Testing Information

Testing Status of Agents at NTP

CAS Registry Number: 65-85-0 Toxicity Effects

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Selected toxicity information from HSDB, one of the National Library of Medicine's databases. 1

Names (NTP)

  • Benzoic acid
  • BENZENECARBOXYLIC ACID

Human Toxicity Excerpts

  • HUMAN EXPOSURE STUDIES: Of 100 patients with asthma undergoing provocation tests with benzoic acid, 47 showed positive reactions. [Reynolds, J.E.F., Prasad, A.B. (eds.) Martindale-The Extra Pharmacopoeia. 28th ed. London: The Pharmaceutical Press, 1982., p. 1283]**PEER REVIEWED**
  • HUMAN EXPOSURE STUDIES: Daily intake of 4 to 6 g does not cause toxic symptoms aside from slight gastric irritation. Larger doses have systemic effects not unlike those of salicylates. [Gilman, A.G., L.S.Goodman, and A. Gilman. (eds.). Goodman and Gilman's The Pharmacological Basis of Therapeutics. 7th ed. New York: Macmillan Publishing Co., Inc., 1985., p. 961]**PEER REVIEWED**
  • HUMAN EXPOSURE STUDIES: Chamber-Scarification-Test threshold irritating concentration: 1) normal skin: 30% in ethanol 2) scarified skin: 7.5 % in ethanol: moderate irritations; application of 15% in ethanol leads to marked irritation with erosions [European Chemicals Bureau; IUCLID Dataset, Benzoic acid (65-85-0) (2000 CD-ROM edition). Available from the database query page: http://ecb.jrc.it/esis/esis.php?PGM=ein&DEPUIS=autre as of March 22, 2005. ]**PEER REVIEWED**
  • HUMAN EXPOSURE STUDIES: 16 mM benzoic acid (in petrolatum) produced an erythematous reaction in 12 of 13 healthy volunteers on the cheek and in 6 subjects on the forehead, neck and upper back. 8 mM and 4 mM benzoic acid produced only a reaction on cheek. [European Chemicals Bureau; IUCLID Dataset, Benzoic acid (65-85-0) (2000 CD-ROM edition). Available from the database query page: http://ecb.jrc.it/esis/esis.php?PGM=ein&DEPUIS=autre as of March 22, 2005. ]**PEER REVIEWED**
  • HUMAN EXPOSURE STUDIES: Administration of 0.5 to 1.0 g/day (approximately 14 mg/kg BW) for 44 consecutive days or for 3 months produced no evident signs of toxicity in humans. ... Irritation, discomfort, weakness, and malaise were observed in individuals given oral bolus doses of less than or equal to 1.75 g/day (approximately, 25 mg/kg BW) over a 20 day period. [Sheftel, V.O.; Indirect Food Additives and Polymers. Migration and Toxicology. Lewis Publishers, Boca Raton, FL. 2000., p. 448]**PEER REVIEWED**
  • HUMAN EXPOSURE STUDIES: Benzoic acid (5% in petrolatum) did not elicit an allergic reaction when applied to the skin of 10 panelists who, in a previous Kligman-maximization assay, had tested positive for benzoyl peroxide sensitivity. [Cosmetic Ingredient Review Expert Panel; International Journal of Toxicology: 20(suppl. 3): 23-50 (2001) ]**PEER REVIEWED**
  • HUMAN EXPOSURE STUDIES: /Investigators/ reported results of a cosmetic intolerance assay that patch tested 5202 patients with possible allergic contact dermatitis (537 of the patients had a history of "intolerance," allergy, or irritation to cosmetics). ...A reaction to benzoic acid was noted in 34 (0.7% incidence) /patients/. A reaction was /also/ noted in 1 of the 155 patients with cosmetic allergy. [Cosmetic Ingredient Review Expert Panel; International Journal of Toxicology: 20(suppl. 3): 23-50 (2001) ]**PEER REVIEWED**
  • HUMAN EXPOSURE STUDIES: Benzoic acid (50% aqueous isopropanol) was applied to the medial cheek of adult volunteers; a 2% solution led to wheals (11/11), a 0.04% solution lead to (11/11) and pruritus (4/11). [European Chemicals Bureau; IUCLID Dataset, Benzoic acid (65-85-0) (2000 CD-ROM edition). Available from the database query page: http://ecb.jrc.it/esis/esis.php?PGM=ein&DEPUIS=autre as of March 22, 2005. ]**PEER REVIEWED**
  • SIGNS AND SYMPTOMS: Twelve men drank apple juice containing 0.1% sodium benzoate and had the following signs and symptoms: burning taste, fullness in the head, headache, nervousness, nausea, vomiting, itching of the skin, unusual perspiration, constipation, decreased urine flow, increased specific gravity of the urine, and albuminuria. /Sodium Benzoate/ [Cosmetic Ingredient Review Expert Panel; International Journal of Toxicology: 20(suppl. 3): 23-50 (2001) ]**PEER REVIEWED**
  • SIGNS AND SYMPTOMS: In /a/ study participants initially ingested benzoic acid at 1000 mg/day for 5 days and progressed to 1500 then 2000 and finally 2500 mg/day staying at each protocol for 5 days before increasing the dose. Three of the 12 participants took the entire dose of 35 g in 20 days. This total dose produced marked symptoms of discomfort and malaise, which included nausea, headache, weakness, esophageal burning and irritation, hunger, and indigestion. [Cosmetic Ingredient Review Expert Panel; International Journal of Toxicology: 20(suppl. 3): 23-50 (2001) ]**PEER REVIEWED**
