(6R-trans)-7-amino-8-oxo-3-[[(1,2,5,6-tetrahydro-2-methyl-5,6-dioxo-1,2,4-triazin-3-yl)thio]methyl]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid

Endpoint summary

Link to relevant study record(s)

Reference

Endpoint:

basic toxicokinetics in vivo

Type of information:

other: Compilation and interpretation of available data.

Adequacy of study:

key study

Study period:

2018

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Compilation and interpretation of available data.

Objective of study:

absorption

distribution

excretion

metabolism

Qualifier:

equivalent or similar to guideline

Guideline:

other: Section R.7.12.2.1 of the 'Guidance on information requirements and chemical safety assessment'

Version / remarks:

2017

Deviations:

not specified

Principles of method if other than guideline:

Compilation and interpretation of available data.

GLP compliance:

no

Radiolabelling:

no

Details on absorption:

No relevant systemic toxic effects were noted in the acute oral and the acute inhalation toxicity studies.

Guidance for an oral absorption:
Based on the Section R.7.12.2.1 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-ACT has a molecular weight of 371.
- The water solubility of 7-ACT is low: 200 mg/L at 20 °C.
- The low n-octanol/water partition coefficient (log Pow -3.5) for 7-ACT does not enable an extensive absorption by passive diffusion.
These data point to a low to moderate oral absorption - in agreement with no observed toxic effects in the available acute oral toxicity study.

Guidance for an inhalation absorption:
An acute inhalation toxicity study in rats with a MMAD of 3.93 µm did not show systemic toxic effects at the limit concentration of 5.05 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.7.12.2.1 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.

Details on distribution in tissues:

No indication from the available studies was obtained on the possible distribution of the substance in the body.

Details on excretion:

Excretion:
No relevant data are available, which provide evidence on the route of excretion.

Details on metabolites:

Metabolism:
No relevant differences occurred in the mutagenicity studies 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 these studies.

Conclusions:

The toxicokinetic behaviour of the test item was estimated from available data.
No evidence of an oral absorption was obtained from the available acute toxicity test. A low oral absorption is also predicted from the phys.-chem. properties of the substance.
No evidence of an inhalation absorption was obtained from the available acute toxicity test. The dermal absorption is predicted to be 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.

Executive summary:

The toxicokinetic behaviour of the test item was estimated from available data.

No evidence of an oral absorption was obtained from the available acute toxicity test. A low oral absorption is also predicted from the phys.-chem. properties of the substance.

No evidence of an inhalation absorption was obtained from the available acute toxicity test. The dermal absorption is predicted to be 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.

Description of key information

The toxicokinetic behaviour of the test item was estimated from available data.

No evidence of an oral absorption was obtained from the available acute toxicity test. A low oral absorption is also predicted from the phys.-chem. properties of the substance.

No evidence of an inhalation absorption was obtained from the available acute toxicity test. The dermal absorption is predicted to be 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.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential