Sodium benzoate

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics

Type of information:

other: assessment based on all available information

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Non-GLP assessment report

Data source

Reference

Reference Type:

other company data

Title:

Unnamed

Year:

2010

Report date:

2010

Materials and methods

Test material

Test material information

Constituent 1

Reference substance name:

Sodium benzoate

EC Number:

208-534-8

EC Name:

Sodium benzoate

Cas Number:

532-32-1

Molecular formula:

C7H6O2.Na

IUPAC Name:

sodium benzoate

Constituent 2

Reference substance name:

Benzoic acid, sodium salt

IUPAC Name:

Benzoic acid, sodium salt

Results and discussion

Any other information on results incl. tables

For the test substance, information on absorption, distribution, metabolism and excretion is available on experimental animals and on human. An overview of the information is given below.

After oral ingestion of the test substance, there is a rapid absorption from the gastro-intestinal tract in experimental animals and in humans. In the acid conditions of the stomach, benzoate from the test substance would change from the ionized form to the undissociated benzoic acid molecule which should be absorbed rapidly. This is comparable to benzoic acid, for which the equilibrium moves to the undissociated benzoic acid molecule, and is absorbed rapidly. As a result, the metabolism and systemic effects of benzoic acid and the test substance can be evaluated together. Consequently, as for benzoic acid, glycine conjugation is considered to be the main route of metabolism, resulting in the formation of hippuric acid (benzoyl-glycine) which will be excreted in urine. 

For benzoic acid the following information on oral absorption, metabolism and excretion was available: The urinary excretion of orally administered 14C-benzoic acid in man and 20 species of animals was examined by Bridges and coworkers, with hippuric acid (benzoyl-glycine) generally being the major urinary metabolite in the species studied. At an oral dose of 50 mg/kg bw, benzoic acid was excreted by rodents in urine, with 50-100% of the administerd dose within 24 hours. Excretion occurred almost entirely as the metabilote hippuric acid (95-100% of the administered dose excreted within 24 hr). After ip administration of 14C-benzoic acid (100μmol/100 g bw or 200 mg/kg bw), 75-90% of the administered14C excreted in 24 hr, of which 99% hippuric acid and trace of benzoyl glucuronide. An oral dose of 2 mg/kg bw14C-benzoic acid resulted in only 0.04% of the applied dose in urinary benzoylcarnitine.

In man at a dose of 1 mg/kg benzoic acid was excreted entirely as hippuric acid.

Benzoic acid metabolism, as a function of liver mitochondria, depends on the concentrations of ATP, CoA and glycine in the mitochondrial matrix. Although drug metabolism is primarily a liver function, also kidneys have shown to contain appreciable amounts of metabolizing enzymes. The metabolism of benzoic acid to hippuric acid and glucuronide has been studied in viable hepatocytes and renal tubule fragments from rat, hamster, ferret and dog. Hippuric acid formation was observed in hepatocytes and renal tubules from rat and hamster; a small amount of glucuronidation occurred in hepatocytes of all species tested. However, the liver is quantitatively the most important organ because the renal medulla has only low synthetic activity and the mass of the liver exceeds that of the kidneys.

Based on the observations on excretion of hippuric acid after oral benzoic acid administration, it can be concluded that benzoic acid will be absorbed almost completely in the gastro-intestinal tract. For risk assessment purposes the oral absorption of benzoic acid is set at 100% absorption. Experiments on the distribution and elimination in the rat have shown no accumulation of benzoic acid in the body.  

There is no information available on absorption via inhalation. The high boiling point indicates that the test substance will not be available for inhalation as a vapour. The particle size (only 1.3%<125μm) indicates that the amount of inhalable/respirable particles is negligible. Based on these properties, no significant respiratory exposure and hence no significant inhalation absorption is to be expected. If however during use of the substance particles between 100 and 10μm are generated, these will deposit in the nasopharyngeal region and subsequently be coughed or sneezed out of the body or swallowed. Particles below 10μm mightthe tracheobronchial or pulmonary regions. Based on its water solubility (556 g/L) the test substance will disolve in the mucus lining of the repiratory tract, and can be absorbed through aqueous pores (MW<200). As for its hydrophilic character (log Pow = 1.88), the test substance has no potential to be absorbed directly across the repiratory tract epithelium. When the test substance is inhaled (particles < 10μm), the inhalation absorption of the test substance for risk assessment purposes, based on the physical chemical properties of the test substance, is set at 50%.

For the test substance, no data concerning dermal uptake were identified in the literature. the test substance is a solid with a moderate molecular weight and good water solubility, indicative for dermal uptake. However, the log Pow<0 is not favourable for dermal uptake. Based on physical/chemical properties of the test substance, the criteria for 10% dermal absorption as given in the TGD are not met (MW>500 and -1<log Pow>4), meaning that 100 % dermal absorption needs to be considered for risk assessment purposes.

After dermal absorption (similar to oral absorption), it is considered that metabolism and systemic effects of benzoic acid and the test substance can be evaluated together. This means that after dermal absorption, the test substance, comparable to benzoic acid, will be metabolised to hippuric acid.

In the WHO report of benzoic acid and the test substance (Concise International Chemical Assessment Document 26, WHO, 2000) the following was concluded on toxicokinetics:

After oral uptake, benzoic acid and the test substance are rapidly absorbed from the gastrointestinal tract and metabolized in the liver by conjugation with glycine, resulting in the formation of hippuric acid, which is rapidly excreted via the urine. To a lesser extent, benzoates applied dermally can penetrate through the skin. Owing to rapid metabolism and excretion, an accumulation of the benzoates or their metabolites is not to be expected.

 

 

Applicant's summary and conclusion

Conclusions:

Interpretation of results (migrated information): no bioaccumulation potential based on study results
Overall there are signs of systemic absorption via oral and dermal exposures, no evidence of target organs or of excretion. After oral ingestion and dermal absorption, the test substance will be metabolised to hippuric acid. Despite the low log Pow value, results of the 28-day study in rats and the predicted metabolism do not indicate a potential for the substance to bioaccumulate.

Executive summary:

With reviewing the existing data, for the test substance, information on absorption, distribution, metabolism and excretion is available on experimental animals and on human. A toxicokinetic assessment has been performed based on physical chemical properties of the substance and available open literature. Overall there are signs of systemic absorption via oral and dermal exposures, no evidence of target organs or of excretion. After oral ingestion and dermal absorption, the test substance will be metabolised to hippuric acid. Despite the low log Pow value, results of the 28-day study in rats and the predicted metabolism do not indicate a potential for the substance to bioaccumulate.