United States
kS^laMIjk Environmental Protection
^J^iniiil m11 Agency
EPA/690/R-05/008F
Final
3-29-2005
Provisional Peer Reviewed Toxicity Values for
Benzoic Acid
(CASRN 65-85-0)
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

-------
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

-------
3-29-2005
PROVISIONAL PEER REVIEWED TOXICITY VALUES FOR
BENZOIC ACID (CASRN 65-85-0)
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

-------
3-29-2005
Disclaimers
Users of this document should first check to see if any IRIS values exist for the chemical
of concern before proceeding to use a PPRTV. If no IRIS value is available, staff in the regional
Superfund and RCRA program offices are advised to carefully review the information provided
in this document to ensure that the PPRTVs used are appropriate for the types of exposures and
circumstances at the Superfund site or RCRA facility in question. PPRTVs are periodically
updated; therefore, users should ensure that the values contained in the PPRTV are current at the
time of use.
It is important to remember that a provisional value alone tells very little about the
adverse effects of a chemical or the quality of evidence on which the value is based. Therefore,
users are strongly encouraged to read the entire PPRTV manuscript and understand the strengths
and limitations of the derived provisional values. PPRTVs are developed by the EPA Office of
Research and Development's National Center for Environmental Assessment, Superfund Health
Risk Technical Support Center for OSRTI. Other EPA programs or external parties who may
choose of their own initiative to use these PPRTVs are advised that Superfund resources will not
generally be used to respond to challenges of PPRTVs used in a context outside of the Superfund
Program.
Questions Regarding PPRTVs
Questions regarding the contents of the PPRTVs and their appropriate use (e.g., on
chemicals not covered, or whether chemicals have pending IRIS toxicity values) may be directed
to the EPA Office of Research and Development's National Center for Environmental
Assessment, Superfund Health Risk Technical Support Center (513-569-7300), or OSRTI.
INTRODUCTION
The HEAST (U.S. EPA, 1997) lists a subchronic oral RfD value of 4E+0 mg/kg-day for
benzoic acid, with a notation that the chronic oral RfD was adopted for this reference value. The
HEAST references IRIS (U.S. EPA, 2003) for the chronic oral RfD. Benzoic acid and its sodium
salt are used as food preservatives. The chronic oral RfD is based on the estimated human daily
per capita intakes of benzoic acid (0.9 - 34 mg/day) and sodium benzoate (34-328 mg/day)
derived from estimates of their production for use in food (U.S. FDA, 1973). The upper range of
each estimate was considered a NOAEL for the compound, based on the absence of reported
adverse effects at these levels and because these compounds are Generally Recognized as Safe
(GRAS) by U.S. FDA (Informatics, Inc., 1972). U.S. EPA (2003) converted the upper range of
sodium benzoate intake to a benzoic acid equivalent intake of 278 mg/day. The combined daily
intake (34 mg + 278 mg) as benzoic acid was 312 mg/kg. The RfD of 4E+0 was calculated using
2

-------
3-29-2005
an uncertainty factor (UF) and modifying factor (MF) of one each and a default adult body
weight of 70 kg.
The Health and Environmental Effects Document (HEED) (U.S. EPA, 1987a) assigned
benzoic acid to carcinogenicity group D (not classifiable as to human carcinogenic potential), and
no carcinogenicity classification or quantitative assessment of cancer risk is reported in the
HEAST. IRIS (U.S. EPA, 2003) does not list an RfC or quantitative cancer assessment for
benzoic acid, but includes a weight of evidence characterization of D (not classifiable as to
human carcinogenicity). Benzoic acid is not included in the Drinking Water Standards and
Health Advisories List (U.S. EPA, 2002). The CARA list (U.S. EPA, 1991, 1994a) reports the
HEED (U.S. EPA, 1987a) and a Reportable Quantities Document (U.S. EPA, 1987b). ATSDR
(2002) has not published a Toxicological Profile for benzoic acid. WHO (2000) has published a
Concise International Chemical Assessment Document (CICAD) on Benzoic Acid and Sodium
Benzoate and has recently conducted an evaluation of benzoate intake assessments prepared by
nine countries, including the United States (WHO, 1999). The Joint FAO/WHO Expert
Committee on Food Additives (WHO, 1996) lists a Group Acceptable Daily Intake (ADI) of 0-5
mg/kg-bw for benzoic acid and its salts, including benzyl alcohol and related benzyl derivatives
used as flavorings. The European Commission Scientific Committee on Food (ECSCF, 2002)
recently re-evaluated the safety of benzoic acid as a food additive and also adopted a Group ADI
of 0 - 5 mg/kg bw - day for benzoic acid and its salts. The Cosmetic Ingredient Review (CIR)
Expert Panel conducted a safety assessment on the use of benzoic acid and sodium benzoate in
cosmetics and concluded that these compounds could be safely used at concentrations up to 5%
in products intended for adults (CIR, 2001). Neither ACGIH (2001), NIOSH (2002), nor OSHA
(2002) have adopted occupational exposure limits for benzoic acid. Neither NTP (2002) nor
IARC (2002) have evaluated the carcinogenicity of benzoic acid.
Literature searches were conducted from 1988 through March, 2002 for studies relevant
to the derivation of provisional toxicity values for benzoic acid. Databases searched included:
TOXLINE, MEDLINE, TSCATS, RTECS, CCRIS, DART, EMIC/EMICBACK, HSDB,
GENETOX and CANCERLIT. Additional literature searches from April 2002 through
September 2004 were conducted by NCEA-Cincinnati using MEDLINE, TOXLINE, Chemical
and Biological Abstracts databases.
REVIEW OF PERTINENT DATA
Human and animal toxicity data on benzoic acid and sodium benzoate were reviewed for
potential use in derivation of provisional reference values and quantitative cancer assessment.
Consideration of data on sodium benzoate is appropriate for oral exposure because the acid
3

