Toxicological Evaluation and Limit Values for Nonylphenol, Nonylphenol Ethoxylates, Tricresyl, Phosphates and Benzoic Acid

2. Toxicokinetics

2. Toxicokinetics
2.1 Absorption, distribution
2.2 Elimination
2.3 Toxicological mechanisms

Inhalation

No data after inhalation have been found.

Oral, subcutaneous and intraperitoneal exposure

Benzoic acid is rapidly and almost completely absorbed after oral administration in man and oral, intraperitoneal and subcutaneous administration in animals. (JECFA 1983, IUCLID 1996).

Dermal contact

After dermal application of ¹⁴C-labelled benzoic acid to humans in doses of 4, 40, and 2000 µg/cm² a percutaneous absorption at 42.6%, 25.7% and 14.4%, respectively was measured. Studies in rhesus monkeys as well as humans showed that the greater topical doses of benzoic acid the less percutaneous absorption. Studies have shown that percutaneous absorption and absorption rate of benzoic acid is greater in human than in hairless dogs, whereas the absorption in guinea pigs is similar to that in humans (Maibach & Wester 1989 - quoted from IUCLID 1996).

Transdermal absorption of benzoic acid has been studied in vitro in excised human skin and compared to absorption in living man. In equivalent time, 44.9% and 42.6%, respectively of the applied dose was absorbed (Franz 1975 - quoted from IUCLID 1996).

Percutaneous absorption of ¹⁴C-labelled benzoic acid in aged people (> 65 years) was lower than in young people (18-40 years). The cumulative dose absorbed within seven days was 19.5% and 36.2%, respectively (Roskos et al. 1989 - quoted from IUCLID 1996).

Benzoic acid is conjugated in the liver and two metabolites of have been detected: hippuric acid and benzoyl-glucuronic acid.

Endogenous formation of benzoic acid takes place in the organism where phenylalanine and tyrosine are precursors. Experiments with labelled phenylalanine have shown that about 1-2% is metabolised to benzoic acid. This leads to excretion of a few tens of mg benzoic acid/kg bw/day in human urine. (JECFA 1983).

Benzoic acid is nearly completely excreted in urine in animals as well as man. Less than 1% appears in the faeces. The excretion occur mostly in the form of hippuric acid (the glycine conjugate). A smaller part is excreted as benzoyl-glucuronic acid (the glucuronyl conjugate) and free benzoic acid. In man and most experimental animals the liver is the main site of conjugation. Depletion of glycine is the limiting rate of excretion of hippuric acid. Administered benzoic acid (p.o., i.p., s.c.) is excreted within 24 hours. Tissue accumulation does not occur. (JECFA 1983).

In swine dermal exposure lead to urinary excretion of about 20% and faecal excretion of about 3% of the administered dose within six days (Carver & Riviere 1989 - quoted from IUCLID 1996).

2.3 Toxicological mechanisms

Depletion of glycine, due to the formation of the main metabolite glycine conjugate (hippuric acid), may explain some of the adverse effects seen in experimental animals and man. Experiments in rats have shown that addition of glycine to the diet reduced the toxicity of benzoic acid (Griffith 1929 and Kowalewski 1960 - quoted from JECFA 1983).

Although glycine is not an essential amino acid it appears that in growing animals or in animals subjected to injury there is a narrow margin between the metabolic demand of glycine and the rate at which glycine is formed or made available in the body. Further, shortage of glycine in the body can lead to disturbances in the acid-base equilibrium due to increased concentrations of benzoic acid in the organism. High doses of benzoic acid per se may also lead to disturbances in the body acid-base balance. (JECFA 1983).