Bis[2-[2-(1-methylethyl)-3-oxazolidinyl]ethyl] hexan-1,2-diylbiscarbamate

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics in vitro / ex vivo

Type of information:

other: Expert statement

Adequacy of study:

key study

Study period:

2018

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:

2018

Report date:

2018

Materials and methods

Test guideline

Qualifier:

no guideline required

Principles of method if other than guideline:

Expert statement

GLP compliance:

no

Test material

Test material information

Constituent 1

Reference substance name:

Bis[2-[2-(1-methylethyl)-3-oxazolidinyl]ethyl] hexan-1,2-diylbiscarbamate

EC Number:

261-879-6

EC Name:

Bis[2-[2-(1-methylethyl)-3-oxazolidinyl]ethyl] hexan-1,2-diylbiscarbamate

Cas Number:

59719-67-4

Molecular formula:

C24H46N4O6

IUPAC Name:

bis[2-(2-isopropyl-1,3-oxazolidin-3-yl)ethyl] hexane-1,6-diylbiscarbamate

Test material form:

liquid

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on absorption:

Incozol 4 was shown to rapidly hydrolyse when getting in contact with water, especially at low pH values. Therefore, bioavailability after oral exposure was assessed only for the hydrolysis products isobutyraldehyde and several “hydrolysed Incozol 4 structures”. Based on their molecular weight and physico-chemical properties, dissolution in the gastro-intestinal fluids and contact with the mucosal surface might occur and may allow direct uptake into the systemic circulation through aqueous pores or via carriage of the molecules across the membrane with the bulk passage of water.
There are no indications of bioavailability after a single administration of 5000 mg Incozol 4/kg bw as diuresis was the only clinical finding. Long-term administration of Incozol 4 revealed ambiguous findings in the 1000 mg/kg bw/day dose group. Bioavailability after repeated oral administration of high doses of Incozol 4 or rather its hydrolysis products could therefore not be excluded.
Based on the vapour pressure of approximately 0.0005 Pa at 20°C Incozol 4 is not expected to become airborne in its vapour form. However, if Incozol 4 is degraded hydrolytically, inhalation exposure of isobutyraldehyde, one of the hydrolysis products, is expected due to its high vapour pressure. If the substance reaches the lungs, absorption directly across the respiratory tract epithelium by passive diffusion is likely to occur due to its log Pow value (0.77) and water solubility (60 g/L). Systemic signs of toxicity were observed when isobutyraldehyde was administered by inhalation in a 90 day-toxicity study on rats, indicating, that the substance is bioavailable after inhalation exposure (ECHA).
Uptake of Incozol 4 into the stratum corneum is assumed due to the lipophilic properties of the substance. However, transfer into the epidermis might be limited by the low water solubility. It is general accepted that if a compound’s water solubility falls between 1-100 mg/L, absorption can be anticipated to be low to moderate. Therefore, based on the molecular weight and physico–chemical properties of Incozol 4 dermal penetration of the substance might be slow. However, results achieved from an LLNA revealed that Incozol 4 has skin sensitising properties and dermal uptake must have occurred, although it may only has been a small fraction of the applied dose. Further, hydrolytical degradation of Incozol 4 in the moisture of the skin and uptake of the hydrolysis products could not be excluded.
Taken together, physico-chemical properties and experimental data indicate a low bioavailability of Incozol 4 via oral and dermal route. Exposure via inhalation route of the non-hydrolysed product is considered to be unlikely.

Details on distribution in tissues:

Assuming that Incozol 4 or rather its hydrolysis products “hydrolysed Incozol 4 structures” and isobutyraldehyde are absorbed into the body following oral intake, they may be distributed via the blood stream over the whole organism. Extracellular concentration is expected to be higher than intracellular due to their water solubility and low log Pow values. Direct transport through aqueous pores is likely to be the main route within systemic circulation
Based on their BCF values both, the parent molecule Incozol 4 and its hydrolysis products have no potential to bioaccumulate in the human body.

Details on excretion:

As discussed above, Incozol 4 will be hydrolysed after being in contact with an aqueous solution and will probably not be excreted in its non-hydrolysed form.
The degradation product “hydrolysed Incozol 4 structures” might by excreted via faeces due to its molecular weight (>300 g/mol in rat). In case of further hydrolysis products, renal excretion would be favoured due to increasing water solubility and decreasing molecular weight.
Isobutyraldehyde is oxidised to carbon dioxide and excreted via the exhaled air (DiVincenzo and Hamilton, 1979).

Metabolite characterisation studies

Details on metabolites:

Based on the structure of the molecule, Incozol 4 degraded hydrolytically after being in contact with an aqueous solution. The first degradation product “hydrolysed Incozol 4 structures” may be further degraded hydrolytically to a certain extend to diethanolamine, 1,6-hexanediamine and carbon dioxide under basic conditions.
Isobutyraldehyde is estimated to be oxidised to isobutyric acid which was shown to be rapidly oxidised to carbon dioxide (DiVincenzo and Hamilton, 1979).
No metabolic activation of Incozol 4 and its hydrolysis products is expected as indicated by the negative in vitro genotoxicity assays in the presence of S9 mix.

Bioaccessibility (or Bioavailability)

Bioaccessibility (or Bioavailability) testing results:

Taken together, physico-chemical properties and experimental data indicate a low bioavailability of Incozol 4 via oral and dermal route. Exposure via inhalation route of the non-hydrolysed product is considered to be unlikely.

Applicant's summary and conclusion

Conclusions:

Based on physico-chemical characteristics, particularly water solubility and octanol-water partition coefficient absorption via oral and dermal route is expected to be low. Exposure via inhalation route of the non-hydrolysed product is considered to be unlikely. Incozol 4 rapidly hydrolyses into “hydrolysed Incozol 4 structures” and isobutyraldehyde when getting in contact with an aqueous solution. Based on water solubility, extracellular concentration of the hydrolysis products is assumed to be higher than intracellular. Isobutyraldehyde is estimated to be oxidised to isobutyric acid which was shown to be rapidly oxidised to carbon dioxide. “Hydrolysed Incozol 4 structures” may be further degraded hydrolytically to a certain extend to diethanolamine, 1,6-hexanediamine and carbon dioxide under basic conditions. No metabolic activation of Incozol 4 and its hydrolysis products is expected. Excretion via faeces is assumed to be the main excretion pathway of “hydrolysed Incozol 4 structures” due to its molecular weight (>300 g/mol in rat). Based on the oxidation to carbon dioxide, isobutyraldehyde is excreted via the exhaled air. In consideration of the BCF values and the expected metabolism, bioaccumulation of Incozol 4 itself and its hydrolysis products is not likely to occur.