-------
3-29-2005
environment of the stomach (pH = 2) favors conversion of ionized benzoate to undissociated
benzoic acid (pK, = 4.2) (WHO, 2000).
Human Studies
No subchronic or chronic data on human health effects resulting from inhalation exposure
to benzoic acid were located in the literature examined.
Human data on benzoic acid toxicity are available from early oral exposure studies
conducted in human volunteers. Chittenden et al. (1909) observed no apparent effects in six
adult male human volunteers given 300 to 400 mg/day via the diet for up to 62 days. Assuming
an average body weight of 70 kg, the average daily doses of benzoic acid were approximately 4
to 6 mg/kg-day. Gerlach (1909) reported no apparent effects in human volunteers (number not
specified) ingesting daily doses of benzoic acid of 500 or 1000 mg/day for 44 consecutive days;
82 doses of 1000 mg/day over 86 days; or 88 doses of 1000 mg/day over 92 days. These dosing
schedules resulted in average daily doses of up to 14 mg/kg-day, as reported in U.S. EPA
(1987a). Wiley and Bigelow (1908) observed irritation, discomfort, weakness, and malaise in
human volunteers given oral bolus doses of benzoic acid over a 20 day period. Only 3 of 12
volunteers completed the scheduled dose regimen as a result of the observed effects. The total
dose to individuals over the course of the experiment ranged from 13.5 to 35 grams. U.S. EPA
(1987a) estimated an average daily dose of 25 mg/kg-day in this study.
Sodium benzoate is used in the treatment of urea cycle enzymopathies to facilitate
alternative pathways of nitrogen excretion (WHO, 2000). Therapeutic doses are reported to be in
the range of 250 to 500 mg/kg-day and are given over several years. Clinical signs of toxicity are
reported to be rare at this dose level and in most cases limited to anorexia and vomiting,
particularly after bolus intravenous doses.
Some individuals may show greater sensitivity to benzoic acid or sodium benzoate
exposure. Cases of urticaria, asthma, rhinitis or anaphylactic shock have been reported after oral,
dermal, or inhalation exposure to these compounds (WHO, 2000). These symptoms are reported
to occur shortly after exposure and disappear within a few hours (WHO, 2000).
No human data on the carcinogenicity of benzoic acid or sodium benzoate were identified
in the literature examined.
Animal Studies
A single inhalation study is available for benzoic acid. IRDC (1981) reported a study in
which young Sprague-Dawley rats (10/sex/dose) were exposed to benzoic acid dust by whole
body inhalation at target concentrations of 0, 0.02, 0.2, or 2.00 mg/L, 6 hours/day, 5 days/week
4

-------
3-29-2005
for four weeks. The test material was generated as a dust aerosol with an equivalent aerodynamic
diameter (EAD) of 4.7 |im when averaged across the three exposure groups. The individual
EAD values for the low-, mid, and high-exposure groups were 4.6, 4.4, and 5.2 |im, respectively,
with corresponding geometric standard deviations (og) of 3.1, 2.1, and 2.1. Animal care and
environmental conditions were maintained according to standard guidelines. Information on
animal bedding (a potential confounding factor in evaluation of fibrosis) was not provided in the
methods section. The parameters evaluated included clinical signs, morbidity, mortality, body
weight gain, hematology, serum biochemistry (focused on indicators of liver function and
damage), gross pathology, organ weights, extensive histopathology of control and high-dose rats,
and histopathological examination of the lungs of mid- and low-dose animals. The lungs were
removed while in an inflated state. Post sacrifice lungs were deflated and re-inflated, with
buffered 10% neutral formalin. Lung histopathology was evaluated using hematoxylin and eosin
stained paraffin sections taken from each of the five lobes of the lung. The methods section of
the report did not indicate use of a collagen-specific stain for assessment of fibrosis.
Measured concentrations of benzoic acid in the test chambers were 0.025, 0.25, and 1.2
mg/L (0, 25, 250, and 1200 mg/m3). A reddish discharge was observed around the nares of
exposed animals. The occurrence of this discharge was dose-related. All animals in the mid-
and high-dose groups exhibited this sign on study day 4, with the discharge more pronounced in
the high-dose group. The discharge appeared in the mid- and high-dose groups throughout the
study with varying intensity. The discharge was noted in low-dose animals only on study day 13
and was not observed in control animals. Two compound-related deaths (one male and one
female) occurred in the high-dose groups. High-dose rats of both sexes showed significantly
decreased body weights throughout the study (Table 1). Platelet counts were significantly
reduced in high-dose males and females. No compound-related effects were noted for clinical
chemistry parameters. Decreased absolute organ weights and organ-to-brain weight ratios were
observed for the liver in high-dose males and the kidney and trachea/lungs of high-dose females.
Reduced absolute kidney weight was observed in mid-dose females. No compound-related gross
lesions were observed in any of the test animals. Compound-related microscopic lesions were
confined to the lung and consisted of 1) an increase in the extent and intensity of interstitial
inflammatory cell infiltrate (males and females) and 2) an increase in the incidence (males) and
intensity (males and females) of interstitial cell. Incidence data for pulmonary lesions are
summarized in Table 2. Interstitial inflammatory cell infiltrate was observed in all exposed
animals, all female control animals, and 9/10 male control animals. The study authors did not
comment on the high incidence of this lesion in the control groups. Review of the individual
animal data by Syracuse Research Corporation (SRC) indicates that slides from four of the nine
males included in the control incidence showed only subpleural inflammatory cell infiltrate (i.e.,
the pathologist did not specifically record interstitial cell involvement for these animals).
Compound-related changes in the extent of interstitial inflammatory cell infiltrate were assessed
by recording the progression from focal to multifocal and generalized lesions (Table 3). The
5

-------
3-29-2005
Table 1. Group Mean Body Weight (grams) in the 4-Week Inhalation Study
Conducted by IRDC (1981)
Measured
Concentration
mg/L (mg/m3)
Week of Exposure
0
(Pre-exposure)
1
2
3
4
Males
0(0)
199±11.6a
262±15.5
310±23.7
339±31.0
369±37.3
0.025 (25)
199±17.3
261 ±10.8
311 ±14.6
349±19.3
381 ±20.3
0.25 (250)
194±11.0
251±10.6
301 ±13.5
335±14.9
364±20.6
1.2 (1200)
201 ±13.8
242±9.4**
273±14.9**
294±19.2**
315±29.5**
Females
0(0)
163±7.3
194±10.4
218±14.6
234±16.3
249±19.6
0.025 (25)
156±8.1
185±11.7
206±1 5.8
222±17.0
235±19.6
0.25 (250)
148±8.4**
184±8.7
205±10.9
218±10.2*
234±15.7
1.2 (1200)
157±10.9
176±8.5**
200±12.9*
206±13.8**
219±14.1**
Source: Table 6 in IRDC (1981).
a Mean and standard deviation
* Statistically significant from control group mean, p<0.05
** Statistically significant from control group mean, p<0.001
6

