Health Organization (WHO, 2008) had not
assessed the health effects of PETN. The carcinogenicity of PETN had not been assessed by the
International Agency for Research on Cancer (IARC, 2008), and PETN was not included in the
National Toxicology Program's 11th Report on Carcinogens (NTP, 2005). Occupational
exposure limits for PETN had not been derived by the American Conference for Governmental
Industrial Hygienists (ACGIH, 2007), the National Institute for Occupational Safety and Health
(NIOSH, 2005), or the Occupational Safety and Health Administration (OSHA, 2008). CalEPA
(2005, 2006, 2008a,b) had not derived noncancer or cancer risk values for PETN.
Literature searches for studies relevant to the derivation of provisional toxicity values for
PETN were conducted in July 2007 in MEDLINE, TOXLINE special, and DART/ETIC
(1960's-July 2007); BIOSIS (2000-July 2007); TSCATS/TSCATS2, RTECS, CCRIS, HSDB,
GENETOX (not date limited), and Current Contents (January-July 2007). Searches also were
checked for updates in August 2008.
REVIEW OF PERTINENT DATA
PETN is a percussive explosive used in detonating fuses and as an admixture with TNT
in small-caliber projectiles and grenades (Merck Index, 2001; NTP, 1989). PETN also has also
been used therapeutically in the treatment of angina pectoris (Abrams, 1980; Murad, 1990). For
this purpose, PETN was formulated with an inert ingredient, usually lactose, to decrease the
potential explosion hazard (Murad, 1990; NTP, 1989). PETN is not on the Food and Drug
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Administration (FDA) approved drug list and appears not to have been approved or distributed
for drug use in the United States since the early-to-mid 1990's (FDA, 1997, 2010; PDR, 1996;
Robertson and Robertson, 1996). However, Internet searches and recent research papers
indicated that PETN continues to be prescribed in other countries. PETN previously was
available as the prescription drug Peritrate® in the United States.
HUMAN STUDIES
PETN is one of a number of organic nitrates (e.g., nitroglycerin) used therapeutically as a
coronary vasodilator in the treatment of angina pectoris (Abrams, 1980; Murad, 1990). We
located a limited amount of human health effects information specifically for PETN because its
cardiovascular effects generally were grouped with the similar effects of the other
nitrovasodilators. These organic nitrates, including PETN, are metabolized to their active
intermediate in vasodilatory action, nitric oxide (Murad, 1990). Additional metabolic details
have been summarized by Daiber et al. (2008).
The nitrovasodilators relax most smooth muscles, including those in
arteries and veins, and selectively dilate large coronary vessels (Murad, 1990).
Lower doses increase coronary blood flow without significantly affecting
systemic arterial pressure. Higher doses, particularly if repeated at frequent
intervals, decrease systolic and diastolic blood pressure and cardiac output, which
can result in headache, weakness and dizziness, and the activation of
compensatory sympathetic reflexes, such as tachycardia and peripheral arteriolar
vasoconstriction. Smooth muscles in the bronchi, biliary tract, gastrointestinal
tract, ureters, and uterus also can be relaxed by nitrovasodilators (Murad, 1990;
Daiber et al., 2008). PETN seems to be unique among the long-acting
nitrovasodilators in that patients do not appear to develop tolerance to treatment,
resulting in continued induction of vasodilation in humans with ongoing PETN
treatment (Fink and Bassenge, 1997; Jurt et al., 2001; Gori et al., 2003).
Adverse responses to the therapeutic use of PETN have been similar to those of other
organic nitrates and generally secondary to actions on the cardiovascular system (Murad, 1990;
Shrivastava et al., 1983). Headache has been common and can be severe, but it usually decreases
over a few days if treatment is continued and often is controlled by temporarily decreasing the
dose. Transient episodes of lightheadedness, dizziness, weakness, and other manifestations
associated with postural hypotension have developed in patients, particularly when the patient
was standing immobile. On occasion, these symptoms have progressed to loss of consciousness.
All organic nitrates can cause skin rash, but it appears to occur most commonly with PETN
(Murad, 1990).
The usual oral dosage of PETN was 10-40 mg as a tablet four times daily or 30-80 mg
as a sustained release capsule every 12 hours (Murad, 1990; PDR, 1987); the total daily dose
ranged from 40-160 mg/day or 0.6-2.3 mg/kg-day for a 70 kg adult. Doses above 160 mg/day
(2.3 mg/kg-day) generally were not recommended due to the potential for severe hypotensive
effects (Murad, 1990; PDR, 1987), although doses as high as 80 mg every 4-8 hours
(3.4-6.9 mg/kg-day) were necessary to produce a therapeutic effect in some individuals
(Alcocer et al., 1973; Abrams, 1980; Shrivastava et al., 1983).