  • SIGNS AND SYMPTOMS: Cases of urticaria, asthma, rhinitis, or anaphylactic shock have been reported following oral, dermal, or inhalation exposure to benzoic acid and sodium benzoate. The symptoms appear shortly after exposure and disappear within a few hours, even at low doses. [International Programme on Chemical Safety's Concise International Chemical Assessment Documents. Number 26: Benzoic acid and Sodium Benzoate (2000). Available from http://www.inchem.org/pages/cicads.html as of March 24, 2005. ]**PEER REVIEWED**
  • CASE REPORTS: A trained chemical worker suffered from allergic reactions of increasing intensity while being constantly exposed to benzoic acid during work. After oral exposure he suffered a severe anaphylactic shock and showed milder reactions later when eating food containing benzoic acid. [Pevny I et al; Derm Beruf Umwelt 29 (5): 123-30 (1981) ]**PEER REVIEWED**
  • CASE REPORTS: In six men given 0.3-0.4 g benzoic acid in their diet for up to 62 days, no abnormalities were seen in the blood picture, urine composition, nitrogen balance, or well-being. Nine patients on penicillin treatment received 1200 mg benzoic acid daily, in eight doses, over five days for eight subjects and for 14 days in one case. No effect was observed; in particular, no significant change was seen in endogenous creatinine clearance, and routine urine analysis showed no abnormality. [WHO; Food Additive Series 37: Toxicological evaluation of ceratin food additives: Benzyl acetate, Benzyl alcohol, Benzaldehyde, and Benzoic acid and its Salts (1996). Available from: http://www.inchem.org/documents/jecfa/jecmono/v37je05.htm as of March 24, 2005. ]**PEER REVIEWED**
  • CASE REPORTS: Forty-eight female panelists participated in an in-use study that investigated the acnegenic and irritation potential of a liquid/ powder foundation containing 0.2% benzoic acid. …Approximately half of the test population had "mild to moderate" acne. Panelists were instructed to apply the product to the entire face and neck area at least twice a day for 45 days. Acne lesions and irritation were evaluated by a dermatologist on days 0, 3, 7, 10, 28, and 45. Objective and subjective evaluations of irritation were made by a nurse or technician on days 15, 21, and 35. Panelists also maintained daily response logs. The dermatologist noted "no significant changes the lesion counts of the non acne subjects and the acne subjects had a decrease. … Panelists' logs recorded occasional instances of dryness, itching, and flakiness. [Cosmetic Ingredient Review Expert Panel; International Journal of Toxicology: 20(suppl. 3): 23-50 (2001) ]**PEER REVIEWED**
  • CASE REPORTS: An eye shadow plus base containing 0.1% benzoic acid was tested in a 28-day in-use study using 52 women. Half of the panelists were contact lens wearers. Panelists were instructed to use the product at least twice a day. Examinations were made at the beginning and end of the study by an ophthalmologist, weekly by a nurse or technician, and the panelists maintained daily logs. Slight conjunctival hyperemia without chemosis was noted in eight women; the condition was nonpersistent in all cases. Another two women presented with slight hyperemia and were also experiencing allergy symptoms; erythema was noted around the eye of one of these two panelists. One panelist had an incidence of red and mildly swollen caruncles at the fifth observation. Four other panelists reported occasional itching; dryness was reported by another two panelists. One panelist reported redness, puffiness, and irritation of the left upper eyelid that prevented her from wearing her contact lenses for 2 days. [Cosmetic Ingredient Review Expert Panel; International Journal of Toxicology: 20(suppl. 3): 23-50 (2001) ]**PEER REVIEWED**
  • OTHER TOXICITY INFORMATION: Large oral doses of benzoic acid used therapeutically to alleviate the effects of inherited urea cycle disorders were studied with respect to their effect on intermediary metabolism. Documented effects on the urea cycle, gluconeogenesis, fatty acid metabolism, carnitine status, and the tricarboxylic acid cycle were attributed to sequestering of coenzyme A by benzoate as a result of glycine depletion required for the formation of hippuric acid from benzoyl coenzyme A. In addition, binding of benzoate to albumin results in toxic reactions due to the displacement of other metabolites from albumin-binding sites; e.g. bilirubin toxicity and appetite suppression result from increased serum tryptophan levels, which increase the turnover of brain serotonin [WHO; Food Additive Series 37: Toxicological evaluation of ceratin food additives: Benzyl acetate, Benzyl alcohol, Benzaldehyde, and Benzoic acid and its Salts (1996). Available from: http://www.inchem.org/documents/jecfa/jecmono/v37je05.htm as of March 24, 2005. ]**PEER REVIEWED**

