Registration Dossier

Administrative data

Endpoint:
basic toxicokinetics
Type of information:
other: Compilation of available data
Adequacy of study:
supporting study
Study period:
2015
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Compilation and estimations.
Cross-reference
Reason / purpose for cross-reference:
reference to other study

Data source

Reference
Reference Type:
other: compilation and estimations
Title:
Unnamed
Year:
2017
Report date:
2017

Materials and methods

Objective of study:
other: Estimatons based on available toxicity data and phys.-chem. properties.
GLP compliance:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
-
EC Number:
477-080-2
EC Name:
-
Cas Number:
103121-85-3
Molecular formula:
C13 H19 N3 O3 S . HCl (Hill Formula) C13 H20 N3 O3 S . Cl (CAS Formula)
IUPAC Name:
1-{[(6R,7R)-7-amino-2-carboxy-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-3-yl]methyl}-1-methylpyrrolidin-1-ium chloride

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on absorption:
No relevant systemic effects were detected in the repeated oral dose study and the screening OECD 421 study. No indication of an absorption of the test substance in the gastrointestinal tract and a distribution in the body was obtained.
No relevant systemic toxic effects were noted in the acute oral, the acute dermal 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:
- A medium molecular mass of 334. Generally the smaller the molecule the more easily it may be taken up. Molecular weights below 500 are favourable for absorption.
- A high water solubility of 111 g/L at 20.0 °C. Water-soluble substances will readily dissolve into the gastrointestinal fluids. Absorption of very hydrophilic substances by passive diffusion may be limited by the rate at which the substance partitions out of the gastrointestinal fluid.
- A low n-octanol/water partition coefficient of log Pow = <-3.3 will not favour an oral absorption.
These data, especially the low log Pow and the high water solubility, do not favour a crossing of biological membranes. It is therefore not expected that an oral absorption will occur to a relevant degree. This is in agreement with no observed toxic effects in the acute and subacute 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.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.
Details on distribution in tissues:
No hint is obtained from the available data that a distribution occurs.
Transfer into organs
Observation:
other: No relevant data are available.
Details on excretion:
No relevant data are available, which provide evidence on the route of excretion.

Metabolite characterisation studies

Details on metabolites:
No relevant difference in genotoxicity was 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

Accumulation: No accumulation is expected, based on the low log Pow and the high water solubility.

Applicant's summary and conclusion

Conclusions:
No relevant oral absorption is expected.
Accumulation: No accumulation is expected, based on the low log Pow and the good water solubility.
Metabolism: No relevant differences in genotoxicity was 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.
Executive summary:

No 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.