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Single oral doses of 100 mg PETN did not significantly change the resting heart rate, but
it decreased resting systolic blood pressure 6 hours after ingestion by 6.1% (p < 0.05) in supine
patients with stable angina and by 5.9% (p < 0.05) in standing patients. Kosmicki et al. (2005)
observed no postural hypotension in any of the 15 treated patients. Diastolic blood pressure
significantly decreased only in the standing position by 6.8% (p < 0.05) after 6 hours. During
maximal exercise, no significant reduction of systolic blood pressure occurred, but there was a
significant reduction in diastolic blood pressure 6 hours after ingestion. Kosmicki et al. (2005)
reported no adverse effects after a single dose of 50 mg PETN. However adverse effects after
ingestion of 100 mg PETN included headaches in 3 of 15 patients vs. 1/15 patients treated with a
placebo.
ANIMAL STUDIES
Oral Exposure
The National Toxicology Program (NTP, 1989; Bucher et al., 1990) conducted
subchronic and chronic studies in rats and mice using diets containing National Formulary Grade
PETN, a 1:4 formulation of PETN and D-lactose monohydrate typically used in human
therapeutics. Lactose also was present in the base diet (normal concentration approximately 1%)
and the purity of the PETN was >99%. Due to low toxicity, the doses in most of these studies
were based on the maximum dietary concentration of 5% (50,000 ppm) recommended by NTP
conventions for 2-year studies. While NTP (1989; Bucher et al., 1990) conducted relatively
comprehensive evaluations of the exposed animals, they did not report any tests related to
cardiac function that might have revealed effects similar to those revealed in human subjects.
F344/N rats (10/gender/dose) were fed diets containing 0, 3100, 6200, 12,500, 25,000, or
50,000 ppm of the 1:4 PETN-lactose mixture, equivalent to 0, 620, 1240, 2500, 5000, or
10,000 ppm PETN, for 14 weeks (NTP, 1989; Bucher et al., 1990). Based on feed consumption
data for Week 7, we estimated the average daily consumption of PETN as 39, 88, 190, 330, or
630 mg/kg-day, respectively, for males and 43, 86, 200, 370, or 830 mg/kg-day, respectively, for
females. The endpoints investigated included clinical signs, body weight, feed consumption,
whole-blood methemoglobin concentration, and urinary nitrate concentration. NTP (1989;
Bucher et al., 1990) performed necropsies and measured weights for the brain, heart, right
kidney, liver, lungs, and thymus of all sacrificed animals. NTP also conducted comprehensive
histological examinations in the control and high-dose groups of both genders; evaluations at
lower doses were limited to the Zymbal gland in females at 370 mg/kg-day. NTP (1989)
reported no exposure-related effects in the male rats. Effects in treated female rats included
•	6~7% lower final body weights than controls and 17-18%) lower body weight gains
(/>values not reported) at >370 mg/kg-day
•	6-8%) higher relative brain weights than controls (p < 0.05 or 0.01) at >200 mg/kg-day
•	6% higher relative kidney weights than controls (p < 0.05) at 830 mg/kg-day
•	an adenoma of the Zymbal gland in one rat at 830 mg/kg-day.
Absolute organ weights were not reported. In male rats, this subchronic study identified a
NOAEL of 630 mg/kg-day and no LOAEL, while in female rats, the NOAEL was
200 mg/kg-day and the LOAEL was 370 mg/kg-day, for reduced body weight gain.
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NTP (1989; Bucher et al., 1990) fed F344/N rats (50/gender/dose) the 1:4 PETN-lactose
mixture for 2 years in dietary concentrations of 0, 25,000, or 50,000 ppm (0, 5000, or
10,000 ppm PETN) for males and 0, 6200, or 12,500 ppm (0, 1240, or 2500 ppm PETN) for
females. The lower dietary concentrations of the PETN-lactose mixture were selected for the
female rats because higher concentrations caused 17-18% decreases in body weight gains in the
14-week study summarized above. The reported average daily consumption of PETN was
approximately 240 or 490 mg/kg-day for males and 80 or 165 mg/kg-day for females. Clinical
signs, body weights, and feed consumption were evaluated throughout the study. Necropsies
were performed on each rat. Comprehensive histological 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 genders; the brain, pancreas, and testes in males; and the esophagus, lungs, thyroid, and
uterus in females. NTP (1989) reported no exposure-related clinical signs, or effects on survival,
or feed consumption. Mean body weights were 2-9% lower than controls throughout the study
and 7%> lower than controls at study termination in the 490 mg/kg-day males. However, the
mean body weights for the low-dose males and all dosed females remained similar to controls
throughout the study. No exposure-related nonneoplastic lesions were observed in either gender.
This chronic study identified freestanding NOAELs of 490 mg/kg-day in male rats and
165 mg/kg-day in female rats.
