Absorption, Distribution and Excretion
Overall, there are indications that this substance can be absorbed systemically via oral and dermal exposure, but no evidence of target organ or excretion has been found. Following oral and dermal absorption, the test substance is metabolized to hippuric acid. Despite low log Pow values, results from a 28-day rat study and predicted metabolic outcomes suggest that the substance has no potential for bioaccumulation. In laboratory animals or humans, undissociated benzoic acid is rapidly absorbed from the gastrointestinal tract following oral administration of benzoic acid and sodium benzoate. …Absorption can be considered 100%. In humans, peak plasma concentrations are reached within 1–2 hours. Hippuric acid is rapidly excreted in the urine. In humans, following oral doses up to 160 mg/kg body weight, 75–100% of the administered dose is excreted as hippuric acid within 6 hours of administration, with the remainder excreted over 2–3 days.
Distribution and elimination studies of (14) C-benzoate in rats showed that sodium benzoate or benzoic acid does not accumulate in the body.
For more complete data on the absorption, distribution, and excretion of sodium benzoate (6 items), please visit the HSDB record page.

---

Metabolism/Metabolites
After oral and dermal absorption, benzoate is metabolized in the liver by binding with glycine to produce hippuric acid. Sodium benzoate has a high bioconversion rate in humans: after oral administration of 40, 80, or 160 mg/kg body weight, its conversion to hippuric acid is dose-independent—approximately 17–29 mg/kg body weight per hour, equivalent to approximately 500 mg/kg body weight per day. Other studies have obtained even higher values, ranging from 0.8–2 g/kg body weight per day. Another metabolite of benzoate is benzoyl glucuronide. The metabolism of benzoate consumes glycine, and therefore may alter the glycine-dependent metabolism of other compounds. A study has shown that sodium benzoate can compete with aspirin for glycine, thereby increasing the concentration and duration of salicylic acid in the body. This study highlights the importance of cinnamon (a widely used food spice and flavoring agent) and its metabolite sodium benzoate (NaB, a widely used food preservative and FDA-approved drug for treating human urea cycle disorders) in increasing the levels of neurotrophic factors such as brain-derived neurotrophic factor (BDNF) and neurotrophic factor-3 (NT-3) in the central nervous system (CNS). Sodium benzoate (NaB), rather than sodium cinnamate (NaFO), was able to dose-dependently induce the expression of BDNF and NT-3 in primary human neurons and astrocytes. Interestingly, oral administration of cinnamon powder increased the levels of sodium benzoate in the serum and brain tissue of mice and upregulated the levels of these neurotrophic factors in the mouse CNS in vivo. Therefore, oral administration of sodium cinnamate (NaB), rather than sodium cinnamate (NaFO), also increased the levels of these neurotrophic factors in the mouse CNS. NaB activates protein kinase A (PKA) but not protein kinase C (PKC); the PKA inhibitor H-89 eliminates NaB-induced elevations in neurotrophic factor levels. Furthermore, NaB activates cAMP response element-binding protein (CREB) but not NF-κB; siRNA knockdown of CREB eliminates NaB-induced neurotrophic factor expression; NaB recruits CREB and CREB-binding protein to the BDNF promoter region, all indicating that NaB exerts its neurotrophic effect by activating CREB. Correspondingly, cinnamon feeding also increases PKA activity and phosphorylated CREB levels in the mouse central nervous system. These results highlight the novel neurotrophic properties of cinnamon and its metabolite NaB through the PKA-CREB pathway, which may be beneficial for various neurodegenerative diseases.

