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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Benzoic acid and sodium benzoate are used as preservatives in pharmaceuticals and foods, and also as buffering agents.

Specific Substances

    A) Benzoic Acid
    1) Acidum benzoicum
    2) Benzenecarboxylic acid
    3) Benzoesaure
    4) Dracylic acid
    5) Phenylformic acid
    6) CAS 65-85-0
    Sodium Benzoate
    1) Natrii benzoas
    2) Natrium benzoicum
    3) Sodii benzoas
    4) CAS 532-32-1

    1.2.1) MOLECULAR FORMULA
    1) Sodium benzoate: C7H5NaO2

Available Forms Sources

    A) FORMS
    1) Sodium benzoate is available in combination with sodium phenylacetate as a 10%/10% aqueous solution in a single use 50-mL glass vial for injection (Prod Info AMMONUL(R) IV injection, 2011).
    B) USES
    1) Benzoic acid and sodium benzoate are widely used as preservatives in foods and pharmaceuticals (HSDB , 2001).
    2) Benzoic acid 6% in combination with 3% salicylic acid has been used as an antifungal and as an external treatment for dermatitis, as well as for treatment of insect bites and burns (Prod Info BENSAL HP(R) topical ointment, 2006).
    3) An injectable preparation of sodium benzoate and caffeine has been used as a CNS stimulant (Prod Info caffeine sodium benzoate intramuscular injection solution, intravenous injection solution, 2005).
    4) Sodium benzoate in combination with sodium phenylacetate is approved as adjunctive therapy for the treatment of acute hyperammonemia in adult and pediatric patients with urea cycle enzyme deficiencies (Prod Info AMMONUL(R) IV injection, 2011).
    5) Diazepam IV contains 5% sodium benzoate and benzoic acid as buffering agents (Prod Info diazepam IM, IV injection, 2008)

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Benzoates are widely used as preservatives in foods and pharmaceuticals; they are also used as buffering agents. Benzoic acid in combination with salicylic acid has been used as an antifungal agent. Sodium benzoate in combination with sodium phenylacetate is approved as adjunctive therapy for the treatment of acute hyperammonemia in adult and pediatric patients with urea cycle enzyme deficiencies.
    B) TOXICOLOGY: Benzoic acid is thought to inhibit oxidative enzymes in the tricarboxylic acid cycle, similar to salicylates, and may result in secondary lactic acid production. Metabolic acidosis may also be explained by a direct action of benzoic acid. Metabolism of benzyl alcohol to benzoic acid is postulated as the mechanism for toxicity in premature infants.
    C) EPIDEMIOLOGY: Benzoate exposures are extremely common due to their frequent use as preservatives and buffering agents, however, significant toxicity is rare.
    D) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: The primary effect expected from ingestion of moderate amounts of benzoates is gastrointestinal irritation with symptoms including nausea, vomiting, diarrhea, and abdominal pain. Benzoic acid is more irritating than benzoate salts. A non-immunologic contact dermatitis commonly occurs following dermal exposure. Renal tubular dysfunction and elevated free bilirubin levels may occur in a small number of cases.
    2) SEVERE TOXICITY: Large ingestions of benzoates may cause metabolic acidosis, elevated serum lactate levels, and associated tachypnea and Kussmaul respirations. Hypokalemia and hypocalcemia may also occur. Administration of benzyl alcohol to neonates has been associated with metabolic acidosis and gasping respirations. Seizures have been reported in experimental animals.

