United States
Environmental Protection
1=1 m m Agency
EPA/690/R-04/012F
Final
12-21-2004
Provisional Peer Reviewed Toxicity Values for
Octadecanoic Acid (Stearic Acid)
(CASRN 57-11-4)
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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12-21-04
PROVISIONAL PEER REVIEWED TOXICITY VALUES FOR
OCTADECANOIC ACID (STEARIC ACID, CASRN 57-11-4)
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 Headquarters 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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12-21-04
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
Octadecanoic acid, an 18-carbon saturated fatty acid also known as stearic acid, is
synthesized in the body and is a vital component of the cell membrane. It is a normal constituent
of the diet found in vegetable oils and animal fats. Neither a subchronic nor chronic RfD for
octadecanoic acid is listed on IRIS (U.S. EPA, 2003) or in the HEAST (U.S. EPA, 1997) or
Drinking Water Standards and Health Advisories list (U.S. EPA, 2002). The CARA list (U.S.
EPA, 1991, 1994) does not report any relevant documents for octadecanoic acid. ATSDR
(2002), IARC (2002) and WHO (2002) have not published review documents for octadecanoic
acid. Computer literature searches of TOXLINE (1965-1994), TSCATS, and RTECS were
initially performed in May, 1994. Update literature searches for the years 1993-2003 were
conducted on TOXLINE, MEDLINE, CANCERLIT, CCRIS, TSCATS, HSDB, RTECS,
GENETOX, DART/ETICBACK, and EMIC/EMICBACK in January, 2003. The NTP (2002)
2

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12-21-04
status report was also searched for relevant information. Additional literature searches were
conducted by the NCEA-Cincinnati from February 2003 through May 2004 using TOXLINE,
MEDLINE, Chemical and Biological Abstracts databases.
REVIEW OF THE PERTINENT LITERATURE
Much of the research on the toxicity of fatty acids has focused on establishing a
relationship between a high fat diet and coronary heart disease (CHD), 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, as 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 epidemiology
studies, dietary intervention studies, and animal studies. A number of epidemiology 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 epidemiology 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 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
3

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12-21-04
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 coronary heart disease risk.
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
who were at high risk for developing coronary heart disease were given stepped-care treatment
for hypertension, counseling for quitting smoking, 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.
Several dietary studies in humans have reported that saturated fatty acids with 12, 14, or
16 carbons increase plasma cholesterol, whereas octadecanoic acid (with 18 carbons) has a
neutral effect on plasma cholesterol (see Bonanome and Grundy, 1989; Emken et al., 1993;
Grundy, 1994; Rhee et al., 1997; Snook et al., 1999 for reviews).
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). 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
(length of fatty acid carbon chain:number of double bonds, 16:0), followed by myristic acid
(14:0), caprylic acid (8:0), octadecanoic acid (18:0), and lauric acid (12:0). 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.
In addition to the role dietary fatty acid plays in atherosclerosis, there are human and
animal experimental 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
4

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12-21-04
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 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 and animal studies have demonstrated that a high fat diet results in
increased platelet turnover, platelet adhesiveness, and the formation of thrombi (Renaud et al.,
1970; Baghurst and Truswell, 1979). 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).
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 man who
smokes cigarettes, has a systolic blood pressure of 120 mm Hg and a blood cholesterol level of
210 mg/dl has a probability (per 1000) of 92 for developing cardiovascular disease in 8 years; if
the individual did not smoke the probability would be 55 per 1000 (Castelli, 1983).
FEASIBILITY OF DERIVING PROVISIONAL SUBCHRONIC AND CHRONIC
RfDs FOR OCTADECANOIC ACID
There is limited information on the toxicity of octadecanoic acid. 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. 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 nondietary (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 (Zollner and Tato, 1992). Octadecanoic
acid is just one of the many saturated fatty acids found in the diet. Without recommendations for
safe dietary levels of octadecanoic acid, health-based guidelines for environmental ingestion (i.e.,
subchronic or chronic p-RfDs) of octadecanoic acid cannot be made.
