reaction mass of bis(2-propylheptyl) hexanedioate and O6-[2,2-bis[[6-oxo-6-(2-propylheptoxy)hexanoyl]oxymethyl]butyl] O1-(2-propylheptyl) hexanedioate

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics

Type of information:

other: Expert statement

Adequacy of study:

key study

Study period:

2014-06-4

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Expert statement, no study available

Data source

Reference

Reference Type:

other: Expert statement

Title:

Unnamed

Year:

2016

Report date:

2016

Materials and methods

Principles of method if other than guideline:

Expert statement

GLP compliance:

yes

Test material

Test material information

Constituent 1

Reference substance name:

reaction mass of bis(2-propylheptyl) hexanedioate and O6-[2,2-bis[[6-oxo-6-(2-propylheptoxy)hexanoyl]oxymethyl]butyl] O1-(2-propylheptyl) hexanedioate

EC Number:

942-066-1

Molecular formula:

unspecified

IUPAC Name:

reaction mass of bis(2-propylheptyl) hexanedioate and O6-[2,2-bis[[6-oxo-6-(2-propylheptoxy)hexanoyl]oxymethyl]butyl] O1-(2-propylheptyl) hexanedioate

Test material form:

other: liquid

Test animals

Details on test animals or test system and environmental conditions:

not applicable

Administration / exposure

Details on exposure:

not applicable

Duration and frequency of treatment / exposure:

not applicable

Doses / concentrations

Remarks:

Doses / Concentrations:
not applicable

No. of animals per sex per dose / concentration:

not applicable

Positive control reference chemical:

not applicable

Details on study design:

not applicable

Details on dosing and sampling:

not applicable

Statistics:

not applicable

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on absorption:

Generally, oral absorption is favoured for molecular weights below 500 g/mol, which is only the case for the main component. But, due to the extremely low water solubility oral absorption might be limited. As the compound is lipophilic (log Pow >6.5), it may thus be taken up by micellular solubilisation, but taken together the compound is most probably poorly absorbed via the oral route. The molecule will not directly enter the systemic circulation by passive diffusion. However acute oral toxicity data show that absorption takes place at least to a very small extent: The oral LD50 value was found to be greater than 5000 mg/kg bw in Wistar rats, but some clinical signs were noted (piloerection). No clinical signs were observed up to 2000 mg/kg bw. The second component of the reaction mass is unlikely to be absorbed via oral, inhalation and dermal route due to the high molecular weight.

Furthermore the reaction mass will hardly become available for inhalation because of the low vapour pressure. If the substance would reach the lungs in its vapour or gaseous state, absorption directly across the respiratory tract epithelium by passive diffusion is unlikely to occur due to its limited water solubility. In general a substance could be taken up by micellular solubilisation if it is lipophilic enough, which might be the case for the main component. But absorption via respiratory route was not confirmed by an acute inhalation toxicity study in Wistar rats with the read-across substance bis(2-ethylhexyl) adipate (EC 203-090-1), where the animals were exposed to the test substance as an aerosol at a high (limit) concentration of 5.7 mg/L air. No mortality occurred and no pathologic findings were recorded.

Similarly, based on physico–chemical properties of the compound, primarily water solubility, dermal uptake will be low. As mentioned above, the second component of the reaction mass (O6-[2,2-bis[[6-oxo-6-(2-propylheptoxy)hexanoyl]oxymethyl]butyl] O1-(2-propylheptyl) hex-anedioate) will not be able to penetrate skin based on the size of the molecule. Due to the high log Pow value, bis(2-propylheptyl) hexanedioate is unlikely to be taken up. Indeed, in an acute dermal toxicity study in Wistar rats the LD50 value was found to be above 5000 mg/kg bw and no local effects on the skin were observed.
Taken together, physico-chemical properties and experimental data indicate low bioavailability of the test substance via oral, dermal and inhalation route.

Details on distribution in tissues:

Assuming that the test substance is absorbed into the body following oral intake, it may be distributed into the interior part of cells due to its lipophilic properties and in turn the intracellular concentration may be higher than the extracellular concentration particularly in adipose tissues. As mentioned above, the physico-chemical properties, especially the higher molecular weight and low water solubility, do not favour absorption, but clinical signs observed in the acute oral toxicity study indicate that systemic absorption has occurred at least to a small extend.
The read-across substance Bis(2-ethylhexyl) adipate was found to be distributed to the body fat, liver and kidneys. Besides that, the metabolites were also distributed into the foetus of pregnant mice. Little accumulation was observed in the foetus and in the amniotic fluid. In another (pharmacokinetic) study using Wistar rats no evidence of bioaccumulation was found (ECHA disseminated dossier of Bis(2-ethylhexyl) adipate).

Details on excretion:

The read-across substance Bis(2-ethylhexyl) adipate was rapidly excreted via urine, feces and exhaled air. The substance was found to be excreted within 48 hours, predominantly via urine, in a toxikokinetic study conducted with male Wistar rats. A study conducted with monkeys confirmed the results, except for one female monkey showing a higher rate of renal excretion. In females the amounts of excretion products was similar. Excretion via exhaled air was less important.

Metabolite characterisation studies

Details on metabolites:

In the ECHA disseminated Dossier of the main component Bis (2-propylheptyl) hexanedioate a study is described which was conducted similar to OECD Guideline 417 to investigate the metabolism of the read-across substance Bis(2-ethylhexyl) adipate in vivo in Fischer 344 rats. Metabolites present in the GI tract, liver and urine were identified. As a result, the substance was found to be metabolised to a large extend via oxidation reactions in the liver and glucoronidation of the metabolites. Other studies conducted with rats revealed that adipic acid was found to be the main urinary metabolite; which was also present in the digestive tract, blood and liver. A similar metabolism is expected for the registered substance.