-------
3-29-2005
Table 2. Terminal Incidence of Compound-Related Pulmonary Lesions in the 4-Week
Inhalation Study Reported by IRDC (1981)
Measured Concentration
mg/L (mg/m3)
Lesion
Interstitial Inflammatory Cell Infiltrate
Interstitial Fibrosis
Males
0(0)
9/10
1/10
0.025 (25)
10/10
5/10
0.25 (250)
10/10
5/10b
1.2 (1200)a
9/9
5/9*
Females
0(0)
10/10
3/10
0.025 (25)
10/10
5/10b
0.25 (250)
10/10
6/10
1.2 (1200)a
9/9
3/9
Source: Table 20 (Individual Animal Data) in IRDC (1981).
a One male and one female died on study and were not included in this evaluation.
b Incidences determined from individual animal data differed from summary data reported in Table 21 of the
study report.
* Statistically significant from control group (p=0.046) when analyzed by SRC using Fisher's Exact Test.
7

-------
3-29-2005
Table 3. Incidence of Compound-Related Pulmonary Lesions Categorized By Extent and Severity (IRDC, 1981)
Measured
Concentration
mg/L (mg/m3)
n
Interstitial Inflammatory Cell Infiltrate
Interstitial Fibrosis
Focal
Multifocal
Generalized
Focal
Multifocal
Generalized
Very
Slight
Slight
Very
Slight
Slight
Very
Slight
Slight
Very
slight
Slight
Very
Slight
Slight
Very
Slight
Slight
Males
0(0)
10
4
3
1
1


1





0.025 (25)
10


1
6
1
2


1
4


0.25 (250)
10



6

4

1

2

2
1.2 (1200)'
9



2

7

1

1

3
Females
0(0)
10
8

2



2

1



0.025 (25)
10
1
1
1
7





5


0.25 (250)
10



5
1
4

2

3

1
1.2 (1200)'
9



1
2
6

2



1
Source: Data are from an unnumbered table on page 18 of the study report; some incidences have been corrected based on review of individual animal data presented in Table 20 of the study
report.
a One male and one female in the high dose group died on study and were not included in this evaluation.
8

-------
3-29-2005
number of animals with lesions classified as multifocal or generalized increased with dose in
both sexes. The intensity of the lesion increased with dose as judged by the greater number of
animals with slight versus very slight severity. The incidence of interstitial fibrosis was
increased in exposed males when compared to the control group (Table 2). This response
reached statistical significance in high dose males only (p=0.046 as determined by SRC using
Fisher's Exact Test). The intensity of this lesion appeared to increase with dose in males and
females (Table 3). The alterations in both types of pulmonary lesions were attributed to a
persistent irritating effect of benzoic acid on the lung. The weight of evidence suggests a
LOAEL of 0.025 mg/L (25 mg/m3) based on the occurrence of clinical signs of respiratory
irritation and changes in the extent and/or incidence of histopathological changes in the lungs of
exposed animals. A NOAEL could not be determined.
Subchronic data are available from oral exposure studies of benzoic acid and sodium
benzoate. Shtenberg and Ignat'ev (1970) administered daily 80 mg/kg gavage doses of benzoic
acid (vehicle not reported ) to male and female white mice (50/sex) for three months. A control
group was included in the experiment, but details on treatment and number of animals
maintained were not provided by the study authors. Clinical signs, survival, food and water
intake and body weight gain were monitored during the study. Responses of the test animals to
stressors including starvation and carbon tetrachloride poisoning were assessed at the end of the
exposure period. Body weight gain was significantly reduced by 63% in dosed males and 71% in
dosed females relative to the controls, although food intake by control and dosed animals was
similar. Dosed mice showed greater mortality when stressed by poisoning with carbon
tetrachloride.
Kreis et al. (1967) fed diets containing 1.1 % benzoic acid to Royal Wistar rats for 35
days and observed significantly decreased weight gain. No effects were evident on behavior,
gross pathology, or histopathology of the heart, liver, kidneys or brain.
U.S. EPA (1987a) summarized several subchronic dietary studies that examined the effect
of sodium benzoate on growth. Griffith (1929) fed diets containing sodium benzoate at
concentrations of 0, 1.5, 2.0, 2.5, or 3 % to young male white rats for 40 days. Exposure to
sodium benzoate had no effect on food consumption at any dietary level. Growth was reduced at
the high dose of 3% and one third of the rats in that exposure group died. The incorporation of
glycine or gelatin in the 3% diet resulted in a normal growth rate (sodium benzoate is detoxified
by glycine conjugation). White (1941) observed marked stunting in rats fed 5% sodium benzoate
in the diet after three to six weeks of treatment. Gross signs of toxicity were observed in a few
rats that did not tolerate the sodium benzoate. Harshbarger (1942) pair-fed diets containing 3%
sodium benzoate to young male white rats for four to five weeks and observed marked reduction
in growth rate and food conversion efficiency in the treated groups. Two of eight animals on the
3% diet died. Addition of 1% sodium benzoate to a basal diet had no effect on growth or
survival. In a range-finding study, Smyth and Carpenter (1948) fed Sherman rats (5/sex/dose)
9

