Registration Dossier

Administrative data

Endpoint:
basic toxicokinetics
Type of information:
other: Expert statement
Adequacy of study:
key study
Study period:
2013
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:
2013
Report Date:
2013

Materials and methods

Test guideline
Qualifier:
no guideline followed
Guideline:
other: Expert statement
Principles of method if other than guideline:
Expert statement
GLP compliance:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent
Type:
Constituent
Test material form:
other: Pale yellow liquid

Test animals

Details on test animals 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:
not applicable
Positive control:
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:
Incozol EH was shown to immediately hydrolyse when getting in contact with water. Therefore, bioavailability after oral exposure was assessed only for the hydrolysis products 2-ethylhexanal and “fully hydrolysed Incozol EH”. Based on physico-chemical properties especially water solubility and log Pow value of “fully hydrolysed Incozol EH”, 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. Passive diffusion might be a preferred entry route of 2-ethylhexanal into systemic circulation as it has lipophilic properties and a low water solubility. Clinical signs after a single administration of 2000 mg Incozol EH/kg bw in 1,2-propanediol in an acute oral toxicity study performed on rats were considered to be treatment-related and not associated to bioavailability of the test item. However, long-term administration of high doses of Incozol EH in a 28-day repeated dose toxicity study on rats indicated that the compound or rather its hydrolysis products became bioavailable.
Based on the vapour pressure of approximately 0.001 Pa at 20°C Incozol EH is not expected to become airborne in its vapour form. However, if Incozol EH is degraded hydrolytically, inhalation exposure of 2-ethylhexanal, one of the hydrolysis products, could not be excluded due to its higher vapour pressure in comparison to Incozol EH itself. If the substance would reach the lungs, absorption directly across the respiratory tract epithelium by passive diffusion is likely to occur due to its log Pow value (3.07) and water solubility (450 mg/L).
Based on the molecular weight and physico–chemical properties of Incozol EH dermal penetration of the substance might be slow. It is general accepted that if a compound’s molecular weight is above 500 g/mol and water solubility falls between 1-100 mg/L, absorption can be anticipated to be low to moderate. These assumptions based on the physico-chemical properties are further supported by the results achieved from a GPMT which revealed that Incozol EH has skin sensitising properties and is thus absorbed dermally to a certain extent.
Details on distribution in tissues:
Assuming that 2-ethylhexanal as one of the hydrolysis products is absorbed into the body following oral intake, it may be distributed into the interior part of the cells by passive diffusion due to its lipophilic properties and in turn the intracellular concentration may be higher than extracellular concentration particularly in adipose tissues. Direct transport through aqueous pores is likely to be an entry route to the systemic circulation of “fully hydrolysed Incozol EH” due to its higher water solubility compared to 2-ethylhexanal.
Based on its log Pow and BCF value Incozol EH might have a weak bioaccumulation potential. However, as it immediately hydrolyses when getting in contact with water bioaccumulation in the human body can be excluded. This assumption is supported by the lower BCF values of the hydrolysis products compared to Incozol EH.
Details on excretion:
As discussed above, Incozol EH will be hydrolysed after being in contact with an aqueous solution and will probably not be excreted in its unhydrolysed form. The degradation product “fully hydrolysed Incozol EH” might be biliary excreted due to its molecular weight (> 300 g/mol in rat). Renal excretion might be a preferred excretion pathway of degradation products of “fully hydrolysed Incozol EH” described above. Oxidation and conjugation products of 2-ethylhexanal were shown to be excreted via urine (English et al, 1998).

Metabolite characterisation studies

Details on metabolites:
Based on the structure of the molecule, Incozol EH immediately degraded hydrolytically after being in contact with an aqueous solution. The first degradation product “fully hydrolysed Incozol EH” may be further degraded hydrolytically to a certain extend to diethanolamine, 1,6-hexanediamine and carbon dioxide under basic conditions. 2-ethylhexanal is estimated to be oxidised to 2-ethylhexanoic acid which was shown to be conjugated with glucuronic acid or further oxidised to 2-ethyl-1,6-hexanedioic acid, 2-ethyl-6-hydroxyhexanoic acid and 2-ethylketohexanoic acid (English et al, 1998). No metabolic activation of Incozol EH and its hydrolysis products is expected as indicated by the negative in vitro genotoxicity assays in the presence of S9 mix.

Bioaccessibility

Bioaccessibility testing results:
Taken together, physico-chemical properties and experimental data indicate a low bioavailability of Incozol EH via oral and dermal route. Bioavailability after inhalation exposure is considered to be unlikely due to the low vapour pressure of the non-hydrolysed compound.

Applicant's summary and conclusion

Conclusions:
Interpretation of results (migrated information): no bioaccumulation potential based on study results
Based on physico-chemical characteristics, particularly water solubility and octanol-water partition coefficient absorption via oral and inhalation route is expected to be low. However, slow dermal absorption could not be excluded. Incozol EH is immediately hydrolysed into “fully hydrolysed Incozol EH” and 2-ethylhexanal. If absorbed, passive diffusion and active transport through aqueous pores is likely to be an entry routes to the systemic circulation. No metabolic activation of Incozol EH and its hydrolysis products is expected. Excretion via faeces is assumed to be the main excretion pathway of “fully hydrolysed Incozol EH” due to its molecular weight. Oxidation and conjugation products of 2-ethylhexanal were shown to be excreted via urine. Based on hydrolytical conversion of Incozol EH bioaccumulation is not likely to occur based on physico-chemical properties of the hydrolysis products.