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Benzoic acid
CASRN 65-85-0
Contents
0355
Benzoic acid; CASRN 65-85-0
Health assessment information on a chemical substance is included in IRIS only
after a comprehensive review of chronic toxicity data by U.S. EPA health
scientists from several Program Offices and the Office of Research and
Development. The summaries presented in Sections I and II represent a
consensus reached in the review process. Background information and
explanations of the methods used to derive the values given in IRIS are
provided in the Background Documents.
STATUS OF DATA FOR Benzoic acid
File On-Line 09/07/1988
Category (section) Status Last Revised
----------------------------------------- -------- ------------
Oral RfD Assessment (I.A.) on-line 07/01/1993
Inhalation RfC Assessment (I.B.) no data
Carcinogenicity Assessment (II.) on-line 05/01/1991
_I. CHRONIC HEALTH HAZARD ASSESSMENTS FOR NONCARCINOGENIC EFFECTS
__I.A. REFERENCE DOSE FOR CHRONIC ORAL EXPOSURE (RfD)
Substance Name -- Benzoic acid
CASRN -- 65-85-0
Last Revised -- 07/01/1993
The oral Reference Dose (RfD) is based on the assumption that thresholds exist
for certain toxic effects such as cellular necrosis. It is expressed in units
of mg/kg-day. In general, the RfD is an estimate (with uncertainty spanning
perhaps an order of magnitude) of a daily exposure to the human population
(including sensitive subgroups) that is likely to be without an appreciable
risk of deleterious effects during a lifetime. Please refer to the Background
Document for an elaboration of these concepts. RfDs can also be derived for
the noncarcinogenic health effects of substances that are also carcinogens.
Therefore, it is essential to refer to other sources of information concerning
the carcinogenicity of this substance. If the U.S. EPA has evaluated this
substance for potential human carcinogenicity, a summary of that evaluation
will be contained in Section II of this file.
___I.A.1. ORAL RfD SUMMARY
Critical Effect Experimental Doses* UF MF RfD
-------------------- ----------------------- ----- --- ---------
No adverse effects NOAEL: 34 mg/day 1 1 4E+0
observed benzoic acid and 328 mg/kg/day
mg/day for sodium
Human daily per benzoate (converted
capita intakes to 312 mg/day
benzoic acid)
FDA, 1973;
Selected Committee LOAEL: none
on Review of the
GRAS List
*Conversion Factors: 328 mg/day sodium benzoate x [122.12 (MW benzoic
acid)/144.11 (MW sodium benzoate)] = 278 mg/day benzoic acid. 278 mg/day
benzoic acid from sodium benzoate + 34 mg/day benzoic acid = 312 mg/day;
assuming adult human body weight of 70 kg, the exposure dose is 312 divided
by 70 = 4.4 mg/kg/day.
___I.A.2. PRINCIPAL AND SUPPORTING STUDIES (ORAL RfD)
FDA (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-223837/6.
Early studies (Gerlach, 1909) indicate that laboratory animals are
inappropriate models for studying the toxicity of benzoic acid in humans
(FDRL, 1972) (see Additional Comments). Based on data regarding the amounts
of benzoic acid and sodium benzoate produced as a food preservative, FDA
(1973) estimated a daily per capita intake of 0.9-34 mg for benzoic acid and
34-328 mg for sodium benzoate. At these levels, there are no reports of toxic
effects in humans. These compounds have Generally Recognized as Safe (GRAS)
status by FDA. Therefore, the upper ranges can be considered NOAELs for
benzoic acid and sodium benzoate. In the stomach, both benzoic acid and
sodium benzoate exist in their ionized form, benzoate, which is absorbed
rapidly and completely by the GI tract. Therefore, exposure to sodium
benzoate is comparable to exposure to benzoic acid if molecular weight
differences are corrected for; here, 328 mg sodium benzoate is equivalent to
278 mg benzoic acid. Adding 278 to the daily intake for benzoic acid of 34 mg
yields a total of 312 mg benzoic acid (see Conversion Factors). If no
uncertainty factor is used, the RfD is 312 mg/day for a 70 kg human or 4
mg/kg/day.
___I.A.3. UNCERTAINTY AND MODIFYING FACTORS (ORAL RfD)
UF -- An uncertainty factor of 10 for the protection of sensitive subgroups
was considered unnecessary; although reactions to benzoate and structurally
related compounds do occur, an uncertainty factor of 10 would be of little
value to the sensitive individuals.