Laboratory Monitoring

    A) Monitor serum electrolytes, renal function, liver enzymes, blood gases, and lactate levels in patients with evidence of toxicity.
    B) Institute cardiac monitoring and obtain an ECG in patients with toxicity.
    C) Benzoate concentrations are not widely available or clinically useful for acute management.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Treatment of mild to moderate toxicity consists of predominantly symptomatic and supportive care.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Treatment for severe toxicity consists of predominantly symptomatic and supportive care. Treat severe metabolic acidosis (pH less than 7.1) with sodium bicarbonate 1 to 2 mEq/kg to maintain hemodynamic stability, however the long-term benefit of this treatment has not been shown. Seizures should be treated with benzodiazepines as needed; NOTE: diazepam IV contains 5% sodium benzoate and benzoic acid as buffering agents, therefore, an alternative benzodiazepine such as lorazepam or midazolam may be a better choice.
    C) DECONTAMINATION
    1) PREHOSPITAL: Gastrointestinal decontamination is not generally recommended as acute toxicity is limited. Remove contaminated clothing and wash exposed skin with soap and water. Irrigate exposed eyes with copious amounts of water.
    2) HOSPITAL: Gastrointestinal decontamination is not generally recommended as acute toxicity is limited. Remove contaminated clothing and wash exposed skin with soap and water. Irrigate exposed eyes with copious amounts of 0.9% saline or water.
    D) AIRWAY MANAGEMENT
    1) Rarely, patients with marked CNS depression or acidosis may need intubation for respiratory support.
    E) ANTIDOTE
    1) None
    F) ENHANCED ELIMINATION
    1) Efficacy of enhanced elimination techniques is unknown. Hemodialysis may be useful to treat severe acidosis or in cases that develop renal failure.
    G) PATIENT DISPOSITION
    1) OBSERVATION CRITERIA: Patients with known large ingestions may be watched clinically for the development of toxicity such as gastrointestinal irritation and acidosis.
    2) ADMISSION CRITERIA: Patients who develop gastrointestinal irritation or other signs of benzoate toxicity after a known exposure should be admitted to the hospital. Patients who develop evidence of severe toxicity with acidosis, tachypnea, altered mental status, or seizures should be admitted to an ICU.
    3) CONSULT CRITERIA: Contact your local poison center for a toxicology consult for any patient with suspected benzoate toxicity and acidosis, seizures, or other end-organ toxicity.
    H) PITFALLS
    1) Missing an ingestion of another chemical or other possible etiologies for a patient’s symptoms.
    I) PHARMACOKINETICS
    1) Benzoic acid is rapidly absorbed from the gastrointestinal tract. The volume of distribution is small (estimated 0.14 L/kg in neonates). Benzoic acid is conjugated in the liver with glycine to form hippuric acid, the major metabolite. In healthy adults, up to 97% of the dose of sodium benzoate is excreted as hippuric acid in the urine within 4 hours.
    J) TOXICOKINETICS
    1) Benzoate exhibits nonlinear kinetics (prolonged elimination half-life) at higher doses.
    K) DIFFERENTIAL DIAGNOSIS
    1) Includes other agents that may cause metabolic acidosis.
    0.4.4) EYE EXPOSURE
    A) Irrigate exposed eyes with copious amounts of 0.9% saline or water.
    B) Patients with persistent irritation, pain, swelling, lacrimation, or photophobia after irrigation should have a thorough ophthalmologic exam, including slit lamp.
    0.4.5) DERMAL EXPOSURE
    A) OVERVIEW
    1) Remove contaminated clothing and wash exposed skin with soap and water.
    2) Dermal exposure commonly causes an acute non-immunologic contact urticaria. Urticaria typically occurs within 30 minutes of exposure, and is transient, lasting only 20 to 40 minutes. Administration of oral indomethacin has reportedly blocked this reaction.

Range Of Toxicity

    A) TOXICITY: ADULT: Ingestion of benzoic acid in amounts of 1 to 1.5 g in adults produced gastric pain, nausea, and vomiting; Sodium benzoate ingestions of up to 20 to 60 g daily have been tolerated. PEDIATRIC: 200 to 300 mg/kg/day orally, given to infants, caused lactic acidosis. Inadvertent oral administration of 800 mg/kg of sodium benzoate over 24 hours to a neonate with hyperammonemia resulted in vomiting and irritability. Oral administration of 1000 mg/kg/day to a 5.5-month-old child with nonketotic hyperglycemia resulted in metabolic acidosis, renal tubular dysfunction, hypokalemia, and hypocalcemia. Anion gap metabolic acidosis, agitation, and tachypnea developed in 3 pediatric patients (ages ranging from 2 to 6 years) following inadvertent IV overdoses of sodium benzoate and sodium phenylacetate, ranging from 750 mg/kg infused over 10 hours to 1750 mg/kg infused over 18 hours. Despite aggressive supportive care, 2 of the 3 patients developed cerebral edema and died within hours.
    B) THERAPEUTIC DOSE: ADULT: 55 mL/m(2) of Ammonul(R) IV over 90 to 120 minutes (loading dose), followed by the same dose over 24 hours (maintenance dose); provides 5.5 g/m(2) sodium phenylacetate, 5.5 g/m(2) sodium benzoate. CHILD: 0 TO 20 KG: 2.5 mL/kg of Ammonul(R) IV over 90 to 120 minutes (loading dose), followed by the same dose over 24 hours (maintenance dose); provides 250 mg/kg sodium phenylacetate, 250 mg/kg sodium benzoate. GREATER THAN 20 KG: 55 mL/m(2) of Ammonul(R) IV over 90 to 120 minutes (loading dose), followed by the same dose over 24 hours (maintenance dose); provides 5.5 g/m(2) sodium phenylacetate, 5.5 g/m(2) sodium benzoate.

