Registration Dossier

Administrative data

Endpoint:
basic toxicokinetics, other
Remarks:
Assessment based on data set
Type of information:
calculation (if not (Q)SAR)
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
accepted calculation method
Justification for type of information:
Assessment has been based on existing data set for the substance and through assessment of similar substances in this class.

Data source

Reference
Reference Type:
other company data
Title:
Unnamed
Year:
2019
Report Date:
2020

Materials and methods

Objective of study:
absorption
distribution
excretion
metabolism
toxicokinetics
Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
The approach taken is to consider the chemical structure and class of this substance and to look at the existing data set.
Literature checks were also made on the class of substance including other azo-dyes as well as considering the impact of lithium.
There were many references found in relation to both lithium ion in pharmaceutical uses and to other common sulphonated azo substances.
Searches for similar substances have been performed using commercial directories and the ECHA web-site to help provide a weight of evidence.
GLP compliance:
not specified

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
solid: particulate/powder
Radiolabelling:
no

Results and discussion

Main ADME resultsopen allclose all
Type:
absorption
Results:
Evidence of at least some oral and dermal absorption.
Type:
distribution
Results:
Effect on colour of kidneys and excretion in urine suggests transportation
Type:
metabolism
Results:
No evidence of metabolic processes. Urine colour similar to test material (diluted colour?) and no significant biodegradation
Type:
excretion
Results:
Feacal excretion noted shortly after oral ingestion due to colour change. Urine discolouration lasted up to 5 days after acute dosing.

Toxicokinetic / pharmacokinetic studies

Details on absorption:
There is evidence of absorption following ingestion (coloured urine) from the water soluble substances in this class, but no evidence of direct organ toxicity.
For EC 942-710-1, a 28-day oral study in rats resulted in no clinical signs other than discolouration and all animals survived the maximum dose of 1000 mg/kg/day. Blood parameter changes were seen in higher dose group animals, but these were very likely adaptive changes, perhaps due to high intake of sodium or lithium.

Animal testing performed for non-EU regulatory purposes resulted in a positive guinea pig maximisation test.
This class of substances are typically classified as sensitisers from in-vivo testing and it is considered that the substance under review will also absorb through the skin. Older testing done by non-maximised methods such as the Buehler method (ie topical application only) failed to give positive responses and this may be in part due to due to low levels of dermal penetration. However, results of testing by maximised methods (Magnusson and Kligman) where the substance is injected are more likely to have positive responses; these methods still rely on topical challenge so some dermal absorption is still necessary.
It is also noted that many older in-vivo assessments failed to see weak reactions due to local skin discolouration from dermal application of the dyes on tested animals.
Details on distribution in tissues:
Minor changes were seen in some animals following repeated dosing, but these were very likely adaptive changes or non-treatment related background variations. The kidneys showed minor colour change and urine was discolored.
Transfer into organs
Test no.:
#1
Transfer type:
other: Kidneys
Observation:
distinct transfer
Remarks:
Discolouration of kidneys
Details on excretion:
The substance, or similar-coloured metabolite will be excreted in urine and will pass through the kidneys. In the acute oral study, the discolouration lasted 5 days after treatment
From oral testing, most material seems to pass through and quickly excreted in feaces.

Metabolite characterisation studies

Metabolites identified:
no
Details on metabolites:
None found.
Evidence from biodegradation testing and effect or S-9 activation suggests little if any metabolic degradation.

Any other information on results incl. tables

  

 

 

Observations

Acute oral tox

> 2000 mg/kg

No adverse effects. 

Red / orange urine and faeces for up to 5 days post treatment.

Some skin and mucous membrane discolouration, but may be from indirect contact with urine/faeces.

Discoloured kidneys.

 

Acute dermal tox

> 2000 mg/kg

No direct testing but assessment based on similar substances indicate no adverse effects

Skin discolouration noted, persisting for the duration of observations in some cases.

Grooming may have led to oral exposure in some cases

No direct evidence of absorption.

 

Skin irritation

Not classified

In-vivo testing performed for non-EU regulatory processes; no significant effects

 

Eye irritation

Not classified

In-vivo testing performed for non-EU regulatory processes; no significant effects

Slight discolouration of iris quickly resolved

 

Skin sensitisation

Positive

In-vivo testing performed for non-EU regulatory processes; maximised Guinea pig study positive.

Some dermal absorption is assumed.

 

In-vitro mutagenicity

Negative

Tests on bacterial and mammalian cells were conducted at up to the maximum recommended concentrations with no evidence of cyto-toxicity or mutagenic potential.

The present of S-9 metabolic fraction had no impact on the findings; this does not mean that there is no metabolic process, but that any direct metabolites are similarly non-biologically active.

Sub-acute toxicity

NOAEL 100 mg/kg/day

The NOAEL is based on maximum dose level of 1000 mg/kg/day.

Red / orange staining of urine and discoloured kidneys is evidence of absorption, distribution and excretion.

Biodegradation

No significant biodegradation

This endpoint can indicate aerobic metabolic processes by eukaryotic cells. The absence of apparent effects suggest that there could be a low rate of metabolism, and it is probably that excretion in urine is the main route of elimination.

 

 

Applicant's summary and conclusion

Conclusions:
• The substance has low toxicity with no specific target organ identified. Lithium is known to have neurological effects at relatively high concentrations, but at levels far greater than any accidental ingestion of the substance.
• There is evidence of oral and dermal absorption, but also significant faecal excretion suggesting relatively low rates of oral absorption
• The substance, or similar-coloured metabolite will be excreted in urine and will pass through the kidneys
• Evidence from biodegradation testing and effect or S-9 activation suggests little if any metabolic degradation.
• Lithium and sodium ions are readily absorbed by ingestion and will be distributed in blood; as part of the natural ionic balance, excess sodium and lithium are excreted.