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Non-Human Toxicity Excerpts

  • LABORATORY ANIMALS: Acute Exposure: In a maximization test, none of 15 guinea-pigs reacted positively after induction and challenge with a 10-20% solution of benzoic acid in water. In addition, the substance also tested negative in a Buehler test with guinea-pigs and in an ear swelling test and local lymph node assay with mice. The concentrations used for induction and challenge were 10-20% in acetone or water. However, a dose-dependent positive result was obtained in an ear swelling test with 5 guinea-pigs (induction with 0.2, 1, 5, or 20% in absolute ethyl alcohol; no challenge) used as a model for detecting agents causing non-immunological contact urticaria in humans. At several other regions (back, abdomen, flank site), a concentration of 20% failed to produce any reactions. [International Programme on Chemical Safety's Concise International Chemical Assessment Documents. Number 26: Benzoic acid and Sodium Benzoate (2000). Available from http://www.inchem.org/pages/cicads.html as of March 24, 2005. ]**PEER REVIEWED**
  • LABORATORY ANIMALS: Acute Exposure: In four cats given diets containing 0 or 1% benzoic acid (approximately 0 or 450-890 mg/kg bw), aggression, hyperesthesia, and collapse starting 14-16 hr after feed uptake were seen at a dose level equal to 630 mg/kg bw. The duration of the syndrome was about 18-176 hr, and the mortality rate was 50%. The histopathological examination of the two cats that died revealed degenerative changes in liver, kidneys, and lung, but no pathological findings in brain or spinal cord. The authors attributed the higher toxicity of benzoic acid in cats compared with other species to the low capacity of cats for glucuronidation. [International Programme on Chemical Safety's Concise International Chemical Assessment Documents. Number 26: Benzoic acid and Sodium Benzoate (2000). Available from http://www.inchem.org/pages/cicads.html as of March 24, 2005. ]**PEER REVIEWED**
  • LABORATORY ANIMALS: Acute Exposure: Clinical signs of intoxication (reported for rats only) included diarrhea, muscular weakness, tremors, hypoactivity, and emaciation. [International Programme on Chemical Safety's Concise International Chemical Assessment Documents. Number 26: Benzoic acid and Sodium Benzoate (2000). Available from http://www.inchem.org/pages/cicads.html as of March 24, 2005. ]**PEER REVIEWED**
  • LABORATORY ANIMALS: Acute Exposure: The effects of benzoic acid and its analogues on insulin and glucagon secretion were investigated in conscious sheep. Intravenous injections of benzoic acid increased plasma insulin and glucagon concentrations in a dose-dependent manner between 39-1250 umol/kg, with ED50s for increasing both hormones of about 625 umol/kg. Various derivatives of benzoic acid (625 umol/kg) were administered and structure-activity relationships were examined. A single carboxylic group was essential for stimulating insulin and glucagon secretion, since both hormone responses were abolished with compounds in which the carboxylic group was replaced by sulfonic or phosphoric groups, or in which another carboxylic element was introduced (phthalic acids). Most of the compounds which introduced other elements (amino and hydroxy groups, and halogens) onto the benzene ring had an altered stimulating activity. Thus the pancreatic endocrine system can recognize the chemical structure of benzoic acid and its derivatives in detail and induce insulin and glucagon secretion in sheep. [Mineo,H et al; Eur J Pharmacol 280 (2): 149-154 (1995) ]**PEER REVIEWED** PubMed Abstract
  • LABORATORY ANIMALS: Acute Exposure: A 4% soln ... was injected iv daily /in brown rabbits/. ... Animals were killed with a gas embolus after 12 hr to 3 days. Histologically, exudative detachment of the retinal neuroepithelium from the pigment epithelium was found. The toxic /effects/ appeared ... predominantly on the layer of rods and cones. ... Acid mucopolysaccharides appeared to be increased in the rod and cone layer, but also irregularly in other parts of the retina. [Grant, W.M. Toxicology of the Eye. 3rd ed. Springfield, IL: Charles C. Thomas Publisher, 1986., p. 142]**PEER REVIEWED**
  • LABORATORY ANIMALS: Acute Exposure: An early fall in blood bilirubin concn without any change in skin bilirubin content was observed in rats after ip benzoic acid administration. Under these conditions blood bilirubin concn remained low. A dose-dependent decrease in skin bilirubin content was observed 24 and then 48 hr after injection. At 8 days after benzoic acid injection, blood and skin bilirubin contents had returned to control values. Apparently, the effect of benzoic acid on bilirubin levels is due to a shift in the distribution equilibrium of the pigment between serum, skin, and other tissues. [Bessard G et al; Biol Neonate 44 (5): 315-20 (1983) ]**PEER REVIEWED**
  • LABORATORY ANIMALS: Acute Exposure: Royal Wistar rats dosed with 3% for 1, 2, 3, or 5 days (approx.1500 mg/kg/day); basal diet followed for 19 to 30 days. Fourteen of 35 rats dosed for 5 days died; necrosis of parenchymal cells noted in brain in all 5-day treated rats and occasionally in 3-day treated rats. [Cosmetic Ingredient Review Expert Panel; International Journal of Toxicology: 20(suppl. 3): 23-50 (2001) ]**PEER REVIEWED**
