#ll.	United States
Environmental Protection
^^LbI M % Agency
EPA/690/R-05/014F
Final
6-07-2005
Provisional Peer Reviewed Toxicity Values for
Hexadecanoic acid
(CASRN 57-10-3)
Derivation of Subchronic and Chronic Oral RfDs
Superfund Health Risk Technical Support Center
National Center for Environmental Assessment
Office of Research and Development
U.S. Environmental Protection Agency
Cincinnati, OH 45268

-------
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
1

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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
|j,mol
micromoles
voc
volatile organic compound
11

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6-7-05
PROVISIONAL PEER REVIEWED TOXICITY VALUES FOR
HEXADECANOIC ACID (CASRN 57-10-3)
Derivation of Subchronic and Chronic Oral RfDs
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.
1

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6-7-05
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
Hexadecanoic acid, also called palmitic acid, is a saturated long hydrocarbon chain
carboxylic acid. This 16-carbon saturated fatty acid is found in practically all vegetable oils and
animal fats (Anonymous, 1987). A subchronic or chronic RfD for hexadecanoic acid is not
available on IRIS (U.S. EPA, 2003), the HEAST (U.S. EPA, 1997), or the Drinking Water
Standards and Health Advisories list (U.S. EPA, 2002). No relevant documents were located on
the CARA list (U.S. EPA, 1991, 1994). ATSDR (2003), NTP (2003), IARC (2003), and WHO
(2003) have not produced documents regarding hexadecanoic acid. Literature searches of the
following databases were conducted in 1991 for hexadecanoic acid: TOXLIT (1965-1991),
TOXLINE (1981-1991), MEDLINE (1980-1991), CANCER (1963-1991), ETIC, HSDB, and
RTECS. Literature searches of TOXLINE, RTECS, and TSCATS were conducted again in May
1994. Update literature searches from 1994 through June 2003 were conducted in the following
2

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6-7-05
databases: TOXLINE (supplemented with BIOSIS andNTIS updates), CANCERLIT,
MEDLINE, CCRIS, GENETOX, HSDB, DART/ETICBACK, EMIC/EMICBACK, RTECS and
TSCATS. Additional literature searches from June 2003 through July 2004 were conducted by
NCEA-Cincinnati using MEDLINE, TOXLINE, Chemical and Biological Abstracts databases.
REVIEW OF PERTINENT DATA
Human Studies
No data were located on the health effects of hexadecanoic acid itself in humans.
However, there is an extensive database establishing a link between a diet high in saturated fatty
acids and an increased risk of coronary heart disease, and in particular atherosclerosis.
Atherosclerosis is characterized by the presence of plaques in the intimal layer of large and
medium-sized arteries. In the developing atherosclerotic lesion, there is an accumulation of
lipids, especially cholesterol and cholesterol esters. The etiology of atherosclerosis is equivocal,
but is generally believed to be multifactorial. The primary risk factors are hypertension, elevated
blood lipid levels, and smoking. Age, heredity, sex, lack of exercise, and personality type are
also risk factors (Barna and Biro, 1989; Castelli, 1983). Both the total intake of dietary fat and
the type of fat can influence plasma cholesterol levels. As reviewed by Connor and Connor
(1990), a positive correlation has been established between dietary saturated fatty acids and
plasma cholesterol levels (discussed below). The rise in plasma cholesterol levels associated
with dietary saturated fatty acids is primarily due to an increase in low density lipoprotein (LDL)
cholesterol. Dietary saturated fatty acids suppress hepatic LDL receptor activity and decrease the
removal of LDL from blood, resulting in an increase in LDL cholesterol levels in the blood.
As reviewed by Nordoy and Goodnight (1990), Connor and Connor (1990), and Zemel
and Sowers (1990), the evidence relating diet to atherosclerosis is largely based on
epidemiological studies, dietary intervention studies, and animal studies. A number of
epidemiological studies have been conducted. For the most part, these studies have found
significant correlations between mortality from coronary-heart disease and dietary intake of
saturated fats and cholesterol. One of the largest epidemiological studies comparing different
populations was the Seven Countries Study, conducted by Keys (1970). Using men aged 40-59
years from 18 communities in Finland, Greece, Italy, Japan, Netherlands, United States, and
Yugoslavia, the rate of coronary heart disease (myocardial infarction and death from coronary
heart disease) was compared to components of the diet (dietary information was collected from
7-day food records). A positive statistically significant correlation was found between coronary
heart disease rate, serum cholesterol, and dietary intake of saturated fat. In another study (Kato et
al., 1973), referred to as the Ni-Hon-San study, dietary habits and coronary heart disease
mortality were examined in men of Japanese ancestry living in Nissei (Japan), Honolulu, and San
Francisco. The percentage of calories from saturated fat was 7% in Nissei, 12% in Honolulu, and
3