-------
3-29-2005
diets containing doses of sodium benzoate ranging from 16 to 1009 mg/kg-day for 30 days. No
adverse effects were reported on survival, appetite, or growth rate or on histopathology of a
limited number of tissues.
Deuel et al. (1954) fed male and female Sherman rats (5/sex/dose) diets containing 0, 1,
2, 4, or 8% sodium benzoate for 90 days. The tested dietary levels corresponded to doses of
approximately 0, 640, 1320, 2620, and 6290 mg/kg-day, respectively, as calculated by the
investigators. Experimental results for both sexes were combined. Four study animals died from
infections. In addition, four treatment-related deaths occurred at the 8% level. A decreased rate
of body weight gain and increased relative liver and kidney weights occurred in rats on the 8%
diet. The investigators reported "frequent pathological lesions" in the 8% group but did not
report incidences or provide descriptions of the lesions.
Fanelli and Halliday (1963) fed diets containing 0, 2, or 5% sodium benzoate to young
Sherman rats (6/sex/dose) for 28 days. The estimated equivalent doses of sodium benzoate at the
2% level were 2002 and 2171 mg/kg-day for males and females, respectively. All rats on the 5%
diet died between the first and second weeks of the study after exhibiting severe signs of central
nervous system toxicity. The rate of body weight gain was slightly, but significantly (p< 0.05),
depressed in males fed the 2% diet.
Limited data for chronic oral exposure are available from studies of benzoic acid in rats
and mice. No chronic oral exposure data were located for sodium benzoate. Marquardt (1960)
exposed Wistar rats (20 females and 30 males) to a diet containing 1.5% benzoic acid
(approximately 750 mg/kg-day). The control group included 12 females and 13 males. At 18
months, animals fed benzoic acid showed increased mortality, decreased food intake, and
suppressed growth. In a second experiment, Marquardt (1960) fed male Wistar and male
Osborne-Mendel rats (20/strain) a diet containing 1.5% benzoic acid. The control group
contained 10 male rats of each strain. Exposed animals gained less weight and had reduced feed
intake, as observed in the previous experiment.
Ignat'ev (1965) conducted an 18 month oral exposure study of benzoic acid in male and
female mice. As reported by Informatics, Inc. (1972), the mice (25/sex/dose) were fed 0, 40, or
80 mg/kg-day for 3, 8, or 18 months. The parameters evaluated included general appearance,
viability (survival), reproduction, food and water consumption, weight gain, blood and urine
parameters, histopathology, carcinogenicity, and response to various stressors. Numerical data
were presented for body weight gain, food and water consumption, and viability in the 80 mg/kg-
day group. Statistical analysis of these data was not reported. Relative body weight gain was
reduced in male and female mice treated with 80 mg/kg-day relative to the controls. There were
possible compound-related decreases in food and water consumption and viability in 80 mg/kg-
day females relative to the control. Dosed mice were reported (without supporting data) to have
increased liver weights; enlarged spleens, ovaries, and lungs; and decreased detoxifying capacity
10

-------
3-29-2005
for carbon tetrachloride. In assessing the quality of this study, Informatics, Inc. (1972) noted that
"This study was reported in several other papers, none of which provided data sufficient to justify
the conclusions reached." In a parallel study, Ignat'ev (1965) fed male and female rats 0, 40, or
80 mg/kg-day for 3, 8, or 18 months. There were no apparent effects on body weight gain,
viability, or gross appearance or histopathology of "parenchymatous" organs after treatment with
80 mg/kg-day for 18 months.
Shtenberg and Ignat'ev (1970) gave 40 mg/kg-day ofbenzoic acid to male and female
white mice (25/sex) for 17 months. The benzoic acid was administered daily as a paste before
the main feeding. A control group of unspecified size was included in the study. Although data
for body weight, food consumption, clinical signs, survival, organ weight, and response to
stressors were collected, only the results for stress response at 17 months were reported. Animals
treated with benzoic acid showed increased mortality (50.0% vs. 12.5%) and weight loss (26.0%
vs. 17.8%>) relative to control mice when subjected to a 5-day fast period during which benzoic
acid treatment was continued by gavage. Mice treated with benzoic acid required 2.7 days to
regain lost weight compared to 1.6 days for control mice when feeding was resumed.
Ohno et al. (1978) fed Sprague-Dawley rats (20/sex/dose) a diet containing 0.5%) or 2%
benzoic acid for one year. No effect of treatment was observed at 0.5%. A slight reduction of
growth was noted at the 2% level.
Limited information is available on the carcinogenicity ofbenzoic acid or sodium
benzoate in animals. Toth (1984) exposed albino Swiss mice (50/sex/dose, 99/sex/control) to 0
or 2% sodium benzoate in drinking water from 39 days of age throughout their lifetime. The
estimated daily dose was approximately 5920 to 6200 mg/kg-day. No effects were observed on
survival or tumor incidence. Sodemoto and Enomoto (1980) fed sodium benzoate to male and
female F344 rats (50 male and 52 female rats/sex/dose, 25 male and 43 female rats/sex/control)
at levels of 0, 1, or 2% in the diet for 18-24 months. The estimated doses of sodium benzoate
were 0, 700, or 1400 mg/kg-day in males and 0, 290, or 580 mg/kg-day in females. Survival was
poor in all dose groups as a result of sialodacryoadenitis and mycoplasma infections. No
treatment-related adverse clinical signs were observed and only negligible differences in
mortality and body weight occurred in exposed and control animals. No compound-related
changes in tumor incidence were identified. Shtenberg and Ignat'ev (1970) reported an increased
incidence of malignant tumors in mice administered 40 mg/kg-day, but the results of the study
were inadequately documented.
Few data are available on the reproductive toxicity ofbenzoic acid or sodium benzoate.
No adverse effects on fertility or lactation were observed in Bayer-Elberfeld rats in a four-
generation study where benzoic acid was administered in the diet at concentrations up to 1%
(Kieckebusch and Lang, 1960). No adverse effects on the testes were observed in albino rats
treated with benzoic acid for 4 weeks at doses up to 647 mg/kg-day via the diet (Bio-Fax, 1973)
11