  • LABORATORY ANIMALS: Acute Exposure: In an acute eye irritation/corrosion study with rabbits conducted according to OECD Guideline 405, some eye irritation was reported after application of benzoic acid in the form of a paste. Within 72 hr, the scores for chemosis, reddening of the conjunctivae, iritis, and keratitis always remained at <2. In different non-standardized experiments with the solid substance, moderately irritating to severely irritating effects on the eye were noted (score 65/110; no score given; score up to 108/110 [eyes rinsed after instillation] or up to 50/100 [eyes not rinsed]; score 35 according to the scheme of Kay & Calandra, 1962). [International Programme on Chemical Safety's Concise International Chemical Assessment Documents. Number 26: Benzoic acid and Sodium Benzoate (2000). Available from http://www.inchem.org/pages/cicads.html as of March 24, 2005. ]**PEER REVIEWED**
  • LABORATORY ANIMALS: Subchronic or Prechronic Exposure: 0.5% /benzoic acid was given/ in diet (approx. 300-420 mg/kg/day) /to/ cats /for/ 3-4 days continuously in diet. 4 cats were tested; initial body weight: 1.42-2.0 kg. /Effects include/ convulsions, hyperaesthesia, apprehension, swollen hepatocytes with infiltrations of macrophages and fibroblasts, swollen kidney tubules, no pathological findings in brain and spinal cord; mortality: 2/4. [European Chemicals Bureau; IUCLID Dataset, Benzoic acid (65-85-0) (2000 CD-ROM edition). Available from the database query page: http://ecb.jrc.it/esis/esis.php?PGM=ein&DEPUIS=autre as of March 22, 2005. ]**PEER REVIEWED**
  • LABORATORY ANIMALS: Subchronic or Prechronic Exposure: F344 rats received 1.81, 2.09, or 2.4% sodium benzoate, and B6C3F1 /mice/ received 2.08, 2.50, or 3.0% sodium benzoate in their diet for 10 days. In male rats of the 2.4% group, relative liver and kidney weight, serum levels of albumin, total protein, and gamma-glutamyl transpeptidase were significantly increased; enlarged hepatocytes with glassy cytoplasma were seen. In male mice of the 3.0% group, absolute liver weights and serum cholesterol and phospholipid levels were increased, and enlargement, vacuolation and necrosis of hepatocytes were evident. /Sodium benzoate/ [Sheftel, V.O.; Indirect Food Additives and Polymers. Migration and Toxicology. Lewis Publishers, Boca Raton, FL. 2000., p. 448]**PEER REVIEWED**
  • LABORATORY ANIMALS: Subchronic or Prechronic Exposure: Mice /were given/ daily 80 mg/kg/day /benzoic acid/. /Effects include/ reduced weight gain without reduced food intake; mortality rate at week 10: 32% in males and females. [European Chemicals Bureau; IUCLID Dataset, Benzoic acid (65-85-0) (2000 CD-ROM edition). Available from the database query page: http://ecb.jrc.it/esis/esis.php?PGM=ein&DEPUIS=autre as of March 22, 2005. ]**PEER REVIEWED**
  • LABORATORY ANIMALS: Subchronic or Prechronic Exposure: Ten CD rats per sex per group were exposed to 0, 25, 250, or 1200 mg benzoic acid dust aerosol/cu m (analytical concentration; mass aerodynamic diameter [MAD]/sigma g (standard deviation): 0, 4.6/3.1, 4.4/2.1, 5.2/2.1; mass median aerodynamic diameter [MMAD]: 4.7 um) for 6 hr/day and 5 days per week over 4 weeks. After this time, various serum biochemical, hematological, organ weight, and histopathological examinations were conducted. At >25 mg/cu m, an increased incidence of interstitial inflammatory cell infiltrate and interstitial fibrosis in the trachea and lungs in treated animals compared with controls was seen. Although the number of these microscopic lesions was higher in treated animals than in controls, there was no clear dose dependency for this effect. A concentration of >250 mg/cu m resulted in upper respiratory tract irritation, as indicated by inflammatory exudate around the nares, and significantly decreased absolute kidney weights in females. In the highest dose group, one rat per sex died, and the body weight gain was significantly decreased in males and females compared with controls. In addition, a significant decrease in platelets (males/females), absolute/relative liver weights (males), and trachea/lung weights (females) was noted. [International Programme on Chemical Safety's Concise International Chemical Assessment Documents. Number 26: Benzoic acid and Sodium Benzoate (2000). Available from http://www.inchem.org/pages/cicads.html as of March 24, 2005. ]**PEER REVIEWED**
  • LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity: Seventeen dogs given diets containing sodium benzoate or benzoic acid at 1000 mg/kg bw for 250 days showed no effect on growth, appetite, or well-being; but at higher doses ataxia, epileptic convulsions, and death occurred. [WHO; Food Additive Series 37: Toxicological evaluation of ceratin food additives: Benzyl acetate, Benzyl alcohol, Benzaldehyde, and Benzoic acid and its Salts (1996). Available from: http://www.inchem.org/documents/jecfa/jecmono/v37je05.htm as of March 24, 2005. ]**PEER REVIEWED**
  • LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity: 40 Sprague-Dawley rats (20 each sex) received feed containing either 0.5% or 2% for 1 year. Some other groups also received sorbic acid. No effect noted at 0.5%; slight reduction of growth rate noted at 2%. No additive toxicity noted of benzoic acid plus sorbic acid. [Cosmetic Ingredient Review Expert Panel; International Journal of Toxicology: 20(suppl. 3): 23-50 (2001) ]**PEER REVIEWED**
  • LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity: Administration of 80 mg /benzoic acid/ (BA)/kg BW for 18 months caused no adverse effects on BW gain, survival, or gross microscopic pathology in rats and mice. Mice were fed 40 mg BA/kg BW for 1.5 years. The treatment caused a decrease in the resistance to stress and reduction in food and water intake and BW gain. Rats received 1.5% BA in their diet (750 mg/kg BW). The treatment decreased food intake and BW gain. [Sheftel, V.O.; Indirect Food Additives and Polymers. Migration and Toxicology. Lewis Publishers, Boca Raton, FL. 2000., p. 448]**PEER REVIEWED**