MF -- None
___I.A.4. ADDITIONAL COMMENTS (ORAL RfD)
Sodium benzoate appeared to have no maternal toxicity, fetal toxicity, or
teratogenicity in mice, rats, hamsters, or rabbits when given orally (FDRL,
1972). The highest doses tested were 175.0 in mice and rats, 300.0 in
hamsters, and 250.0 mg/kg/day in rabbits.
The only chronic oral data available involve administration of benzoic acid to
rats and mice (Shtenberg and Ignat'ev, 1970; Ignat'ev, 1965; Marquardt, 1960).
A dose of 40 mg/kg/day for 17 months was associated with decreased resistance
to stress in mice and possibly with reduced food and water intake in rats
after 18 months (Shtenberg and Ignat'ev, 1970). However, another report from
this laboratory (Ignat'ev, 1965) indicated that 80 mg/kg/day in rats for 18
months was not associated with adverse effects on body weight, survival, or
gross or microscopic pathology. If 40 mg/kg/day in mice in the study by
Shtenberg and Ignat'ev (1970) is considered to be the LOAEL, application of an
uncertainty factor of 1000 would result in an RfD of 0.04 mg/kg/day or 2.8
mg/day, which is near the lower end of the range of the estimated daily human
exposure to benzoic acid (not including exposure to sodium benzoate). The
lower RfD based on animal data is not unexpected, however, since application
of uncertainty factors is intentionally conservative in the absence of human
data. Since human data are available in this case, it is not appropriate to
use the animal data for the RfD.
Other long-term dietary studies (Marquardt, 1960) showed decreased food intake
and body weight in rats fed 1.5% benzoic acid (750 mg/kg/day); at a dose of
1.0% in the diet (50 mg/kg/day) there were no signs of toxicity or adverse
reproductive effects.
Gerlach (1909) reported no externally visible effects in humans ingesting
benzoic acid at 0.5-1.0 g/day for 44 consecutive days or for 82/86 or 88/92
days. Assuming a human body weight of 70 kg, this level corresponds to a dose
of 14 mg/kg/day. Wiley and Bigelow (1908), however, observed irritation,
discomfort, weakness, and malaise in humans given oral bolus doses of less
than or equal to 1.75 g/day over a 20-day period (25 mg/kg/day). The RfD (4
mg/kg/day) is well below these doses.
___I.A.5. CONFIDENCE IN THE ORAL RfD
Study -- Medium
Data Base -- Medium
RfD -- Medium
Medium confidence is placed in the FDA (1973) estimate of per capita intake.
Medium confidence in the data base reflects the inappropriateness of using
animal data as the basis of the RfD for humans and the lack of reported
effects in humans at the estimated intakes. Thus, confidence in the RfD is
medium.
___I.A.6. EPA DOCUMENTATION AND REVIEW OF THE ORAL RfD
Source Document -- U.S. EPA, 1987
Limited peer review and extensive Agency-wide review 1987.
Other EPA Documentation -- None
Agency Work Group Review -- 09/17/1987
Verification Date -- 09/17/1987
___I.A.7. EPA CONTACTS (ORAL RfD)
Please contact the Risk Information Hotline for all questions concerning this
assessment or IRIS, in general, at (513)569-7254 (phone), (513)569-7159 (FAX)
or RIH.IRIS@EPAMAIL.EPA.GOV (internet address).
__I.B. REFERENCE CONCENTRATION FOR CHRONIC INHALATION EXPOSURE (RfC)
Substance Name -- Benzoic acid
CASRN -- 65-85-0
Not available at this time.
_II. CARCINOGENICITY ASSESSMENT FOR LIFETIME EXPOSURE
Substance Name -- Benzoic acid
CASRN -- 65-85-0
Last Revised -- 05/01/1991
Section II provides information on three aspects of the carcinogenic
assessment for the substance in question; the weight-of-evidence judgment of
the likelihood that the substance is a human carcinogen, and quantitative
estimates of risk from oral exposure and from inhalation exposure. The
quantitative risk estimates are presented in three ways. The slope factor is
the result of application of a low-dose extrapolation procedure and is
presented as the risk per (mg/kg)/day. The unit risk is the quantitative
estimate in terms of either risk per ug/L drinking water or risk per ug/cu.m
air breathed. The third form in which risk is presented is a drinking water
or air concentration providing cancer risks of 1 in 10,000, 1 in 100,000 or 1
in 1,000,000. The rationale and methods used to develop the carcinogenicity
information in IRIS are described in The Risk Assessment Guidelines of 1986
(EPA/600/8-87/045) and in the IRIS Background Document. IRIS summaries
developed since the publication of EPA's more recent Proposed Guidelines for
Carcinogen Risk Assessment also utilize those Guidelines where indicated
(Federal Register 61(79):17960-18011, April 23, 1996). Users are referred to
Section I of this IRIS file for information on long-term toxic effects other
than carcinogenicity.