5

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12-21-04
REFERENCES
ATSDR (Agency for Toxic Substances and Disease Registry). 2002. Internet HazDat
Toxicological Profile Query. U.S. Department of Health and Human Services, Public Health
Service. Atlanta, GA. Online. http://www.atsdr.cdc.gOv//qsql/toxprof.script
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.
Bonanome, A. and S.M. Grundy. 1989. Intestinal absorption of stearic acid after consumption
of high fat meals in humans. J. Nutr. 119:1556-1560.
Castelli, W.P. 1983. Cardiovascular disease and multifactorial risk: challenge of the 1980s.
Am. Heart J. 106:1191-1200.
Connor, W.E. and S.L. Connor. 1990. Diet, atherosclerosis, and fish oil. Adv. Intern. Med. 35:
139-171.
Emken, E.A., R.O. Adolf, W.K. Rohwedder and R.M. Gulley. 1993. Influence of linoleic acid
on desaturation and uptake of deuterium-labeled palmitic and stearic acids in humans. Biochem.
Biophys. Acta. 1170:173-181.
Grundy, S.M. 1994. Influence of stearic acid on cholesterol metabolism relative to other long-
chain fatty acids. Am. J. Clin. Nutr. 60(suppl): 986S-990S.
IARC (International Agency for Research on Cancer). 2002. IARC Agents and Summary
Evaluations. Online. http://193.51.164.ll/cgi/iHound/Chem/iH Chem Frames.html
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. Tissue Reac. 13:
59-65.
Multiple Risk Factor Intervention Trial Research Group. 1982. Multiple Risk Factor
Intervention Trial. J. Am. Med. Assoc. 248: 1465-1477.
NTP (National Toxicology Program). 2002. Management Status Report. Online.
http://ntp-server.niehs.nih.gov/cgi/iH Indexes/Res Stat/iH Res Stat Frames.html
Nordoy, A. and S.H. Goodnight. 1990. Dietary lipids and thrombosis. Relationships to
atherosclerosis. Atherosclerosis. 10: 149-163.
Renaud, S. 1968. Thrombotic, atheroscerotic 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.
Rhee, S.K., A.J. Kayani, A Ciszek and J.T. Brenna. 1997. Desaturation and interconversion of
dietary stearic and palmitic acids in human plasma and lipoproteins. Am. J. Clin. Nutr. 65:
451-458.
Snook, J.T., S. Park, G. Williams et al. 1999. Effect of synthetic triglycerides of myristic,
palmitic, and stearic acid on serum lipoprotein metabolism. Eur. J. Clin. Nutr. 53: 597-605.
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. 2002. 2002 Edition of the Drinking Water Standards and Health Advisories. Office
of Water, Washington, DC. 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). 2002. Online Catalogs for the Environmental Criteria
Series. Online, http://www.who.int/dsa/cat98/zehc.htm
Zemel, P.C. and J.R. Sowers. 1990. Relation between lipids and atherosclerosis: epidemiologic
evidence and clinical implications. Am. J. Cardiol. 66: 71-121..
Zollner, N. and F. Tato. 1992. Fatty acid composition of the diet: impact on serum lipids and
atherosclerosis. Clin. Investig. 70: 968-1009.
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Provisional Peer Reviewed Toxicity Values for
Octadecanoic Acid (Stearic Acid)
(CASRN 57-11-4)
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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12-21-04
PROVISIONAL PEER REVIEWED TOXICITY VALUES FOR
OCTADECANOIC ACID (STEARIC ACID, CASRN 57-11-4)
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 Headquarters 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

-------
12-21-04
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
Octadecanoic acid, an 18-carbon saturated fatty acid also known as stearic acid, is
synthesized in the body and is a vital component of the cell membrane. It is a normal constituent
of the diet found in vegetable oils and animal fats. Neither a subchronic nor chronic RfC for
octadecanoic acid is listed on IRIS (U.S. EPA, 2003) or in the HEAST (U.S. EPA, 1997). The
CARA list (U.S. EPA, 1991, 1994) does not report any relevant documents for octadecanoic
acid. ATSDR (2002), IARC (2002) and WHO (2002) have not published review documents for
octadecanoic acid. Occupational exposure limits for octadecanoic acid have not been established
by ACGIH (2002), NIOSH (2002), or OSHA (2002a,b). Literature searches for inhalation data
were conducted for the years 1965-2003 in January, 2003. The databases searched were
TOXLINE, MEDLINE, CANCERLIT, CCRIS, TSCATS, HSDB, RTECS, GENETOX,
DART/ETICBACK, and EMIC/EMICBACK. The NTP (2002) status report was also searched
2

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12-21-04
for relevant information. Additional literature searches were conducted by the NCEA-Cincinnati
from February 2003 through May 2004 using TOXLINE, MEDLINE, Chemical and Biological
Abstracts databases.