  • LABORATORY ANIMALS: Developmental or Reproductive Toxicity: Benzoic acid at doses of 6, 30, 60, and 600 mg/kg was administered by stomach tube to groups of 21 to 24 pregnant golden hamsters on GDs 6 to 10. Two negative-control groups were maintained; one was treated with water, the other with 0.5%carboxymethylcellulose. A positive-control group received either thalidomide or aspirin. Dams were killed on day 16. No adverse effect in maternal survival was noted. A significant number of resorptions was noted in hamsters which received /greater than or equal to/ 30 mg/kg. The incidence of fetal malformations reached statistical significance at >600 mg/kg. [Cosmetic Ingredient Review Expert Panel; International Journal of Toxicology: 20(suppl. 3): 23-50 (2001) ]**PEER REVIEWED**
  • LABORATORY ANIMALS: Developmental or Reproductive Toxicity: Benzoic acid at doses of 5, 25, 50, and 500mg/kg was administered by stomach tube to groups of 20 pregnant Wistar rats on GDs 6 to 15. Two negative-control groups were maintained; one was treated with water, the other with 0.5% carboxymethylcellulose (used to keep the benzoic acid in suspension). A positive control group received either thalidomide or aspirin. Dams were killed on day 21. Maternal survival was similar for treated and control groups. A significant number of resorptions /were/ noted in rats which received /greater than or equal to/ 25 mg/kg. The incidence of fetal malformations in /benzoic acid/ treated rats did not reach statistical significance. [Cosmetic Ingredient Review Expert Panel; International Journal of Toxicology: 20(suppl. 3): 23-50 (2001) ]**PEER REVIEWED**
  • LABORATORY ANIMALS: Developmental or Reproductive Toxicity: In a four-generation study with male and female rats, no adverse effects on fertility or lactation (only investigated parameters) were seen after dosing with benzoic acid at up to 1% in the diet (approximately 500 mg/kg bw/day). In studies with repeated oral application, no effects on the testes were observed in rats after dosing with benzoic acid at up to 647 mg/kg bw/day in the diet for 4 weeks or in mice after lifelong application of 6200 mg sodium benzoate/kg bw/day via drinking-water. [International Programme on Chemical Safety's Concise International Chemical Assessment Documents. Number 26: Benzoic acid and Sodium Benzoate (2000). Available from http://www.inchem.org/pages/cicads.html as of March 24, 2005. ]**PEER REVIEWED**
  • LABORATORY ANIMALS: Neurotoxicity: Royal Wistar rats (number not stated) dosed with 1.1% for 7, 14, or 35 days (approx. 550 mg/kg/day). Significantly poor weight gain; no signs of neurotoxicity or pathological changes in the brain /were observed/. [Cosmetic Ingredient Review Expert Panel; International Journal of Toxicology: 20(suppl. 3): 23-50 (2001) ]**PEER REVIEWED**
  • LABORATORY ANIMALS: Neurotoxicity: Groups of eight Wistar dams received feed containing 0.1%, 0.5%, or 1.0% sodium benzoate beginning on gestation day (GD) 5 and continuing throughout pregnancy and lactation. The control group was untreated. At birth, the number of pups in each litter was equalized to eight. Locomotor activity of the pups was measured on various days. One pup from each litter was killed on days 9, 15, and 21 and the brain removed and examined. On day 22, pups were weaned onto the same diet as their respective dam. On day 24, one male pup from each litter was caged individually and monitored for spontaneous locomotor activity. Rats were killed on day 45 and brain concentrations of norepinephrine, dopamine, and serotonin were measured. No significant difference was noted in feed intake and body weight gain of dams and pups of the treated groups compared to controls. No consistent differences in motor activity and monoamine concentrations were noted. /Sodium Benzoate/ [Cosmetic Ingredient Review Expert Panel; International Journal of Toxicology: 20(suppl. 3): 23-50 (2001) ]**PEER REVIEWED**
  • GENOTOXICITY: Benzoic acid tested negative in several Ames tests and in one DNA damage assay with different Salmonella typhimurium strains in the presence or absence of metabolic activation. Only in one recombination assay with Bacillus subtilis H17 and M45 was a positive result obtained. However, due to missing experimental details (only results given), the validity of this study cannot be judged. There was no indication of genotoxic activity (chromosome aberrations, sister chromatid exchange) in tests with mammalian cells (Chinese hamster CHL and CHO cells, human lymphoblastoid cells, human lymphocytes) without metabolic activation. [International Programme on Chemical Safety's Concise International Chemical Assessment Documents. Number 26: Benzoic acid and Sodium Benzoate (2000). Available from http://www.inchem.org/pages/cicads.html as of March 24, 2005. ]**PEER REVIEWED**
  • ALTERNATIVE IN VITRO TESTS: In an in vitro study hippurate and its parent compound sodium benzoate had antitumor effects on cells derived from Skalsky lymphoma, N´emeth-Kellner lymphoma (LYNK), L-asparaginase-sensitive 6C3HED Gardner lymphoma (GS), and LP-2 plasmacytoma. /Sodium Benzoate/ [Cosmetic Ingredient Review Expert Panel; International Journal of Toxicology: 20(suppl. 3): 23-50 (2001) ]**PEER REVIEWED**
  • OTHER TOXICITY INFORMATION: Benzoic acid (2%) as found in some preserved pet foods was toxic to cats. The /investigators/ suggest that the largest amount that could be fed daily to cats was 0.2 g/kg. [Beford PGC, Clarke ECG; Vet Rec 90: 53-8 (1972) ]**PEER REVIEWED**
  • OTHER TOXICITY INFORMATION: Flower-inducing effect of benzoic acid in various strains of Lemna paucicostata and L minor was investigated. Benzoic acid is more effective than salicylic acid for all strains of L pauciostata, but the contrary is true for two L minor strains. [Kaihara S et al; Plant Cell Physiol 22 (5): 819-25 (1981) ]**PEER REVIEWED**