Clinical Effects

Summary Of Exposure

    A) USES: Benzoates are widely used as preservatives in foods and pharmaceuticals; they are also used as buffering agents. Benzoic acid in combination with salicylic acid has been used as an antifungal agent. Sodium benzoate in combination with sodium phenylacetate is approved as adjunctive therapy for the treatment of acute hyperammonemia in adult and pediatric patients with urea cycle enzyme deficiencies.
    B) TOXICOLOGY: Benzoic acid is thought to inhibit oxidative enzymes in the tricarboxylic acid cycle, similar to salicylates, and may result in secondary lactic acid production. Metabolic acidosis may also be explained by a direct action of benzoic acid. Metabolism of benzyl alcohol to benzoic acid is postulated as the mechanism for toxicity in premature infants.
    C) EPIDEMIOLOGY: Benzoate exposures are extremely common due to their frequent use as preservatives and buffering agents, however, significant toxicity is rare.
    D) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: The primary effect expected from ingestion of moderate amounts of benzoates is gastrointestinal irritation with symptoms including nausea, vomiting, diarrhea, and abdominal pain. Benzoic acid is more irritating than benzoate salts. A non-immunologic contact dermatitis commonly occurs following dermal exposure. Renal tubular dysfunction and elevated free bilirubin levels may occur in a small number of cases.
    2) SEVERE TOXICITY: Large ingestions of benzoates may cause metabolic acidosis, elevated serum lactate levels, and associated tachypnea and Kussmaul respirations. Hypokalemia and hypocalcemia may also occur. Administration of benzyl alcohol to neonates has been associated with metabolic acidosis and gasping respirations. Seizures have been reported in experimental animals.

Heent

    3.4.2) HEAD
    A) MELKERSSON-ROSENTHAL SYNDROME: One case of a rare disorder involving recurrent upper lip and gum swelling has been associated with ingestion of sodium benzoate (Pachor et al, 1989).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) RESPIRATORY INSUFFICIENCY
    1) WITH POISONING/EXPOSURE
    a) Respiratory insufficiency progressing to gasping respirations has been noted in neonates receiving intravenous benzyl alcohol-containing fluids (Gershanik et al, 1982).
    B) HYPERVENTILATION
    1) CASE SERIES: Tachypnea and Kussmaul respirations were reported in three pediatric patients (ages ranging from 2 to 6 years) who developed metabolic acidosis after inadvertently receiving intravenous overdoses of sodium benzoate and sodium phenylacetate for treatment of acute hyperammonemia (Praphanphoj et al, 2000).

Neurologic

    3.7.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) SEIZURES
    a) Animals receiving lethal doses of sodium benzoate intravenously (LD50 1.7 g/kg) developed tremors, and clonic and tetanic seizures (Hager et al, 1942).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) GASTRITIS
    1) Ingestion of benzoic acid in amounts of 1 to 1.5 g in adults produced gastric pain, nausea, and vomiting (Hager et al, 1942; HSDB , 2001). Up to 500 mg is considered harmless (Lehman, 1912).
    B) DECREASED BODY GROWTH
    1) Infants receiving therapeutic doses of sodium benzoate for urea cycle disorders have been noted to have feeding disturbances and growth retardation. This may be attributed to mesaconic acid, a metabolite of a contaminant in sodium benzoate products (Matsuo et al, 1988).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) HYPERBILIRUBINEMIA
    1) Benzoic acid displaces bilirubin from albumin and may result in elevated free bilirubin levels (Schiff et al, 1971).

Genitourinary

    3.10.2) CLINICAL EFFECTS
    A) RENAL TUBULAR DISORDER
    1) CASE REPORT: Renal tubular dysfunction was reported in an infant who received 1 g/kg/day of sodium benzoate (Wolff et al, 1986).

