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Key value for chemical safety assessment

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With respect to molecular weight and their physico-chemical properties, it can be concluded that X-110/X-500 and Cargill BP-A are poorly absorbed as such. A metabolic step by enzyme lipases is however likely to happen in the gastrointestinal tract to form better absorbable substrates. By hydrolysis, some parts of X-110/X-500 and Cargill BP-A are assumed to be cleaved in epoxidized fatty acids and glycerol. While X-110/X-500 and Cargill BP-A themselves are probably poorly absorbed, their cleavage products are likely to be absorbed somewhat more effectively than the parental compounds. With respect to their chain length, fatty acid epoxides are assumed to be absorbed in the gastro-intestinal tract by carrier-mediated transport, as known for structurally related long-chain fatty acids. Data from studies in humans and animals indicate glycerol is rapidly absorbed in the intestine and distributed throughout the blood. The probable bioavailability of such cleavage products is affirmed by studies with the structure-related ESBO. Its cleavage products, comparable to those of X-110/X-500 and Cargill BP-A, might be bioavailable to some extent and the slight organ weight changes in liver and kidney after repeated administration may be attributable to their systemic exposure.
Absorption of X-110/X-500 and
Cargill BP-A via skin is expected to be very low, since molecular weight and its high log POW impede skin permeability. This is supported by the absence of systemic toxicity in the acute dermal study conducted with ESBO. Inhalative exposure to X-110/X-500 and Cargill BP-A is of no relevance due to the low vapour pressure.

Metabolism from X-110/X-500 and Cargill BP-A and their cleavage products is assumed to occur already in the gastrointestinal tract. In principle, the epoxide moieties may be metabolically inactivated in the body by two different enzymatic routes: conjugation of the epoxide moiety with the endogenous tripeptide glutathione (GSH) catalysed by glutathione S-transferase (GST) or hydrolysis of the epoxide moiety catalysed by epoxide hydrolase (EH), yielding the corresponding 1,2-diols. The X-110/X-500 and Cargill BP-A cleavage products fatty acid epoxides are classically hydrated by soluble epoxide hydrolase (sEH). Although epoxy-fatty acids are relatively poor substrates for microsomal epoxide hydrolase (mEH) compared to sEH, the former enzyme hydrolyzes them with a high enantioselectivity, whereas the latter shows little or no enantiomeric preference.

EH and GST are both mainly expressed in liver and the GI-tract mucosa, where detoxification of epoxy-fatty acids presumably proceeds. This is confirmed by repeated dose effects in liver induced by the structure-related ESBO, which are probably correlated to the metabolic detoxification of the cleavage products.
Glycerol is phosphorylated to alpha-glycerophosphate by glycerol kinase predominantly in the liver (80-90%) and kidneys (10-20%) and incorporated in the standard metabolic pathways to form glucose and glycogen. Glycerol may also be combined with free fatty acids in the liver to form triglycerides (lipogenesis). The turnover rate is directly proportional to plasma glycerol levels.

Due to their low absorption rate, X-110/X-500 and Cargill BP-A are assumed to be eliminated predominantly via faeces.