BENZOIC ACID

Toxicology

After oral ingestion of benzoic acid and sodium benzoate, there is a rapid and extensive absorption (of undissociated benzoic acid) from the gastrointestinal tract.  In humans, the peak plasma concentration is
reached within 1-2 h (IPCS,2000).

Benzoic acid/salt has a small volume of distribution (estimated 0.14 L/kg in neonates).

Benzoic acid is poorly absorbed by the dermal route.

In the liver, the absorbed benzoic acid is metabolized rapidly in the liver by conjugation with glycine resulting in the formation of hippuric acid. Hippuric acid is rapidly excreted in urine within 4 hours (IPCS,2000). However, Benzoate exhibits nonlinear kinetics (prolonged elimination half-life) at higher doses.

The limiting factor in the metabolism of benzoic acid is the availability of glycine. In the presence of a large ingestion, the body glycine levels are exhausted by the detoxification process. This then affects any metabolic process in which glycine is involved; for example, it leads to a reduction in creatinine, glutamine, urea, and uric acid levels (IPCS,2000).

Other benzoic acid metabolites include benzoyl glucuronide, minor amounts of unchanged benzoic acid, are also excreted in the urine (IPCS,2000).

Toxic effects of benzoic acid may result from inhibition of metabolic processes-urea cycle, gluconeogenesis, fatty acid metabolism, carnitine status, and the tricarboxylic acid cycle (similar to salicylates and may result in lactic acidosis)-attributed to depletion of coenzyme A by benzoate (forms benzoyl coenzyme A intermediate) as a result of glycine depletion.

The acute toxicity of benzoic acid and its salts is low (Rat,Oral LD50, 3040mg/kg bw). It is slightly irritating to skin and the eye (IPCS,2000)

In a study with volunteers given doses ranging from 1000-2500 mg/day for 5 days each, there were symptoms of toxicity including malaise, nausea, headache, weakness, burning and irritation of esophagus (IPCS,2000).

The clinical signs of intoxication reported in rats  included diarrhoea, muscular weakness, tremors, and hypoactivity (IPCS,2000).

Benzoic acid may be sensitizing to a small group of individuals. Cases of urticaria, asthma, rhinitis, or anaphylactic shock have occurred following exposure to benzoic acid and sodium benzoate.

Metabolic acidosis may also occur due to TCA cycle blockade and  by a direct action of benzoic acid.

Clinical Manifestation

Ingestion of moderate amounts of benzoates may cause gastrointestinal irritation with symptoms including
nausea, vomiting, diarrhea, and abdominal pain. some few patients may experience renal tubular dysfunction and elevated free bilirubin levels.

Large ingestions of benzoic acid my result in metabolic acidosis, high serum lactate associated tachypnea and Kussmaul  breathings. Seizures, hypokalemia and hypocalcemia may also occur.

 

 

Clinical Management

Treatment of intoxication is predominantly symptomatic and supportive.

Gastrointestinal decontamination is not generally recommended due to its low acute toxicity potential.
Remove contaminated clothing and wash exposed skin with soap and water.

Treat severe metabolic acidosis (pH less than 7.1) with sodium bicarbonate 1-2 mEq/kg to maintain hemodynamic stability.

Treat seizures with benzodiazepines such as lorazepam or midazolam . AVOID diazepam IV which contains 5% sodium benzoate and benzoic acid as buffering agents.

Hemodialysis may be helpful in managing severe acidosis or in cases of renal failure

Monitor serum electrolytes, renal function, liver enzymes, blood gases, and lactate levels

Note

The fate of glucuronidated drugs in urine or bile depends on their molecular size. Compounds with relatively low molecular weights are almost completely excreted in urine, whereas those with high molecular weights (>500) are eliminated almost entirely in bile (IPCS,2000).

Ingestion of 1 to 1.5 g benzoic acid in adults produced gastrointestinal toxicity, although sodium benzoate ingestions of up to 20 to 60 g daily have been tolerated.

200 to 300 mg/kg/day orally, given to infants, caused lactic acidosis.

References

IPCS, International Programme on Chemical Safety, (2000). Concise International Chemical assessment Documents No 26. Benzoic acid and sodium benzoate.https://www.inchem.org/documents/cicads/cicads/

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