Adenomas or carcinomas of the Zymbal gland occurred in all chronically treated groups
of male and female rats, but the incidences were low and demonstrated neither statistical
significance when compared with no incidence in controls, nor dose-related trends (see Table 1)
(NTP, 1989; Bucher et al., 1990). The incidences of Zymbal gland neoplasms also exceeded the
mean historical incidences for each gender, but they were within the upper ranges previously
seen in the control groups (see Table 1). There were no increases in hyperplasia to suggest an
increase of proliferative lesions of the Zymbal gland. Based on the occurrence of 9 total Zymbal
gland neoplasms in dosed rats compared with none in controls and considering the occurrence of
a Zymbal gland tumor in 1 high-dose female rat (1/10 compared to 0/10 in controls) in the
14-week study summarized above, NTP concluded that the results of the chronic study suggested
a possible PETN-related effect.
Thyroid gland follicular cell adenomas or carcinomas (combined) occurred in
3/50 high-dose female rats. Although this incidence was not significantly higher than in controls
(0/50), the incidence exceeded historical control incidences (see Table 1). Because there were no
indications of increased follicular cell adenomas or carcinomas or increased follicular cell
hyperplasia in males, NTP (1989; Bucher et al., 1990) considered the marginal increase in
follicular cell tumors in females to be not PETN-related. Other 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.
NTP (1989; Bucher et al., 1990) fed B6C3Fi mice (10/gender/dose) diets containing 0,
3100, 6200, 12,500, 25,000, or 50,000 ppm of the 1:4 PETN-lactose mixture (0, 620, 1240, 2500,
5000, or 10,000 ppm PETN) for 13 weeks. Based on feed consumption data for Week 7, the
estimated average daily consumption of PETN was 110, 303, 363, 925, or 2140 mg/kg-day,
respectively, for males and 172, 306, 633, 1335, or 3120 mg/kg-day, respectively, for females.
The endpoints evaluated included clinical signs, body weights, feed consumption, and
whole-blood methemoglobin concentrations. Necropsies and measurements of brain, heart, right
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kidney, liver, lungs, and thymus weights were performed on all animals. Comprehensive
histological examinations were conducted in the control and high-dose groups of both genders;
histological evaluations at lower doses were limited to the liver in females at 1335 mg/kg-day.
There were no exposure-related clinical signs or effects on survival, body weight, or
methemoglobin concentration, although dosed male mice consumed less feed than controls.
Small, but statistically significant, increases in relative kidney weights (8% higher than controls)
and relative liver weights (7% higher than controls) occurred in female mice at 3120 mg/kg-day,
but there were no effects on organ weights in males or exposure-related nonneoplastic or
neoplastic lesions in either gender. Because the increased kidney and liver weights were
considered not to be adverse, this subchronic study identified freestanding NOAELs of
2140 mg/kg-day in male mice and 3120 mg/kg-day in female mice.
Table 1. Incidences of Zymbal Gland and Thyroid Gland Tumors in Rats Exposed to
PETN in the Diet for Two Yearsa
Male
0 mg/kg-day
240 mg/kg-day
490 mg/kg-day
Zymbal Gland
Adenoma or Carcinomab
0/49 (0%)
3/45 (7%)
2/41 (4%)
Logistic Regression Testsc
p = 0.135
p = 0.108
p = 0.219
Cochran-Armitage Testc
p = 0.157
NA
NA
Fisher Exact Testc
NA
p = 0.106
p = 0.205
Female
0 mg/kg-day
80 mg/kg-day
165 mg/kg-day
Zymbal Gland
Adenoma or Carcinomad
0/36 (0%)
1/37 (3%)
3/35 (9%)
Logistic Regression Tests
p = 0.055
p = 0.492
p = 0.116
Cochran-Armitage Test
p = 0.055
NA
NA
Fisher Exact Test
NA
p = 0.507
/> = 0.115
Thyroid Gland
Follicular Cell Adenoma or
Carcinoma6
0/50 (0%)
0/48 (0%)
3/50 (6%)
Logistic Regression Tests
p = 0.033
NA
/> = 0.110
Cochran-Armitage Test
p = 0.038
NA
NA
Fisher Exact Test
NA
NA
p = 0.121
aNTP, 1989; Bucher et al., 1990.
bHistorical incidence at the study laboratory (mean± SD): 4/599 (0.7% ± 1.0%); historical incidence inNTP studies:
19/1936 (1.0% ± 1.7%, range 0%-8%).
°Beneath the control incidence are /^-values for the trend test. Beneath the dosed group incidence are the /^-values
for pairwise comparisons between that dose group and the controls. The logistic regression test regards tumors in
animals dying prior to terminal kill as nonfatal. The Cochran-Armitage and Fisher exact tests compare directly the
overall incidence rates.
historical incidence at the study laboratory (mean ± SD): 1/649 (0.2% ± 0.6%); historical incidence in NTP studies:
11/1983 (0.6% ± 1.3%, range 0%-6%).
