Reaction mass of diisobutyl adipate and diisobutyl glutarate and diisobutyl succinate

Endpoint summary

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

BASIC TOXICOKINETICS

 There are very few data available for the reaction mass of diisobutyl 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 isobutyl esters (isobutanol, succininc acid, glutaric acid and adipic acid)

 

Absorption :

Inhalation:

The substance has a low volatility as evidenced by thelow 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 diisobutyl esters. Due to the presence of carboxylesterases in the upper respiratory tract it is predicted that any isobutyl 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. It is expected that absorption of these will be similar to that via the oral route.

 

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. Following ingestion, the isobutyl 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 (isobutanol 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 184 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 isobutanol and mono- and/or diacids by ubiquitous non-specific esterases present in various organs, and therefore would not remain unchanged. The hydrolysis products (isobutanol and adipic, glutaric and succinic 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.

 

It is likely that the component acids will enter the body’s natural metabolic processes as they are endogenous. Succinic acid will be taken into the citric acid cycle and used as a hydrogen donator, converting FAD to FADH₂. 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, isobutanol is absorbed through the skin, lungs, and gastrointestinal tract. It is metabolized by alcohol dehydrogenase to isobutyric acid via the aldehyde and may enter the tricarboxylic acid cycle. Small amounts of isobutanol 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, isobutylaldehyde, and isovaleric 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.