United States
Environmental Protection
1=1 m m Agency
EPA/690/R-04/01IF
Final
11-23-2004
Provisional Peer Reviewed Toxicity Values for
Nicotinonitrile
(CASRN 100-54-9)
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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Acronyms and Abbreviations
bw	body weight
cc	cubic centimeters
CD	Caesarean Delivered
CERCLA	Comprehensive Environmental Response, Compensation and Liability Act
of 1980
CNS	central nervous system
cu.m	cubic meter
DWEL	Drinking Water Equivalent Level
FEL	frank-effect level
FIFRA	Federal Insecticide, Fungicide, and Rodenticide Act
g	grams
GI	gastrointestinal
HEC	human equivalent concentration
Hgb	hemoglobin
i.m.	intramuscular
i.p.	intraperitoneal
i.v.	intravenous
IRIS	Integrated Risk Information System
IUR	inhalation unit risk
kg	kilogram
L	liter
LEL	lowest-effect level
LOAEL	lowest-observed-adverse-effect level
LOAEL(ADJ)	LOAEL adjusted to continuous exposure duration
LOAEL(HEC)	LOAEL adjusted for dosimetric differences across species to a human
m	meter
MCL	maximum contaminant level
MCLG	maximum contaminant level goal
MF	modifying factor
mg	milligram
mg/kg	milligrams per kilogram
mg/L	milligrams per liter
MRL	minimal risk level
MTD	maximum tolerated dose
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MTL
median threshold limit
NAAQS
National Ambient Air Quality Standards
NOAEL
no-observed-adverse-effect level
NOAEL(ADJ)
NOAEL adjusted to continuous exposure duration
NOAEL(HEC)
NOAEL adjusted for dosimetric differences across species to a human
NOEL
no-observed-effect level
OSF
oral slope factor
p-IUR
provisional inhalation unit risk
p-OSF
provisional oral slope factor
p-RfC
provisional inhalation reference concentration
p-RfD
provisional oral reference dose
PBPK
physiologically based pharmacokinetic
PPb
parts per billion
ppm
parts per million
PPRTV
Provisional Peer Reviewed Toxicity Value
RBC
red blood cell(s)
RCRA
Resource Conservation and Recovery Act
RDDR
Regional deposited dose ratio (for the indicated lung region)
REL
relative exposure level
RfC
inhalation reference concentration
RfD
oral reference dose
RGDR
Regional gas dose ratio (for the indicated lung region)
s.c.
subcutaneous
SCE
sister chromatid exchange
SDWA
Safe Drinking Water Act
sq.cm.
square centimeters
TSCA
Toxic Substances Control Act
UF
uncertainty factor
Hg
microgram
|j,mol
micromoles
voc
volatile organic compound
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11-23-2004
PROVISIONAL PEER REVIEWED TOXICITY VALUES FOR
NICOTINONITRILE (CASRN 100-54-9)
Background
On December 5, 2003, the U.S. Environmental Protection Agency's (EPA's) 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 (PPRTV) 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 Integrated Risk Information System (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 two EPA scientists and external peer review by three independently
selected scientific experts. PPRTVs differ from IRIS values in that PPRTVs do not receive the
multi-program 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 science and available information evolve, PPRTVs are initially derived with a
three-year life-cycle. However, EPA Regions (or the EPA HQ Superfund Program) sometimes
request that a frequently used PPRTV be reassessed. 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 manuscripts conclude that a PPRTV cannot be derived
based on inadequate data.
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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 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.
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 manuscript 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
The HEAST (U.S. EPA, 1997) does not list subchronic or chronic reference dose (RfD)
or reference concentration (RfC) values for nicotinonitrile (3-cyanopyridine; C6H4N2), noting that
data were inadequate for quantitative risk assessment, and does not include any cancer
assessment for the chemical. A Health and Environmental Effects Document (HEED) for
Selected Nitriles (U.S. EPA, 1987), that was listed in the HEAST as a reference for subchronic
and chronic toxicity, reported no chronic or subchronic toxicity studies of nicotinonitrile and
assigned the chemical to U.S. EPA (1999) cancer weight-of-evidence Group D {not classifiable
as to human carcinogenicity) based on no human or animal cancer data. Nicotinonitrile is not
listed on IRIS (U.S. EPA, 2003) or the Drinking Water Standards and Health Advisories list
(U.S. EPA, 2002). No relevant documents, other than the previously mentioned HEED, were
located in the CARA list (U.S. EPA, 1991, 1994). IARC (2003), NTP (2003), and ACGIH
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11-23-2004
(2002) have not assessed the carcinogenicity of nicotinonitrile. ACGIH (2002), NIOSH (2003)
and OSHA (2003a,b) have not established occupational exposure limits for nicotinonitrile.
ATSDR (2003) and WHO (2003) have not published toxicological review documents on
nicotinonitrile. Patty's Toxicology (2001) was consulted for relevant information. Literature
searches were conducted from 1986 thru December 2002 for studies relevant to the derivation of
provisional toxicity values for nicotinonitrile. Databases searched included: TOXLINE,
MEDLINE, CANCERLIT, BIOSIS, TSCATS, RTECS, CCRIS, DART/ETICBACK,
EMIC/EMICBACK, HSDB and GENETOX. Additional literature searches from December
2002 through September 2004 were conducted by NCEA-Cincinnati using MEDLINE,
TOXLINE, Chemical and Biological Abstracts databases.