"Historical incidence at the study laboratory (mean± SD): 5/627 (0.8% ± 1.3%); historical incidence inNTP studies:
19/1938 (1.0% ± 1.2%, range 0%-4%).
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NTP (1989; Bucher et al., 1990) fed B6C3Fi mice (50/gender/dose) diets containing 0,
25,000, or 50,000 ppm of the 1:4 PETN-lactose mixture (0, 5000, or 10,000 ppm PETN) for
2 years. The reported average daily consumption of PETN was approximately 0, 810, or
1620 mg/kg-day, respectively, for males and 0, 1020, or 1936 mg/kg-day, respectively, for
females. Clinical signs, body weights, and feed consumption were evaluated 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 genders, and the liver and spleen in females. NTP (1989; Bucher et al., 1990)
reported there were no exposure-related clinical signs, decreases in survival, effects on body
weight or food consumption, or increases in nonneoplastic 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. Tumors in the male mice control group occurred at a rate nearly five
times higher than in historical controls, but NTP proposed no rationale for this discrepancy. This
chronic study identified freestanding NOAELs of 1620 mg/kg-day in male mice and
1936 mg/kg-day in female mice.
Additional information on the chronic toxicity of PETN is available from a limited study
in which groups of 45 albino rats of mixed genders were fed PETN in dietary doses of 0 or
2 mg/kg-day for one year (von Oettingen et al., 1944). Body weight was measured weekly;
hematology (erythrocyte count, hemoglobin concentration, total and differential leukocyte
counts) was evaluated monthly. Gross pathology, organ weights and volumes (liver, kidneys,
spleen, heart with lungs, brain and testes), and histology (liver, kidneys, spleen, heart, lungs,
brain and femur) were evaluated at the end of the study. Particular attention was paid to
histological changes in the vascular walls of these tissues. An additional parameter reported was
organ density calculated as the ratio of organ weight to volume, von Oettingen et al. (1944)
noted a tendency for slightly higher erythrocyte and hemoglobin values in the dosed rats, but the
values remained within the normal ranges. There were no clear PETN-related body weight
changes, histopathology, or effects on any other endpoints. Mortality in both control and dosed
groups (46.6 and 20%, respectively) was attributed to an infestation of parasitic tapeworm larvae
in the livers of a large number of rats. This study identified a freestanding chronic NOAEL of
2 mg/kg-day in rats, although the results were compromised by the parasitic infestation and the
resulting large numbers of premature deaths.
Effects of subchronic exposure to PETN on the cardiovascular system have been studied
using animal models, including cholesterol-fed rabbits for atherosclerosis, and spontaneously
hypertensive rats for hypertension. In the study 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 vaso-relaxing potency of PETN in aortic rings
(Kojda 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).
A study in spontaneously hypertensive rats (a genetic model of hypertension) found that
exposure to 200 mg/kg-day PETN (100 mg/kg twice daily) by gavage for 6 weeks increased
blood platelet cyclic guanosine 3c,5c-monophosphate (cGMP) content and decreased aortic
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nitrogen oxide (NO) synthase activity, but caused no significant changes in general
cardiovascular system parameters such as blood pressure, heart rate or relative heart weight, or
the geometry of conduit arteries including inner diameter, wall thickness or cross-sectional area
of thoracic aorta, carotid artery, and coronary artery (Kristek et al., 2003). In another study in
spontaneously hypertensive rats, gavage exposure to 200 mg/kg-day PETN (100 mg/kg twice
daily) for 5 weeks from the prehypertensive period at 4 weeks of age, to adulthood (9 weeks old)
did not appear to delay the development of pathological changes in the cardiovascular system
(Kristek et al., 2007). In particular, PETN had no clear beneficial effect on the myocardium or
geometry of the carotid and coronary arteries as shown by assessments that included systolic
blood pressure and arterial inner circumference, wall thickness, cross-sectional area, and
circumferential stress.
Inhalation Exposure
No information was located regarding effects of subchronic or chronic inhalation
exposure to PETN.
OTHER STUDIES
"Military grade" PETN solutions in dimethylsulfoxide did not induce reverse mutations
in Salmonella typhimurium strains TA98, TA100, TA1535, TA1537, or TA1538 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 was not mutagenic in Salmonella typhimurium
strains TA98, TA100, TA1535, or TA1537 when tested with or without metabolic activation in a
preincubation assay (Mortelmans et al., 1986; NTP, 1989). The 1:4 PETN-lactose mixture
caused a small increase in sister chromatid exchanges in cultured Chinese hamster ovary (CHO)
cells in the presence or absence of metabolic activation, but the response was not clearly
dose-related and cell cycle delay was not induced (NTP, 1989). The 1:4 PETN-lactose mixture
did not induce chromosomal aberrations in CHO cells when tested with or without metabolic
activation (NTP, 1989).
