% niA United States
Environmental Protection
mmAgency
EPA/690/R-12/014F
Final
8-15-2012
Provisional Peer-Reviewed Toxicity Values for
N, N- D i n i tro sopentam ethy l en etetram in e
(CASRN 101-25-7)
Superfund Health Risk Technical Support Center
National Center for Environmental Assessment
Office of Research and Development
U.S. Environmental Protection Agency
Cincinnati, OH 45268

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AUTHORS, CONTRIBUTORS, AND REVIEWERS
CHEMICAL MANAGER
Carrie R. Fleming, PhD
National Center for Environmental Assessment, Cincinnati, OH
CONTRIBUTOR
Jason C. Lambert, PhD, DABT
National Center for Environmental Assessment, Cincinnati, OH
DRAFT DOCUMENT PREPARED BY
National Center for Environmental Assessment, Cincinnati, OH
This document was externally peer reviewed under contract to
Eastern Research Group, Inc.
110 Hartwell Avenue
Lexington, MA 02421-3136
Questions regarding the 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).
i	N, iV-Dinitrosopentam ethyl enetetramine

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TABLE OF CONTENTS
COMMONLY USED ABBREVIATIONS	iii
BACKGROUND	1
DISCLAIMERS	1
QUESTIONS REGARDING PPRTVs	1
INTRODUCTION	2
REVIEW OF POTENTIALLY RELEVANT DATA (CANCER AND NONCANCER)	4
DERIVATION 01 PROVISIONAL VALUES	6
CANCER WOE DESCRIPTOR	6
MODE-OF-ACTION DISCUSSION	6
REFERENCES	6
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COMMONLY USED ABBREVIATIONS
BMC
benchmark concentration
BMCL
benchmark concentration lower bound 95% confidence interval
BMD
benchmark dose
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
POD
point of departure
p-OSF
provisional oral slope factor
p-RfC
provisional reference concentration (inhalation)
p-RfD
provisional reference dose (oral)
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
111
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PROVISIONAL PEER-REVIEWED TOXICITY VALUES FOR
AyV-DINITROSOPENTAMETHYLENETETRAMINE (CASRN 101-25-7)
BACKGROUND
A Provisional Peer-Reviewed Toxicity Value (PPRTV) is defined as a toxicity value
derived for use in the Superfund Program. PPRTVs are derived after a review of the relevant
scientific literature using established Agency guidance on human health toxicity value
derivations. All PPRTV assessments receive internal review by a standing panel of National
Center for Environment Assessment (NCEA) scientists and an independent external peer review
by three scientific experts.
The purpose of this document is to provide support for the hazard and dose-response
assessment pertaining to chronic and subchronic exposures to substances of concern, to present
the major conclusions reached in the hazard identification and derivation of the PPRTVs, and to
characterize the overall confidence in these conclusions and toxicity values. It is not intended to
be a comprehensive treatise on the chemical or toxicological nature of this substance.
The PPRTV review process provides needed toxicity values in a quick turnaround
timeframe while maintaining scientific quality. PPRTV assessments are updated approximately
on a 5-year cycle for new data or methodologies that might impact the toxicity values or
characterization of potential for adverse human health effects and are revised as appropriate. It is
important to utilize the PPRTV database (http://hhpprtv.ornl.gov) to obtain the current
information available. When a final Integrated Risk Information System (IRIS) assessment is
made publicly available on the Internet (www.epa. gov/iris). the respective PPRTVs are removed
from the database.
DISCLAIMERS
The PPRTV document provides toxicity values and information about the adverse effects
of the chemical and the evidence on which the value is based, including the strengths and
limitations of the data. All users are advised to review the information provided in this
document to ensure that the PPRTV used is appropriate for the types of exposures and
circumstances at the site in question and the risk management decision that would be supported
by the risk assessment.
Other U.S. Environmental Protection Agency (EPA) programs or external parties who
may choose to use PPRTVs are advised that Superfund resources will not generally be used to
respond to challenges, if any, of PPRTVs used in a context outside of the Superfund program.
QUESTIONS REGARDING PPRTVs
Questions regarding the contents and appropriate use of this PPRTV assessment should
be directed to the EPA Office of Research and Development's National Center for
Environmental Assessment, Superfund Health Risk Technical Support Center (513-569-7300).
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INTRODUCTION
A', A'-Di nitrosopentam ethyl enetetrami ne (systematic name 3,7-dinitroso-
l,3,5,7-tetraazabicyclo-(3,3,l)-nonane), CAS No. 101-25-7, is used as a blowing agent for
production of polyvinyl chloride (PVC) plastisols, polyester and silicon resins, and unicellular
rubber (both natural and synthetic, which are used in carpet underlay, thermal insulation, weather
stripping, cushioning, and flotation devices) (HSDB. 2003). The chemical structure of
A', A'-di nitrosopentam ethylenetetramine is given in Figure 1. A table of available
physicochemical properties of A', A'-di nitrosopentam ethyl enetetrami ne is provided below (see
Table 1).