REVIEW OF THE PERTINENT LITERATURE
Human Studies
No studies were located regarding inhalation exposure of humans to octadecanoic acid.
Animal Studies
No studies were located regarding inhalation exposure of animals to octadecanoic acid.
FEASIBILITY OF DERIVING PROVISIONAL SUBCHRONIC AND CHRONIC
RfCs FOR OCTADECANOIC ACID
In the absence of subchronic or chronic inhalation data on the toxicity of octadecanoic
acid, derivation of a provisional subchronic or chronic RfC is precluded.
REFERENCES
ACGIH (American Conference of Governmental Industrial Hygienists). 2002. 2002 Threshold
Limit Values for Chemical Substances and Physical Agents and Biological Exposure Indices.
Cincinnati, OH.
ATSDR (Agency for Toxic Substances and Disease Registry). 2002. Internet HazDat
Toxicological Profile Query. U.S. Department of Health and Human Services, Public Health
Service. Atlanta, GA. Online. http://www.atsdr.cdc.gOv//qsql/toxprof.script
I ARC (International Agency for Research on Cancer). 2002. IARC Agents and Summary
Evaluations. Online. http://193.51.164.ll/cgi/iHound/Chem/iH Chem Frames.html
NIOSH (National Institute for Occupational Safety and Health). 2002. Online NIOSH Pocket
Guide to Chemical Hazards. Index of Chemical Abstract Numbers (CAS No.). Online.
http://www.cdc.gov/niosh/npg/npgdcas.html
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NTP (National Toxicology Program). 2002. Management Status Report. Online.
http://ntp-server.niehs.nih.gov/cgi/iH Indexes/Res Stat/iH Res Stat Frames.html
OSHA (Occupational Safety and Health Administration). 2002a. OSHA Standard 1910.1000
Table Z-2. Part Z, Toxic and Hazardous Substances. Online.
http://www.osha-slc.gov/OshStd data/1910 1000 TABLE Z-2.html
OSHA (Occupational Safety and Health Administration). 2002b. OSHA Standard 1915.1000
for Air Contaminants. Part Z, Toxic and Hazardous Substances. Online.
http://www.osha-slc.gov/OshStd data/1915 1000.html
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). 2002. Online Catalogs for the Environmental Criteria
Series. Online, http://www.who.int/dsa/cat98/zehc.htm
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Provisional Peer Reviewed Toxicity Values for
Octadecanoic Acid (Stearic Acid)
(CASRN 57-11-4)
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 VALUES FOR
OCTADECANOIC ACID (STEARIC ACID, CASRN 57-11-4)
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 Headquarters 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
Octadecanoic acid, an 18-carbon saturated fatty acid also known as stearic acid, is
synthesized in the body and is a vital component of the cell membrane. It is a normal constituent
of the diet found in vegetable oils and animal fats. A carcinogenicity assessment for
octadecanoic is not available on IRIS (U.S. EPA, 2003), in the HEAST (U.S. EPA, 1997), or in
the Drinking Water Standards and Health Advisories List (U.S. EPA, 2002). The CARA list
(U.S. EPA, 1991, 1994) does not report any relevant documents for octadecanoic acid. IARC
(2002), ACGIH (2002), and NTP (2002) have not assessed the carcinogenicity of octadecanoic
acid. ATSDR (2002) and WHO (2002) have not published review documents for octadecanoic
acid. Computer literature searches of TOXLINE (1965-1994), TSCATS, and RTECS were
initially performed in May, 1994. Update literature searches for the years 1993-2003 were
conducted on TOXLINE, MEDLINE, CANCERLIT, CCRIS, TSCATS, HSDB, RTECS,
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GENETOX, DART/ETICBACK, and EMIC/EMICBACK in January, 2003. Additional
literature searches were conducted by the NCEA-Cincinnati from February 2003 through May
2004 using TOXLINE, MEDLINE, Chemical and Biological Abstracts databases.