Acid-Base

    3.11.2) CLINICAL EFFECTS
    A) ACIDOSIS
    1) BENZYL ALCOHOL: A syndrome in premature infants which included metabolic acidosis was attributed to the use of large volume parenterals containing benzyl alcohol preservatives. The acidosis was attributed to the benzoic acid metabolite (Gershanik et al, 1982) Brown et al, 1982).
    2) SODIUM BENZOATE: Metabolic acidosis was reported in an infant who received 1 g/kg/day orally of sodium benzoate (Wolff et al, 1986).
    3) CASE SERIES: Metabolic acidosis with increased anion gaps were reported in 3 pediatric patients (ages ranging from 2 to 6 years) following inadvertent intravenous overdoses of sodium benzoate and sodium phenylacetate, ranging from 750 mg/kg infused over 10 hours to 1750 mg/kg infused over 18 hours. The recommended dose of intravenous sodium benzoate and sodium phenylacetate is 250 mg/kg each infused over 90 minutes followed by 250 mg/kg each infused over 24 hours. Each patient also experienced agitation, tachypnea and Kussmaul respirations. Despite aggressive supportive care, two of the three patients died within hours after receiving the overdoses. Both patients had developed cerebral edema and one of the two patients also developed disseminated intravascular coagulation and hypotension prior to death (Praphanphoj et al, 2000).
    B) LACTIC ACIDOSIS
    1) Lactic acidosis has been observed in neonates treated with oral sodium benzoate, 200 to 300 mg/kg/day, to control hyperammonemia (Shinka et al, 1985).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) URTICARIA
    1) ONSET/DURATION: Dermal exposure to benzoic acid and sodium benzoate produces an immediate (within 30 minutes) erythema and edema in the majority of exposed individuals. The reaction is transient, lasting 20 to 40 minutes. Benzoic acid is more irritating than sodium benzoate (Munoz et al, 1996; Nethercott et al, 1984).
    2) The skin of the back is more sensitive to benzoic acid sensitivity than the hands, forearms, or soles of feet (Lahti, 1980).
    3) Another study showed the greatest sensitivity on the face, with decreasing reactivity when applied to the antecubital space, inner forearm, lower back, and leg (Gollhausen & Kligman, 1985).
    4) The cheek area is the most sensitive part of the face (Larmi et al, 1989).
    5) INCIDENCE: The application of 5% benzoic acid to the back will produce contact dermatitis in 80% of test subjects (Lahti, 1980).
    6) CASE REPORT: A 5-year-old boy experienced perioral erythema within minutes after brushing his teeth with a toothpaste containing sodium benzoate 4%. The erythema spontaneously disappeared within 30 minutes after discontinuing use of the toothpaste. The boy experienced a similar erythema of the face and neck after application of a lotion containing benzoic acid. Open and closed patch tests with sodium benzoate 4% were positive (Munoz et al, 1996).

Immunologic

    3.19.2) CLINICAL EFFECTS
    A) ANAPHYLACTOID REACTION
    1) CASE REPORT: Anaphylactoid reactions (chest pain, dyspnea, shock) were reported in a 24-year-old man with severe liver failure who received 6 grams of sodium benzoate orally on 2 occasions. Granulocytopenia and eosinophilia were also present (Kinsey & Wright, 1944).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor serum electrolytes, renal function, liver enzymes, blood gases, and lactate levels in patients with evidence of toxicity.
    B) Institute cardiac monitoring and obtain an ECG in patients with toxicity.
    C) Benzoate concentrations are not widely available or clinically useful for acute management.
    4.1.2) SERUM/BLOOD
    A) BLOOD/SERUM CHEMISTRY
    1) Monitor serum electrolytes, renal function, liver enzymes, blood gases, and lactate levels in patients with evidence of toxicity.
    2) Benzoate concentrations are not widely available or clinically useful for acute management.
    B) ACID/BASE
    1) Monitor acid-base (arterial blood gases, pH) status in large ingestions.
    4.1.3) URINE
    A) OTHER
    1) HIPPURIC ACID: Elevated hippuric acid levels may be seen in the urine; a relationship of these levels to toxicity has not been established.
    4.1.4) OTHER
    A) OTHER
    1) ECG
    a) Institute cardiac monitoring and obtain an ECG in patients with toxicity.

Methods

    A) CHROMATOGRAPHY
    1) Benzoate can be measured by high pressure liquid chromatography (Green et al, 1983).

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.1) ADMISSION CRITERIA/ORAL
    A) Patients who develop gastrointestinal irritation or other signs of benzoate toxicity after a known exposure should be admitted to the hospital. Patients who develop evidence of severe toxicity with acidosis, tachypnea, altered mental status, or seizures should be admitted to an ICU.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Contact your local poison center for a toxicology consult for any patient with suspected benzoate toxicity and acidosis, seizures, or other end-organ toxicity.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Patients with known large ingestions may be watched clinically for the development of toxicity such as gastrointestinal irritation and acidosis.

