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Administrative data

Link to relevant study record(s)

Description of key information

Metabolism
Next to a full toxicokinetic assesment (Pelgrom 2010), several studies investigating metabolism and excretion of the test substances are available. The test substance is metabolised to hippuric acid with glycine depletion being the rate limiting factor (Michaelis-Menten saturation kinetcs). When this primary pathway is staturated, formation of glucuronide conjugates is obeserved. Total excretion is reached within ca 24-48 hours after administration. The same metabolic pathway is described in rabbits (Bray 1950, rats (Kazuki 1992, Jones 1992) and man (Shigeo 1994) when the testsubstance was administerd via the oral, iv or ip route. Glycine pre-treatment (Bray 1950) showed increases of the amounts of hippuric acid excreted in rabbits, while proteine (thus glycine) low diets in rats gave a decreased amount of hippuric acid in urine (Thabrew 1980).
Oral absorption: From the outcome of the studies it can be concluded that the test substance is absorbed rapidly via the oral route. The oral absorption is set at 100%
Inhalation absorption: Pelgrom (2010) also indicates that rapid absorption via the inhalation route should be possible, but this is unlikely in view of the particle size of the test substance that does not allow the test substance to penetrate into the deeper layers of the respiratory tract and the lungs.
Dermal absorption: Based on the available in vivo results the dermal absorption of the test substance is set at 50% in a worst case approach. It has to be noted that a clear species difference becomes apparent. The mass balance was not properly maintained in most of the available studies, which renders the results less reliable. In vitro data support this percentage, but it should be noted that many of the in vivo studies had a relatively long exposure period (24 h standard according to the guideline for reasons of loss of viability) and thus may over estimate absorption rates.
In a weight of eveidence approach the 50% seems to be justified.

Key value for chemical safety assessment

Bioaccumulation potential:
no bioaccumulation potential
Absorption rate - dermal (%):
50

Additional information

Next to a full toxicokinetic assesment (Pelgrom 2010), several studies investigating metabolism and excretion of the test substances are available. The test substance is metabolised to hippuric acid with glycine depletion being the rate limiting factor (Michaelis-Menten saturation kinetcs). When this primary pathway is staturated, formation of glucuronide conjugates is obeserved. Total excretion is reached within ca 24-48 hours after administration. The same metabolic pathway is described in rabbits (Bray 1950, rats (Kazuki 1992, Jones 1992) and man (Shigeo 1994) when the testsubstance was administerd via the oral, iv or ip route. Glycine pre-treatment (Bray 1950) showed increases of the amounts of hippuric acid excreted in rabbits, while proteine (thus glycine) low diets in rats gave a decreased amount of hippuric acid in urine (Thabrew 1980).

Based on the available in vivo results the dermal absorption of the test substance is set at 50% in a worst case approach. In vitro data support this percentage, but it should be noted that many of the in vitro studies had a relatively long exposure period (24 h standard according to the guideline for reasons of loss of viability) and thus may over estimate absorption rates.

From the outcome of the studies it can be concluded that the test substance is absorbed rapidly via the oral route. Pelgrom (2010) also indicates that rapid absorption via the inhalation route should be possible, but is unlikely in view of the particle size of the test substance.

In vitro and ex-vivo experiments (Mose 2007, Utoguchi 1999, Poulsen 2009) have shown that the test substance is easily transfered across the placenta or taken up by specific (BoWe) cell-lines. The suitability of the models used to assess placental transfer in vivo needs to be further investigated.