-------
3-29-2005
or in albino Swiss mice after lifetime exposure to 6200 mg/kg-day doses of sodium benzoate via
the drinking water (Toth, 1984).
The developmental toxicity of benzoic acid or sodium benzoate has been evaluated in
several studies. Pregnant rats given a single 510 mg/kg gavage dose of benzoic acid on gestation
day 9 showed no indication of an increase in resorption rates or malformations (Kimmel et al.,
1971). In a series of tests conducted by U.S. FDA, no effects were observed in dams or offspring
of rats, mice, rabbits, or hamsters given gavage doses of up to 175-300 mg/kg-day (high dose
differed by species) during gestation (FDRL, 1972). CIR (2001) cited data from developmental
studies conducted in golden hamsters and Wistar rats by the Polish Academy of Sciences (1977).
Survival of pregnant golden hamsters was reported to be unaffected by gavage doses of benzoic
acid of up to 600 mg/kg-day given on gestation days 6 to 10. The incidence of resorptions in this
study was significantly (p< 0.05) increased at doses of 30 mg/kg-day and above and the number
of malformations was significantly increased at 600 mg/kg-day. In a study of pregnant Wistar
rats conducted by the same group, no effect on survival was seen at benzoic acid doses of up to
500 mg/kg-day when given by gavage on gestation days 6 to 15 (Polish Academy of Sciences,
1977). The incidence of resorptions was significantly (p< 0.05) increased at doses of 25 mg/kg-
day and above. In a dietary study, severe maternal toxicity (including loss of body weight, failure
to gain weight, and increased mortality) was observed in rats provided with feed containing 4%
or 8% sodium benzoate (Onodera et al., 1978). The estimated doses at these concentrations were
1875 and 965 mg/kg-day, respectively. Embryo- and fetotoxic effects and malformations
observed in the offspring may have been secondary to maternal malnutrition resulting from
decreased food intake. WHO (2000) identified a NOAEL of approximately 1310 mg/kg-day for
this study.
Other Data
Benzoic acid has tested negative for reverse mutation in Salmonella typhimurium strains
TA 92, TA94, TA 97, TA98, TA 100, TA1535, TA1537, and TA1538 (Litton Bionetics, 1974;
McCann et al., 1975; Ishidate et al., 1984; and Zeiger et al., 1988). Negative results were
obtained for a DNA damage test in S. typhimurium strain TA1535/pSK 1002 (Nakamura et al.,
1987). Positive results have been reported for a recombination assay in Bacillus subtilis, but no
information on the test conditions was provided (Nonaka, 1989). Benzoic acid was negative for
sister chromatid exchange (SCE) in transformed human lymphoblastoid cells (Tohda et al.,
1980), human lymphocytes (Jansson et al., 1988), and Chinese hamster ovary (CHO) cells
(Oikawa et al., 1980). Equivocal results were obtained for chromosome aberration in Chinese
hamster lung (CHL) cells (Ishidate et al., 1984). No in vivo studies of benzoic acid genotoxicity
were identified in the literature examined.
Sodium benzoate has tested negative for reverse mutation in S. typhimurium strains TA
92, TA94, TA98, TA 100, TA1535, TA1537, and TA1538 ( Ishidate et al., 1984; Prival et al.,
12

-------
3-29-2005
1991) and Escherichia coli WP2 (Prival et al, 1991). Positive (Nonaka, 1989) or weakly
positive (Ishizaki and Ueno, 1989) results have been reported for a recombination assay in
Bacillus subtilis. Negative results were obtained in a cytogenetic assay performed in WI-38 cells
(Litton Bionetics, 1974). Positive results were obtained for chromosome aberrations in CHL
(Ishidate et al., 1984, 1988; Ishidate and Odashima, 1977) and Chinese hamster DON cells (Abe
and Sasaki, 1977). A weakly positive response without dosage effect was obtained for SCE in
Chinese hamster DON cells (Abe and Sasaki, 1977). Sodium benzoate gave a positive response
for SCE in human lymphocytes (Xing and Zhang, 1990). Negative results were obtained in an in
vivo bone marrow cytogenetic assay and a host-mediated assay in mice (Litton Bionetics, 1974).
Positive results were obtained in a dominant lethal assay conducted in rats (Litton Bionetics,
1974).
Information on the absorption, distribution, metabolism, and excretion of benzoic acid
following oral exposure have been reviewed by WHO (2000). No toxicokinetic data were
located for the inhalation route. Rapid absorption occurs after oral ingestion; excretion data
suggest that 100% absorption can be assumed for humans. After uptake, benzoic acid is
metabolized in the liver by conjugation with glycine, resulting in the formation of hippuric acid.
The rate of biotransformation to hippuric acid in humans is high and is independent of dose for
oral doses of 40 mg/kg or higher. The hippuric acid formed by biotransformation of benzoic acid
is rapidly excreted in the urine. In humans, 75-100% of applied oral doses of up to 160 mg/kg
were excreted as hippuric acid within six hours of administration. The remainder of the dose was
excreted within 2-3 days. Experiments conducted in rats using 14C-labeled benzoate have shown
no evidence for accumulation in the body (WHO, 2000).
DERIVATION OF PROVISIONAL SUBCHRONIC AND CHRONIC
ORAL RfD VALUES FOR BENZOIC ACID
A chronic p-RfD of 4E+0 mg/kg-day is listed for benzoic acid on IRIS (U.S. EPA,
2003) based on human daily per capita intakes and human health experience, which precludes
derivation of a provisional chronic RfD for this chemical. The available animal data on the oral
toxicity of benzoic acid and sodium benzoate were evaluated with regard to derivation of a
provisional subchronic RfD, but were found to be of limited use for assessment of subchronic
health effects. The majority of existing studies were not conducted using current methodologies,
assessed a limited number of endpoints, and were poorly documented. The predominate health
effect identified in these studies was reduction of body weight gain. Target organ effects were
not clearly identified in any of the reviewed toxicity studies. Developmental effects were
observed in adequately documented studies only at high doses and in association with severe
maternal toxicity. None of these data were considered adequate for derivation of a provisional
13

