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Environmental Protection
^^LbI mm Agency
EPA/690/R-05/015F
Final
5-10-2005
Provisional Peer Reviewed Toxicity Values for
Lactonitrile
(CASRN 78-97-7)
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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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
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MTD
maximum tolerated dose
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
|imol
micromoles
VOC
volatile organic compound
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PROVISIONAL PEER REVIEWED TOXICITY VALUES FOR
LACTONITRILE (CASRN 78-97-7)
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
No RfD, RfC, or quantitative cancer assessments for lactonitrile are available in the
HE AST (U.S. EPA, 1997), which instead includes a notation that the data are inadequate for risk
assessment for this chemical. The source document for the HEAST was a Health and
Environmental Effects Document (HEED) for Cyanohydrins (U.S. EPA, 1988) [misidentified as
the HEED for Selected Nitriles (U.S. EPA, 1987) in the HEAST], Lactonitrile is not listed on
IRIS (U.S. EPA, 2003) or the Drinking Water Standards and Health Advisories list (U.S. EPA,
2002). The HEED is the only relevant document included in the CARA list (U.S. EPA, 1991,
1994). ATSDR (2003) has not produced a toxicological profile for lactonitrile and no
Environmental Health Criteria Document is available (WHO, 2003). Neither NTP (2003) nor
IARC (2003) has assessed the carcinogenicity of lactonitrile. ACGIH (2003), NIOSH (2003),
and OSHA (2003) have not recommended occupational exposure limits for lactonitrile.
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Literature searches were conducted from 1987 through August 2003 for studies relevant to the
derivation of provisional toxicity values for lactonitrile. Databases searched included: TOXLINE
(supplemented with BIOSIS andNTIS updates), MEDLINE, CANCERLIT, TSCATS, RTECS,
CCRIS, DART, EMIC/ EMICBACK, HSDB, and GENETOX. Additional literature searches
from August 2003 through October 2004 were conducted by NCEA-Cincinnati using MEDLINE,
TOXLINE, Chemical and Biological Abstracts databases.
REVIEW OF PERTINENT DATA
Human Studies
No data regarding the toxicity of lactonitrile to humans following chronic or subchronic
oral exposure were located. A fatal case of poisoning, attributed to lactonitrile, was reported in a
worker exposed to lactonitrile while cleaning discharge pipes in a factory where acrylonitrile was
produced (Nagata, 1968). The man experienced severe headache, nausea, palpitation, and
abdominal pain while working. He was found unconscious after leaving work and admitted to a
hospital under a preliminary diagnosis of cyanide poisoning. Despite medical intervention, the
patient died. Autopsy observations included intense lividity posteriorly, petechial hemorrhages
in conjunctiva and in mucosa of kidney pelvis, blood and fluid in pericardium, and marked
congestion of all viscera. Gas chromatography was used to verify the presence of acrylonitrile,
but showed that lactonitrile was present in much higher quantities in the waste products collected
from the factory discharge pipes, the deceased patient's clothing (some items of which, most
notably the undershirt and mask, had no acrylonitrile at all), and blood and urine collected post
mortem. The researchers hypothesized that in the heavy rain that was falling, lactonitrile
dissolved into the water easily and accumulated in the thick, tight clothing worn by the victim,
from which it was absorbed into the body.
Animal Studies
No data regarding the toxicity of lactonitrile to animals following chronic or subchronic
exposure were located.
Oral LD50 values of 21-87 mg/kg have been reported in rats, with deaths occurring as low
as 10 mg/kg (Smyth et al., 1969; Hartung, 1993). An inhalation study reported no deaths among
6 rats exposed to 62.5 ppm of lactonitrile for 4 hours and 6/6 deaths after exposure to 125 ppm
for 4 hours. A single application of lactonitrile to the skin of rabbits resulted in an LD50 value of
20 mg/kg (Smyth et al., 1969; Lewis, 1999). An LD50 value of 15 mg/kg was reported in mice
receiving lactonitrile via intraperitoneal (ip) administration (Kaplita and Smith, 1986). Clinical
signs of toxicity exhibited were dyspnea, ataxia, hypothermia, and convulsions. No other details
regarding toxic effects were provided.
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Lactonitrile was not mutagenic to Salmonella typhimurium strains TA1535, TA1537,
TA1538, TA 97, TA98, or TA100, with or without metabolic activation (Zeiger et al, 1992), but
did induce chromosomal malsegregation and respiratory deficiency in Saccharomyces cerevisiae
strain D61.M (Zimmermann and Mohr, 1992).
DERIVATION OF PROVISIONAL SUBCHRONIC AND CHRONIC
ORAL RfD VALUES FOR LACTONITRILE
No chronic or subchronic oral exposure studies examining the effects of lactonitrile in
humans or animals were located, thereby precluding derivation of p-RfD values for lactonitrile.
