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Basic toxicokinetics

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basic toxicokinetics
Type of information:
other: Compilation of available data
Adequacy of study:
key study
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Compilation of data and estimations.

Data source

Reference Type:
other: compilation and estimations
Report date:

Materials and methods

Objective of study:
other: Compilation of available data and estimations based on phys.-chem. properties.
Test guideline
equivalent or similar to guideline
other: other: ECHA Guidance on Information Requirement, R.7.12 Guidance on Toxicokinetics.
Version / remarks:
June 2017
Principles of method if other than guideline:
Compilation of available data and estimations based on phys.-chem. properties.
GLP compliance:

Test material

Constituent 1
Chemical structure
Reference substance name:
EC Number:
EC Name:
Cas Number:
Molecular formula:
C9H12N2O4S (Hill formula) C9H12N2O4S (CAS formula)
(6R,7R)-7-amino-3-(methoxymethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid
Details on test material:
See the individual records on toxicological endpoints.

Results and discussion

Main ADME results

Toxicokinetic / pharmacokinetic studies

Details on absorption:
Absorption, distribution:
Minor systemic effects were detected in the repeated oral dose study and the screening OECD 421 study. These effects indicate an absorption of the test substance in the gastrointestinal tract and a distribution in the body.
No relevant systemic toxic effects were noted in the acute oral, the acute dermal and the acute inhalation toxicity studies.

Guidance for a oral absorption:
Based on the Section R. of the 'Guidance on information requirements and chemical safety assessment' some of the relevant physical-chemical properties for an oral absorption are:
- Ionic groups in the molecule are present and do not favour an absorption. The low pH of stomach may favour the absorption of the acidic molecule, but not of the contained amino-group.
- Molecular weights below 500 are favourable for absorption. 7-AMCA has a molecular weight of 244.
- The water solubility of 7-AMCA is low: 88 mg/L at 20 °C.
- The low n-octanol/water partition coefficient (log Pow = -1.2) for 7-AMCA does not enable an extensive absorption by passive diffusion.
These data point to a low to moderate oral absorption - in agreement with the observed (non to low) toxic effects in the available oral toxicity studies.

Guidance for an inhalation absorption:
An acute inhalation toxicity study in rats with a MMAD of 3.81 µm did not show systemic toxic effects at the limit concentration of 5.12 mg/L, therefore no indication of an absorption was obtained. The relevant parameters for absorption at inhalation exposure are not very different to those for oral absorption, as described in the Section R. of the 'Guidance on information requirements and chemical safety assessment'.

Guidance for a dermal absorption:
For dermal absorption an even lesser absorption is predicted compared to the oral route, based on the following criteria:
- Molecular Weight: The range between 100 and 500 favours dermal uptake.
- n-octanol/water partition coefficient: For substances with log P values <0, poor lipophilicity will limit penetration into the stratum corneum and hence dermal absorption. Values <–1 suggest that a substance is not likely to be sufficiently lipophilic to cross the stratum corneum, therefore dermal absorption is likely to be low.
- Water Solubility: The substance must be sufficiently soluble in water to partition from the stratum corneum into the epidermis. Between 1-100 mg/L the absorption is anticipated to be low to moderate.

Details on distribution in tissues:
The repeated dose toxicity study and the screening OECD 421 study provide a hint that a distribution occurs.
Transfer into organs
other: No relevant data are available.
Details on excretion:
No relevant data are available, which provide evidence on the route of excretion.
Toxicokinetic parameters
Toxicokinetic parameters:
other: No relevant data are available.

Metabolite characterisation studies

Details on metabolites:
Metabolism: No relevant differences in genotoxicity were detected with and without the addition of a metabolising system. Therefore no indication of the importance of the metabolism of the test substance was obtained from the mutagenicity studies.

Any other information on results incl. tables

Bioaccumulation: No accumulation is expected, based on the low log Pow.

Applicant's summary and conclusion

Executive summary:

An only low evidence of an oral absorption was obtained from the available acute and subacute/subchronic tests. Only low oral absorptions are also predicted from the phys.-chem. properties of the substance.

No evidence of a dermal absorption was obtained from the available toxicity test. The dermal absorption is predicted to be even lower compared to the oral route.

No evidence of a distribution or of the way of excretion was obtained.

No evidence of metabolisation was obtained from the mutagenicity tests with and without metabolising systems.

No bioaccumulation is expected, based on the low log Pow.