DERIVATION OF PROVISIONAL SUBCHRONIC AND CHRONIC ORAL RFD
VALUES FOR PENTAERYTHRITOL TETRANITRATE
SUBCHRONIC p-RfD
Information on the health effects of PETN in humans is available via clinical experience
from its use as a venous dilator for the long-term treatment of angina pectoris. The
recommended daily dose ranged from 40-160 mg/day (0.6-2.3 mg/kg-day for a 70 kg adult),
usually administered as a 10-40 mg tablet 4 times a day (Murad, 1990; PDR, 1987). Adverse
responses to the therapeutic use of PETN were similar to those of other nitrovasodilators and
generally were secondary to effects on the cardiovascular system (Murad, 1990;
Shrivastava et al., 1983). Doses in the recommended range have caused transient effects such as
headache, lightheadedness, dizziness, weakness, and other manifestations associated with
postural hypotension. Doses above 160 mg/day (-2.3 mg/kg-day) generally were not
recommended due to the potential for more severe hypotensive effects, such as shortness of
breath and unconsciousness. We located no additional information regarding the adverse effects
of PETN in humans unrelated to its actions on the cardiovascular system.
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Subchronic oral toxicity in rats exposed to PETN in the diet for 13-14 weeks (NTP,
1989; Bucher et al., 1990) resulted in small decreases in body weight gain (17% less than
controls) and final body weight (6% less than controls), as well as small increases in relative
brain and kidney weights (6-8% higher than controls) in females; no clear histopathological or
other changes presented in either gender. A NOAEL of 200 mg/kg-day and LOAEL of
370 mg/kg-day were identified in rats based on the female body weight data. Effects in mice fed
PETN in the diet for 13-14 weeks (NTP, 1989; Bucher et al., 1990) consisted of small increases
in relative kidney and liver weights (7-8% higher than controls) in females. A NOAEL of
3120 mg/kg-day with no LOAEL was identified in mice. The small, but statistically significant,
organ weight changes in mice were not considered to be toxicologically relevant and they were
unaccompanied by any histopathological or other changes.
Because the hypotensive effects of PETN exposure could result in adverse consequences
among people with normal and low blood pressure, we concluded that the minimum
recommended human therapeutic dose of 0.6 mg/kg-day (Murad, 1990; PDR, 1987) provided the
most conservative POD for deriving a subchronic RfD for PETN. Much higher doses in the
subchronic animal studies were essentially nontoxic, as shown by the NOAELs of approximately
200 mg/kg-day in rats and 3120 mg/kg-day in mice, and the LOAEL of 370 mg/kg-day in rats at
which only decreased weight gain was observed (NTP, 1989; Bucher et al., 1990). This
suggested either that humans might be more sensitive to the effects of PETN than experimental
rats and rabbits or that many adverse effects noted in humans (e.g., headache, lightheadedness,
and other manifestations associated with postural hypotension) were difficult to observe in
experimental animals.
The 0.6 mg/kg-day minimum recommended therapeutic dose of PETN in humans is
considered a LOAEL because treated hypertensive patients have reported clinical symptoms,
such as headache, dizziness, weakness, and other manifestations associated with postural
hypertension at this dose (Murad, 1990; PDR, 1987). Vasodilation in normal, healthy adults is
likely to lead to postural hypotension, as well, and potentially could cause more serious effects in
humans who already are hypotensive. The human LOAEL of 0.6 mg/kg-day was divided by a
composite uncertainty factor (UF) of 300, explained in the next paragraph, to derive a
subchronic p-RfD as follows:
Subchronic p-RfD = NOAEL UF
= 0.6 mg/kg-day -^300
= 0.002 or 2 x 10 3 mg/kg-day
The composite UF of 300 includes factors of 10 each for using a LOAEL point of departure
(POD) and for human variability, and a factor of 3 for database deficiencies. A human
variability UF of 3 was applied to account for variations in sensitivity within human populations.
Although there is limited information on the degree to which humans of different genders, ages,
health statuses, or genetic makeups might vary in the disposition of, or response to PETN, the
lowest therapeutic dose already represents an extremely conservative POD in a population that
could be considered sensitive (cardiac patients). The UF of 10 for extrapolation from a LOAEL
to a NOAEL was not reduced, despite the mild nature of anticipated adverse effects because of
the unknown slope of the dose-response curve. An UF of 10 for database deficiencies was
applied due to the lack of information on reproductive and developmental toxicity.
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Confidence in the human LOAEL is high because it is the minimum recommended
therapeutic dose at which clinical experience has demonstrated adverse effects in treated patients
(Murad, 1990; PDR, 1987). In addition, effects have been observed in experimental rats only at
much higher doses (von Oettingen et al., 1944; NTP, 1989; Bucher et al., 1990; Kristek et al.,
2003, 2007), and the rabbit studies (Kojda et al., 1995; Hacker et al., 2001) suggested potentially
beneficial effects such as reduced serum cholesterol. Confidence in the database is medium.