DERIVATION OF PROVISIONAL SUBCHRONIC AND CHRONIC
INHALATION RfC VALUES FOR LACTONITRILE
No chronic or subchronic inhalation exposure studies examining the effects of lactonitrile
in humans or animals were located, thereby precluding derivation of p-RfC values for
lactonitrile.
DERIVATION OF A PROVISIONAL CARCINOGENICITY ASSESSMENT
FOR LACTONITRILE
No data in humans or animals are available to assess the carcinogenic potential of
lactonitrile. The chemical was not mutagenic in bacteria in one study (Zeiger et al., 1992), but
did produce chromosomal malsegregation in a study in yeast (Zimmermann and Mohr, 1992).
The available data are inadequate to assess carcinogenic potential in animals or humans as
outlined in the Guidelines for Carcinogen Risk Assessment (U.S. EPA, 2005).
Derivation of quantitative estimates of cancer risk for lactonitrile is precluded by the
absence of carcinogenicity data for lactonitrile.
REFERENCES
ACGIH (American Conference of Governmental Industrial Hygienists). 2003. TLVs® and
BEIs®: Threshold Limit Values for Chemical Substances and Physical Agents, Biological
Exposure Indices. Cincinnati, OH.
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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
Hartung, R. 1993. Cyanides and Nitriles. In: Patty's Industrial Hygiene and Toxicology. Vol.2
C: Toxicology. Fourth edition. G.D. Clayton and F.E. Clayton, Ed. John Wiley & Sons, Inc.,
New York, NY. p. 3148-3149.
IARC (International Agency for Research on Cancer). 2003. Search IARC Monographs.
Online, http://www-cie.iarc.fr/cgi-bin/htsearch
Kaplita, P.V. and R.P. Smith. 1986. Pathways for the bioactivation of aliphatic nitriles to free
cyanide in mice. Toxicol. Appl. Pharmacol. 84: 533-540.
Lewis, R.J. 1999. SAX'S Dangerous Properties of Industrial Materials. Tenth edition. CD-
ROM.
Nagata, T., H. Fukumoto, K. Fukumoto and T. Kojima. 1968. A fatal case of lactonitrile
poisoning. Jap. J. Legal Med. 22(3): 252-256.
NIOSH. 2003. Online NIOSH Pocket Guide to Chemical Hazards. Index by CASRN. Online.
http://www.cdc.gov/niosh/npg/npgdcas.html
NTP (National Toxicology Program). 2003. Management Status Report. Online.
http://ntp-server.niehs.nih.gov/
OSHA (Occupational Safety and Health Administration). 2003. OSHA Standard 1910 SubPart
Z, Toxic and Hazardous Substances, Table Z-l Limits for Air Contaminants. Online.
http://www.osha.gov/pls/oshaweb/owadisp.show document?p table=STANDARDS&p id=999
2&p text version=FALSE
Smyth, H.F., C.P. Carpenter, C.S. Weil et al. 1969. Range-finding toxicity data: List VII. Am.
Ind. Hyg.Assoc. J. 30: 470-476.
U.S. EPA. 1987. Health and Environmental Effects Document for Selected Nitriles. Prepared
by the Office of Health and Environmental Assessment, Environmental Criteria and Assessment
Office, Cincinnati, OH for the Office of Solid Waste and Emergency Response, Washington,
DC.
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U.S. EPA. 1988. Health and Environmental Effects Document for Cyanohydrins. Prepared by
the Office of Health and Environmental Assessment, Environmental Criteria and Assessment
Office, 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 (HEAST). 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 PB97-921199.
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/
U.S. EPA. 2005. Guidelines for Carcinogen Risk Assessment. Office of Research and
Development, National Center for Environmental Assessment, Washington, DC.
EPA/63 0/P-03/001F.
WHO (World Health Organization). 2003. Online Catalogs for the Environmental Criteria
Series. Online, http://www.who.int/pcs/pubs/pub ehc alph.htm
Zeiger, E., B. Anderson, S. Haworth et al. 1992. Salmonella Mutagenicity Tests. V. Results
from the testing of 311 chemicals. Environ. Mol. Mutagen. 19 (Suppl. 21): 2-141.
Zimmerman, F.K. and A. Mohr. 1992. Formaldehyde, glyoxal, urethane, methyl carbamate, 2,3-
butanedione, 2,3-hexanedione, ethyl acrylate, dibromoacetonitrile, and 2-hydroxypropionitrile
induce chromosome loss in Saccharomyces cerevisiae. Mutat. Res. 270: 151-166.
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