Toxicity Summary
Identification and Uses: Sodium benzoate is a colorless crystalline powder. It is used as a food preservative, disinfectant, pharmaceutical, tobacco product, pharmaceutical preparation, dye production intermediate, and rust and mildew inhibitor. Human Exposure and Toxicity: A study involving 2045 dermatology outpatients showed that only 5 (approximately 0.2%) reacted positively in patch tests; while among 5202 patients with contact urticaria, 34 (approximately 0.7%) reacted positively. Symptoms such as urticaria, asthma, rhinitis, or anaphylactic shock have been reported after oral ingestion, skin contact, or inhalation of sodium benzoate. These symptoms usually appear shortly after exposure and disappear within hours. Chromosomal aberration tests were performed on sodium benzoate using human embryonic lung culture cells. At dose levels of 0, 2.0 μg/mL, 20 μg/mL, and 200 μg/mL, sodium benzoate did not cause a significant increase in the frequency of late-stage chromosomal aberrations. In human embryonic lung cells (WI-38) treated with sodium benzoate, chromosomal abnormalities and mitotic indices were within the normal range. Sodium benzoate is mutagenic and cytotoxic to lymphocytes, causing micronucleus formation and chromosome breakage. Animal experiments: Acute skin irritation/corrosion tests showed that sodium benzoate had no irritant effect on rabbit skin. Sodium benzoate caused only mild eye irritation. In a 90-day study, rats were given 0%, 1%, 2%, 4%, or 8% sodium benzoate via diet, with the highest dose group (approximately 6290 mg/kg body weight/day) showing a mortality rate of approximately 50%. Other adverse effects in this group of rats included reduced weight gain, increased relative weight of the liver and kidneys, and pathological changes in these organs. Starting from week 5, sodium benzoate was added to the drinking water of 50 female and 50 male mice until their death. The average daily sodium benzoate intake was 119.2 mg for female mice and 124.0 mg (approximately 5.95–6.2 g/kg body weight/day) for male mice. The survival rate of mice in the treated group was not affected compared with the untreated control group. There was no significant difference in tumor distribution between the sodium benzoate treated group and the untreated control group. In a developmental study, rats were intraperitoneally injected with 100, 315, or 1000 mg/kg sodium benzoate on days 9–11 or 12–14 of gestation. The highest dose group showed decreased fetal weight, increased intrauterine mortality (12%), and significant malformations. No teratogenicity was observed in rats administered 510 mg/kg sodium benzoate by gavage on days 9–11 of gestation. The teratogenicity of sodium benzoate (up to 3.0 mg/plate) was tested in the Salmonella/microsome assay using Salmonella typhimurium strains TA 92, TA 94, TA 98, TA 100, TA 1535, and TA 1537. At the maximum dose, the number of revertant mutant colonies in all Salmonella typhimurium strains did not increase significantly. Cytogenetic testing (bone marrow) was negative in rats after single or multiple oral administrations of sodium benzoate at doses up to 5000 mg/kg body weight. Host-mediated assays in mice also showed no mutagenic activity.
Interactions
The GRAS report cites studies showing that sodium benzoate intake reduces glycine-dependent creatine, glutamine, urea, and uric acid production and enhances the effects of procaine, lidocaine, cocaine, tetracaine, and debucaine. Benzoate can increase and prolong serum penicillin concentrations under severe fluid and salt restriction.
This study investigated the interaction between sodium benzoate (SB) and calf thymus DNA using UV-Vis absorption spectroscopy, fluorescence spectroscopy, and circular dichroism spectroscopy, combined with DNA melting experiments and viscosity measurements, in a simulated physiological buffer (pH 7.4) with acridine orange (AO) dye as a fluorescent probe. The extended UV-Vis spectral data matrix was analyzed using multivariate curve-resolved alternating least squares (MCR-ALS). Equilibrium concentration curves for SB, DNA, and the DNA-SB complex, as well as pure spectra from the highly overlapping complexation response, were obtained. The results indicate that SB can bind to DNA, with hydrophobic interactions and hydrogen bonds playing crucial roles in the binding process. Furthermore, SB can quench the fluorescence of the DNA-AO complex using a static method. The observed quenching suggests an embedded interaction mode between sodium benzoate and DNA, supported by melting experiments, viscosity measurements, and circular dichroism spectroscopy.

---

Non-human toxicity values
LC50 Rat inhalation >12,200 mg/m³ air/4 hours
LD50 Rat oral administration 3450 mg/kg body weight
LD50 Rabbit oral administration 2000 mg/kg
LD50 Mouse intramuscular injection 2306 mg/kg
For more complete non-human toxicity data for sodium benzoate (out of 8), please visit the HSDB record page.

[1]. Pharmaceutical excipients - quality, regulatory and biopharmaceutical considerations. Eur J Pharm Sci. 2016 May 25;87:88-99.