REVIEW OF THE PERTINENT LITERATURE
Over 50 years ago, a relationship between a diet high in fat and an increased carcinogenic
risk was first established in laboratory animals (Kristiansen et al., 1993; Boutwell, 1992).
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, as well as 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, intake of other macronutrients and micronutrients,
and genetic factors (Boutwell, 1992; Birt, 1990; Carroll, 1991; Macrae, 1993).
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
potential for a high fat diet to promote cancer (Carroll, 1991). 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; Carroll,
1991). Increases in the incidence of spontaneous tumors have also been observed in animals fed
high fat diets, suggesting that dietary fat may be a complete carcinogen. The results from older
studies suggested that unsaturated fatty acids were tumorigenic and a diet 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 complex
and that the concentration of essential fatty acids in the diet, the degree of unsaturation, and the
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 in the diet. Several studies have shown that
caloric restriction reduces the incidence of spontaneous and chemically-induced tumors in
animals fed high fat diets (Boutwell, 1992). Animal studies examining the carcinogenicity of a
high fat diet, where the principal fatty acid was octadecanoic acid, are discussed below. The
objective of most of these studies was to examine the carcinogenic potential of octadecanoic acid
in a particular tissue, and other tissues were not examined histologically. Complete histological
examinations were conducted in the Kristiansen et al. (1993) study.
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Kristiansen et al. (1993) examined the influence of a diet high in saturated fat on the
incidence of spontaneous tumors. Groups of 110 male and 110 female Wistar rats were fed a
basal diet which was supplemented with saturated fatty acids (total fat content was 16%) for 129-
134 weeks. The saturated fat was 85% octadecanoic acid and 13% hexadecanoic acid; the diet
also contained 4% soybean oil and provided recommended essential fatty acids. The control
group (59/sex) received the basal diet, which had a fat content of 4% (from soybean oil). No
unusual clinical signs or increase in mortality were observed. Body weight, weight gain and food
consumption were similar for the two groups. From week 38 to the end of the study, an increase
in the number of neutrophils and a decrease in the number of lymphocytes were observed in the
female rats fed the high fat diet (the differences were statistically significant beginning at week
87); no change in the number of total leukocytes were observed. No significant differences in
time to occurrence of organ-specific tumors were observed between the two groups. A
statistically significant increase in the incidence of fibroadenomas of the mammary gland was
observed in the female rats fed the high fat diet; when the incidence of benign mammary tumors
(adenomas and fibroadenomas) were combined, the difference between the groups was no longer
statistically different. In the male control group, significant increases in the incidence of
adenoma of the parathyroid gland and medullary carcinoma of the adrenal gland were observed.
Swern et al. (1970) conducted a series of 7 experiments to determine the carcinogenicity
of octadecanoic acid using female BALB/c or Swiss Webster mice. Using the following dosing
schedule, groups of BALB/c mice received repeated subcutaneous injections of octadecanoic
acid in tricaprylin in approximately the same site of the inguinal and axillary regions: 10 mice
received 82 doses of 1 mg, 2 times per week; groups of 10 mice received 114 doses of either 0.05
or 0.5 mg, 2 times/week; and 15 mice received 0.05 mg doses administered twice weekly for 104
injections. Swiss Webster mice were similarly exposed using the following protocols: 15 mice
received 10 doses of 1.0 mg, 3 times/week; and groups of 16 mice received 26 doses of either
0.05 or 0.5 mg administered once a week. Control groups consisting of untreated mice or mice
receiving the tricaprylin vehicle only were similarly exposed. The incidences of subcutaneous
sarcomas, pulmonary tumors, breast cancers, lymphomas and other tumors for mice alive at 6
months (data collapsed across experimental groups) were 4/83, 3/83, 0/83, 1/83, and 1/83,
respectively, as compared to 1/104, 5/104, 2/104, 0/104, and 4/104 in the vehicle control group.