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6-7-05
14% in San Francisco. The lowest rate of mortality from coronary heart disease was found in the
men living in Nissei. The mortality rate was 1.7 times higher in the Honolulu population and 2.8
times higher in the San Francisco population. These findings suggest an association between
intake of saturated fatty acids and coronary heart disease.
A number of large-scale dietary intervention studies have been performed to assess the
role of dietary changes in the reduction of serum cholesterol and risk of coronary heart disease.
Dietary intervention studies are designed to determine if experimentally manipulating the diet
(e.g., decreasing cholesterol and saturated fatty acid intake, or increasing intake of
polyunsaturated fatty acids) will result in a decrease in coronary heart disease. Studies such as
the Multiple Risk Factor Intervention Trial (MRFIT) have suggested that a reduction in serum
cholesterol by changes in the diet is associated with a lower mortality from coronary heart
disease (Kannel et al., 1986). In the MRFIT study, approximately 6500 men aged 35-57 years at
high risk for developing coronary heart disease were given stepped-care treatment for
hypertension, counseling for smoking cessation, and dietary advice for lowering blood
cholesterol. A similar control group was referred to usual sources of health care in the
community. The men were followed for 7 years (Multiple Risk Factor Intervention Trial
Research Group, 1982). The dietary intervention studies are often difficult to interpret because
most of the studies involve the simultaneous reduction of several risk factors and the study
population is typically individuals who had an initial increased risk of coronary heart disease.
Although the evidence associating a diet high in saturated fatty acids to an increased risk
of coronary heart disease is fairly strong, a cause and effect relationship has not be established.
The etiology of coronary heart disease is likely to be multifactorial. The Framingham Study and
other large prospective studies have identified a number of risk factors for coronary heart disease.
The Framingham Study followed approximately 5000 men and women over a period of 18 years
(Castelli, 1983). This study identified the following risk factors for coronary heart disease:
elevated blood cholesterol levels, low high density lipoprotein (HDL) cholesterol, elevated LDL
cholesterol, hypertension, left ventricular hypertrophy, high serum glucose levels, excess body
weight, cigarette smoking, lack of exercise, and Type A personality type. The Framingham
Study also demonstrated interactions between the risk factors. For example, a 50 year old man
who smokes cigarettes, with a systolic blood pressure of 120 mm Hg, and a blood cholesterol
level of 210 mg/dl has a probability of 92/1000 for developing cardiovascular disease in 8 years;
if the individual did not smoke, the probability would be 55 per 1000 (Castelli, 1983).
In addition to the role dietary fatty acid plays in atherosclerosis, there are human data
linking dietary saturated fatty acids with thrombosis and impaired platelet function (Nordoy and
Goodnight, 1990; Connor and Connor, 1990). Thrombosis is intimately related to
atherosclerosis. It contributes to the progression of atherosclerotic lesions and is also responsible
for many of the clinical complications of atherosclerosis (i.e., a thrombus may occlude a coronary
artery). A diet high in saturated fatty acids may influence platelet and endothelial cell function
4