-------
3-29-2005
subchronic RfD value. A provisional subchronic RfD of 4E+0 mg/kg-day is derived by
adopting the chronic p-RfD of 4E+0 mg/kg-day as a health protective estimate of the subchronic
RfD.
DERIVATION OF PROVISIONAL SUBCHRONIC AND CHRONIC
INHALATION RfC VALUES FOR BENZOIC ACID
No human inhalation data on benzoic acid or sodium benzoate were available for
derivation of a subchronic inhalation p-RfC. The database for inhalation toxicity consists of a
single four week exposure study of benzoic acid conducted in rats (IRDC, 1981). To calculate
the provisional subchronic RfC, the LOAEL of 25 mg/m3 in rats identified in this study is first
adjusted for intermittent exposure as follows (U.S. EPA, 1994b):
LOAELadj	= (LOAELr vi ) (hours/24 hours) (days/7 days)
= (25 mg/m3) (6 hours/24 hours) (5 days/7 days)
= 4.46 mg/m3
For pulmonary effects caused by benzoic acid dust aerosol, the LOAELm< (human equivalent
concentration) is calculated as follows (U.S. EPA, 1994b):
LOAELjjgc = (LOAELAI)J) (RDDRp)
where:
L0AELAI)I = LOAEL adjusted for intermittent exposure
RDDRp = Regional Deposited Ratio, rat/human for pulmonary effects
In the IRDC (1981) study, the mean EAD at 25 mg/m3 was 4.7 |im with a geometric
standard deviation (og) of 3.1. Using version 2.3 of the RDDR program, an RDDRP of 0.419 for
pulmonary effects was calculated from the EAD and the og reported by IRDC (1981), the average
body weight estimated from reported data (300 g), and the default values for the other rat and
human parameters. The human equivalent LOAEL is calculated as follows:
LOAELfjgc = (4.46 mg/m3) (0.419) = 1.9 mg/m3
The following uncertainty factors were applied to the LOAELhec: 3 for extrapolation to
humans using dosimetric adjustments, 3 for use of a subacute study, 3 for use of a conservative
LOAEL (minimal compound-related effects observed at LOAEL concentration), 10 to protect
sensitive individuals (reactions to benzoate and structurally-related compound have been
documented), and 3 for lack of developmental and reproductive data by the inhalation route (no
14

-------
3-29-2005
studies are available). The total uncertainty factor was 1000. A provisional subchronic RfC of
2E-3 mg/m3 for benzoic acid was derived as follows:
subchronic p-RfC = LOAELm < ^ (UF)
= 1.9 mg/m3 -^(1000)
= 0.002 or 2E-3 mg/m3
Confidence in the principal study is low. The study was GLP-compliant and appropriate
endpoints were evaluated in an adequate number of animals, but the duration of exposure was
short (28 days). Perfusion of the lungs and use of a collagen-specific stain to facilitate evaluation
of pulmonary fibrosis were not reported. High control incidences for interstitial inflammatory
cell infiltrate (9/10, males; 10/10 females) were observed, but possible causes were not
addressed. Comparison of data reported for individual animals with lesion incidences reported in
the summary tables of the study report revealed several discrepancies, suggesting possible quality
assurance issues in spite of GLP-compliance. Confidence in the database is low because there
are no subchronic, chronic, developmental, or reproductive toxicity studies by the inhalation
route of exposure. Low confidence in the subchronic p-RfC follows.
No human inhalation data or longer-term animal inhalation data on benzoic acid or
sodium benzoate were available for derivation of a provisional chronic inhalation RfC. The four-
week inhalation exposure study of benzoic acid conducted in rats was considered inadequate for
derivation of a chronic p-RfC for benzoic acid because of the short (less than subchronic)
duration of exposure. In the absence of suitable inhalation data, a provisional chronic RfC
cannot be derived.
DERIVATION OF A PROVISIONAL CARCINOGENICITY ASSESSMENT
FOR BENZOIC ACID
Human data on the carcinogenic effects of benzoic acid or sodium benzoate are not
available. The carcinogenicity of sodium benzoate has been evaluated in three oral exposure
studies conducted in rats or mice (Shtenburg and Ignat'ev,1970; Sodemoto and Enomoto, 1980;
Toth, 1984). These studies are insufficient for quantification of carcinogenic effects because they
either used too few doses, were poorly documented and were compromised by low survival of
the test animals, or did not observe a compound-related tumor response. Therefore, quantitative
cancer assessments cannot be performed for the oral or inhalation exposure routes.
The available in vitro assays indicate low genotoxic potential for benzoic acid. No in
vivo genotoxicity data for benzoic acid were identified. Genotoxicity assays of sodium benzoate
have yielded mixed results. Negative results were obtained for mutagenicity in bacteria, a host-
mediated assay in mice, and an in vivo bone marrow cytogenetic assay in mice, while positive or
15

-------
3-29-2005
weakly positive results were obtained for chromosome aberrations and SCE in cultured
mammalian cells and for a dominant lethal assay in rats. Under the proposed guidelines (U.S.
EPA, 1999), the data for carcinogenicity of benzoic acid are inadequate for an assessment of
human carcinogenic potential.
Derivation of quantitative estimates of cancer risk for benzoic acid is precluded by the
absence of reliable carcinogenicity data for this chemical.
REFERENCES
Abe, S. and M. Sasaki. 1977. Chromosome aberrations and sister chromatid exchanges in
Chinese hamster cells exposed to various chemicals. J. Natl. Cancer Inst. 58(6): 1635-1641.
ACGIH (American Conference of Governmental Industrial Hygienists). 2001. 2001 Threshold
Limit Values for Chemical Substances and Physical Agents and Biological Exposure Indices.
ACGIH, Cincinnati, OH.
ATSDR (Agency for Toxic Substances and Disease Registry). 2002. Internet HazDat-
Toxicological Profile Query. Online, http://www.atsdr.cdc.gov/toxpro2.html
Bio-Fax. 1973. Benzoic Acid. Northbrook, IL. Industrial Bio-Test Laboratories, Inc. (Cited in
WHO, 2000)
Chittenden, R.H., J.H. Long and C.A. Herter. 1909. Chemical Bulletin, 88. U.S. Department of
Agriculture. (Cited in WHO, 2000)
CIR (Cosmetic Industry Review). 2001. Final report on the safety assessment of benzyl alcohol,
benzoic acid, and sodium benzoate. Int. J. Toxicol. 20(Suppl.): 23-50.
Deuel, J.H., Jr., R. Alfin-Slater, C.S. Weil and H.F. Smyth, Jr. 1954. Sorbic acid as a fungistatic
agent for foods. I. Harmlessness of sorbic acid as a dietary component. Food Res. 19: 1-12.
(Cited in Informatics, Inc., 1972; U.S. EPA, 1987a)
ECSCF (European Commission Scientific Committee on Foods). 2002. Opinion of the
Scientific Committee on Food on Benzoic Acid and its Salts. Document No.
SCF/CS/ADD/CONS/48/Final. September 17, 2002.
FDRL (Food and Drug Research Labs., Inc.). 1972. Teratologic Evaluation of FDA 71-37
(Sodium Benzoate). p. 75-79. (Cited in U.S. EPA, 1987a; CIR, 2001)
16