The 4 sarcomas seen in the octadecanoic acid exposed mice were seen in mice exposed to 0.05
mg twice weekly for a total of 114 doses; sarcomas were not seen in mice similarly exposed to
higher concentrations. The authors could not find an explanation for this finding and noted that
these animals were housed in the same cage (with 4 other animals).
In a replication of the Swern et al. (1970) study, groups of 15 female ICR/Ha Swiss
Millerton mice and 16 female Swiss Webster were exposed to 0.05 or 0.5 mg/day octadecanoic
acid in tricaprylin (Van Duuren et al., 1972). The four groups of mice received subcutaneous
injections in the inguinal area once a week for 26 weeks. Of the mice that were alive after 6
months, no injection site sarcomas were observed, and 3/15 ICR mice exposed to 0.05 mg/day
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and 1/14 ICR mice exposed to 0.5 mg/day had tumors at other sites. In the vehicle only control
groups, the incidences of injection site sarcomas were 0/16 and 0/15 for the ICR and Swiss
Webster mice, respectively, and the incidences of other tumors were 0/16 and 1/15, respectively.
Herting and Harris (1959) examined the incidence of lipogranulomas in groups of 4 male
and 4 female Holtzman rats fed high fat diets containing 50.4% octadecanoic acid for 24 weeks.
After the exposure period, the rats were fed a diet containing 20% corn oil for 24 weeks. The
control group were fed diets containing 4% corn oil and 10% triacetin (supplying acetyl
equivalent to that in a diet containing 54% of distilled partially acetylated monoglycerides) for 48
weeks. The incidences of lipogranulomas in perigonadal fat after 8, 16, or 24 weeks on the
octadecanoic acid diet were 5/7, 3/6, and 5/5, respectively. After 8, 16, or 24 weeks on corn oil
diet, the incidences of lipogranulomas were 1/4, 3/5, and 2/5, respectively. No lipogranulomas
were seen in the control group. The lipogranulomas observed in the rats exposed to the diet high
in octadecanoic acid are not considered neoplastic.
Groups of 26 female weanling A/St mice and 23 adult (11.5 months of age) were placed
on a high fat diet (13.1% of the diet consisted of octadecanoic acid, and the total fat content was
15%) (Bennett, 1984). The comparison groups were 27 weanling female mice and 65 adult
female mice fed a low fat diet (total dietary fat was 4.5% with 0.3% octadecanoic acid). By age
24 months, 17/26 mice placed on the high fat diet at weaning developed mammary
adenocarcinomas, and the average age at tumor development was 15.7 months. In the weanling
control group, 20/27 mice developed tumors by 24 months of age and the average age at tumor
development was 12.7 months. The age at tumor development was significantly higher in the
high fat diet group as compared to the low fat diet group. The length of time to tumor
development was also significantly higher in the adult mice fed the high fat diet (tumors
developed after an average of 5.0 months) compared to the adult low fat group (tumor
development after 3.0 months).
In a study designed to examine the potential for octadecanoic acid to induce pancreatic
carcinogenesis, groups of 10 male Leed rats were fed a high fat diet (22% fat) for 6 months
(Khoo et al., 1991). The octadecanoic acid content of the diet was 20.05% (87.63% of the total
fat). The control group (10 male rats) was fed a standard diet containing a fat content of 2.5%
(0.06% octadecanoic acid). The animals fed octadecanoic acid weighed significantly less (9.4%)
than the control rats. No significant alterations in the incidence of atypical acinar cell foci
(apparent precursors of acinar cell adenomas and carcinomas) were observed. Another group of
10 rats received repeated intraperitoneal injections of azaserine (30 mg/kg) at age 14, 21, and 28
days, after which they received the high fat diet for 6 months. No significant alterations in
acidophilic acinar cell foci were observed in this group.