Monitoring

    A) Monitor serum electrolytes, renal function, liver enzymes, blood gases, and lactate levels in patients with evidence of toxicity.
    B) Institute cardiac monitoring and obtain an ECG in patients with toxicity.
    C) Benzoate concentrations are not widely available or clinically useful for acute management.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) Gastrointestinal decontamination is not generally recommended as acute toxicity is limited. Remove contaminated clothing and wash exposed skin with soap and water. Irrigate exposed eyes with copious amounts of water.
    6.5.2) PREVENTION OF ABSORPTION
    A) Gastrointestinal decontamination is not generally recommended as acute toxicity is limited.
    6.5.3) TREATMENT
    A) SUPPORT
    1) MANAGEMENT OF MILD TO MODERATE TOXICITY
    a) Treatment of mild to moderate toxicity consists of predominantly symptomatic and supportive care.
    2) MANAGEMENT OF SEVERE TOXICITY
    a) Treatment for severe toxicity consists of predominantly symptomatic and supportive care. Treat severe metabolic acidosis (pH less than 7.1) with sodium bicarbonate 1 to 2 mEq/kg to maintain hemodynamic stability, however the long-term benefit of this treatment has not been shown. Seizures should be treated with benzodiazepines as needed; NOTE: diazepam IV contains 5% sodium benzoate and benzoic acid as buffering agents, therefore, an alternative benzodiazepine such as lorazepam or midazolam may be a better choice.
    B) MONITORING OF PATIENT
    1) Monitor serum electrolytes, renal function, liver enzymes, blood gases, and lactate levels in patients with evidence of toxicity.
    2) Institute cardiac monitoring and obtain an ECG in patients with toxicity.
    3) Benzoate concentrations are not widely available or clinically useful for acute management.
    C) ACIDOSIS
    1) METABOLIC ACIDOSIS: Treat severe metabolic acidosis (pH less than 7.1) with sodium bicarbonate, 1 to 2 mEq/kg is a reasonable starting dose(Kraut & Madias, 2010). Monitor serum electrolytes and arterial or venous blood gases to guide further therapy.
    D) SEIZURE
    1) Seizures should be treated with benzodiazepines as needed; NOTE: diazepam IV contains 5% sodium benzoate and benzoic acid as buffering agents (Prod Info diazepam IM, IV injection, 2008), therefore, an alternative benzodiazepine such as lorazepam or midazolam may be a better choice.
    2) LORAZEPAM
    a) MAXIMUM RATE: The rate of intravenous administration of lorazepam should not exceed 2 mg/min (Brophy et al, 2012; Prod Info lorazepam IM, IV injection, 2008).
    b) ADULT DOSE: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed, if seizures persist (Manno, 2003; Brophy et al, 2012).
    c) PEDIATRIC DOSE: 0.05 to 0.1 mg/kg IV over 2 to 5 minutes, up to a maximum of 4 mg/dose; may repeat in 5 to 15 minutes as needed, if seizures continue (Brophy et al, 2012; Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008; Sreenath et al, 2009; Chin et al, 2008).
    3) PHENOBARBITAL
    a) ADULT LOADING DOSE: 20 mg/kg IV at an infusion rate of 50 to 100 mg/minute IV. An additional 5 to 10 mg/kg dose may be given 10 minutes after loading infusion if seizures persist or recur (Brophy et al, 2012).
    b) Patients receiving high doses will require endotracheal intubation and may require vasopressor support (Brophy et al, 2012).
    c) PEDIATRIC LOADING DOSE: 20 mg/kg may be given as single or divided application (2 mg/kg/minute in children weighing less than 40 kg up to 100 mg/min in children weighing greater than 40 kg). A plasma concentration of about 20 mg/L will be achieved by this dose (Loddenkemper & Goodkin, 2011).
    d) REPEAT PEDIATRIC DOSE: Repeat doses of 5 to 20 mg/kg may be given every 15 to 20 minutes if seizures persist, with cardiorespiratory monitoring (Loddenkemper & Goodkin, 2011).
    e) MONITOR: For hypotension, respiratory depression, and the need for endotracheal intubation (Loddenkemper & Goodkin, 2011; Manno, 2003).
    f) SERUM CONCENTRATION MONITORING: Monitor serum concentrations over the next 12 to 24 hours. Therapeutic serum concentrations of phenobarbital range from 10 to 40 mcg/mL, although the optimal plasma concentration for some individuals may vary outside this range (Hvidberg & Dam, 1976; Choonara & Rane, 1990; AMA Department of Drugs, 1992).
    4) OTHER AGENTS
    a) If seizures persist after phenobarbital, propofol or pentobarbital infusion, or neuromuscular paralysis with general anesthesia (isoflurane) and continuous EEG monitoring should be considered (Manno, 2003). Other anticonvulsants can be considered (eg, valproate sodium, levetiracetam, lacosamide, topiramate) if seizures persist or recur; however, there is very little data regarding their use in toxin induced seizures, controlled trials are not available to define the optimal dosage ranges for these agents in status epilepticus (Brophy et al, 2012):
    1) VALPROATE SODIUM: ADULT DOSE: An initial dose of 20 to 40 mg/kg IV, at a rate of 3 to 6 mg/kg/minute; may give an additional dose of 20 mg/kg 10 minutes after loading infusion. PEDIATRIC DOSE: 1.5 to 3 mg/kg/minute (Brophy et al, 2012).
    2) LEVETIRACETAM: ADULT DOSE: 1000 to 3000 mg IV, at a rate of 2 to 5 mg/kg/min IV. PEDIATRIC DOSE: 20 to 60 mg/kg IV (Brophy et al, 2012; Loddenkemper & Goodkin, 2011).
    3) LACOSAMIDE: ADULT DOSE: 200 to 400 mg IV; 200 mg IV over 15 minutes (Brophy et al, 2012). PEDIATRIC DOSE: In one study, median starting doses of 1.3 mg/kg/day and maintenance doses of 4.7 mg/kg/day were used in children 8 years and older (Loddenkemper & Goodkin, 2011).
    4) TOPIRAMATE: ADULT DOSE: 200 to 400 mg nasogastric/orally OR 300 to 1600 mg/day orally divided in 2 to 4 times daily (Brophy et al, 2012).