Figure 1. jV,jV-Dinitrosopentamethylenetetramine Structure
Table 1. Physicochemical Properties of ^i'V-Dinitrosopentamethylenetetramine
(CASRN 101-25-7)a
Property (unit)
Value
Boiling point (C)
ND
Melting point (C)
203 (decomposes at 207)b
Density (g/cm3)
ND
Vapor pressure (Pa at 25C)
ND
pH (unitless)
ND
Solubility in water (%)
1
Relative vapor density (air =1)
ND
Molecular weight (g/mol)
186.2
aHSDB (2003).
bIARC (1976).
ND = no data.
No reference dose (RfD), reference concentration (RfC), or cancer assessment for
A', A'-di nitrosopentam ethyl enetetrami ne is included in the U.S. Environmental Protection Agency
(U.S. EPA) Integrated Risk Information System (IRIS) (U.S. EPA, 2011b) or on the Drinking
Water Standards and Health Advisories List (U.S. EPA. 2011a). No RfD or RfC values are
reported in the Health Effects Assessment Summary Tables (HEAST) (U.S. EPA. 2003). The
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Chemical Assessments and Related Activities (CARA) list does not include a Health and
Environmental Effects Profile (HEEP) for N,iV-dinitrosopentamethylenetetramine (U.S. EPA.
1994). The toxicity of A', A'-di nitrosopentam ethyl enetetramine has not been reviewed by the
Agency for Toxic Substances and Disease Registry (ATSDR. 2011) or the World Health
Organization (WHO. 2011). The California Environmental Protection Agency (Cal EPA. 2008).
has not derived toxicity values for exposure to A'A-dinitrosopentam ethyl enetetramine. No
occupational exposure limits for N,iV-dinitrosopentamethylenetetramine have been derived or
recommended by the American Conference of Governmental Industrial Hygienists (ACGIH.
2011). the National Institute for Occupational Safety and Health (NIOSH. 2007). or the
Occupational Safety and Health Administration (OSHA. 2006).
The HEAST (U.S. EPA. 2003) does not report a U.S. EPA (1986) cancer weight-of-
evidence (WOE) classification or an oral slope factor. A', A'-di nitrosopentam ethylenetetramine is
not included in the 12th Report on Carcinogens (NTP. 2011). CalEPA (2009) has not prepared a
quantitative estimate of the carcinogenic potential of A'A-dinitrosopentam ethyl enetetramine.
The International Agency for Research on Cancer (IARC) did review the carcinogenic potential
of iV,iV-dinitrosopentamethylenetetramine in 1976 and re-evaluated the carcinogenicity again in
1987. The 1976 review found no observable carcinogenic effects when tested in rats by oral and
intraperitoneal injection (IARC. 1976). and the 1987 subsequent evaluation determined that
A', A'-di nitrosopentam ethyl enetetrami ne is a Class 3 Carcinogen (Not Classifiable as to its
Carcinogenicity to Humans) due to the lack of data in humans and inadequate evidence in
animals (IARC. 1987).
Literature searches were conducted on sources published from 1900 through March 21,
2012 for studies relevant to the derivation of provisional toxicity values for
iV,iV-dinitrosopentamethylenetetramine, CAS No. 101-25-7. Searches were conducted using
U.S. EPA's Health and Environmental Research Online (HERO) database of scientific literature.
HERO searches the following databases: AGRICOLA; American Chemical Society; BioOne;
Cochrane Library; DOE: Energy Information Administration, Information Bridge, and Energy
Citations Database; EBSCO: Academic Search Complete; GeoRef Preview; GPO: Government
Printing Office; Informaworld; IngentaConnect; J-STAGE: Japan Science & Technology;
JSTOR: Mathematics & Statistics and Life Sciences; NSCEP/NEPIS (EPA publications
available through the National Service Center for Environmental Publications [NSCEP] and
National Environmental Publications Internet Site [NEPIS] database); PubMed: MEDLINE and
CANCERLIT databases; SAGE; Science Direct; Scirus; Scitopia; SpringerLink; TOXNET
(Toxicology Data Network): ANEUPL, CCRIS, ChemlDplus, CIS, CRISP, DART, EMIC,
EPIDEM, ETICBACK, FEDRIP, GENE-TOX, HAPAB, HEEP, HMTC, HSDB, IRIS, ITER,
LactMed, Multi-Database Search, NIOSH, NTIS, PESTAB, PPBIB, RISKLINE, TRI; and
TSCATS; Virtual Health Library; Web of Science (searches Current Content database among
others); World Health Organization; and Worldwide Science. The following databases outside
of HERO were searched for risk assessment values: ACGIH, ATSDR, CalEPA, U.S. EPA IRIS,
U.S. EPA HEAST, U.S. EPA HEEP, U.S. EPA OW, U.S. EPA TSCATS/TSCATS2, NIOSH,
NTP, OSHA, and RTECS.