The genotoxicity of octadecanoic acid was tested using the spot test, a qualitative form of
the Salmonella/microsome test (Blevins and Taylor, 1982). Negative results were found, with
5

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and without S9 activation, using Salmonella typhimurium strains TA1538, TA1537, TA1535,
TA100, and TA98.
PROVISIONAL WEIGHT-OF-EVIDENCE CLASSIFICATION
Although the results in humans are inconsistent, animal data suggest that a high fat diet
may increase the susceptibility to cancer. Although many variables may be responsible, the
degree of unsaturation of the dietary fat is an important determining factor (Birt, 1990). No
human studies examining the influence of octadecanoic acid on the carcinogenic potential of a
high fat diet were located. Animal studies have shown that under the conditions tested, an
increased carcinogenic risk is not associated with a diet high in octadecanoic acid. The
usefulness of most of the animal studies for assessing carcinogenicity is limited because a very
small number of tissues were histologically examined and the animals were exposed for less than
a lifetime. The Kristiansen et al. (1993) study involved lifetime exposure and histological
examination of most tissues and/or organs; however the results were inconclusive with regard to
the carcinogenic potential of octadecanoic acid.
Under the proposed U.S. EPA (1999) cancer guidelines, the available data are inadequate
for an assessment of human carcinogenic potential.
QUANTITATIVE ESTIMATES OF CARCINOGENIC RISK
Lack of adequate human or animal cancer data precludes derivation of quantitative
estimates of cancer risk for octadecanoic acid.
REFERENCES
ACGIH (American Conference of Governmental Industrial Hygienists). 2002. 2002 Threshold
Limit Values for Chemical Substances and Physical Agents and Biological Exposure Indices.
Cincinnati, OH.
ATSDR (Agency for Toxic Substances and Disease Registry). 2002. Internet HazDat
Toxicological Profile Query. U.S. Department of Health and Human Services, Public Health
Service. Atlanta, GA. Online. http://www.atsdr.cdc.gOv//qsql/toxprof.script
Bennett, A.S. 1984. Effect of dietary stearic acid on the genesis of spontaneous mammary
adenocarcinomas in strain A/ST mice. Int. J. Cancer. 34: 529-533.
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Birt, D.F. 1990. The influence of dietary fat on carcinogenesis: Lessons from experimental
models. Nutr. Rev. 48: 1-5.
Blevins, R.D. and D.E. Taylor. 1982. Mutagenicity screening of twenty-five cosmetic
ingredients with the Salmonella/microsome test. J. Environ. Sci. Health. A17: 217-239.
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. and P.L. Harris. 1959. Lipogranuloma from dietary saturated fats: production and
reversal. Toxicol. Appl. Pharmacol. 1:505-514.
I ARC (International Agency for Research on Cancer). 2002. IARC Agents and Summary
Evaluations. Online. http://193.51.164.ll/cgi/iHound/Chem/iH Chem Frames.html
Khoo, D.E., B. Flaks, H. Oztas et al. 1991. Effects of dietary fatty acids on the early stages of
neoplastic induction in the rat pancreas. Changes in fatty acid composition and development of
atypical acinar cell nodules. Int. J. Exp. Pathol. 72: 571-80.
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). 2002. Management Status Report. Online.
http://ntp-server.niehs.nih.gov/cgi/iH Indexes/Res Stat/iH Res Stat Frames.html
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.
U.S. EPA. 1994. Chemical Assessments and Related Activities (CARA). Office of Health and
Environmental Assessment, Washington, DC. December.
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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. 1999. Proposed Guidelines for Cancer Risk Assessment. July. Office of Research
and Development, National Center for Environmental Assessment, Washington, DC.
U.S. EPA. 2002. 2002 Edition of the Drinking Water Standards and Health Advisories. Office
of Water, Washington, DC. 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). 2002. Online Catalogs for the Environmental Criteria
Series. Online, http://www.who.int/dsa/cat98/zehc.htm
Van Duuren, B.L., C. Katz, M.B. Shimkin et al. 1972. Replication of low-level carcinogenic
activity bioassays. Cancer Res. 32:880-881.
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