Eye Exposure

    6.8.1) DECONTAMINATION
    A) EYE IRRIGATION, ROUTINE: Remove contact lenses and irrigate exposed eyes with copious amounts of room temperature 0.9% saline or water for at least 15 minutes. If irritation, pain, swelling, lacrimation, or photophobia persist after 15 minutes of irrigation, an ophthalmologic examination should be performed (Peate, 2007; Naradzay & Barish, 2006).
    6.8.2) TREATMENT
    A) SUPPORT
    1) Patients with persistent irritation, pain, swelling, lacrimation, or photophobia after irrigation should have a thorough ophthalmologic exam, including slit lamp.
    B) Treatment should include recommendations listed in the ORAL EXPOSURE section when appropriate.

Dermal Exposure

    6.9.1) DECONTAMINATION
    A) DERMAL DECONTAMINATION
    1) DECONTAMINATION: Remove contaminated clothing and wash exposed area thoroughly with soap and water for 10 to 15 minutes. A physician may need to examine the area if irritation or pain persists (Burgess et al, 1999).
    6.9.2) TREATMENT
    A) ACUTE ALLERGIC REACTION
    1) CONTACT URTICARIA induced by benzoates is transient, usually lasting 20 to 40 minutes. Indomethacin 50 mg three times a day given orally has been demonstrated to block this reaction (Lahti et al, 1983).
    B) Treatment should include recommendations listed in the ORAL EXPOSURE section when appropriate.

Enhanced Elimination

    A) SUMMARY
    1) Efficacy of enhanced elimination techniques is unknown. Hemodialysis may be useful to treat severe acidosis or in cases that develop renal failure.
    B) PERITONEAL DIALYSIS
    1) Unconjugated benzoate was not removed by peritoneal dialysis in neonates (Green et al, 1983).

Abstracts

Case Reports

    A) INFANT
    1) Inadvertent oral administration of 800 mg/kg of sodium benzoate over 24 hours to a neonate with hyperammonemia resulted in vomiting and irritability. The plasma benzoate level peaked at 123 mg/dL. Symptoms resolved within 12 hours of discontinuation (Batshaw et al, 1982).
    2) Administration of 792 mg/kg/day for 2 days of sodium benzoate orally to a 30-month-old girl with argininosuccinicaciduria resulted in irritability and vomiting, which resolved within 12 hours of discontinuation. The serum benzoate level rose from undetectable to 124 mg/dL. No electrolyte abnormalities, hepatic, or renal dysfunction were noted (Batshaw et al, 1981).
    3) Oral administration of 1000 mg/kg/day to a 5-1/2 month old child with nonketotic hyperglycemia resulted in renal tubular dysfunction, metabolic acidosis, a potassium level of 2.4 mEq/L, bicarbonate level of 16 mEq/L, and calcium level of 8 mg/dL which decreased to 4.8 mg/dL five days later. Septic shock developed. Discontinuation of benzoate resulted in normalization of electrolyte abnormalities (Wolff et al, 1986).