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Human Toxicity Values

  • None found

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Non-Human Toxicity Values

  • LD50 Cat oral 2000 mg/kg [Lewis, R.J. Sax's Dangerous Properties of Industrial Materials. 9th ed. Volumes 1-3. New York, NY: Van Nostrand Reinhold, 1996., p. 352]**PEER REVIEWED**
  • LD50 Dog oral 2000 mg/kg [Lewis, R.J. Sax's Dangerous Properties of Industrial Materials. 9th ed. Volumes 1-3. New York, NY: Van Nostrand Reinhold, 1996., p. 352]**PEER REVIEWED**
  • LD50 Mouse intraperitoneal 1460 mg/kg [Lewis, R.J. Sax's Dangerous Properties of Industrial Materials. 9th ed. Volumes 1-3. New York, NY: Van Nostrand Reinhold, 1996., p. 352]**PEER REVIEWED**
  • LD50 Mouse oral 1940 mg/kg [Lewis, R.J. Sax's Dangerous Properties of Industrial Materials. 9th ed. Volumes 1-3. New York, NY: Van Nostrand Reinhold, 1996., p. 352]**PEER REVIEWED**
  • LD50 Rat oral 1700 mg/kg [Lewis, R.J. Sax's Dangerous Properties of Industrial Materials. 9th ed. Volumes 1-3. New York, NY: Van Nostrand Reinhold, 1996., p. 352]**PEER REVIEWED**
  • LC50 Rat inhalation >0.026 mg/L/1 hr [European Chemicals Bureau; IUCLID Dataset, Benzoic acid (65-85-0) (2000 CD-ROM edition). Available from the database query page: http://ecb.jrc.it/esis/esis.php?PGM=ein&DEPUIS=autre as of March 22, 2005. ]**PEER REVIEWED**
  • LD50 Rabbit dermal > 5000 mg/kg bw [European Chemicals Bureau; IUCLID Dataset, Benzoic acid (65-85-0) (2000 CD-ROM edition). Available from the database query page: http://ecb.jrc.it/esis/esis.php?PGM=ein&DEPUIS=autre as of March 22, 2005. ]**PEER REVIEWED**

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Absorption, Distribution and Excretion