__II.A. EVIDENCE FOR CLASSIFICATION AS TO HUMAN CARCINOGENICITY
___II.A.1. WEIGHT-OF-EVIDENCE CLASSIFICATION
Classification -- D; not classifiable as to human carcinogenicity
Basis -- No human data and inadequate data from animal bioassays.
___II.A.2. HUMAN CARCINOGENICITY DATA
None.
___II.A.3. ANIMAL CARCINOGENICITY DATA
Inadequate. In a lifetime study, Toth (1984) administered sodium benzoate
(of 99% purity) to 50 male and 50 female 5 week-old albino Swiss mice at a
level of 2% in the drinking water. Control groups consisted of 100 mice/sex.
The dose level was selected based on results of a subchronic study in which
levels of 4 and 8% were considered to be too toxic. The 2% level was
equivalent to sodium benzoate doses of 4133 mg/kg/day for males and 3973
mg/kg/day for females. Based on average measured daily water consumptions of
6.2 mL for males and 5.9 mL for females and an assumed average body weight of
0.03 kg. The equivalent benzoic acid doses, adjusted for moleculer weight
differences between sodium benzoate and benzoic acid, are 3502 mg/kg/day and
3367 mg/kg/day for males and females, respectively. Histopathologic
examinations of all mice included 11 organs and all gross lesions. The
treatment had no apparent effect on survival or tumor incidence.
As part of a 5-generation reproduction study, Shtenberg and Ignat'ev
(1970) administered test compounds in a paste in daily doses of 40 mg/kg
benzoic acid combined with 80 mg/kg sodium bisulfite in a paste before feeding
an otherwise unspecified basic diet to a group of 50 white cross-bred mice/sex
for 17 months. Another group received benzoic acid only; no further details
were given. An unspecified number of control animals received only basic
diet. Malignant tumors (not otherwise specified) occurred in 8/100 treated
mice and 1/8 mice in the third generation of the treated group. Tumor
incidences were not reported for untreated mice.
___II.A.4. SUPPORTING DATA FOR CARCINOGENICITY
Dinerman and Ignat'ev (1966) reported that a 3-month exposure to 0.2%
benzoic acid in the diet increased the susceptibility of mice to the
development of carcinomas following intraperitoneal inoculation with Erlich
ascites carcinoma cells. Tumors developed in 62/90 (68.8%) of benzoic acid-
treated mice and in 16/49 (32.6%) of the control mice.
Benzoic acid and sodium benzoate have been tested for mutagenicity or
genotoxicity in prokaryotes (McCann et al., 1975), eukaryotes (Litton
Bionetics, Inc., 1974), and several mammalian test systems (Litton Bionetics,
Inc., 1974, 1975; Oikawa et al., 1980). No positive results have been
reported.
__II.B. QUANTITATIVE ESTIMATE OF CARCINOGENIC RISK FROM ORAL EXPOSURE
Not available.
__II.C. QUANTITATIVE ESTIMATE OF CARCINOGENIC RISK FROM INHALATION EXPOSURE
Not available.
__II.D. EPA DOCUMENTATION, REVIEW, AND CONTACTS (CARCINOGENICITY ASSESSMENT)
___II.D.1. EPA DOCUMENTATION
Source Document -- U.S. EPA, 1987
The 1987 Health and Environmental Effects Document has received OHEA review.
___II.D.2. REVIEW (CARCINOGENICITY ASSESSMENT)
Agency Work Group Review -- 03/01/1989
Verification Date -- 03/01/1989
___II.D.3. U.S. EPA CONTACTS (CARCINOGENICITY ASSESSMENT)
Please contact the Risk Information Hotline for all questions concerning this
assessment or IRIS, in general, at (513)569-7254 (phone), (513)569-7159 (FAX)
or RIH.IRIS@EPAMAIL.EPA.GOV (internet address).
