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ABSORPTION

Studies with the rat everted intestinal sac model in vitroindicated that no hydrocarbon constituents of NEXBTL renewable diesel were present in the serosal fluid of the intestinal sac at levels greater than the limit of detection (for the main constituents C15-C18 approximately 1% of the starting concentration). This implies that the main constituents of NEXBTL renewable diesel are not readily absorbed across the gut wall and are therefore not highly bioavailable. The lower carbon chain length alkanes present in NEXBTL renewable diesel were also not detected in the serosal fluid from the intestinal sacs. When a n-alkane mixture was studied with the same model n-decane (C10) and to lesser extent n-dodecane (C12) were absorbed into the serosal fluid. However, n-hexadecane (C16), n-octadecane (C18) and n-eicosane (C20) were not detected, implying that longer chain alkanes are not absorbed.

Based on physicochemical considerations (log Pow, water solubility), uptake of NEXBTL renewable diesel from the gastrointestinal tract may occur after ingestion. Experimental data indicate that the extent of this absorption will be inversely related to carbon number, with negligible uptake for C29 and above. Applying this information to the proportions of i-alkane and n-alkane species present in NEXBTL renewable diesel leads to a calculated gastrointestinal uptake of approximately 50%.

Based on physicochemical considerations (log Pow, water solubility), uptake of NEXBTL renewable diesel across skin will be low.

Based on physicochemical considerations (log Pow, water solubility), uptake of NEXBTL renewable diesel by lung may occur following inhalation exposure. Experimental results indicate that tissue concentrations of three i-alkanes (C8, C9, C10) increased with increasing carbon number in rats exposed by inhalation (greatest for C10). Taken together this information supports potential uptake of the alkane species present in NEXBTL renewable diesel vapour by the lung.

DISTRIBUTION

Experimental data demonstrate systemic distribution of C8, C9 and C10 i-alkanes in the rat following inhalation exposure, with internal concentrations being greatest in fat and lowest in blood (relative tissue concentrations: fat>>kidney, brain, liver>>blood). The results suggest that i-alkane components present in NEXBTL renewable diesel will also be distributed within the body after inhalation exposure.

METABOLISM

In vitro studies with the rat liver microsomal preparation and the rat hepatocyte culture indicated no metabolic loss of any of the constituents of NEXBTL renewable diesel. Nor was the metabolite formation of chosen representative constituents of NEXBTL renewable diesel (C10, C12, C14, C16, C18 and C20 n-alkanes) detected in the samples from the rat liver microsomal preparation and the rat hepatocyte culture. This could be due to the limits of detection for the lower carbon chain length alkane metabolites in the used LC-MS system and the very small amounts of lower carbon chain length alkanes present in incubations performed using NEXBTL renewable diesel. The absence of detectable metabolism of NEXBTL renewable diesel constituents recorded in this study is consistent with the published data showing a negative correlation between metabolic clearance and chain length of n-alkanes (Anand et al., 2007). The results are also consistent with published data showing virtually no biotransformation of related alkane structures by rat and human microsomal fractions in vitro and by rats in vivo (reviewed by INRA, 2012). This could be due to the limits of detection for alkane metabolites in the LC-MS system used in this investigation.

Michaelis-Menten constants (Km, Vmax) for a series of C6-C10 iso- and normal alkanes were generally greater for n-alkanes relative to the corresponding i-alkanes when determined in vitro using a rat liver slice head-space technique. Other data indicate that metabolic clearance by rat liver microsomes (as predicted by Vmax) was inversely related to carbon number as follows: C9>C10>>>C14 (no detectable removal of n-tetradcane under the conditions of the study). By analogy, the C14, C15, C16, C17 and C18 i-alkane species that predominate in NEXBTL renewable diesel (accounting for approx. 80% of the total) are expected to undergo negligible hepatic metabolism.

EXCRETION

Experimental data demonstrate removal of C8, C9 and C10 i-alkanes from rat kidney, brain, liver and blood 12 hours after inhalation exposure ceased, with detectable (but greatly reduced) levels present in fat only.