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In studies performed in vivo, clinical observations during the acute oral study noted the presence of red discoloration of urine at dose levels with deaths and in a repeated dose study hematological changes indicate that 2-butoxyethyl benzoate (BEB) causes hematoxicity. The similarity of these findings to those seen with 2-butoxyethanol (2BE) and the fact that BEB has been shown to be metabolized to 2BE and butoxyacetic acid (BAA), indicates that the hematoxic effects of BEB are due to 2BE/BAA.Mechanistic studies have shown that 2 -butoxyethanol (2BE) causes haematotoxicity in vivo in rats and that butoxyacetic acid (BAA) causes the same effects in vitro at very low concentration. When metabolic pathways leading to the formation of BAA were blocked, no effects were seen on red blood cells (RBCs). It can be concluded that the metabolite BAA is responsible of hematotoxicity in vivo and not 2BE or BEB themselves.

Some species are very sensitive to 2BE- or BAA-induced haemolysis (rat, mouse, hamster, baboon, rabbit) whereas other species are resistant to these effects (dog, guinea pig, pig, cat, humans). Humans are 30 x less sensitive than rats. In animal studies, an increased sensitivity to haemolysis was seen in old animals and in females in vitro and in vivo with BAA, showing that the differences of metabolism between male and female could not explain totally sex difference.

In one study, it was demonstrated that the type of analyser was important to detect early changes in blood parameters (increase of HCT and MCV). An impedance based analyser was more sensitive than a laser based analyser.

In vivo or in vitro, haemolysis was due to a decrease of erythrocyte deformability due to erythrocyte swelling. This also explains the formation of thrombosis. Newly formed erythrocytes were more resistant than old ones. It was also showed that 2BE pre-treatment gave a relative “protection” against higher doses administered later through a shift to younger average erythrocyte age. The data demonstrates an adaptive mechanism of “protection” when animals have a period of recovery time before a re-exposure to EGBE.

The mechanism leading to erythrocyte swelling and loss of deformability is for the moment unclear. There is no evidence of oxidative mechanism on erythrocyte membrane. There is data to support the theory that showed that the mode of action of BAA is via a colloid osmotic lysis of the rat red blood cell and that BAA causes sodium and calcium to enter the cell; that calcium initially has a protective effect via the calcium activated potassium channel which facilitates the loss of potassium thereby, compensating for the osmotic effect of increased cell sodium; that calcium subsequently may have other deleterious effects through activation of proteases and externalization of phosphatidylserine in the exterior leaflet of the membrane.

In humans, slight effects were seen with doses of 8 mM and 4 mM of BAA in vitro. The dog appears to be unusual in that it is sensitive to 2BE but not BAA which suggests that another mechanism is involved for this species.

In conclusion, whilst haemolysis is a critical effect for the common laboratory species of rat and mouse, it is an effect that humans are markedly resistant to. A conservative assessment is that humans are resistant to at least a factor of 10x the plasma concentration of 2 -butoxyethanol (or its metabolite BAA) and that a toxicodynamic factor of 0.1 is appropriate when carrying out interspecies extrapolations for effects that are mediated by haemolysis. This same assessment factor can also be used for interspecies extrapolation for BEB.