  • Benzoic acid and sodium benzoate are rapidly absorbed from the gastrointestinal tract of mammals and conjugated with glycine in the liver. The resulting hippuric acid is excreted in the urine rapidly (75% to 100% of the dose is excreted within 6 hours; the remaining dose is excreted within 2 to 3 days). [Cosmetic Ingredient Review Expert Panel; International Journal of Toxicology: 20(suppl. 3): 23-50 (2001) ]**PEER REVIEWED**
  • Investigators: reported that 42.6% +/-16.5% of a dermally applied [14C]-Benzoic acid dose (4 ug/sq cm; in acetone)was excreted in the urine within 24 hours. When applied in petrolatum, 60.5% of the dose was absorbed. [Cosmetic Ingredient Review Expert Panel; International Journal of Toxicology: 20(suppl. 3): 23-50 (2001) ]**PEER REVIEWED**
  • By quantifying 24-hour urine excretion, /investigators/ demonstrated that dermal application of 1000 nmol [14C]-Benzoic acid (1.0X10-3 Ci/nmol) produced the following penetration scale: forehead > abdomen > thigh > chest > arm > back. The 4-day penetration through the forehead (27.65 +/- 3.61 nmol/sq cm) was three times greater than absorption through the back (8.55+/- 1.32 nmol/sq cm). Benzoic Acid had been applied to two sites of each body area; one site was tape stripped to determine the amount of test material in the stratum corneum. The quantified values from the urine were comparable to predicted values estimated from the tape stripping. [Cosmetic Ingredient Review Expert Panel; International Journal of Toxicology: 20(suppl. 3): 23-50 (2001) ]**PEER REVIEWED**
  • In a study investigating the effects of aging on dermal absorption, /investigators/ applied [14C]-Benzoic acid (in acetone) to the forearm of two groups of panelists, "young" (22 to 40 years) and "old" (>65 years). A 24-hour protective patch was placed on the skin and the site was washed after patch removal. A second protective patch was then applied and remained in place until day 7. Analysis of 7-day urine excretion indicated that 36.2% +/-4.6% of the applied dose was absorbed by the young panelists, whereas 19.5% +/-1.6% was absorbed by the old panelists. The difference was statistically significant ( p <.01). [Cosmetic Ingredient Review Expert Panel; International Journal of Toxicology: 20(suppl. 3): 23-50 (2001) ]**PEER REVIEWED**
  • No statistical difference (p > .05) was found /for/ the percutaneous absorption of benzoic acid by Asian, Black, and Caucasian panelists. [14C]-Benzoic acid (1 umol/sq cm) was applied to two sites of the upper arm and the sites were washed after 30 minutes of contact. (The two applications occurred on contralateral arms and were made 48 hours apart.) Urine was collected for 24 hours and one site was tape stripped to measure benzoic acid in the stratum corneum. Amounts absorbed were 1.43% +/-0.27% by Asian skin, 1.07% +/-0.17% by Black skin, and 1.2% +/-0.19% by Caucasian skin. [Cosmetic Ingredient Review Expert Panel; International Journal of Toxicology: 20(suppl. 3): 23-50 (2001) ]**PEER REVIEWED**
  • (14)C was excreted at different rates from various species following oral dose of (14)C-benzoic acid. In 24-hr urine, man excreted 100%, hamster 99%, dog 94%, guinea pigs 79%, ferret 69%, rabbit 60%, mouse 55%, pig 50% & squirrel monkey 48%. Man received one-fiftieth of dose (52 + or - 4 mg/kg) given to other species. [The Chemical Society. Foreign Compound Metabolism in Mammals. Volume 2: A Review of the Literature Published Between 1970 and 1971. London: The Chemical Society, 1972., p. 160]**PEER REVIEWED**
  • Biliary excretion ... in different species. Percent of dose excreted in 3 hr: rat 1.2, guinea pig 1.7, rabbit 0.7, dog 0.8, cat 1.2, hen 0.5. [LaDu, B.N., H.G. Mandel, and E.L. Way. Fundamentals of Drug Metabolism and Disposition. Baltimore: Williams and Wilkins, 1971., p. 139]**PEER REVIEWED**
  • The transdermal absorption of benzoic acid was studied in excised human skin and compared to absorption in living man. In equivalent time, the total absorption (% of applied dose) was 42.6% (in vivo) or 44.9 (in vitro). [European Chemicals Bureau; IUCLID Dataset, Benzoic acid (65-85-0) (2000 CD-ROM edition). Available from the database query page: http://ecb.jrc.it/esis/esis.php?PGM=ein&DEPUIS=autre as of March 22, 2005. ]**PEER REVIEWED**
  • The percutaneous absorption and the excretion of benzoic acid were tested in female weanling Yorkshire swine (approximately 20 kg) after topical and intravenous administration. After iv injection of 200 ug (10 uCi)/pig 84.5% of 14C-activity were excreted with urine and 4.6% in feces within 6 days; the radiolabel recovery in carcass was 0.1%. After topical application of the same dose the radiolabel recovery within 6 days (% of applied does) was in urine 20%, feces 2.9%, carcass 0.8%, border 40.2%, dosed skin 12.2% and adjacent skin 9.1%. [European Chemicals Bureau; IUCLID Dataset, Benzoic acid (65-85-0) (2000 CD-ROM edition). Available from the database query page: http://ecb.jrc.it/esis/esis.php?PGM=ein&DEPUIS=autre as of March 22, 2005. ]**PEER REVIEWED**
  • The percutaneous absorption of 14C-labelled benzoic acid was studied in the Mexican hairless dog and compared to human data. Total absorption and maximum absorption rates were greater in humans than in hairless dogs. Surface counting experiments showed that benzoic acid persisted on the dog skin far longer than on human skin (no further information). [European Chemicals Bureau; IUCLID Dataset, Benzoic acid (65-85-0) (2000 CD-ROM edition). Available from the database query page: http://ecb.jrc.it/esis/esis.php?PGM=ein&DEPUIS=autre as of March 22, 2005. ]**PEER REVIEWED**
  • The percutaneous absorption of increasing topical doses of benzoic acid was determined in the Rhesus monkey and humans (dosage: 4, 40, 2000 ug/sq cm; dose absorbed: monkey 59.2%, 3.6%, 17.4%; human 42.6%, 25.7%, 14.4%). In vivo percutaneous absorption was similar, also the dose-response curve was similar in the two species (no further information). [European Chemicals Bureau; IUCLID Dataset, Benzoic acid (65-85-0) (2000 CD-ROM edition). Available from the database query page: http://ecb.jrc.it/esis/esis.php?PGM=ein&DEPUIS=autre as of March 22, 2005. ]**PEER REVIEWED**
  • The percutaneous absorption and metabolism of benzoic acid was determined through hairless guinea pig skin in vitro. The absorption within 48 hr was greater through nonviable skin (60.1% of applied dose) than through viable skin (49.5%). 6.9% of absorbed dose (2 ug/sq cm) were conjugated with glycine to form hippuric acid. [European Chemicals Bureau; IUCLID Dataset, Benzoic acid (65-85-0) (2000 CD-ROM edition). Available from the database query page: http://ecb.jrc.it/esis/esis.php?PGM=ein&DEPUIS=autre as of March 22, 2005. ]**PEER REVIEWED**
  • Damaging the skin (tape stripping, irritation, delipidization) increased absorption of benzoic acid dissolved in acetone (200 ug/mL, 50 uCi; topical application: 4 ug/sq cm) in hairless guinea pigs: 71.1/73.4/94.1% vs 34.2% absorbed in the group with intact skin. [European Chemicals Bureau; IUCLID Dataset, Benzoic acid (65-85-0) (2000 CD-ROM edition). Available from the database query page: http://ecb.jrc.it/esis/esis.php?PGM=ein&DEPUIS=autre as of March 22, 2005. ]**PEER REVIEWED**
  • In humans, the peak plasma concentration is reached within 1-2 hr /afetr oral ingestion/. [International Programme on Chemical Safety's Concise International Chemical Assessment Documents. Number 26: Benzoic acid and Sodium Benzoate (2000). Available from http://www.inchem.org/pages/cicads.html as of March 24, 2005. ]**PEER REVIEWED**
  • Benzoic acid is not completely absorbed by the dermal route. In a study with 6 human subjects, /investigators/ found an uptake of 36% of the applied dose (14C-labelled benzoic acid dissolved in acetone; 4 ug/sq cm; circular area of 13 sq cm; ventral surface of the forearm; non-occlusive) within 12 hr. The total uptake within 5 days was 43%. In a second study with 6-7 subjects (comparable method; application of 3, 400 or 2000 ug/sq cm), the percent absorption decreased from 35% to 14% within 24 hr. However, the total uptake per sq cm increased from 1 to 288 ug. [International Programme on Chemical Safety's Concise International Chemical Assessment Documents. Number 26: Benzoic acid and Sodium Benzoate (2000). Available from http://www.inchem.org/pages/cicads.html as of March 24, 2005. ]**PEER REVIEWED**
  • Hippuric acid is rapidly excreted in urine. In humans, after oral /benzoic acid/ doses of up to 160 mg/kg bw, 75-100% of the applied dose is excreted as hippuric acid within 6 hr after administration, and the rest within 2-3 days. [International Programme on Chemical Safety's Concise International Chemical Assessment Documents. Number 26: Benzoic acid and Sodium Benzoate (2000). Available from http://www.inchem.org/pages/cicads.html as of March 24, 2005. ]**PEER REVIEWED**

