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Description of key information

A toxicokinetic review  and assesment was prepared (NOTOX 2010) that confirmed the reasoning and review of the WHO CICAD report (CICAD 26, 2005). In addition two toxicokinetic studies with human volunteers (Kubota 1990, MacArthur 2003) indicated that the test substance and benzoic acid are metabolised to hippuric acid  via Michaelis-Menten (saturisation) kinetics following a one compartment model. Elimination at higher doses was reported to be non-linear. This pathway is confirmed in humans by the findings of Albert (1925) and Griffith (1929) and several case studies (Busulow 1979, Schachter 1956).  

Based on toxicokinetic considerations it is concluded that the test substance and benzoic acid are expected to lead to similar toxicodynamic effects, as the entity entering the body is undissociated benzoic acid for both substances.

Key value for chemical safety assessment

Bioaccumulation potential:
no bioaccumulation potential

Additional information

After oral ingestion benzoic acid and the test substance are rapidly absorbed (100% assumed). Dermal absorption is less effective and inversely proportional to the dose (14 -43%). No data on uptake after inhalation is available.

Benzoic acid and the test substance are primarily metabilised by conjugation with glycine, resulting in the formation of hippuric acid. After depletion of glycine (Michaelis-Manten kinetics) conjugation with glucuronide is reported. Neonates are capable of clearance of the testsubstance and hippuric acid in a slightly less efficient way (Green 1983). Experiments on the distribution and elimination of 14C-benzoate in the rat have shown no accumulation of the test substance or benzoic acid in the body. Excretion of the metabolites is rapid via urine.

This pathway is confirmed in humans by the findings of Albert (1925) and Griffith (1929) and several case studies (Busulow 1979, Schachter 1956) that show large amounts of hippuric acid in urine after exposure to the test substance.

In the acid conditions of the stomach, the equilibrium moves to the undissociated benzoic acid molecule, which should be absorbed

rapidly. Benzoate from the test substance would change from the ionized form to the undissociated benzoic acid molecule. As a result, the metabolism and systemic effects of benzoic acid and the test substance can be evaluated together.