Range Of Toxicity

Therapeutic Dose

    7.2.1) ADULT
    A) 55 mL/m(2) of Ammonul(R) IV over 90 to 120 minutes (loading dose), followed by the same dose over 24 hours (maintenance dose); provides 5.5 g/m(2) sodium phenylacetate, 5.5 g/m(2) sodium benzoate. Both the loading and maintenance doses should be given in combination with arginine HCl 10% IV 2 mL/kg (for patients with carbamyl phosphate synthetase (CPS) or ornithine transcarbamylase (OTC) deficiency), which provides 200 mg/kg of arginine HCl, or 6 mL/kg (for patients with argininosuccinate synthetase (ASS) or argininosuccinate lyase (ASL) deficiency), which provides 600 mg/kg of arginine HCl (Prod Info AMMONUL(R) IV injection, 2011)
    7.2.2) PEDIATRIC
    A) 0 TO 20 KG
    1) 2.5 mL/kg of Ammonul(R) IV over 90 to 120 minutes (loading dose), followed by the same dose over 24 hours (maintenance dose); provides 250 mg/kg sodium phenylacetate, 250 mg/kg sodium benzoate. Both the loading and maintenance doses should be given in combination with arginine HCl 10% IV 2 mL/kg (for patients with carbamyl phosphate synthetase (CPS) or ornithine transcarbamylase (OTC) deficiency), which provides 200 mg/kg of arginine HCl, or 6 mL/kg (for patients with argininosuccinate synthetase (ASS) or argininosuccinate lyase (ASL) deficiency), which provides 600 mg/kg of arginine HCl (Prod Info AMMONUL(R) IV injection, 2011)
    B) GREATER THAN 20 KG
    1) 55 mL/m(2) of Ammonul(R) IV over 90 to 120 minutes (loading dose), followed by the same dose over 24 hours (maintenance dose); provides 5.5 g/m(2) sodium phenylacetate, 5.5 g/m(2) sodium benzoate. Both the loading and maintenance doses should be given in combination with arginine HCl 10% IV 2 mL/kg (for patients with carbamyl phosphate synthetase (CPS) or ornithine transcarbamylase (OTC) deficiency), which provides 200 mg/kg of arginine HCl, or 6 mL/kg (for patients with argininosuccinate synthetase (ASS) or argininosuccinate lyase (ASL) deficiency), which provides 600 mg/kg of arginine HCl (Prod Info AMMONUL(R) IV injection, 2011)

Minimum Lethal Exposure

    A) CASE SERIES/CHILD: Metabolic acidosis with increased anion gaps were reported in 3 pediatric patients (ages ranging from 2 to 6 years) following inadvertent intravenous overdoses of sodium benzoate and sodium phenylacetate, ranging from 750 mg/kg infused over 10 hours to 1750 mg/kg infused over 18 hours. The recommended dose of intravenous sodium benzoate and sodium phenylacetate is 250 mg/kg each infused over 90 minutes followed by 250 mg/kg each infused over 24 hours. Each patient also experienced agitation, tachypnea and Kussmaul respirations.
    1) Despite aggressive supportive care, two of the three patients died within hours after receiving the overdoses. Both patients had developed cerebral edema and one of the two patients also developed disseminated intravascular coagulation and hypotension prior to death (Praphanphoj et al, 2000).

Maximum Tolerated Exposure

    A) ADULT
    1) Ingestion of benzoic acid in amounts of 1 to 1.5 grams in adults produced gastric pain, nausea, and vomiting (Hager et al, 1942; HSDB , 2001).
    2) Older reports indicate that oral ingestion of doses as large as 25 to 60 grams daily of sodium benzoate in adults can be tolerated (Bryan, 1925).
    B) INFANT
    1) Lactic acidosis has been noted in infants receiving 200 to 300 mg/kg/day of sodium benzoate orally (Shinka et al, 1985).
    2) Inadvertent oral administration of 800 mg/kg of sodium benzoate over 24 hours to a neonate with hyperammonemia resulted in vomiting and irritability. The plasma benzoate level peaked at 123 mg/dL. Symptoms resolved within 12 hours of discontinuation (Batshaw et al, 1982).
    3) Oral administration of 1000 mg/kg/day to a 5-1/2 month old child with nonketotic hyperglycemia resulted in renal tubular dysfunction, with metabolic acidosis, a potassium level of 2.4 mEq/L, bicarbonate level of 16 mEq/L, and calcium level of 8 mg/dL which decreased to 4.8 mg/dL five days later. Septic shock developed. Discontinuation of benzoate resulted in normalization of electrolyte abnormalities (Wolff et al, 1986).

