Registration Dossier

Administrative data

Link to relevant study record(s)

Description of key information

Key value for chemical safety assessment

Bioaccumulation potential:
no bioaccumulation potential
Absorption rate - oral (%):
100
Absorption rate - dermal (%):
100
Absorption rate - inhalation (%):
100

Additional information

Although there are no data on metabolism available for the propyl propionate, it is believed that the ester connecting the propionic acid group to the alcohol will be readily metabolised by the body. This is supported by the ready and rapid hydrolysis of primary amyl acetate (mix of pentyl acetate and 2 -methylbutyl acetate). Carboxylesterases are widely distributed in the body of mammalian species and can hydrolyse esters in various compounds, without being necessarily substrate-specific. It is expected that they would play a major role in the metabolism of the propionates at various potential entry sites such as nasal epithelium, gastrointestinal tract and possibly skin. Following oral exposure, salivary and gut flora carboxylesterase activity would begin the hydrolysis prior to intestinal absorption (Lindqvist and Augustinsson, 1975; Inoue et al., 1979). During absorption from the gut lumen into periportal/hepatic circulation, there is a second round of esterase-dependent hydrolysis present in the mucosa of the small intestine. Studies of other esters have shown a significant impact of intestinal wall esterase activity on the absorption of esters (Harrison and Webster, 1971; White et al., 1980; Andreasen et al., 2001; Longland et al., 1977). Upon entering the liver, and transitioning from the periportal to the central vein, any remaining 'un-hydrolysed ester' will encounter the third phase of hepatic esterase activity. While in periportal circulation and after exiting the hepatic circulation to begin its journal via venous circulation, into the lungs, and then into arteriole circulation before reaching the placenta and fetus (when applicable), esters would be subjected to an extensive fourth round of plasma carboxylesterase dependent hydrolysis. Therefore it is expected based on what is known about the body’s capacity to hydrolyse esters that there will be minimal systemic exposure to the parent compound. Via inhalation, there are also carboxylesterases in upper respiratory tract that can act on the compound. These are responsible for the irritancy that is observed with this type of compound. Specifically, the carboxylesterases metabolise propionates and acetates releasing these acids which can then cause local irritation of the respiratory tract epithelia. Therefore, following inhalation, the metabolism of esters also occurs prior to the substances becoming systemically available. This ester metabolism also occurs in the eyes, typically leading to the substance being irritating to some extent, although the degree of irritation varies from ester to ester.

Once metabolism of the ester occurs, the propionic acid can be further metabolised. Propionic acid is endogenous and much is known of its subsequent metabolism, excretion and potential toxicity. Propionic acid occurs naturally in foods, and together with other short-chain fatty acids, is ubiquitous in the gastrointestinal tract of humans and other mammals as end products of microbial digestion (Mellon 2000). Propionic acid occurs physiologically as an intermediate in breakdown of odd-numbered fatty acids, cholesterol and amino acids (valine, isoleucine, norleucin, methionine, and threonine). Up to four percent of volatile fatty acids in blood of humans (0.28-0.32 mmol/l) are propionic acid (Baessler 1959). The metabolism of propionic acid has been thoroughly studied. Propionic acid is readily absorbed in the gastrointestinal tract and metabolized in mammals rapidly and entirely. In rats, the rate of absorption in the intestines is similar to that of acetates. Irrespective of the route of exposure, parent propionic acid is not identified in urine even after dosing with high doses (Baessler 1959). Studies with radioactively (C11) labelled propionic acid indicated that up to 54% of the carbon atoms in propionic acid end up in exhaled carbondioxide. The rest ends up in glucose, glycogen, lipids, amino acids, and proteins (Buchanan 1943; Eckstein 1933; Deuel 1935). The metabolism of propionic acid starts with the catalytic conjugation with Coenzyme A to propionyl-CoA. The conjugation step is catalysed by acetate thiokinase with the consumption of ATP. In the next step catalysed by the propionyl carboxylase, activated CO2 (carbonyl phosphate) is incorporated in propionyl-CoA to form methylmalonyl-CoA. In the subsequent rate determining transcarboxylisation step, catalysed by the Vit B-dependent methylmalonylmutase, methylmalonyl-CoA is converted to succinyl -CoA. After deacylation, succinate is released which can be incorporated in the citric acid cycle.

The pentanol released following metabolism of the ester can be excreted as it is (urine or exhaled air), or metabolized through to the aldehyde and acid via alcohol and aldehyde dehydrogenase. Oxidation by cytochrome P450 or conjugation with glucuronic acid are also possible routes of metabolism. Metabolism data are available for pentanol that indicates it is both rapid and thorough. Prior to metabolism, pentanol is readily water soluble indicating that it should not accumulate in any tissue, passing freely between blood and perfused tissues.

No data on dermal penetration are available for the propyl propionate, however data on the analagous substance primary amyl acetate indicate that this substance will penetrate the skin fairly well with the pentyl acetate absorbed at a rate of 123μg/cm2/h (Kp = 2.16 x 10-4cm/h).

References:

Andreasen, M.F., Kroon, P.A., Williamson, G., Garcia-Conesa, M.T. 2001 Esterase activity able to hydrolyze dietary antioxidant hydroxycinnamates is distributed along the intestine of mammals. J. Agric Food Chem 49: 5679-5684 

 

Harrison, D.D. and Webster, H.L.  1971 Proximal to distal variations in enzymes of the rat intestine. Biochmica et Biophys Acta 244: 432-436 

 

Imai, T. and Ohura, K.  2010 The role of intestinal carboxylesterase in the oral absorption of prodrugs.  Current Drug Metab 11: 793-805 

 

Inoue, M., Morikawa, M., Tsuboi, M. and Sugiura, M. 1979 Species differences and characterization of intestinal esterase on the hydrolyzing activity of ester-type drugs.  Jpn. J. Pharmacol 29: 9-16 

 

Lindqvist, L and Augustinsson, K.B. 1975 Esterases in human saliva. Enzyme 20: 277-291 

 

Longland, R.C., Shilling, W.H. and Gangolli, S.D. 1977 The hydrolysis of flavouring esters by artificial gastrointestinal juices and rat tissue preparations. Toxicol 8: 197-204 

White, R.D., Carter, D.E., Earnest, D. and Mueller, J.  1980 Absorption and metabolism of three phthalate diesters by the rat small intestine. Fd. Cosmet Toxicol 18: 383-386 K.-H.Baessler, Z. Lebensm. Unters. Forsch. 110 (1959) 28 – 42.