Registration Dossier

Administrative data

Endpoint:
basic toxicokinetics, other
Remarks:
At this tonnage band a expert statement is sufficient to fullfill the data requirements
Type of information:
other: expert statement
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Evaluation of available toxicity studies with regard to toxico kinetic behaviour

Data source

Reference
Reference Type:
other company data
Title:
Unnamed
Year:
2017
Report Date:
2017

Materials and methods

Objective of study:
other: overall expert evaluation of available data
Test guideline
Qualifier:
no guideline required
Principles of method if other than guideline:
Evaluation of available toxicity data with regard to toxicokinetic information.
GLP compliance:
no
Remarks:
not required

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
Test item: Sanodal Gold 4N trocken
Chemical Name: Reaction mass of sodium sulphate and trisodium trioxalatoferrate
Batch number: CHA0 122713
CAS number 555-34-0 trisodium trioxalatoferrate (constitutent 1)
7757-82-6 sodium sulphate (constitutent 2)
Purity 56.6% (w/w) constitutent 1
35.2% (w/w) constitutent 2
Molecular formula: C6O12Na3Fe
Molecular weight: 388.88 g/mol
Water solubility: > 10 g/L (20°C) (20°C)
pH value: 3.5 – 4.5 (20 °C, 30 g/L)
Appearance: Green powder
Expiry date: 2024-10-09 (Statement of producer)
Recommended storage: Room temperature, dry, in the tightly closed container, on a well ventilated place

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on absorption:
Based on the subacute (28-day) oral toxicity study absorption of toxicologically significant amounts of Sanodal Gold 4N via the gastrointestinal tract has to be assumed since effects in the stomach and kidneys were observed. Systemic availability seems to be negligible after dermal exposure since no systemic signs of intoxication were seen after occlusive administration of 5000 mg Sanodal Gold 4N 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. The notion of very limited dermal absorption is also corroborated by the high water solubility of 257 g/L.
Details on distribution in tissues:
Based on the results of the subacute oral toxicity study findings observed in the stomach and kidneys, it can be concluded, that Sanodal Gold 4N is absorbed through the gastrointestinal tract and systemically available within the organism. Histopathological findings do not indicate a deposition of the material as such in the affected tissues but the formation of oxalic acid and calcium oxalate in the kidneys.
There were no signs of bioaccumulation of the test material. This view is supported by the physical-chemical properties (high solubility in water) and the molecular structure.
Details on excretion:
Taking into account the physico-chemical properties and the molecular structure of the material it can be assumed that the main route of excretion will be the kidney. Nevertheless, a significant part of the dose is expected to just pass through the digestive tract without being absorbed. This notion is confirmed by the high water solubility and the limited capacity of the mammalian organism to absorb highly charged ionic compounds

Metabolite characterisation studies

Metabolites identified:
no
Details on metabolites:
Sanodal Gold 4N proved to be inactive in the Ames-test with and without exogenous metabolic activation. It was not genotoxic in the HPRT and chromosomal aberration assay in vitro. This indicates that Sanodal Gold 4N does not form mutagenic metabolites. Probable metabolites are oxalic acid and the corresponding calcium salt. Modelling of the metabolic fate of the test material using NEXUS-METEOR did also give an indication of hydrolysis as the probable metabolism.
Effects were seen in the subacute study in directly (stomach) and indirectly (kidney) exposed tissues. Functional and structural impairments were detected. Therefore, Sanodal Gold 4N is considered to pass through the organism with significant metabolism. The interaction being attributed to hydrolysis with the formation of free iron3+ and oxalic acid giving rise to the effects observed in stomach and kidneys. Depending on the dose the capacity of the excretion mechanisms may become exhausted leading to a temporary deposition of the components, especially calcium oxalate crystals in the kidneys.

Any other information on results incl. tables

Toxicokinetic parameters such as uptake, distribution, metabolism and excretion form part of the essential toxicological profile of a substance. Although the toxicokinetic behaviour of substances does not describe a toxicological endpoint itself, an approximate indication of the individual toxicokinetic parameters absorption, distribution, metabolism and excretion (ADME) can be gained from the results of basic toxicity testing. In this respect, the following evaluation discusses results and observations from basic toxicity studies, which can be used as approximate indications for the description of the individual toxicokinetic parameters. Such an approach is justified by animal welfare considerations because additional animal testing can be avoided. The assessment of the toxicokinetic properties of Sanodal Gold 4N given below is based on the results obtained for the following toxicological endpoints:

 

 

·               Acute oral toxicity

·               Acute dermal toxicity

·               Skin irritation

·               Eye Irritation

·               Skin sensitisation

·               HGPRT-test

·               In vitro cytogenetic assay

·               Subacute (28-day) oral toxicity

·               Reproductive toxicity screening

 

 

These studies mostly were carried out according to the principles of Good Laboratory Practice and met the requirements of the OECD and EU-Guidelines for the Testing of Chemicals.

 

 

Simultaneously reference to physico-chemical data such as solubility, log Powand hydrolytic stability are included in the evaluation. This information gives additional indications regarding special toxicokinetic parameters, e.g. distribution, metabolism and excretion.

Applicant's summary and conclusion

Conclusions:
Based on all available data, Sanodal Gold 4N 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 do not indicate that Sanodal Gold 4N has a definite dermal absorptive potential. Sanodal Gold 4N is absorbed from the gastrointestinal tract in significant amounts.
Metabolism via hydrolysis to form oxalic acid is considered probable. A bio-accumulative potential is not expected as the material as well as the expected metabolites are water soluble and no delayed toxicity occurred. Additionally no increase in severity of systemic effects was observed in the subacute oral toxicity study compared to the acute studies, which points to no bio-accumulation potential as well as to effective excretion of Sanodal Gold 4N and/or metabolites.
Executive summary:

Based on the available data base on Sanodal Gold 4N 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 Sanodal Gold 4N. The data indicate that there is no relevant dermal absorption. On the other hand, Sanodal Gold 4N is absorbed from the gastro-intestinal tract in toxicologically significant amounts. Metabolism via hydrolysis to form oxalic acid is considered probable. Indications of a bio-accumulative potential as well as a metabolism towards genotoxic sub-structures do not exist. Excretion of systemically available Sanodal Gold 4N and/or potential metabolites via the kidney can be assumed.