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REVIEW OF POTENTIALLY RELEVANT DATA
(CANCER AND NONCANCER)
The literature search revealed no usable human or animal studies (acute-, short term-,
subchronic-, or chronic-duration) for development of toxicity values for
N,A'-di nitrosopentam ethylenetetramine. Three studies (Hadidian et al.. 1968; Griswold et al..
1966; Weisburger et al.. 1966) were identified that examined tumor formation in animals treated
with A'A-di nitrosopentam ethyl enetetramine; however, none of these were suitable for
development of toxicity values. They are summarized below and in Table 2. Wherever the word
significant is used below, it refers to a change that the study authors reported to be statistically
significant.
In a single-dose study by Griswold et al. (1966). no tumors were observed in 20 female
Sprague-Dawley rats 6 months after a single gavage dose of 90 mg
iV,iV-dinitrosopentamethylenetetramine, and mortality did not differ significantly from controls.
In another study by Weisburger et al. (1966). Fisher rats (15 male and 15 female) treated with
unspecified doses up to 9 mg/animal-day A'A-di nitrosopentam ethyl enetetramine 5 days per week
for 1 year and then observed for another 6 months had no tumors. In a third study by
Hadidian et al. (1968). Fisher rats were dosed by gavage 5 days per week for 52 weeks with 0,
0.03, 0.1, 0.3, 1, 3, or 9 mg/animal-day N,/V-dinitrosopentamethylenetetramine and observed for
another 6 months afterward. This study shares authors with the study by Weisburger et al.
(1966) and may be a more detailed report of the same experiments. Hadidian et al. (1968)
utilized 3 animals/sex/dose group for all doses except there were 15 animals/sex in the
3 mg/animal-day group. The study authors reported no significant changes in survival, body
weight, or liver weight and no significant increase in tumor incidence. Due to low group sizes
and/or short dosing duration, the negative results from these studies are inconclusive and do not
support development of toxicity values for iV,/V-dinitrosopentamethylenetetramine. In all three
of these studies, the authors performed preliminary range-finding studies aimed at identifying the
maximally tolerated dose (MTD); these experiments were aimed at identifying doses at which
mortality occurred, and, therefore, also do not support development of provisional reference
values for /V,/V-dinitrosopentamethyl enetetramine.
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Table 2. Summary of Potentially Relevant Data for j^j^Dinitrosopentamethylenetetramine (CASRN 101-25-7)
Category
Number of
Male/Female, Strain,
Species, Study Type,
Study Duration
Dosimetry"
Critical Effects
NOAELb
BMDL/
BMCLb
LOAELb
Reference
Comments
Carcinogenic
0/20, Sprague-Dawley
rat, gavage, once, 6 mo
follow-up
90 mg
No tumors observed
NR
NC
NR
(Griswold et al..
1966)
Animals were dosed once
orally (presumably via
gavage) and observed for
tumors after 6 mo.

15/15, Fischer rat,
gavage, 5 d/wk, 1 yr,
6 mo follow-up
9 mg/animal-d
No tumors observed
NR
NC
NR
(Weisbureer et
al.. 1966s)
Animals were treated for
1 yr, then maintained for an
additional 6 mo before
examining for tumors.

3-15/3-15, Fischer rat,
gavage, 5 d/wk, 1 yr,
6 mo follow-up
0,0.03,0.1,
0.3, 1, 3,
9 mg/animal-d
No significant
increase in tumors
observed; one
squamous cell
carcinoma on the
tongue of a female
administered 1 mg/d
NR
NC
NR
(Hadidian et al..
1968)
Animals were treated for
52 wk, then observed for
an additional 6 mo after
end of treatment. There
were controls (negative,
untreated, or vehicle; stated
to be 30/sex) for each
chemical tested, but it
appears that the results
were combined into one
table. There were only
3 animals/sex/treatment in
all groups except the
3 mg/d/animal group,
which had 15 animals/sex.
Tor this document, these values have not been converted to adjusted daily dose (ADD in mg/kg-d), human equivalent dose (HED in mg/kg-d), or human equivalent
concentration (HEC in mg/m3) units.
bNR = Not relevant; NC = Not calculated.
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DERIVATION OF PROVISIONAL VALUES
Limitations in the available data preclude development of both cancer and noncancer
toxicity values for A', A'-dinitrosopentamethylenetetramine.
CANCER WOE DESCRIPTOR
Limitations in the available data preclude development of a WOE descriptor.