Therapeutic Uses
Antifungal agents; food preservatives. Sodium phenylacetate and sodium benzoate can be used as adjunctive therapy for acute hyperammonemia and related encephalopathy in patients with urea cycle disorders (i.e., enzyme deficiency). Sodium phenylacetate and sodium benzoate have been designated orphan drugs by the U.S. Food and Drug Administration (FDA) for this use. /EXPL THER/ In addition to dopaminergic hyperactivity, N-methyl-D-aspartate receptor (NMDAR) dysfunction plays an important role in the pathophysiology of schizophrenia. Enhancing NMDAR-mediated neurotransmission is considered a novel therapeutic approach. To date, several trials of adjunctive NMDA enhancers have shown benefits for positive symptoms, negative symptoms, and cognitive function, but with limited efficacy. Another approach to enhancing NMDA receptor function is to increase its levels by inhibiting D-amino acid metabolism. Sodium benzoate is a D-amino acid oxidase inhibitor. This study aims to investigate the clinical efficacy, cognitive efficacy, and safety of sodium benzoate as adjunctive therapy for schizophrenia. This was a randomized, double-blind, placebo-controlled trial conducted at two major medical centers in Taiwan, enrolling 52 patients with stable chronic schizophrenia who had received antipsychotic medication for 3 months or longer. The intervention included the addition of 1 gram of sodium benzoate or a placebo daily for 6 weeks. The primary efficacy endpoint was the total score of the Positive and Negative Syndrome Scale (PANSS). Clinical efficacy and adverse reactions were assessed every two weeks. Cognitive function was measured before and after adjunctive therapy. Benzoate improved the total PANSS score by 21%, and showed large effect sizes (range 1.16–1.69) on the total PANSS score and its subscales, the 20-item Negative Syndrome Assessment Scale, the Overall Functional Assessment Scale, the Quality of Life Scale, and the Clinical Global Impression Scale. Furthermore, benzoate improved neurocognitive subtests, in line with the recommendations of the National Institute of Mental Health's "Study on Improving Cognitive Measurement and Treatment in Patients with Schizophrenia" program, including processing speed and visual learning ability. Benzoate was well tolerated, with no significant adverse reactions observed. Benzoate adjunctive therapy significantly improved various symptoms and neurocognitive function in patients with chronic schizophrenia. Preliminary results suggest that D-amino acid oxidase inhibitors hold promise as a new strategy for drug development in the treatment of schizophrenia. N-methyl-D-aspartate receptor (NMDAR)-mediated neurotransmission is crucial for learning and memory. It has been reported that NMDAR dysfunction plays a role in the pathophysiology of Alzheimer's disease (AD), especially in its early stages. Enhancing NMDAR activation may be a novel therapeutic approach. One way to enhance NMDAR activity is by blocking the metabolism of NMDA receptor agonists to increase their levels. This study aimed to investigate the efficacy and safety of the D-amino acid oxidase inhibitor sodium benzoate in treating amnesic mild cognitive impairment and mild AD. We conducted a randomized, double-blind, placebo-controlled trial at four major medical centers in Taiwan. Sixty patients with amnesic mild cognitive impairment or mild Alzheimer's disease received either sodium benzoate (250–750 mg/day) or placebo for 24 weeks. The Alzheimer's Disease Assessment Scale Cognitive Subscale (the primary outcome measure) and overall functioning (assessed by the Clinician Interview Impression of Change and Caregiver Opinion Assessment) were measured every 8 weeks. An additional cognitive comprehensive score was measured at baseline and at the endpoint. Compared with placebo, sodium benzoate showed greater improvement on the Alzheimer's Disease Assessment Scale Cognitive Subscale (p = 0.0021, 0.0116, and 0.0031 at weeks 16, 24, and the endpoint, respectively), the additional cognitive comprehensive score (p = 0.007 at the endpoint), and both the Clinician Interview Impression of Change and Caregiver Opinion Assessment (p = 0.015, 0.016, and 0.012 at weeks 16, 24, and the endpoint, respectively). Sodium benzoate was well tolerated with no significant side effects. Sodium benzoate significantly improved cognitive and overall function in patients with early-stage Alzheimer's disease. Preliminary results suggest that D-amino acid oxidase inhibitors hold promise as a novel approach for treating early-stage dementia. A recent clinical study demonstrated that sodium benzoate (SB), a typical competitive D-amino acid oxidase inhibitor, is effective in treating various symptoms, such as positive and negative symptoms and cognitive impairment in patients treated with schizophrenia medications. This study aimed to investigate the effects of a single injection of the N-methyl-D-aspartate (NMDA) receptor antagonist phencyclidine (PCP) on behavioral abnormalities in mice, such as prepulse inhibition (PPI) deficiency and hyperactivity. The study also examined the effects of SB on behavioral abnormalities (PPI deficiency and hyperactivity) in mice after PCP injection. Furthermore, the effects of SB on amino acid levels in tissues were also investigated. A single oral dose of SB (100, 300, or 1000 mg/kg) dose-dependently alleviated PPI deficiency induced in mice following subcutaneous PCP (3.0 mg/kg). Conversely, the NMDA receptor glycine antagonist L-701,324 (10 mg/kg) did not affect the ameliorative effect of SB (1000 mg/kg) on PCP-induced PPI deficiency. Furthermore, a single oral dose of SB (1000 mg/kg) significantly reduced hyperactivity induced in mice following subcutaneous PCP (3.0 mg/kg). However, a single oral dose of SB (1000 mg/kg) did not cause changes in D-serine levels in plasma or in the frontal cortex, hippocampus, and striatum of these animals. This study suggests that SB induces an antipsychotic effect in a PCP-induced schizophrenia model, although it does not increase D-serine levels in the brain.

---

Drug Warning
At therapeutic dose levels, clinical signs of toxicity are rare, and in most cases are limited to anorexia and vomiting, especially after intravenous bolus injection.

C7H5NAO2

144.10

144.018

532-32-1

Benzoate-d5 sodium;62790-26-5

517055

White to off-white solid powder

1,44 g/cm3

249.3ºC at 760 mmHg

>300 °C(lit.)

111.4ºC

0.05

0

2

1

10

108

0

WXMKPNITSTVMEF-UHFFFAOYSA-M

InChI=1S/C7H6O2.Na/c8-7(9)6-4-2-1-3-5-6;/h1-5H,(H,8,9);/q;+1/p-1

sodium;benzoate

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO: 5 mg/mL (34.70 mM)

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

---

Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

View More

Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

---

Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

View More

Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

---

Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

---

 (Please use freshly prepared in vivo formulations for optimal results.)