5-({4-chloro-6-[ethyl(phenyl)amino]-1,3,5-triazin-2-yl}amino)-4-hydroxy-3-[(1-sulfo-2-naphthyl)diazenyl]naphthalene-2,7-disulfonic acid, lithium sodium salts

Basic toxicokinetics

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:

2020

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

Test material information

Constituent 1

Reference substance name:

Reaction products of 2,7-Naphthalenedisulfonic acid, 4-amino-6-[2-[5-[(4-amino-6-chloro-1,3,5-triazin-2-yl)amino]-2-sulfophenyl]diazenyl]-3-[2-(2,5-disulfophenyl)diazenyl]-5-hydroxy-, pentasodium salt and lithium chloride

EC Number:

942-709-6

Molecular formula:

Not applicable; this UVCB substance contains: C25H14ClN10O16S5.xLi.yNa, (x + y) = 5; 0 < (x,y) < 5 with 940.9 < MW < 1021.1 g/mol (UVCB substance), and traces of NaCl.

IUPAC Name:

Reaction products of 2,7-Naphthalenedisulfonic acid, 4-amino-6-[2-[5-[(4-amino-6-chloro-1,3,5-triazin-2-yl)amino]-2-sulfophenyl]diazenyl]-3-[2-(2,5-disulfophenyl)diazenyl]-5-hydroxy-, pentasodium salt and lithium chloride

Test material form:

solid: particulate/powder

Remarks:

migrated information: powder

Radiolabelling:

no

Results and discussion

Main ADME results

Main ADME results 1

Type:

absorption

Results:

Evidence of at least some dermal absorption. No direct evidence or oral absorption.

Main ADME results 2

Type:

distribution

Results:

Effect on colour of kidneys and excretion in urine suggests transportation

Main ADME results 3

Type:

metabolism

Results:

No evidence of metabolic processes. No significant biodegradation suggesting biological stability.

Main ADME results 4

Type:

excretion

Results:

Feacal excretion noted shortly after oral ingestion due to colour change. No reported urine discolouration after dosing.

Toxicokinetic / pharmacokinetic studies

Details on absorption:

There is evidence of absorption following dermal administration, but no evidence of direct organ toxicity.
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.

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

Observation:

no transfer detectable

Details on excretion:

From oral testing, most material seems to pass through the GI tract 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.  Some skin and mucous membrane discolouration, but may be from indirect contact with faeces.
Acute dermal tox	> 2000 mg/kg	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; moderate eye irritation
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.
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 no evidence of oral absorption and from coloured faecal excretion, it is likely a significant proportio passes through the GI tract unchanged. Results from in-vivo skin sensitisation testing suggests dermal penetration can occur.
• Thre is no evidence that the substance, or any similar-coloured metabolite, is excreted in urine
• 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.