MODE-OF-ACTION DISCUSSION
Limitations in the available data preclude a mode-of-action discussion.
REFERENCES
ACGIH (American Conference of Governmental Industrial Hygienists). (2011). 2011 TLVs and
BEIs: Based on the documentation of the threshold limit values for chemical substances
and physical agents and biological exposure indices. Cincinnati, OH.
http ://www. acgih. org/ store/ProductDetail. cfm?id=2147.
AT SDR (Agency for Toxic Substances and Disease Registry). (2011). Toxicological profiles:
Information about contaminants found at hazardous waste sites, from
http://www.atsdr.cdc.gov/toxprofiles/index.asp
Cal EPA (California Environmental Protection Agency). (2008). OEHHA acute, 8-hour and
chronic Reference Exposure Levels (chRELs) [Database], Retrieved from
http://www.oehha.ca.gov/air/allrels.html
Cal EPA (California Environmental Protection Agency). (2009). Appendix A: Hot spots unit risk
and cancer potency values. Sacramento, CA: Office of Environmental Health Hazard
Assessment, http://www.oehha.ca.gov/air/hot spots/2009/AppendixA.pdf.
Griswold, DP, Jr; Casey, AE; Weisburger, EK; Schabel, FM, Jr. (1966). On the carcinogenicity
of a single intragastric dose of hydrocarbons, nitrosamines, aromatic amines, dyes,
coumarins, and miscellaneous chemicals in female Sprague-Dawley rats. Cancer Res 26:
619-625.
Hadidian, Z; Fredrickson, TN; Weisburger, EK: Weisburger, JH; Glass, RM; Mantel, N. (1968).
Tests for chemical carcinogens: Report on the activity of derivatives of aromatic amines,
nitrosamines, quinolines, nitroalkanes, amides, epoxides, aziridines, and purine
antimetabolites. J Natl Cancer Inst 41: 985-1036.
HSDB (Hazardous Substances Data Bank). (2003). Dinitrosopentamethylenetetramine -
CASRN: 101 25 7. Washington, DC: National Library of Medicine.
IARC (International Agency for Research on Cancer). (1976).
Dinitrosopentamethylenetetramine. In Cadmium, nickel, some epoxides, miscellaneous
industrial chemicals and general considerations on volatile anaesthetics (Vol. 11). Lyon,
France.
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I ARC (International Agency for Research on Cancer). (1987). Overall evaluations of
carcinogenicity: An updating of IARC monographs volumes 1 to 42 (Vol. Suppl. 7).
Lyon, France.
NIOSH (National Institute for Occupational Safety and Health). (2007). NIOSH pocket guide to
chemical hazards. (2005-149). Cincinnati, OH.
NTP (National Toxicology Program). (2011). Report on carcinogens: Twelfth edition.
Washington, DC: U.S. Department of Health and Human Services.
http://ntp.niehs.nih.gov/ntp/roc/twelfth/rocl2.pdf.
OSHA (Occupational Safety & Health Administration). (2006). Table Z-l limits for air
contaminants. Occupational Safety and Health Administration.
http://www.osha.gov/pls/oshaweb/owadisp.show document?p table=STANDARDS&p
id=9992.
U.S. EPA (U.S. Environmental Protection Agency). (1986). Guidelines for carcinogen risk
assessment. (EPA/630/R-00/004). Washington, DC: U.S. Environmental Protection
Agency, Risk Assessment Forum.
http://epa.gov/raf/publications/pdfs/CA%20GUIDELINES 1986.PDF.
U.S. EPA (U.S. Environmental Protection Agency). (1994). Chemical assessments and related
activities (CARA). (600R94904; OHEA-I-127). Washington, DC: Office of Health and
Environmental Assessment, Office of Research and Development.
http://nepis.epa. gov/Exe/ZvPURL.cgi?Dockev=6000 lG8L.txt.
U.S. EPA (U.S. Environmental Protection Agency). (2003). Health Effects Assessment
Summary Tables (HEAST), from http://epa-heast.ornl.gov/
U.S. EPA (U.S. Environmental Protection Agency). (201 la). 2011 Edition of the drinking water
standards and health advisories. (EPA 820-R-11-002). Washington, DC.
http://water.epa.gov/action/advisories/drinking/drinking index.cfm.
U.S. EPA (U.S. Environmental Protection Agency). (201 lb). Integrated risk information system
(IRIS), from http://www.epa.gov/iris/index.html
Weisburger. JH; Weisburger. EK; Mantel N. (1966). New carciogenic nitrosamines in rats.
Naturwissenschaften 53: 508.
WHO (World Health Organization). (2011). Online catalog for the Environmental Health
Criteria Series, from http://www.who.int/ipcs/publications/ehc/en/
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