1,2,3-Propanetricarboxylic acid, 2-hydroxy-, tri-C14-15-alkyl esters

Endpoint summary

Link to relevant study record(s)

Reference

Endpoint:

basic toxicokinetics in vitro / ex vivo

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

other information

Justification for type of information:

Please see Analogue Approach

Reason / purpose for cross-reference:

read-across source

Metabolites identified:

not measured

Key value for chemical safety assessment

Bioaccumulation potential:

low bioaccumulation potential

Additional information

The water solubility of target substance 1,2,3-Propanetricarboxylic acid, 2-hydroxy-, tri-C14-15-alkyl esters and the source substances is very low (< 1 mg/L), therefore dissolution is regarded to be the rate limiting step for gastrointestinal absorption. The similar substance stearyl citrate is hydrolysed readily to stearyl alcohol and citric acid in dogs, and to a lesser extent, in rats. Stearyl citrate, predominantly as distearyl citrate, added to the fee of rats at a concentration of 2.5-10 % was poorly absorbed . These data that the intact substance is not likely to be absorbed, but will be hydrolysed by gastro-intestinal esterases. Hydrolysis in the rat is readily saturated and is insignificant at high levels of exposure, whereas a higher level of hydrolysis (~50%) is seen in the dog at high dose levels. The limited absorption seen with the test material used in this study is likely to be due largely to the mono-citrate, the results therefore indicate that the absorption of the registered substance (which consists of tri-esters only) will be even more limited in the rat.

Dermal absorption of the substances is not predicted based on its physicochemical properties. Inhalation exposure to the substance is not predicted based on its physicochemical properties.

Systemic distribution of the intact substances are not predicted. Following gastrointestinal hydrolysis, absorption and subsequent distribution of the hydrolysis product citric acid is likely. Citric acid is a normal metabolic intermediate; citric acid resulting from hydrolysis of the target substances and the Source substances and will be distributed systemically but will be indistinguishable from the large amounts of citric acid normally present in the body.

Orally administered the metabolite citric acid is well absorbed and largely metabolized. Exogenous and endogenous citric acid can be completely metabolized and serve as a source of energy. Citric acid is an intermediate in the Krebs cycle. Citric acid completes the breakdown of pyruvate, formed from glucose through glycolysis, and it liberates carbon dioxide. Approximately 2 kg of citric acid are formed and metabolized every day in humans. Ten to 35 % of filtered citrate is excreted in the urine. The normal blood citrate level in humans is approximately 25 mg/L.

The initial step in the mammalian metabolism of primary alcohols is the oxidation to the corresponding carboxylic acid, with the corresponding aldehyde being a transient intermediate. These carboxylic acids are susceptible to further degradation via acyl-CoA intermediates by the mitochondrial ß-oxidation process. This mechanism removes C2 units in a stepwise process and linear acids are more efficient in this process than the corresponding branched acids. In the case of unsaturated carboxylic acids, cleavage of C2-units continues until a double bond is reached. Since double bonds in unsaturated fatty acids are in the cis-configuration, whereas the unsaturated acyl-CoA intermediates in the ß-oxidation cycle are trans, an auxiliary enzyme, enoyl-CoA isomerase catalyses the shift from cis to trans. Thereafter, ß-oxidation continues as with saturated carboxylic acids.

An alternative metabolic pathway for aliphatic acids exists through microsomal degradation via omega-or omega–1 oxidation followed by β-oxidation. This mechanism provides an efficient stepwise chain-shortening pathway for branched aliphatic acids.

The acids formed from the longer chained aliphatic alcohols can also enter the lipid biosynthesis and may be incorporated in phospholipids and neutral lipids. A small fraction of the aliphatic alcohols may be eliminated unchanged or as the glucuronide conjugate.

With regards to the blood-brain barrier a chain-length dependent absorption potential exists with the lower aliphatic alcohols and acids more readily being taken up than aliphatic alcohols/acids of longer chain-length. Taking into account the efficient biotransformation of the alcohols and the physico-chemical properties of the corresponding carboxylic acids the potential for elimination into breast milk is considered to be low.

The long chain aliphatic carboxylic acids are efficiently eliminated and aliphatic alcohols are therefore not expected to have a tissue retention or bioaccumulation potential. Longer chained aliphatic alcohols within this category may enter common lipid biosynthesis pathways and will be indistinguishable from the lipids derived from other sources (including dietary glycerides).

A comparison of the linear and branched aliphatic alcohols shows a high degree of similarity in biotransformation. For both sub-categories the first step of the biotransformation consists of an oxidation of the alcohol to the corresponding carboxylic acids, followed by a stepwise elimination of C2 units in the mitochondrial β-oxidation process. The metabolic breakdown for both the linear and mono-branched alcohols is highly efficient and involves processes for both sub-groups of alcohols. The presence of a side chain does not terminate the β-oxidation process, however in some cases a single Carbon unit is removed before the C2 elimination can proceed.

In summary, long chained alcohols are generally highly efficiently metabolised and there is limited potential for retention or bioaccumulation for the parent alcohols and their biotransformation products.

The high log Pow value of the both target substances implies that they have the potential to accumulate in adipose tissue. However, as they undergo esterase-catalysed hydrolysis, the accumulation potential of the cleavage products has to be considered. Substances with high water solubility, like the alcohol, do not have the potential to accumulate in adipose tissue due to their low log Pow. Overall, the available information indicates that no significant bioaccumulation in adipose tissue is anticipated.