Reaction mass of dimethyl adipate and dimethyl glutarate and dimethyl succinate

Endpoint summary

Additional information

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

 

Physico-chemical properties :

Water solubility: 4.0 to 40.5 g/L (at 20°C)

Partition coefficient in octanol/water: 0.6 to 1.4

Vapour pressure: 0.47 to 9.4 Pa (at 25°C)

Boiling point: 209.3°C

 

Absorption :

Inhalation:

The substance has a relatively low volatility for a solvent, as evidenced by the vapour pressures of its components and its 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.

 

Distribution :

It is likely that the parent substance is rapidly metabolised to methanol and mono- and/or diacids 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 four 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.

No metabolic alteration was observed in repeated dose toxicity assays in organs such as liver or kidneys. The outcome of the in vitro bacterial reverse mutation assay was unaffected by the presence of metabolic activation or not. There was a significant difference in the response of human lymphocytes with or without metabolic activation, as clastogenic effects were only observed in the presence of liver microsomal fraction. However, this was not reproduced in vivo following inhalation exposure in a mouse bone marrow micronucleus assay, with intact metabolic capacities.

 

Excretion :

No data are available with regard to the excretion properties of the test substance.

 

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.