Registration Dossier

Administrative data

Endpoint:
basic toxicokinetics
Type of information:
other: Expert statement
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Expert statement

Data source

Reference
Reference Type:
other company data
Title:
Unnamed
Year:
2016
Report date:
2016

Materials and methods

Objective of study:
other: ADME
Test guideline
Qualifier:
no guideline required

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on absorption:
Absorption:
Based on the subacute (28-day) oral toxicity study absorption of toxicologically significant amounts of Genamin 3920 via the gastrointestinal tract has to be assumed since obvious destruction of the mucous membranes of the inner organs was observed in the stomach.
The dermal irritation as well as dermal toxicity studies indicate some local dermal bioavailability. However, systemic availability seems to be negligible after dermal exposure since no systemic signs of intoxication were seen after occlusive administration of 2000 mg Genamin 3920 per kg body weight in rats in the acute dermal toxicity study. Indications of a significant dermal absorptive potential were also not revealed by testing for primary irritation in rabbits.
Details on distribution in tissues:
Genamin 3920 is soluble in water as well as in organic solvents and damages the mucous membranes of the gastrointerstinal tract. Thus it can be concluded, that Genamin 3920 is absorbed through the gastrointestinal tract and systemically available within the organism. Histopathological findings indicate no deposition in the affected tissues. There were no signs of bioaccumulation and the solubility indicates a rather quick excretion via the kidneys. This view is supported by the physical-chemical properties (solubility in water) and the molecular structure.
Details on excretion:
Taking into account the physico-chemical properties and the molecular structure of the substance as well as the probable metabolites it is assumed that the main route of excretion will be the kidney. A significant fraction of the dose, however, may also be degraded.

Metabolite characterisation studies

Metabolites identified:
not specified
Details on metabolites:
Metabolism:
Genamin 3920 proved to be inactive in the Ames-test with and without exogenous metabolic activation. It was not genotoxic in the HPRT in vitro and the micronucleus assay in vivo.
No systemic effects were seen in the subacute study. No functional or structural impairments were detected. Nevertheless, the molecular structure indicates a potential for degradation by the liver.
A computational model of the probable metabolism indicates a potential for oxidative dealkylation in alpha-positions meighbouring the nitrogen atom. The resulting metabolites (octanoic acid, diethanolamine and 2-hydorxy-acetic acid) are most probably more easily degraded or exctreted than the mother-compound.
Thus metabolites of Genamin 3920, if any are formed, are not more toxic than the parent compound.

Any other information on results incl. tables

Genamin 3920 proved to be inactive in the Ames-test with and without exogenous metabolic activation. It was not genotoxic in the HPRT in vitro and the micronucleus assay in vivo.

No systemic effects were seen in the subacute study. No functional or structural impairments were detected. Nevertheless, the molecular structure indicates a potential for degradation by the liver.

A computational model of the probable metabolism indicates a potential for oxidative dealkylation in alpha-positions meighbouring the nitrogen atom. The resulting metabolites (octanoic acid, diethanolamine and 2-hydorxy-acetic acid) are most probably more easily degraded or exctreted than the mother-compound.

Thus metabolites of Genamin 3920, if any are formed, are not more toxic than the parent compound

Applicant's summary and conclusion

Conclusions:
Interpretation of results (migrated information): other: no bioaccumulation potential expected
Based on all available data, Genamin 3920 does not exhibit conspicuous toxicokinetic behaviour in the sense of accumulative and/or delayed effects with regard to the individual parameters absorption, distribution, metabolism and excretion.
The results from studies with dermal exposure indicate that Genamin 3920 has a small but definite dermal absorptive potential. Genamin 3920 is most probably absorbed from the gastrointestinal tract in significant amounts.
Indications of an intense metabolism or a bio-accumulative potential do not exist, though the molecular structure indicates a potential for degradation in the organism. Additionally no increase in severity of systemic effects was observed in the subacute oral toxicity study, which also points to no bio-accumulation potential as well as to excretion of Genamin 3920 and/or metabolites.
Executive summary:

Based on the available data base on Genamin 3920 relevant information exists to make a qualitative evaluation of the toxicokinetic profile of this compound. This is in line with animal welfare considerations because additional animal tests can be avoided by such an evaluation.

 

The results of basic toxicity testing give no reason to anticipate unusual characteristics with regard to the toxicokinetics of Genamin 3920. The data indicate that there is little dermal absorption. On the other hand, Genamin 3920 is absorbed from the gastro-intestinal tract in toxicologically significant amounts. The structure as well as a computational model indicate a potential metabolism mainly via oxidative de-alkylation of the amine. Indications of a bio-accumulative potential as well as a metabolism towards genotoxic sub-structures do not exist. Excretion of systemically available Genamin 3920 and/or metabolites can be assumed.