The database included 13-14 week studies in rats and mice that assessed systemic toxicity at
doses much higher than the recommended human dose, but it lacked reproductive and
developmental toxicity studies. Considering the levels of confidence in the human LOAEL and
database, confidence in the subchronic p-RfD is medium.
CHRONIC p-RfD
PETN has been used as a coronary vasodilator for the long-term treatment of angina
pectoris in humans (Abrams, 1980; Murad, 1990). As discussed for the subchronic RfD, the
usual daily dose ranged from 0.6-2.3 mg/kg-day (Murad, 1990; PDR, 1987) and doses above
2.3 mg/kg-day generally were not recommended due to the potential for severe hypotensive
effects (Murad, 1990; PDR, 1987). Although humans tend to develop tolerance to treatment
with most organic nitrovasodilators, PETN seems to be unique in that patients experience
continued induction of vasodilation with ongoing PETN treatment (Fink and Bassenge, 1997;
Jurt et al., 2001; Gori et al., 2003).
Chronic oral toxicity was evaluated in rats exposed to PETN in the diet for one year
(von Oettingen et al., 1944) and in rats and mice exposed to PETN in the diet for 2 years (NTP,
1989; Bucher et al., 1990). Body weight and limited hematology, organ weight, gross pathology,
and histopathology evaluations were performed in the one-year rat study (von Oettingen et al.,
1944). There were no clear exposure-related effects in the one-year study and a freestanding
chronic NOAEL of 2 mg/kg-day was identified. The only nonneoplastic effect identified in the
NTP (1989; Bucher et al., 1990) studies was a small decrease in final body weight (7% less than
controls) in high-dose male rats; no adverse effects were observed in mice at any dose. Because
the reduced final weight in rats was minimal, these studies identified chronic NOAELs of
490 mg/kg-day in rats and 3120 mg/kg-day in mice, with no LOAELs.
The minimum recommended human therapeutic dose of 0.6 mg/kg-day (Murad, 1990;
PDR, 1987) was a LOAEL, and it provided the best basis for a chronic p-RfD for PETN, as it did
for the subchronic derivation. Although the recommended human dose was based on
hypotensive effects, the animal studies indicated that this dose is unlikely to cause chronic
systemic toxicity unrelated to the effects of PETN on the cardiovascular system. In particular,
similar and much higher doses in the chronic animal studies were nontoxic, as shown by the
freestanding chronic NOAELs of 2 mg/kg-day (von Oettingen et al., 1944) and 490 mg/kg-day
NTP (1989; Bucher et al., 1990) in rats, and 3120 mg/kg-day in mice (NTP, 1989; Bucher et al.,
1990).
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As was done for the subchronic p-RfD, the human LOAEL of 0.6 mg/kg-day PETN was
divided by a composite UF of 300, which is explained in the next paragraph, to derive a chronic
p-RfD as follows:
Chronic p-RfD = NOAEL UF
= 0.6 mg/kg-day -^300
= 0.002 or 2 x 10 3 mg/kg-day
The composite UF of 300 included factors of 10 for extrapolating from a LOAEL to a
NOAEL, a 3 for human variability, and a factor of 10 for database deficiencies. The UF for
using a LOAEL for the POD was not reduced, despite the mild nature of anticipated adverse
effects because of the unknown slope of the dose-response curve. The human variability UF of
3 was used to account for variation in sensitivity within human populations. Although there is
limited information on the degree to which humans of different genders, ages, health statuses, or
genetic makeups might vary in the disposition of, or response to PETN, the lowest therapeutic
dose already represents an extremely conservative POD in a population that could be considered
sensitive (cardiac patients). An UF of 10 for database deficiencies was applied due to the lack of
reproduction and developmental toxicity studies. An UF for extrapolation from a less than
chronic study was not needed because the adverse effects noted in human patients were
considered to be reversible and appeared unlikely to increase with duration of exposure.
Confidence in the human LOAEL is high because it was the minimum recommended
therapeutic dose based on clinical experience. In addition, effects have been observed in
experimental animals only at much higher doses (von Oettingen et al., 1944; NTP, 1989;
Bucher et al., 1990; Kristek et al., 2003, 2007), and the rabbit studies (Kojda et al., 1995;
Hacker et al., 2001) suggested potentially beneficial effects (reduced serum cholesterol).
Confidence in the database is medium. The database included 2-year studies in rats and mice
that assessed systemic toxicity at doses much higher than the recommended human dose, but
they lacked reproductive and developmental toxicity studies. Considering the levels of
confidence in the human LOAEL and database, confidence in the chronic p-RfD is medium.