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6-7-05
by altering the fatty acid composition of these cells. Saturated fatty acids with a carbon chain
length of 12 or higher appear to be thrombogenic, activating the coagulation cascade and
aggregating platelets (Nordoy and Goodnight, 1990; Connor and Connor, 1990). Human studies
have demonstrated that a high fat diet results in increased platelet turnover, platelet adhesiveness,
and the formation of thrombi (Baghurst and Truswell, 1979).
Animal Studies
The association between dietary saturated fatty acids and atherosclerosis has also been
demonstrated in animals studies. Hypercholesterolemia and atherosclerotic lesions were
observed in animals fed diets high in saturated fatty acids (as reviewed by Nordoy and
Goodnight, 1990; Kritchevsky, 1991). Atherosclerotic lesions were noted in rats fed 6%
hexadecanoic acid for 16 weeks (Sullivan and Krieger, 1992). Saturated fatty acids of different
carbon chain lengths are not equally hypercholesterolemic. In a study conducted in rats by
Renaud (1968), the most hypercholesterolemic fatty acid (as measured by blood cholesterol
levels) was hexadecanoic acid (saturated, length of carbon chain, 16), followed by myristic acid
(14), caprylic acid (8), octadecanoic acid (18), and lauric acid (12). Although a relationship
between dietary saturated fatty acid intake and atherosclerotic lesions has been established in
animal models, Nordoy and Goodnight (1990) caution against extrapolating from animal models
because the animal studies typically use diets that have a very high lipid content, much higher
than seen in human diets. There are also animal experimental data linking dietary saturated fatty
acids with thrombosis and impaired platelet function (Nordoy and Goodnight, 1990; Connor and
Connor, 1990). A high fat diet produced increased platelet turnover, platelet adhesiveness, and
the formation of thrombi in rats (Renaud et al., 1970). In a study comparing the thrombotic
activity in rats fed diets high in several saturated fatty acids, octadecanoic acid produced the
shortest clotting time and the most severe thrombosis, followed (in decreasing order) by
hexadecanoic acid, caprylic acid, lauric acid, and myristic acid (Renaud, 1968).
Other Studies
In an in vitro study (Nonagaki et al., 1994), mouse embryos cultured in medium
containing 50 |j,m of hexadecanoic acid showed significant inhibition of mouse pronuclear and
two-stage embryo development compared to controls. None of the zygotes exposed to
hexadecanoic acid reached the four-cell stage of cell division.
FEASIBILITY OF DERIVING PROVISIONAL SUBCHRONIC AND CHRONIC
RfDs FOR HEXADECANOIC ACID
There is limited information on the toxicity of hexadecanoic acid. However, there is an
extensive database establishing a link between a diet high in saturated fatty acids and an
5