-------
3-29-2005
Gerlach, V. 1909. VII. Summary of the results. In: Physiological activity of benzoic acid and
sodium benzoate, Verlag von Heinrich Stadt, V. Gerlach Ed., p. 90-92. (Cited in Informatics,
Inc., 1972)
Griffith, W.H. 1929. Growth of rats on diets containing sodium benzoate. Proc. Soc. Exp. Biol.
Med. 26:354-355. (Cited in U.S. EPA, 1987a)
Harshbarger, H.E. 1942. Report of a study on the toxicity of several food preserving agents. J.
Dairy Sci. 25: 169-174. (Cited in U.S. EPA, 1987a)
Fanelli, G.M. and S.L. Halliday. 1963. Relative toxicity of chlortetracycline and sodium
benzoate after oral administration to rats. Arch. Int. Pharmacodyn. 144:120-125. (Cited in U.S.
EPA, 1987a)
IARC (International Agency for Research on Cancer). 2002. Search IARC Monographs.
Online. http://193.51.164.ll/cgi/iHound/Chem/iH Chem Frames.html
Informatics, Inc. 1972. GRAS (Generally Recognized as Safe) Food Ingredients: Benzoic Acid
and Sodium Benzoate. Prepared for U.S. Food and Drug Administration. PB 221 208.
Ignat'ev, A.G. 1965. Experimental information contributing to a hygienic characterization of
the combined effect produced by some food presentations. Vop. Pitan. 24(3): 61-68. (Cited in
Informatics, Inc., 1972; U.S. EPA, 1987a)
IRDC (International Research and Development Corporation). 1981. 4-week subacute
inhalation toxicity study of benzoic acid in rats with amendment. FYI Submission by Velsicol
Chemical Corporation to Office of Toxic Substances, U.S. Environmental Protection Agency,
Washington DC. FYI-OTS-1281-0147.
Ishidate, M.J., T. Sofuni, K. Yoshikawa et al. 1984. Primary mutagenicity screening of food
additives currently used in Japan. Food Chem. Toxicol. 22:623-636.
Ishidate, M.J., M.C. Harnois and T. Sofuni. 1988. A comparative analysis of data on the
clastogenicity of 951 chemical substances tested in mammalian cell cultures. Mutat. Res. 48:
337-354.
Ishidate, M. and S. Odashima. 1977. Chromosome tests with 134 compounds on Chinese
hamster cells in vitro - a screening for chemical carcinogenesis. Mutat. Res. 48: 337-354.
Ishizaki, M. and E. Ueno. 1989. The DNA damaging activity of natural and synthetic food
additives. Shokuhin Eiseigaku Zasshi. 30:447-451. (Cited in WHO, 2000)
17

-------
3-29-2005
Jansson, T., M. Curvall, A. Hedin et al. 1988. In vitro studies of the biological effects of
cigarette smoke condensate. HI. Induction of SCE by some phenolic and related constituents
derived from cigarette smoke. Mutat. Res. 206:17-24. (Cited in WHO, 2000)
Kieckebusch, W. and K. Lang. 1960. Tolerance of benzoic acid in chronic feeding.
Arzneimittel-Forsch. 10:1001-1003. (Cited in Informatics, Inc., 1972)
Kimmel, C.A., J.G. Wilson, and H.J. Schumacher. 1971. Studies on metabolism and
identification of the causative agent in aspirin teratogenesis in rats. Teratology. 4:15-24. (Cited
in WHO, 2000)
Kreis, H., F. Frese and G. Wilmes. 1967. Physiologische und morphologische Veranderungen
an Ratten nach peroralen Verabreichung von Benzoesaure. Food Cosmet. Toxicol. 5: 505-511.
(Cited in WHO, 2000)
Litton Bionetics, Inc. 1974. Mutagenic Evaluation of Compound FDA 71-37, Sodium Benzoate.
Report No. LBI2446-297; FDABF-GRAS-297, U.S. Food and Drug Administration,
Washington, DC. PB-245-453/6.
Marquardt, P. 1960. Tolerance of benzoic acid. Arzneimittel-Forsch. 10:1033. (Cited in
Informatics, Inc., 1972; U.S. EPA, 1987a)
McCann, J., E. Choi, E. Yamasaki et al. 1975. Detection of carcinogens as mutagens in the
Salmonella microsome test: assay of 300 chemicals. Proc. Natl. Acad. Sci. U.S.A. 72(12):
5135-5139. (Cited in WHO, 2000)
Nakamura, S.I., Y. Oda, T. Shimada et al. 1987. SOS-inducing activity of chemical carcinogens
and mutagens in Salmonella typhimurium TA1535/pSK1002: examination with 121 chemicals.
Mutat. Res. 192:239-246. (Cited in WHO, 2000)
NIOSH (National Institute for Occupational Safety and Health). 2002. Online NIOSH Pocket
Guide to Chemical Hazards. Index by CASRN. Online.
http ://www. cdc. go v/niosh/npg/npgdcas .html
Nonaka, M. 1989. DNA repair tests on food additives. Environ. Mol. Mutat. 14(Suppl. 15):
143. (Cited in WHO, 2000)
NTP (National Toxicology Program). 2002. Management Status Report. Online.
http://ntp-server.niehs.nih.gov/cgi/iH Indexes/ALL SRCH/iH ALL SRCH Frames.html
18