FEASIBILITY OF DERIVING PROVISIONAL SUBCHRONIC AND CHRONIC
INHALATION RFC VALUES FOR PENTAERYTHRITOL TETRANITRATE
No information was available on the subchronic or chronic inhalation toxicity of PETN,
and no toxicokinetic data was available to inform extrapolation from the oral data, precluding
derivation of p-RfC values for PETN.
PROVISIONAL CARCINOGENICITY ASSESSMENT FOR
PENTAERYTHRITOL TETRANITRATE
WEIGHT-OF-EVIDENCE DESCRIPTOR
The carcinogenicity of PETN was evaluated by NTP (1989; Bucher et al., 1990) in 2-year
dietary studies in F344/N rats and B6C3Fi mice. There were no exposure-related increases in
neoplasms in male or female mice. Neoplastic findings in the rats included thyroid gland
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follicular cell adenomas or carcinomas in a small number of high-dose females; incidences of
combined tumors in the control, low-, and high-dose groups were 0/50, 0/48, and 3/50. The
high-dose incidence was not statistically significantly higher than that in controls, but the
incidence exceeded historical control incidences (see Table 1). 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.
The rats in the NTP (1989; Bucher et al., 1990) chronic study also had low incidences of
Zymbal gland carcinomas or adenomas in all treated groups of both genders; incidences in the
control, low-, and high-dose groups were 0/49, 3/45, and 2/41 in males and 0/36, 1/37, and
3/35 in females, respectively. The incidences did not reach statistical significance when
compared with control group incidences, nor did they show statistically significant dose-related
trends. However, they did exceed mean historical incidences for each gender (see Table 1).
Considering the occurrence of Zymbal gland tumors in nine dosed rats compared with none in
the controls, and a Zymbal gland tumor in one high-dose female rat in the NTP 14-week study,
NTP concluded that the Zymbal gland tumors were possibly related to PETN exposure. Based
on a marginal increase in neoplasms of the Zymbal gland, NTP (1989; Bucher et al., 1990)
concluded that this study provided equivocal evidence of carcinogenic activity of PETN for male
and female F344/N rats.
A limited amount of information was available on the genotoxicity and mutagenicity of
PETN. In vitro studies found that PETN did not induce reverse mutations in various strains of
Salmonella typhimurium (Mortelmans et al., 1986; NTP, 1989; Whong et al., 1980) or
chromosomal aberrations in CHO cells (NTP, 1989). However, PETN exposure caused a small
increase in sister chromatid exchanges in CHO cells in vitro, but the response was not clearly
dose-related (NTP, 1989); the results suggested that PETN might have been weakly genotoxic in
this assay.
As discussed above, the carcinogenicity of PETN was evaluated in chronic oral studies in
rats and mice (NTP, 1989; Bucher et al., 1990). There was no evidence of carcinogenicity in
mice. There was a marginal increase in Zymbal gland tumors in rats that suggests a possible
PETN-related effect, but it did not provide unequivocal evidence of carcinogenicity.
Genotoxicity studies of PETN were negative for mutagenicity (mutations in S. typhimurium and
sister chromatid exchanges in CHO cells) or suggestive of other genotoxic activity
(chromosomal aberrations in CHO cells). In accordance with the EPA (2005) Guidelines for
Carcinogen Risk Assessment, there was "Suggestive Evidence of Carcinogenic Potential" for
PETN, but the data were weak.
QUANTITATIVE ESTIMATES OF CARCINOGENIC RISK
Derivation of quantitative estimates of cancer risk for PETN was not supported by the
existing data. However, the Appendix of this PPRTV document contains a Screening Value that
might be useful in certain instances. Please see the attached Appendix A for details.
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APPENDIX A. DERIVATION OF A SCREENING ORAL SLOPE FACTOR FOR
PENTAERYTHRITOL TETRANITRATE (PETN)
For reasons noted in the main PPRTV document, it is inappropriate to derive provisional
toxicity values for 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 Superfund Health Risk Technical Support
Center summarizes available information in an Appendix and develops a "screening value."
Appendices receive the same level of internal and external scientific peer review as the PPRTV
documents to ensure their appropriateness within the limitations detailed in the document. Users
of screening toxicity values in an appendix to a PPRTV assessment should understand that there
is considerably more uncertainty associated with the derivation of an appendix screening toxicity
value than for a value presented in the body of the assessment. Questions or concerns about the
appropriate use of screening values should be directed to the Superfund Health Risk Technical
Support Center.
Data presented in Table 1 suggests female mice exhibited a slight dose-response
relationship between dietary exposure to PETN and Zymbal Gland tumors and, possibly, also for
thyroid follicular cell tumors (NTP, 1989; Bucher et al., 1990). Zymbal Gland tumors also were
observed in treated male rats but without apparent dose-dependency. Although none of these
relationships exhibited statistically significant trends, we attempted benchmark dose (BMD)
modeling of these data to illustrate the relationships and to attempt to derive a Screening oral
slope factor (OSF). This effort was justified, in part, because the rarity of Zymbal Gland tumors
suggested potential biological relevance of their presence in every group of treated rats.