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increased risk of coronary heart disease. A cause and effect relationship has not been established
for coronary heart disease, largely because the etiology of coronary heart disease is multifactorial.
A number of dietary (e.g., high intake of saturated fatty acids, low intake of polyunsaturated fatty
acids) and non-dietary (e.g., hypertension, cigarette smoking, lack of exercise) factors contribute
to the overall risk for coronary heart disease. The data are not adequate to make population-
based dietary recommendations for saturated fatty acids (Zoller and Tato, 1992). Hexadecanoic
acid is one of the many saturated fatty acids found in the diet; the lack of data to set
recommendations for total saturated fatty acids precludes setting recommendations for a
particular saturated fatty acid. Without recommendations for safe dietary levels of hexadecanoic
acid, provisional values (RfDs, subchronic or chronic) for ingestion of hexadecanoic acid cannot
be calculated.
REFERENCES
Anonymous. 1987. Final report on the safety assessment of oleic acid, lauric acid, palmitic acid,
myristic acid, and stearic acid. J. Am. Coll. Toxicol. 6:321-401.
ATSDR (Agency for Toxic Substances and Disease Registry). 2003. Toxicological Profile
Information Sheet. U.S. Department of Health and Human Services, Public Health Service.
Atlanta, GA. Online, http://www.atsdr.cdc.gov/toxpro2.html
Baghurst, K.I. and A.S. Truswell. 1979. Acute effect of three dietary fats on platelet function
and fibrinolysis in man. Nutr. Reports Internat. 20: 39-44.
Barna, M. and G. Biro. 1989. Atherosclerosis: dietary considerations. World Rev. Nutr. Diet.
59: 126-155.
Castelli, W.P. 1983. Cardiovascular disease and multifactorial risk: challenge of the 1980s.
Am. Heart J. 106:1191-1200.
Kannel, W.B., H.E. Thomas and M.O. Kjelsberg. 1986. Overall and coronary heart disease
mortality rates in relation to major risk factors in 325,348 men screened for the MRFIT. Am.
Heart J. 112: 825-836. (Cited in Nordoy and Goodnight, 1990; Zemel and Sowers, 1990)
Kato, H., J. Tillotson, N.A. Nichaman et al. 1973. Epidemiologic studies of coronary heart
disease and stroke in Japanese men living in Japan, Hawaii and California. Serum lipids and diet.
Am. J. Epidemiol. 97: 372-385. (Cited in Zoller and Tato, 1992; Zemel and Sowers, 1990)
Keys, A. 1970. Coronary heart disease in seven countries. Circulation. 41(suppl): 1-211.
(Cited in Zoller and Tato, 1992)
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Kritchevsky, D. 1991. Dietary fat and experimental atherosclerosis. Int. J. Tiss. Reac. 13:59-
65.
IARC (International Agency for Research on Cancer). 2003. IARC Agents and Summary
Evaluations. Online, http://www-cie.iarc.fr/
Multiple Risk Factor Intervention Trial Research Group. 1982. Multiple Risk Factor
Intervention Trial. J. Am. Med. Assoc. 248: 1465-1477.
Nonagaki, T., Y. Noda, Y. Goto et al. 1994. Developmental blockage of mouse embryos caused
by fatty acids. J. Assist. Reprod. Genet. 11(9): 482-488.
Nordoy, A. and S.H. Goodnight. 1990. Dietary lipids and thrombosis. Relationships to
atherosclerosis. Atherosclerosis. 10: 149-163.
NTP (National Toxicology Program). 2003. Management Status Report. Online.
http://ntp-server.niehs.nih.gov/
Renaud, S. 1968. Thrombotic, atherosclerotic and lipemic effects of dietary fats in the rat.
Angiology. 20: 657-669.
Renaud, S., R.L. Kinlough and J.F. Mustard. 1970. Relationship between platelet aggregation
and the thrombotic tendency in rats fed hyperlipemic diets. Lab. Invest. 22: 339-343.
Sullivan, J.B., Jr. and G.R. Krieger. Editors. 1992. Hazardous Materials Toxicology-Clinical
Principles of Environmental Health. Baltimore, MD: Williams and Wilkins. p.778.
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
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
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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/pcs/pubs/pub ehc alph.htm
Zemel, P.C. and J.R. Sowers. 1990. Relation between lipids and atherosclerosis: epidemiologic
evidence and clinical implications. Am. J. Cardiol. 18: 71-121.
Zoller, N. and Tato F. 1992. Fatty acid composition of the diet: impact on serum lipids and
atherosclerosis. Clin. Investig. 70: 968-1009.
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6-7-05
Provisional Peer Reviewed Toxicity Values for
Hexadecanoic acid
(CASRN 57-10-3)
Derivation of Subchronic and Chronic Inhalation RfCs
Superfund Health Risk Technical Support Center
National Center for Environmental Assessment
Office of Research and Development
U.S. Environmental Protection Agency
Cincinnati, OH 45268

-------
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
1

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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
|j,mol
micromoles
voc
volatile organic compound
11

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6-7-05
PROVISIONAL PEER REVIEWED TOXICITY VALUES FOR
HEXADECANOIC ACID (CASRN 57-10-3)
Derivation of Subchronic and Chronic Inhalation RfCs
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.
1

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6-7-05
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
Hexadecanoic acid, also called palmitic acid, is a saturated long hydrocarbon chain
carboxylic acid. This 16-carbon saturated fatty acid is found in practically all vegetable oils and
animal fats (Anonymous, 1987). Hexadecanoic acid is a solid at room temperature with a low
vapor pressure (10 mm Hg); therefore, the potential for vapor inhalation exposure is low.
However, there is a potential for inhalation exposure to particulate during the manufacture and
process handling of the powder form (U.S. EPA, 1990). A subchronic or chronic RfC for
hexadecanoic acid is not available on IRIS (U.S. EPA, 2003) or in the HEAST (U.S. EPA, 1997).
No relevant documents regarding hexadecanoic acid were located in the CARA list (U.S. EPA,
1991, 1994). ATSDR (2003), NTP (2003), IARC (2003), and WHO (2003) have not produced
documents regarding hexadecanoic acid. ACGIH (2003), NIOSH (2003), and OSHA (2003)
have not recommended occupational exposure limits for hexadecanoic acid. Literature searches
2