-------
3-29-2005
Ohno, Y., S. Sekigawa, K. Nakamori et al. 1978. Additive toxicity test of sorbic acid and
benzoic acid in rats. J. Nara. Med. Assoc. 29: 695-708. (Cited in CIR, 2001)
Oikawa, A., H. Tohda, M. Kanai et al. 1980. Inhibitors of poly(adenosine diphosphate ribose)
induced sister chromatid exchange. Biochem. Biophys. Res. Commun. 97(4): 1311-1316.
(Cited in WHO, 2000)
Onodera, H., T. Ogiu, C. Matsuoka et al. 1978. Studies on the effects of sodium benzoate on
fetuses and offspring of Wistar rats. Eisei Shikensho Hokoku. 96:47-55. (Japanese; Cited in
WHO, 2000)
OSHA (Occupational Safety and Health Administration). 2002. 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
Polish Academy of Sciences. 1977. Teratologic examination of benzoic acid in rats.
Teratologic examination of benzoic acid in hamsters. Project # 05-611-4. Submitted by the
FDA to the Cosmetic Ingredient Review in response to a 1995 FOI request. (Cited in CIR, 2001)
Prival, M.J., V.F. Simmon, K.E. Mortelmans. 1991. Bacterial mutagenicity testing of 49 food
ingredients gives very few positive results. Mutat. Res. 260:321-329. (Cited in WHO, 2000)
Shtenberg, A.J. and A.D. Ignat'ev. 1970. Toxicological evaluations of some combinations of
food preservatives. Food Cosmet. Toxicol. 8(4): 369-380. (Cited in Informatics, Inc., 1972;
U.S. EPA, 1987a)
Smyth, H.F., Jr. and C.P. Carpenter. 1948. Further experience with the range finding test in the
industrial toxicology laboratory. J. Ind. Hyg. Toxicol. 30: 63-68. (Cited in U.S. EPA, 1987a)
Sodemoto, Y. and M. Enomoto. 1980. Report of carcinogenesis bioassay of sodium benzoate in
rats: absence of carcinogenicity of sodium benzoate in rats. J. Environ. Pathol. Toxicol. 4: 87-
95. (Cited in WHO, 2000)
Tohda, H., K. Horaguchi, K. Takahashi et al. 1980. Epstein-Barr virus-transformed human
lymphoblastoid cells for study of sister chromatid exchange and their evaluation as a test system.
Cancer Res. 40:4775-4780.
Toth, B. 1984. Lack of tumorigenicity of sodium benzoate in mice. Fund. Appl. Toxicol.
4: 94-496.
19

-------
3-29-2005
U.S. EPA. 1987a. Health and Environmental Effects Document for Benzoic Acid. Prepared by
the Office of Health and Environmental Assessment, Environmental Criteria and Assessment
Office, Cincinnati, OH for the Office of Solid Waste and Emergency Response, Washington,
DC.
U.S. EPA. 1987b. Reportable Quantity Document for Benzoic Acid. Prepared by the Office of
Health and Environmental Assessment, Environmental Criteria and Assessment Office,
Cincinnati, OH for the Office of Solid Waste and Emergency Response, Washington, DC.
U.S. EPA. 1991. Chemical Assessments and Related Activities (CARA). Office of Health and
Environmental Assessment, Washington, DC. April.
U.S. EPA. 1994a. Chemical Assessments and Related Activities (CARA). Office of Health and
Environmental Assessment, Washington, DC. December.
U.S. EPA. 1994b. Methods for Derivation of Inhalation Reference Concentrations and
Application of Inhalation Dosimetry. Office of Research and Development, Office of Health and
Environmental Assessment, Environmental Criteria and Assessment Office, Washington, DC.
October. EPA/600/8-90/066F.
U.S. EPA. 1997. Health Effects Assessment Summary Tables (HEAST). FY-1997 Update.
Prepared by the Office of Research and Development, National Center for Environmental
Assessment, Cincinnati, OH for the Office of Emergency and Remedial Response, Washington,
DC. July. NTIS# PB97-921199.
U.S. EPA. 1999. Proposed Guidelines for Cancer Risk Assessment. Risk Assessment Forum,
National Center for Environmental Assessment, Office of Research and Development,
Washington, DC. July 1999.
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. FDA (U.S. Food and Drug Administration). 1973. Evaluation of the Health Aspects of
Benzoic Acid and Sodium Benzoate as Food Ingredients. DHEW, Washington, DC. Report No.
SCOGS-7. NTIS PB-223 837/6.
20

-------
3-29-2005
White, A. 1941. Growth-inhibition produced in rats by the oral administration of sodium
benzoate: Effects of various dietary supplements. Yale J. Biol. Med. 13:759-768. (Cited in
U.S. EPA, 1987a)
WHO (World Health Organization). 1996. Toxicological evaluation of certain food additives.
Prepared by the 46th meeting of the Joint FAO/WHO Expert Committee on Food Additives
(JECFA). Geneva, World Health Organization. WHO Food Additives Series 37. Online.
http://www.inchem.org/documents/iecfa/iecmono/v37ie01 .htm
WHO (World Health Organization). 1999. Safety Evaluation of Certain Food Additives.
Evaluation of National Assessments of Intake of Benzoates. Prepared by the 51st meeting of the
Joint FAO/WHO Expert Committee on Food Additives. WHO Food Additives Series: 42.
Online, www.inchem.org/documents/iecfa/iecmono/v042ie22.htm
WHO (World Health Organization). 2000. Benzoic Acid and Sodium Benzoate. Concise
International Chemical Assessment. Document No. 26. WHO, Geneva.
Wiley, H.M. and W.D. Bigelow. 1908. Influence of benzoic acid and benzoates on digestion
and health. Bulletin 84, Part IV. Bureau of Chemistry, U.S. Department of Agriculture. (Cited
in Informatics, Inc., 1972)
Xing, W. and Z. Zhang. 1990. A comparison of SCE test in human lymphocytes and Vicia faba:
a hopeful technique using plants to detect mutagens and carcinogens. Mutat. Res. 241: 109-113.
(Cited in WHO, 2000)
Zeiger, E., B. Anderson, S. Haworth et al. 1988. Salmonella mutagenicity tests. IV. Results
from the testing of 300 chemicals. Environ. Mol. Mutagen. 1 l(Suppl.412): 1-158.
21

-------