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Metabolism/Metabolites

  • Benzoic acid ... conjugated with glycine to give hippuric acid in ... many mammals (man, monkeys, pig, rabbit, rodents, cat, dog, ferret & hedgehog). Dog, ferret, & hedgehog also excreted ... benzoyl glucuronide ... but indian fruit bat excreted almost all dose as benzoyl glucuronide. [The Chemical Society. Foreign Compound Metabolism in Mammals. Volume 2: A Review of the Literature Published Between 1970 and 1971. London: The Chemical Society, 1972., p. 407]**PEER REVIEWED**
  • Investigators/ demonstrated that biotransformation of Benzoic acid to hippuric acid follows saturable or Michaelis-Menten kinetics in humans following ingestion of sodium benzoate. /Sodium Benzoate/ [Cosmetic Ingredient Review Expert Panel; International Journal of Toxicology: 20(suppl. 3): 23-50 (2001) ]**PEER REVIEWED**
  • The availability of glycine was the rate-limiting factor in the formation of hippuric acid. When insufficient glycine was available benzoyl glucuronide was formed. [Cosmetic Ingredient Review Expert Panel; International Journal of Toxicology: 20(suppl. 3): 23-50 (2001) ]**PEER REVIEWED**
  • Investigators: reported that both lipoic acid and valproic acid reduced the clearance of Benzoic acid in rats that had been "loaded" with glycine. Both acids reduced the availability of hepatic coenzyme A that is needed for the adenosine triphosphate (ATP)-dependent conjugation with glycine. [Cosmetic Ingredient Review Expert Panel; International Journal of Toxicology: 20(suppl. 3): 23-50 (2001) ]**PEER REVIEWED**
  • Yields benzoyl-beta-d-glucuronic acid in rabbit, hen, dog, rat, monkey, pig, ferret, hedgehog, bat, pigeon; man; guinea pig, cat, rabbit; duck, goose, pigeon, crow, and parrot; yields benzoyl-beta-d-glucose in cockroach; yields benzoylagmatine in scorpion and in peripatus; yields benzoylarginine in scorpion peripatus; boophilus, eperia, tegenaria, mitopus, and Phalangium; yields benzaldehyde in aspergillus neurospora, and polystictus; yields benzoylglutamine in mitopus; yields benzoylhistidine in peripatus. /from table/ [Goodwin, B.L. Handbook of Intermediary Metabolism of Aromatic Compounds. New York: Wiley, 1976., p. B-7]**PEER REVIEWED**
  • Yields m-hydroxybenzoic acid in rabbit; yields m-hydroxybenzoic acid, p-hydroxybenzoic acid in aspergillus; yields p-hydroxybenzoic acid in plants; yields p-hydroxybenzoic acid in polyporus trichoderma, and yeast. /from table/ [Goodwin, B.L. Handbook of Intermediary Metabolism of Aromatic Compounds. New York: Wiley, 1976., p. B-8]**PEER REVIEWED**
  • In birds classed as anseriformes (duck, goose) & galliformes (hen, turkey), glycine is replaced by ornithine so that benzoic acid is excreted as dibenzoylornithine (ornithuric acid). ... Ornithine conjugation does not occur in all classes of birds. [LaDu, B.N., H.G. Mandel, and E.L. Way. Fundamentals of Drug Metabolism and Disposition. Baltimore: Williams and Wilkins, 1971., p. 195]**PEER REVIEWED**
  • In most animals, the conversion of benzoic acid to hippuric acid has been found to occur in the kidney, with conversion possible in the liver when kidney malfunction exists. The monkey metabolized benzoic acid only in the liver. [European Chemicals Bureau; IUCLID Dataset, Benzoic acid (65-85-0) (2000 CD-ROM edition). Available from the database query page: http://ecb.jrc.it/esis/esis.php?PGM=ein&DEPUIS=autre as of March 22, 2005. ]**PEER REVIEWED**
  • The limiting factor in the biosynthesis of hippuric acid is the availability of glycine. The utilization of glycine in the detoxification of benzoate results in a reduction in the glycine level of the body. Therefore, the ingestion of benzoic acid or its salts affects any body function or metabolic process in which glycine is involved; for example, it leads to a reduction in creatinine, glutamine, urea, and uric acid levels. [International Programme on Chemical Safety's Concise International Chemical Assessment Documents. Number 26: Benzoic acid and Sodium Benzoate (2000). Available from http://www.inchem.org/pages/cicads.html as of March 24, 2005. ]**PEER REVIEWED**

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TSCA Test Submissions

  • The effects of subchronic exposure to benzoic acid (BA) were evaluated in male and female Sprague-Dawley rats (10/sex/group) exposed by inhalation to 0, 0.025, 0.25 or 1.2 mg BA/L (generated as a dust aerosol with an equivalent aerodynamic diameter of 4.7 um) for 6 hrs/day, 5 days/week for 4 weeks. All high- and mid-dose animals exhibited upper respiratory tract irritation (red material around the nares). Two animals (1/sex) died in the high-dose group. There were statistically significant differences observed between treated and control animals in the following (high-dose group unless noted otherwise): decreased body weight gain, random differences in hematological data and serum biochemical evaluation (not considered to be exposure related except for a related decrease in the number of platelets), and decreased absolute and relative weights of liver (males), kidney (females, high- and mid-dose levels), and trachea/lung (females). The incidence of slight multifocal and generalized interstitial fibrosis and inflammatory cell infiltrate in treated animals were high compared to controls (not dose-related). No compound-related macroscopic lesions were observed in any of the rats. There were no deaths, no significant effects on body weight gain, and hematologic or biochemical parameters in the low- or mid-dose animals relative to the negative controls.[International Research and Development Corp.; Four Week Subacute Inhalation Toxicity Study of Benzoic Acid in Rats. (1981), EPA Document No. FYI-OTS-1281-0147, Fiche No. OTS0000147-0]**UNREVIEWED**

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Footnotes

1 Source: the National Library of Medicine's Hazardous Substance Database, 10/28/2007.

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Web page last updated on May 14, 2008