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6-7-05
of the following databases were conducted in 1991 for hexadecanoic acid: TOXLIT (1965-1991),
TOXLINE (1981-1991), MEDLINE (1980-1991), CANCER (1963-1991), ETIC, HSDB, and
RTECS. Literature searches of TOXLINE, RTECS, and TSCATS were conducted again in May
1994. Update literature searches from 1994 through June 2003 were conducted in the following
databases: TOXLINE (supplemented with BIOSIS andNTIS updates), CANCERLIT,
MEDLINE, CCRIS, GENETOX, HSDB, DART/ETICBACK, EMIC/EMICBACK, RTECS and
TSCATS. Additional literature searches from June 2003 through July 2004 were conducted by
NCEA-Cincinnati using MEDLINE, TOXLINE, Chemical and Biological Abstracts databases.
REVIEW OF THE PERTINENT DATA
Human Studies
No data regarding the toxicity of hexadecanoic acid to humans following inhalation
exposure were located. However, there is some information on the toxicity of airborne lauric
acid. Lauric acid is a 12-carbon saturated fatty acid. In a NIOSH Health Hazard Evaluation
report (as reviewed in Anonymous, 1987), 7 workers reported eye, nose, throat, and skin
irritation following exposure to airborne lauric acid. The workers were involved in the flaking
and bagging operation at a manufacturing facility. It is not known if hexadecanoic acid would
have similar irritative effects.
Animal Studies
No data regarding the toxicity of hexadecanoic acid to animals following inhalation
exposure were located.
FEASIBILITY OF DERIVING PROVISIONAL SUBCHRONIC AND CHRONIC
RfCs FOR HEXADECANOIC ACID
In the absence of subchronic or chronic inhalation data on the toxicity of hexadecanoic
acid, derivation of a provisional subchronic or chronic RfC is precluded.
REFERENCES
ACGIH (American Conference of Governmental Industrial Hygienists). 2003. 2003 Threshold
Limit Values for Chemical Substances and Physical Agents and Biological Exposure Indices.
Cincinnati, OH.
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Anonymous. 1987. Final report on the safety assessment of oleic acid, lauric acid, palmitic acid,
myristic acid, and stearic acid. J. Am. Coll. Toxicol. 6:321-401.
ATSDR (Agency for Toxic Substances and Disease Registry). 2003. Toxicological Profile
Information Sheet. U.S. Department of Health and Human Services, Public Health Service.
Atlanta, GA. Online, http://www.atsdr.cdc.gov/toxpro2.html
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. NIOSH Pocket Guide to
Chemical Hazards. Online. http://www.cdc.gOv/niosh/npg/npgd0000.html#F
NTP (National Toxicology Program). 2003. Management Status Report. Online.
http://ntp-server.niehs.nih.gov/
OSHA (Occupational Safety and Health Administration). 2003. OSHA Standard 1910.1000
Table Z-l. Part Z, Toxic and Hazardous Substances. Online.
http://www.osha-slc.gov/OshStd data/1910 1000 TABLE Z-l.html
U.S. EPA. 1990. Chemical Information Sheets: Hexadecanoic Acid, Methyl Octanoate, and 2-
Methyl-Propanoic Acid. U.S. EPA/OPTS FicheNo. OTS 0532708. Document No. 40-
90127013. Produced:07/23/90.
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 PB97-921199.
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/pcs/pubs/pub ehc alph.htm
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Provisional Peer Reviewed Toxicity Values for
Hexadecanoic acid
(CASRN 57-10-3)
Derivation of a Carcinogenicity Assessment
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
|j,mol
micromoles
voc
volatile organic compound
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PROVISIONAL PEER REVIEWED TOXICITY VALUE FOR
HEXADECANOIC ACID (CASRN 57-10-3)
Derivation of a Carcinogenicity Assessment
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
Hexadecanoic acid, also called palmitic acid, is a saturated long hydrocarbon chain
carboxylic acid. This 16-carbon saturated fatty acid is found in practically all vegetable oils and
animal fats (Anonymous, 1987). A carcinogenicity assessment for hexadecanoic acid is not
available on IRIS (U.S. EPA, 2003), the HEAST (U.S. EPA, 1997), or the Drinking Water
Standards and Health Advisories list (U.S. EPA, 2002). No relevant documents were located in
the CARA list (U.S. EPA, 1991, 1994). ATSDR (2003), NTP (2003), IARC (2003), and WHO
