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Reference
Endpoint:
basic toxicokinetics
Adequacy of study:
other information

Description of key information

Available experimental data showed limited signs of absorption and distribution of the test substance or its metabolites following inhalation exposure as evidenced by local changes in the upper respiratory tract and the absence of other target organ or tissue. There were no systemic effects observed following dermal or oral exposure (acute or subacute exposures) that would provide evidence of significant absorption or distribution. The parent substance is expected to be hydrolysed by carboxylesterases at its entry sites.The available experimental data provided no indication on excretion however due to the ready metabolism of the ester bonds it is unlikely that the parent will be excreted intact and the predicted metabolites are likely to be readily excreted.

Key value for chemical safety assessment

Bioaccumulation potential:
no bioaccumulation potential

Additional information

Assessment of absorption, distribution, metabolisation and excretion of the substance is based on the available experimental data.

 

Physico-chemical properties :

Water solubility: 29.9g/L (at 20°C)

Partition coefficient in octanol/water: 1.03

Vapour pressure: 0.06 Pa (at 25°C)

Boiling point: 230.9°C

 

Absorption :

Inhalation:

The substance has a relatively low volatility for a solvent, as evidenced by its vapour pressure and elevated boiling point. The acute toxicity study by inhalation showed no mortality up to 11 mg/L, and no significant effects that were indicative of systemic effects resulting from absorption. Literature data on similar substances have shown a potential hydrolysis of methyl esters in the upper respiratory pathway, in particular by carboxylesterases that are present in the nasal epithelium. It is thus expected that the parent substance will be undergoing rapid enzymatic hydrolysis in the upper respiratory tract and will not be absorbed further as is.

 

Oral route:

There was no mortality or evidence of systemic toxicity in the acute oral toxicity study in rats at the dose of 5000 mg/kg bw. Apart from initial and sporadic decrease in body weight and body weight gain at the high dose levels, there were no signs of systemic toxicity in the 14-day dietary toxicity study in rats.

 

Dermal route:

There was no evidence of systemic toxicity in the acute dermal toxicity study in rats at the dose of 2000 mg/kg bw. There were neither any signs of toxicity or sensitisation effects after cutaneous exposure on the mouse ears in the LLNA assay. Given the log Kow (1.03) and molecular weight (174) of DMA, DERMWIN version 2.01 calculates a Kp value of 0.0008 and Flux rate of 0.024 microgram/cm2/hr. This indicates that material will pass through the skin but it is unlikely there would be 100% dermal penetration. It is likely to be closer to be 40 -50% availability.

 

Distribution :

It is likely that the parent substance is rapidly metabolised to methanol and adipic acid by ubiquitous non-specific esterases present in various organs, and therefore would not remain unchanged.

 

Inhalation exposure:

Following inhalation exposure of rats for up to 90 days in three different studies, using both individual methyl-esters or dibasic ester blend, no relevant sign of systemic toxicity allowing the identification of target organs were observed. The main findings consisted of degeneration/atrophy of the olfactory epithelium which can be considered as local effects of the exposure of the upper respiratory tract to the parent substance.

 

Other routes of exposure:

No target organs were identified following repeated administration to rats by oral (dietary) or dermal, although the duration of treatment was relatively limited (14 days) to enable appropriate assessment of subacute toxicity.

 

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 role in the metabolisation of the substance at various potential entry sites such as nasal epithelium, gastrointestinal tract and possibly skin.

Numerous layers of carboxylesterases exist in the body. Salivary and gut flora carboxylesterase activity accounts for a significant proportion of metabolism even before the substance is absorbed (Lindqvist and Augustinsson, 1975; Inoue et al., 1979). During absorption from the gut lumen into periportal/hepatic circulation there is a second ‘layer’ 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, there is a third layer 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 rest of the systemic circulation, there is an extensive fourth round of carboxylesterase dependent hydrolysis in the plasma of the blood. Specific organs within the body (in addition to liver, lungs, skin and kidneys) also have carboxylesterase activity, for example the placenta in pregnant organisms.

Following exposure via the inhalation route, there is a layer of carboxylesterase activity in the nasal mucosa, upper respiratory tract and lung tissue. This activity often causes the release of the acids in the upper respiratory tract leading to some cytotoxicity or irritation. As such, even prior to absorption, the substance will undergo some metabolism of the ester bonds.

Following the hydrolysis of the ester bond, methanol and adipic acid will be released. The emtabolism of methanol is well studied, ultimately resulting in the formation of formic acid, or incorporation into endogenous metabolic processes as a source of a methyl group. 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.

Excretion :

No data are available with regard to the excretion properties of the test substance. However it is expected to be rapidly metabolised to methanol and adipic acid, both of which are subsequently metabolised and exreted via the urine or incorporated into the metabolic processes of the animal.

 

Conclusion :

Available experimental data showed limited signs of absorption and distribution of the test substance or its metabolites following inhalation exposure as evidenced by local changes in the upper respiratory tract and the absence of other target organ or tissue. There were no systemic effects observed following dermal or oral exposure (acute or subacute exposures) that would provide evidence of significant absorption or distribution. The parent substance is expected to be hydrolysed by carboxylesterases at its entry sites.The available experimental data provided no indication on excretion however due to the ready metabolism of the ester bonds it is unlikely that the parent will be excreted intact and the predicted metabolites are likely to be readily excreted.