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basic toxicokinetics, other
QSAR analysis
Type of information:
other: Assessment of toxicokinetic behaviour
Adequacy of study:
key study
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Acceptable, well documented report which meets basic scientific principles

Data source

Reference Type:
other: expert judgement
Atmer 163 (CAS-No. 97925-95-6): Assessment of the toxicokinetic behaviour
Report date:

Materials and methods

Objective of study:
Principles of method if other than guideline:
The toxicokinetic behaviour of Atmer 163 (CAS-No. 97925-95-6) was assessed. The OECD QSAR Application Toolbox was used to make a qualitative prediction of the metabolites formed in liver, skin and gastrointestinal tract. The fate of these metabolites is predicted on the basis of their chemical structure based on expert judgement.

GLP compliance:

Test material

Constituent 1
Reference substance name:
Ethanol, 2,2'-iminobis-, N-(C13-15-branched and linear alkyl) derivs.
EC Number:
EC Name:
Ethanol, 2,2'-iminobis-, N-(C13-15-branched and linear alkyl) derivs.
Cas Number:
Molecular formula:
Not applicable - multiconstituent substance
Ethanol, 2,2'-iminobis-, N-(C13-15-branched and linear alkyl) derivs.

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on absorption:
In an acute oral toxicity study, rats were administered Atmer 163 by gavage. The LD50 was 1500 mg/kg bw for males and 1300 mg/kg bw for females. Clinical signs of systemic toxicity (markedly higher para-sympathetic nervous activity) were observed; indicating that the substance is bioavailable after oral administration (Jackson,S.J. 1979; see Chapter 7.2.1 acute oral toxicity).

In a skin irritation study on rabbits, Atmer 163 was shown to be corrosive. Local effects on the alimentary tract were likewise observed in the 90-day gavage study performed with Sprague-Dawley rats (Zoetis,T. 1991; see Chapter 7.5.1 repeated dose toxicity: oral). In addition, the results indicated a systemic effect, and therefore oral bioavailability of the substance, in line with the results of the acute toxicity study. The absorption has not been quantified; however, using the Danish QSAR database , the gastrointestinal absorption of a closely related substance (CAS No. 68155-05-5, like Fig. 1, but n = 9-15) was predicted to be 100% (1 mg dose).

As Atmer 163 is a corrosive substance, no acute dermal or inhalation toxicity studies were performed. The bioavailability via the dermal route has thus not been examined experimentally. Considering the corrosive nature of the substance, it is reasonable to assume that exposure may cause damage to the skin, subsequently facilitating dermal uptake. Using the Danish QSAR database, the dermal absorption of a similar substance (CAS No. 68155-05-5, like Fig. 1, but n = 9-15) was estimated to be 0.00400 mg/cm²/event, which is relatively low. It is likely that the corrosive effect increases bioavailability due to a loss of skin barrier integrity.

For risk assessment purposes, the bioavailability via the inhalation route is considered to be similar to that of the oral route, i.e. quantitative.

No subchronic dermal or inhalation studies are available.
Details on excretion:
Atmer 163 has a molecular weight lower than 500 u and is relatively water soluble. The QSAR simulation furthermore predicts that Atmer 163 will primarily be metabolised to molecules that are utilized in well-known human metabolic pathways. Therefore, Atmer 163 is likely to be excreted as breakdown products of these metabolic pathways. The secondary route of excretion is expected to be via the urine, including any minor hepatic metabolites.

Metabolite characterisation studies

Metabolites identified:
Details on metabolites:
No information is available regarding the metabolism of Atmer 163 specifically. The potential metabolites of a closely related substance (CAS No. 68155-05-5, side chain length n = 9-15) in liver, skin and gastrointestinal tract were simulated using the QSAR OECD Toolbox 1.1.02. 23 hepatic metabolites were predicted. These metabolites arise from hydroxylation, N-dealkylation, and oxidation, especially beta-oxidation of intermediary fatty acids. The main reaction is most likely a dealkylation, to diethanolamine and a primary alcohol (see Figure 2). The alcohol is typically further metabolized to a fatty acid that enters into fatty acid catabolism, and is ultimately metabolized to carbon dioxide and water. Diethanolamine is readily metabolized to monoethanolamine, which is known to be a part of the phospholipid synthesis pathway (see the KEGG database, In repeated dose studies on rats, exposure to diethanol¬amine bioaccumulated in (among other) liver and kidney tissue lead to increasing levels of aberrant phospholipids and histopathological lesions (Knaak JB et al, 1997; Mathews JM et al, 1995). As the subchronic rat and dog studies did not reveal any significant histopathological changes in liver or kidneys, the bioaccumulation of diethanolamine as a metabolite of Atmer 163 is not expected to occur under experimental dosing conditions.
Diethanolamine may also be excreted via the urine, primarily in its unchanged form (Mathews JM et al, 1997).
In the skin, two metabolites were predicted, with one or two carboxy groups. These are expected to be metabolized via the same pathways as described for the liver metabolism.

Applicant's summary and conclusion

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