(2003) have not produced documents regarding hexadecanoic acid. Literature searches of the
following databases were conducted in 1991 for hexadecanoic acid: TOXLIT (1965-1991),
TOXLINE (1981-1991), MEDLINE (1980-1991), CANCER (1963-1991), ETIC, HSDB, and
RTECS. Literature searches of TOXLINE, RTECS, and TSCATS were conducted again in May
1994. Update literature searches from 1994 through June 2003 were conducted in the following
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databases: TOXLINE (supplemented with BIO SIS andNTIS updates), CANCERLIT,
MEDLINE, CCRIS, GENETOX, HSDB, DART/ETICBACK, EMIC/EMICBACK, RTECS and
TSCATS. Additional literature searches from June 2003 through July 2004 were conducted by
NCEA-Cincinnati using MEDLINE, TOXLINE, Chemical and Biological Abstracts databases.
REVIEW OF THE PERTINENT DATA
Human Studies
No data regarding the possible carcinogenicity specifically in humans for hexadecanoic
acid were located. Over 50 years ago, a relationship between a diet high in fat and an increased
carcinogenic risk was first established in laboratory animals. Subsequently, a large number of
human and animal studies have been conducted to establish the role of the level and nature of
dietary fat in the susceptibility to cancer. The epidemiology studies, including case-control and
cohort studies, do not provide conclusive evidence for an association between dietary fat and
cancer incidence (Birt, 1990; Carroll, 1991). The lack of consistent results from the human
studies may be due to confounding variables such as the difficulty in assessing dietary fat intake
(particularly previous intake); differences in lifestyle (e.g., exercise, smoking); total caloric
intake and intake of other macronutrients and micronutrients; and genetic factors (Boutwell,
1992; Birt, 1990; Carroll, 1991; Macrae, 1993).
Animal Studies
A large number of animal studies have found a positive correlation between the amount
of fat in the diet and the incidence of cancer. A majority of the studies have examined the
relationship between dietary fat and chemically-induced tumors. Increases in the incidence of
chemically-induced tumors of the skin, mammary glands, lungs, intestinal tract, liver and
pancreas have been observed in animals fed high fat diets (Kristiansen et al., 1993). Increases in
the incidence of spontaneous tumors have also been observed in animals fed high fat diets. The
results from older studies suggested that unsaturated fatty acids were tumorigenic and diets high
in saturated fats did not result in increased incidences of cancer (reviewed in Birt, 1990 and
Carroll, 1991). More recent studies have shown that the relationship between dietary fat and
carcinogenesis is more complex, and dependent on more than just the degree of saturation and
may depend on the cancer model under investigation. The concentration of essential fatty acids
in the diet, the degree of unsaturation, and the structural location of the unsaturation are all
important determining factors (Birt, 1990). Additionally, a number of investigators have
provided evidence on the importance of energy balance, rather than the percentage of fat.
Several studies have shown that caloric restriction reduces the incidence of spontaneous and
chemically-induced tumors in animals fed high fat diets (Boutwell, 1992).
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Few studies specifically conducted on hexadecanoic acid were located. Swern et al.
(1970) administered to two groups of 16 female Swiss Webster mice hexadecanoic acid in
tricaprylin at doses of 1.0 mg/day, 3 times/week for 10 subcutaneous injections in the inguinal
area, or 5.0 mg/day, 2 times/week for 25 subcutaneous injections in the inguinal and axillary
regions. There was no increase in tumors associated with injection of hexadecanoic acid at the
injection site or internally. Of the 26 mice that survived at least 6 months (collapsed across
groups), 2 subcutaneous sarcomas, 2 pulmonary tumors, 3 breast cancers, and 1 lymphoma were
observed. In the tricaprylin control group (consisting of 104 Swiss Webster and BALB/c mice
that survived at least 6 months), 1 subcutaneous sarcoma, 5 pulmonary tumors, 2 breast cancers,