Summary

    A) TOXICITY: ADULT: Ingestion of benzoic acid in amounts of 1 to 1.5 g in adults produced gastric pain, nausea, and vomiting; Sodium benzoate ingestions of up to 20 to 60 g daily have been tolerated. PEDIATRIC: 200 to 300 mg/kg/day orally, given to infants, caused lactic acidosis. Inadvertent oral administration of 800 mg/kg of sodium benzoate over 24 hours to a neonate with hyperammonemia resulted in vomiting and irritability. Oral administration of 1000 mg/kg/day to a 5.5-month-old child with nonketotic hyperglycemia resulted in metabolic acidosis, renal tubular dysfunction, hypokalemia, and hypocalcemia. Anion gap metabolic acidosis, agitation, and tachypnea developed in 3 pediatric patients (ages ranging from 2 to 6 years) following inadvertent IV overdoses of sodium benzoate and sodium phenylacetate, ranging from 750 mg/kg infused over 10 hours to 1750 mg/kg infused over 18 hours. Despite aggressive supportive care, 2 of the 3 patients developed cerebral edema and died within hours.
    B) THERAPEUTIC DOSE: ADULT: 55 mL/m(2) of Ammonul(R) IV over 90 to 120 minutes (loading dose), followed by the same dose over 24 hours (maintenance dose); provides 5.5 g/m(2) sodium phenylacetate, 5.5 g/m(2) sodium benzoate. CHILD: 0 TO 20 KG: 2.5 mL/kg of Ammonul(R) IV over 90 to 120 minutes (loading dose), followed by the same dose over 24 hours (maintenance dose); provides 250 mg/kg sodium phenylacetate, 250 mg/kg sodium benzoate. GREATER THAN 20 KG: 55 mL/m(2) of Ammonul(R) IV over 90 to 120 minutes (loading dose), followed by the same dose over 24 hours (maintenance dose); provides 5.5 g/m(2) sodium phenylacetate, 5.5 g/m(2) sodium benzoate.

Serum Plasma Blood Concentrations

    7.5.2) TOXIC CONCENTRATIONS
    A) TOXIC CONCENTRATION LEVELS
    1) PEDIATRIC
    a) The plasma benzoate concentration was 123 milligrams/deciliter in a 4-year-old girl who received 5.6 millimoles/kilogram/day (800 milligrams/kilogram/day); vomiting and irritability were noted (Batshaw et al, 1982).
    b) Toxic effects were only seen with plasma levels greater than 80 milligrams/deciliter (Batshaw et al, 1982).
    c) The serum benzoate level, in a 3-year-old girl, peaked at 10.60 mmol/L four hours after receiving intravenously 915 mg/kg of sodium benzoate and sodium phenylacetate infused over 12 hours. The patient recovered following hemodialysis (Praphanphoj et al, 2000).
    2) NEONATE
    a) It is suggested that serum levels be maintained below 1.6 millimoles/liter in neonates (Green et al, 1983).

Toxicity Information

    7.7.1) TOXICITY VALUES

Pharmacology Toxicology

Toxicologic Mechanism

    A) ACIDOSIS
    1) Benzoic acid inhibits oxidative enzymes in the tricarboxylic acid cycle, similar to salicylates, and may result in secondary lactic acid production (Kaplan et al, 1954).
    2) Metabolic acidosis may also be explained by a direct action of benzoic acid (Menon et al, 1984).
    B) GASPING SYNDROME
    1) Benzyl alcohol is oxidized in the liver to benzoic acid, then conjugated with glycine, and excreted in the urine as hippuric acid. Infants are less able to metabolize benzoic acid to hippuric acid, possibly because of glycine deficiency. Therefore, benzoic acid will be accumulated, causing "gasping syndrome" in the neonates receiving an IV product containing benzyl alcohol (HSDB, 2009).
    2) A comparison of serum and urine benzoic acid and hippuric acid levels, measured in preterm (n=9) and term (n=14) neonates who received loading doses of phenobarbital containing benzyl alcohol, demonstrated that there were higher normalized peak benzoic acid serum levels (2130.6 vs 237.8 kg/L,) and larger normalized AUC (1,253.2 vs 483 kg.h/L) in the preterm neonate, indicating greater accumulation of serum benzoic acid in the preterm neonates than in the term neonates. There were also greater amounts of benzoic acid and less hippuric acid found in the urine of the preterm neonates than in the term neonates, suggesting that the formation of hippuric acid is deficient in the preterm neonate and that the liver and kidney may be too immature to handle detoxification of the benzoic acid load (as the metabolite of benzyl alcohol) via glycine conjugation in order to form hippuric acid (LeBel et al, 1988).

Physicochemical

Physical Characteristics

    A) Benzoic acid: White scales or needle crystals that are odorless or with a slight benzaldehyde-like odor and may have a bitter taste (HSDB , 2001).
    B) Sodium benzoate: White, odorless granules or crystalline powder with a sweetish, astringent taste that is soluble in water and alcohol (Prod Info AMMONUL(R) IV injection, 2011; HSDB , 2001; Budavari, 1996).

Ph

    A) Benzoic acid: 2.8 (for a saturated solution) (HSDB , 2001)
    B) Sodium benzoate: 8 in an aqueous solution (HSDB , 2001)
    C) Sodium benzoate/sodium phenylacetate: 6 to 8 (IV solution) (Prod Info AMMONUL(R) IV injection, 2011)

Molecular Weight

    A) Benzoic acid: 122.13 (HSDB , 2001)
    B) Sodium benzoate: 144.11 (Prod Info AMMONUL(R) IV injection, 2011)

References

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