To determine the POD for derivation of the Screening OSF, BMD modeling was
conducted using the BMD Modeling Software (BMDS Version 1.4.1a; U.S. EPA, 2000) on data
sets for the incidence of Zymbal gland tumors and thyroid tumors in female rats. Applying the
BMD multi-stage cancer model to the Zymbal gland tumor data generated the curves in
Figures A-l and A-2; applying this model to the thyroid tumor data generated the curves in
Figures A-3 and A-4. Models for both data sets resulted in acceptable fit statistics (see
Table A-l). The lowest BMDLio of 108 mg/kg-day from the Zymbal gland tumor data in female
rats was chosen as the POD for deriving a Screening OSF for PETN.
We calculated the human equivalent dose (HED) of 26 mg/kg-day from the BMDLio of
108 mg/kg-day as follows:
BMDLiOHED — BMDLio x (Wanimal ~ Whuman)
= 107.854 mg/kg-day x (0.229 kg - 70 kg)1/4
= 108 mg/kg-day x 0.24
= 26 mg/kg-day
where
Whuman = 70 kg (human reference body weight)
Wanimal = 0.229 kg (average body weight for female F344 rats; NTP, 1989)
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In the absence of a known mode of action (MO A) for carcinogenicity of oral PETN
exposure, we assumed a linear approach to calculate the Screening OSF (U.S. EPA, 2005). To
extrapolate cancer risks linearly from the BMDLiohed to the origin, we calculated a Screening
OSF as the ratio 0. 1/BMDLiohed- Taking the BMDLiohed of 26 mg/kg-day for the maximum
incidence of adenoma or carcinoma in female mice as the POD that would be most protective of
human health, we calculated a Screening OSF as follows:
Screening OSF	= 0.1 ^ BMDLiohed
= 0.1 -^26 mg/kg-day
= 0.0039 or 4 x 10 3 (mg/kg-day)"1
Table A-l. BMD Multi-Stage Model Statistics for Tumors of the Zymbal Gland and
Thyroid in Female Ratsa
Tumor
Degrees Poly
Chi2
p-Value
AIC
BMD
BMDL
Zymbal Gland
1
0.16
0.9220
31.8413
222.416
107.854
Zymbal Gland
2
0
1.0000
33.6702
181.222
110.095
Thyroid
1
1.45
0.4855
27.0489
415.85
183.075
Thyroid
2
0.70
07044
25.9521
239.06
158.616
aNTP, 1989; Bucher et al., 1990.
18
Pentaerythritol tetranitrate (PETN)

-------
FINAL
9-30-2010
Multistage Cancer Model with 0.95 Confidence Level
Dose
12:23 02/07 2008
Figure A-l. BMD Analyses for Zymbal Gland Tumors in Female Rats Fed PETN for
2 Years (NTP, 1989; Bucher et al., 1990)—1 Degree Poly
Multistage Cancer
Linear extrapolation
BMD Lower Bound
BMDL
BMD
19
Pentaerythritol tetranitrate (PETN)

-------
FINAL
9-30-2010
0.3
0.25
TD
CD
% 0.2
.2 0.15
-i—'
o
ro
^ 0.1
0.05
0
Multistage Cancer Model with 0.95 Confidence Level
Multistage Cancer
Linear extrapolation
BMD Lower Bound
50
BMDL
BMD
100
150
200
Dose
12:34 02/07 2008
Figure A-2. BMD Analyses for Zymbal Gland Tumors in Female Rats Fed PETN for
2 Years (NTP, 1989; Bucher et al., 1990)—2 Degrees Poly
20
Pentaerythritol tetranitrate (PETN)

-------
FINAL
9-30-2010
Multistage Cancer Model with 0.95 Confidence Level
Multistage Cancer
Linear extrapolation
BMD Lower Bound
0.15
1
0.05
0
BMDL
150
BMD
0
50
100
200
250
300
350
400
Dose
12:28 02/07 2008
Figure A-3. BMD Analyses for Thyroid Tumors in Female Rats Fed PETN for 2 Years
(NTP, 1989; Bucher et al., 1990)—1 Degree Poly
21	Pentaerythritol tetranitrate (PETN)

-------
FINAL
9-30-2010
Multistage Cancer Model with 0.95 Confidence Level
Multistage Cancer
Linear extrapolation
BMD Lower Bound
0.3
0.25
T3
0.2
o 0.15
1
0.05
0
BMDL
150
BMD
0
50
100
200
250
300
Dose
12:31 02/07 2008
Figure A-4. BMD Analyses for Thyroid Tumors in Female Rats Fed PETN for 2 Years
(NTP, 1989; Bucher et al., 1990)—2 Degrees Poly
22
Pentaerythritol tetranitrate (PETN)

-------