_VI. BIBLIOGRAPHY
Substance Name -- Benzoic acid
CASRN -- 65-85-0
Last Revised -- 08/01/1989
__VI.A. ORAL RfD REFERENCES
FDA (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.
FDRL (Food and Drug Research Labs., Inc.). 1972. Teratologic Evaluation of
FDA 71-37 (Sodium Benzoate). p.\75-79.
Gerlach, V. 1909. VII. Summary of the results. In: Physiological Activity
of Benzoic Acid and Sodium Benzoate, V. Gerlach, Ed. Verlag von Heinrich
Staadt, Wiesbaden. p.\90-92. (Cited in Informatics, Inc., 1972)
Ignat'ev, A.D. 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)
Informatics, Inc. 1972. GRAS (Generally Recognized as Safe) Food
Ingredients: Benzoic Acid and Sodium Benzoate. p. 75-79.
Shtenberg, A.J. and A.D. Ignat'ev. 1970. Toxicological evaluation of some
combinations of food preservatives. Food Cosmet. Toxicol. 8(4): 369-380.
U.S. EPA. 1987. 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.
Wiley, H.M. and W.D. Bigelow. 1908. Influence of benzoic acid and benzo-
ates on digestion and health. Bulletin 84, pt. IV, Bureau of Chemistry,
U.S. Dept. Agriculture. (Cited in Informatics, Inc., 1972)
__VI.B. INHALATION RfD REFERENCES
None
__VI.C. CARCINOGENICITY ASSESSMENT REFERENCES
Dinerman, A.A and A.D. Ignat'ev. 1966. Effect of certain food preservatives
on the development of tumors in mice. Gig. Sanit. 31(9): 38-42. (Eng.
trans.)
Litton Bionetics, Inc. 1974. Mutagenic Evaluation of Compound FDA 71-37,
Sodium Benzoate. Report No. LBI 2446-297, FDA, Washington, DC, PB-245-453/6.
Litton Bionetics, Inc. 1975. Mutagenic Evaluation of Compound FDA 73-70,
Benzoic Acid Certified A.C.S. Report No. LBI-2468-376; FDABF-GRAS-376 PB-245-
500/4.
McCann, J., E. Choi, E. Yamasaki and B.N. Ames. 1975. Detection of
carcinogens as mutagens in the Salmonella/microsome test: Assay of 300
chemicals. Proc. Natl. Acad. Sci. 72: 5135-5139.
Oikawa, A., H. Tohda, M. Kanai, M. Miwa and T. Sugimura. 1980. Inhibitors of
poly(adenosine diphosphate ribose) induced sister chromatid exchanges.
Biochem. Biophys. Res. Commun. 97(4): 1311-1316.
Shtenberg, A.J. and A.D. Ignat'ev. 1970. Toxicological evaluation of some
combinations of food preservatives. Food Cosmet. Toxicol. 8(4): 369-380.
Toth, B. 1984. Lack of tumorigenicity of sodium benzoate in mice. Fund.
Appl. Toxicol. 4(3): 494-496.
U.S. EPA. 1987. 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.
_VII. REVISION HISTORY
Substance Name -- Benzoic acid
CASRN -- 65-85-0
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Date Section Description
-------- -------- --------------------------------------------------------
09/07/1988 I.A. Oral RfD summary on-line
05/01/1989 II. Carcinogen assessment now under review
07/01/1989 I.A. Principal study clarified
07/01/1989 VI. Bibliography on-line
08/01/1989 II. Carcinogen summary on-line
08/01/1989 VI.C. Carcinogen references added
01/01/1991 I.A. Text edited
01/01/1991 II. Text edited
05/01/1991 II.A.3. Text edited
06/01/1991 I.A.1. Conversion Factor text clarified
01/01/1992 I.A.7. Secondary contact changed
01/01/1992 IV. Regulatory Action section on-line
07/01/1993 I.A.6. Source Doc. year corrected; Other EPA Doc. clarified
VIII. SYNONYMS
Substance Name -- Benzoic acid
CASRN -- 65-85-0
Last Revised -- 09/07/1988
65-85-0
benzenecarboxylic acid
Benzoic acid
carboxybenzene
dracylic acid
phenyl carboxylic acid
phenylformic acid
Last updated: 5 May 1998
URL: http://www.epa.gov/iris/SUBST/0355.HTM
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