REVIEW OF PERTINENT DATA
Human Studies
No studies were located regarding the subchronic or chronic toxicity or carcinogenicity of
nicotinonitrile in humans.
Animal Studies
No studies were located regarding the subchronic or chronic toxicity or carcinogenicity of
nicotinonitrile in animals.
Other Studies
Nicotinonitrile was negative for induction of mutation in Salmonella typhimurium strains
TA98, TA100, TA1535, TA1537 and TA1538 when tested with or without S9 metabolic
activation (Florin et al., 1980).
DERIVATION OF PROVISIONAL SUBCHRONIC AND CHRONIC
ORAL RfD VALUES FOR NICOTINONITRILE
Provisional subchronic or chronic oral RfD values for nicotinonitrile cannot be derived
because human and animal toxicity data following subchronic or chronic oral exposure to
nicotinonitrile are lacking.
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11-23-2004
DERIVATION OF PROVISIONAL SUBCHRONIC AND CHRONIC
INHALATION RfC VALUES FOR NICOTINONITRILE
Provisional subchronic or chronic inhalation RfC values for nicotinonitrile cannot be
derived because human and animal toxicity data following subchronic or chronic inhalation
exposure to nicotinonitrile are lacking.
DERIVATION OF A PROVISIONAL CARCINOGENICITY ASSESSMENT
FOR NICOTINONITRILE
No data were located regarding the carcinogenicity of nicotinonitrile in humans or
animals. Nicotinonitrile did not induce mutations in bacteria (Florin et al., 1980). Under the
proposed U.S. EPA (1999) cancer guidelines, the data are inadequate for an assessment of human
carcinogenic potential.
Derivation of quantitative estimates of cancer risk for nicotinonitrile is precluded by the
absence of pertinent carcinogenicity data.
REFERENCES
ACGIH (American Conference of Governmental Industrial Hygienists). 2002. TLVs® and
BEIs®: Threshold Limit Values for Chemical Substances and Physical Agents, Biological
Exposure Indices. ACGIH, Cincinnati, OH.
ATSDR (Agency for Toxic Substances and Disease Registry). 2003. Toxicological Profile
Information Sheet. U.S. Department of Health and Human Services, Public Health Service.
Online, http://www.atsdr.cdc.gov/toxpro2.html
Florin, I., L. Rutberg, M. Curvall and C.R. Enzell. 1980. Screening of tobacco smoke
constituents for mutagenicity using the Ames' test. Toxicology. 18: 219-232.
I ARC (International Agency for Research on Cancer). 2003. IARC Agents and Summary
Evaluations. Online, http://www-cie.iarc.fr/
NIOSH (National Institute for Occupational Safety and Health). 2003. Online NIOSH Pocket
Guide to Chemical Hazards. Index by CASRN. Online, http://www.cdc.gov/niosh/srh-nsh.html
http://ntp-server.ni ehs .nih. gov/cgi/iH Indexes/AI
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OSHA (Occupational Safety and Health Administration). 2003a. OSHA Standard 1910.1000
Table Z-l. Part Z, Toxic and Hazardous Substances. Online.
http://www.osha-slc.gov/OsliStd data/1910 1000 TABLE Z-l.html
OSHA (Occupational Safety and Health Administration). 2003b. OSHA Standard 1915.1000
for Air Contaminants. Part Z, Toxic and Hazardous Substances. Online.
http://www.osha-slc.gov/OshStd data/1915 1000.html
Patty's Toxicology. 2001. 5th ed. E. Bingham, B. Cohrssen and C.H. Powel, Ed. John Wiley
and Sons, New York.
U.S. EPA. 1987. Health and Environmental Effects Document for Selected Nitriles. Prepared
by Environmental Criteria and Assessment Office, Office of Health and Environmental
Assessment, Cincinnati, OH for the Office of Solid Waste and Emergency Response,
Washington, DC.
U.S. EPA. 1991. Chemical Assessments and Related Activities (CARA). Office of Health and
Environmental Assessment, Washington, DC. April.
U.S. EPA. 1994. Chemical Assessments and Related Activities (CARA). Office of Health and
Environmental Assessment, Washington, DC. December.
U.S. EPA. 1997. Health Effects Assessment Summary Tables. FY-1997 Update. Prepared by
the Office of Research and Development, National Center for Environmental Assessment,
Cincinnati OH for the Office of Emergency and Remedial Response, Washington, DC. July.
EPA/540/R-97/036. NTIS 97-921199.
U.S. EPA. 1999. Guidelines for Carcinogenic Risk Assessment. Risk Assessment Forum,
National Center for Environmental Assessment, Office of Research and Development.
Washington, DC. July 1999. Online, http://www.epa.gov/NCEA/raf/crasab.htm
U.S. EPA. 2002. 2002 Edition of the Drinking Water Standards and Health Advisories. Office
of Water, Washington, DC. Summer, 2002. EPA 822-R-02-038. Online.
http://www.epa.gov/waterscience/drinking/standards/dwstandards.pdf
U.S. EPA. 2003. Integrated Risk Information System (IRIS). Office of Research and
Development, National Center for Environmental Assessment, Washington, DC. Online.
http://www.epa.gov/iris/
WHO (World Health Organization). 2003. Online Catalogs for the Environmental Criteria
Series. Online, http://www.who.int/dsa/cat98/zehc.htm
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