0 lymphomas, and 4 other tumors were observed. The untreated control group (202 Swiss
Webster and BALB/c mice that survived at least 6 months) included 1 mouse with subcutaneous
sarcoma, 11 with pulmonary tumors, 14 with breast cancers, 4 with lymphomas, and 2 with other
tumors. Herting et al. (1959) found that male and female Holtzman rats fed high fat diets
containing 50% hexadecanoic acid for 24 weeks developed lipogranulomas in the perigonadal
fat. The lipogranulomas were not seen in controls. The lipogranulomas were reversible upon
diet substitution and were not considered to be neoplastic.
Other Studies
In a dietary study conducted by Record et al. (1992), 17 adult men (aged 32-63 years)
with mild hypercholesterolemia were given dietary supplements (margarine, biscuits, and potato
crisps) high in different oils. The frequency and distribution of micronuclei in peripheral blood
lymphocytes were determined after 3 weeks on the test diets. No significant alterations were
observed in the subjects ingesting diets high in hexadecanoic acid.
PROVISIONAL WEIGHT-OF-EVIDENCE CLASSIFICATION
The human and animal data suggest that a diet high in fat may increase susceptibility to
cancer, but are not conclusive. The limited evidence specifically on hexadecanoic acid are
negative for genotoxicity and carcinogenicity. Under the U.S. EPA (2005) cancer guidelines, the
data are inadequate to assess the carcinogenic potential of hexadecanoic acid. The animal study
described above (Swern et al., 1970) relies on an unconventional approach. The time frame,
method of application (subcutaneous administration), and range of doses individually and
collectively render this study unacceptable for generating a risk assessment.
QUANTITATIVE ESTIMATES OF CARCINOGENIC RISK
Derivation of quantitative estimates of cancer risk for hexadecanoic acid is precluded by
the lack of data demonstrating carcinogenicity associated with hexadecanoic acid exposure.
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REFERENCES
Anonymous. 1987. Final report on the safety assessment of oleic acid, lauric acid, palmitic acid,
myristic acid, and stearic acid. J. Am. Coll. Toxicol. 6:321-401.
ATSDR (Agency for Toxic Substances and Disease Registry). 2003. Toxicological Profile
Information Sheet. U.S. Department of Health and Human Services, Public Health Service.
Atlanta, GA. Online, http://www.atsdr.cdc.gov/toxpro2.html
Birt, D.F. 1990. The influence of dietary fat on carcinogenesis: lessons from experimental
models. Nutr. Rev. 48: 1-5.
Boutwell, R.K. 1992. Caloric intake, dietary fat level, and experimental carcinogenesis. Adv.
Exp. Med. Bio. 322:95-101.
Carroll, K.K. 1991. Dietary fats and cancer. Am. J. Clin. Nutr. 53: 1064S-1067S.
Herting, D.C., P.L. Harris, and R.C. Crain. 1959. Lipogranuloma from dietary saturated fats:
production and reversal. Toxicol. Appl. Pharmacol. 1: 505-514.
I ARC (International Agency for Research on Cancer). 2003. IARC Agents and Summary
Evaluations. Online, http://www-cie.iarc.fr/
Kristiansen, E., C. Madsen, O. Meyer et al. 1993. Effects of high-fat diet on incidence of
spontaneous tumors in Wistar rats. Nutr. Cancer. 19: 99-110.
Macrae, F.A. 1993. Fat and calories in colon and breast cancer: from animal studies to
controlled clinics trials. Prevent. Med. 22: 750-766.
NTP (National Toxicology Program). 2003. Management Status Report. Online.
http://ntp-server.niehs.nih.gov/
Record, I.R., M. Konstaninopoulos and P.J. Nestel. 1992. A comparative study of micronucleus
frequency in peripheral blood lymphocytes of human subjects given dietary cis, trans and
saturated fat. Fd. Chem. Toxicol. 30: 585-588.
Swern, D., R. Wieder, M. McDonough et al. 1970. Investigation of fatty acids and derivatives
for carcinogenic activity. Cancer Res. 30:1037-1046.
U.S. EPA. 1991. Chemical Assessments and Related Activities (CARA). Office of Health and
Environmental Assessment, Washington, DC. April.
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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 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
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