COASOL 290 PLUS

Endpoint summary

Additional information

BASIC TOXICOKINETICS

There are very few data available for the reaction mass of dibutyl esters, therefore an estimation of the potential ADME properties is made by analogy to the reaction mass of methyl esters and the breakdown components of the butyl esters (butanol, glutaric acid and adipic acid)

 

Absorption :

 

Inhalation:

The substance has a low volatility as evidenced by the low vapour pressure and elevated boiling point. The acute toxicity study for the methyl esters by inhalation showed no mortality up to 11 mg/L, and no significant effects that were indicative of systemic effects resulting from absorption. This low toxicity is also considered likely for the dibutyl esters. Due to the presence of carboxylesterases in the upper respiratory tract it is predicted that any butyl esters reaching the upper respiratory tract will be quickly hydrolysed to the alcohol and component acids. These breakdown products will then be absorbed rather than the parent molecules therefore there is expected to be minimal absorption of parent compound via inhalation. It is expected that absorption of these will be similar to that via the oral route.

 

Oral route:

Data available on the isobutyl esters show a lack of acute toxicity via the oral route. There was no mortality or evidence of systemic toxicity in the acute oral toxicity study in rats at the dose of 2000 mg/kg bw. The Butyl esters are considered to behave similarly, and this is supported by the data on dibutyl adipate which showed low acute toxicity with a LD50 of >2000 mg.kg bw. Following ingestion, the butyl esters are expected to be rapidly hydrolysed in the gut to the component acids and alcohols, these then being absorbed well. It is not expected that systemic exposure to the esters will occur. However, it is expected that almost complete absorption of the hydrolysis products (butanol and the acids) will occur.

 

Dermal route: In an acute dermal study of the methyl esters there was no evidence of systemic toxicity in rats at the dose of 2000 mg/kg bw. The median MW of approximately 274 and the log Kow of greater than 4 tend to indicate that some penetration through the skin will occur, but retention in the epidermis may limit the potential for systemic availability. In the skin there are also esterases capable of hydrolysing the esters to the acids and alcohols, so as with the other routes of exposure, systemic exposure will probably be to the constituent alcohol and acids. In the absence of actual absorption data absorption is estimated to be half that via the oral route due to the potential retention by the epidermis.

 

Distribution :

The parent substance will be rapidly metabolised to butanol and mono- and/or diacids by ubiquitous non-specific esterases present in various organs, and therefore would not remain unchanged. The hydrolysis products (butanol and adipic, glutaric acids) are likely to be distributed within the body with minimal potential for accumulation in any particular organ. 

 

Metabolisation :

Carboxylesterases are widely distributed in the body of mammalian species and can hydrolyse various compounds, without being necessarily substrate-specific. It is expected that they would play a major role in the metabolism of the substance at various potential entry sites such as nasal epithelium, gastrointestinal tract and possibly skin. Numerous layers of carboxylesterases exist within the body. Salivary and gut flora carboxylesterase activity would begin the hydrolysis before intestinal absorption even begins (Lindqvist and Augustinsson, 1975; Inoue et al., 1979). During absorption from the gut lumen into periportal/hepatic circulation, thre is a second round of esterase-dependent hydrolysis present in the small intestine mucosa. 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 eta l., 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 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, esters would be subjected to an extensive fourth round of carboxylesterase dependent hydrolysis.  Therefore it is expected based on what is known about the bodies capacity to hydrolyse esters that there will be minimal systemic exposure to the parent compound. Via inhalation, there are also estereases in upper respiratory tract that can act on the compound. However, given the low vapour pressure and boiling point (refer to phys chem section), it is not anticipated that inhalation would be a relevant route of exposure.  

 

Following the initial hydrolysis, the component acids will enter the body’s natural metabolic processes as they are endogenous substances. Glutaric acid is a breakdown product of lysine and tryptophan and can be converted to alphaketoglutaric acid which is an intermediate in the Krebs cycle. Adipic acid also enters the normal metabolic processes in the rat. When radioactive adipic acid was fed to fasted rats, metabolic products identified as urea, glutamic acid, lactic acid, β-ketoadipic acid, and citric acid, as well as adipic acid, were found in the urine.

 

In animals, butanol is absorbed through the skin, lungs, and gastrointestinal tract. It is metabolized by alcohol dehydrogenase to butyric acid via the aldehyde and may enter the tricarboxylic acid cycle. Small amounts of butanol are excreted unchanged (<0.5% of the dose) or as the glucuronide (< 5% of the dose) in the urine. In rabbits, metabolites found in the urine included acetaldehyde, acetic acid, butylaldehyde, and valeric acid.

 

Excretion :

No data are available with regard to the excretion properties of the test substance. However, it is predicted that due to extensive metabolism and incorporation of the hyrolysis products into endogenous processes within the body, there will be no excretion of the parent compound.

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 

 

Bulmer, D. and Fisher, A.W.F. 1970 Studies on the characterization and localization of rat placental esterases. J. Histochem Cytochem 18: 722-729 

  

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 

 

Stoops, J.K., Horgan, D.J., Runnegar, M.T.C., de Jersey, J., Webb, E.C. and Zerner  1969 Carboxylesterase (EC 3.1.1). Kinetic studies on carboxylesterases. Biochem 8: 2026-2033 

 

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