Disodium 4,4'-bis[[6-anilino-4-[(2-hydroxyethyl)methylamino]-1,3,5-triazin-2-yl]amino]stilbene-2,2'-disulphonate

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics in vivo

Type of information:

migrated information: read-across based on grouping of substances (category approach)

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: see 'Remark'

Remarks:

Testing procedures do not follow an official European testing guideline, nevertheless the studies are well documented and the results scientifically acceptable. Justification for Read Across is detailed in the Toxicokinetics summary and in the Category Justification Report attached to the section 13.

Data source

Reference

Reference 1

Reference Type:

study report

Title:

Unnamed

Year:

1972

Report date:

1972

Reference 2

Reference Type:

publication

Title:

Metabolic Behaviour of Water-Soluble Fluorescent Whitening Agents in the Rat and Bean Plant.

Author:

Muecke W. et al.

Year:

1975

Bibliographic source:

Environmental Quality and Safety, Supplement, vol. 4, 174-179.

Materials and methods

Objective of study:

metabolism

Principles of method if other than guideline:

The behaviour of three water-soluble fluorescent whitening agents (FWAs - including the test item) was studied in rats using 14C-labelled compounds. The fate of 14C-labelled test substance was followed in the rat. The animals dosed with 5.97 ± 0.33 mg/kg (actual dose) and faeces, urine and expired CO2 were monitored. After 96 hours animals were killed and tissues analyzed.

GLP compliance:

no

Remarks:

Pre GLP.

Test material

Test material information

Constituent 1

Reference substance name:

Disodium 4,4'-bis[(4-anilino-6-morpholino-1,3,5-triazin-2-yl)amino]stilbene-2,2'-disulphonate

EC Number:

240-245-2

EC Name:

Disodium 4,4'-bis[(4-anilino-6-morpholino-1,3,5-triazin-2-yl)amino]stilbene-2,2'-disulphonate

Cas Number:

16090-02-1

Molecular formula:

C40H40N12O8S2.2Na

IUPAC Name:

disodium 4,4'-bis[(4-anilino-6-morpholino-1,3,5-triazin-2-yl)amino]stilbene-2,2'-disulphonate

Radiolabelling:

yes

Remarks:

14C

Test animals

Species:

rat

Strain:

other: SIV 50

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Ivanovas, Kisslegg, Germany.
- Breeding: under SPF conditions.
- Weight at study initiation: approximately 200 g.

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

water

Duration and frequency of treatment / exposure:

Single application.

Doses / concentrations

Remarks:

Doses / Concentrations:
6.1 ± 0.1 mg/kg for females and 5.9 ± 0.2 mg/kg for males (mean ± SEM)

No. of animals per sex per dose / concentration:

4

Control animals:

no

Details on study design:

ANIMALS CONDITION after dosing
- Housing: the animals were kept in all-glass metabolism cages.
- Food: ad libitum, commericial food.
- Water: ad libitum.
- Sacrifice: the animals were killed after 96 hours by decapitation.

Details on dosing and sampling:

SAMPLES collaction
- Samples before sacrifice: urine, faeces and expired CO2.
- Time and frequency of sampling: 16 or 24, 40 or 48, 64 or 72 hours after application.
- Samples after sacrifice: blood, liver, kidney, brain, muscle and fat.

ANALYSIS
- Method type for identification: liquid scintillation counting (Model 3375 Tricarb).
- Limits of detection and quantification: 0.01 ppm
- Radioactivity: the radioactivity in the dry material was determined by combustion.
- Faeces: TLC (Thin Layer Chromatography).
- Sample preparation: liqui samples were measured directly. Faeces were lyophilized and ground to a fine powder in a disc mill. CO2: expired CO2 was trapped in ethanolamine solution.
- Tissues: animal tissues and blood were solubilized with a 1:1 mixture of 2-propanol:Soluene and the resulting solutions were decolorized with hydrogen peroxide before adding the scintillation cocktail for counting.

Results and discussion

Main ADME results

Type:

excretion

Results:

More than 90 % of the administered radioactive material was excreted within 48 hours.

Toxicokinetic / pharmacokinetic studies

Details on absorption:

The results indicate that there is virtually no absorption from the gut of the test substance.

Details on distribution in tissues:

Residues in all tissues investigated were below the limit of quantitative determination which was 0.005-0.01 ppm test item equivalent.

Details on excretion:

The faeces proved to be practically the only route of elimination for the applied radioactive material. About 90 % of the applied radioactivity was eliminated in faeces within 24 hours of dosing, indicating, in combination with the short half life times, that no significant amounts of test substance were absorbed from the gastro-intestinal tract.
Radioactivity found in urine was at the limit of detection (0.02%. of applied dose).
No radioactivity was found in the expired air (< 0.01%).
No sex differences were observed.
A calculation of the excretion half life using the net rate coefficient of drug elimination (24 hours excretion value) revealed that 50% of the dose had been excreted within 7-13 hours after dosing.

Metabolite characterisation studies

Metabolites identified:

not measured

Details on metabolites:

The results indicate that there is the test substance is not metabolized by the rats.

Any other information on results incl. tables

The radioactive material present in the faeces of the rats treated with the test substance was completely extractable with methanol Thin

layer cltromatography (TLC) revealed the presence in the extract of two compounds which behaved like the cis and trans forms of

compound.

Excretion of radioactivity by rats after oral dose

	Excretion as a percentage of dose (mean± SEM, n= 4)
	Male	Female
Faeces
0-24 hours	76.4	89.6
24-48 hours	20.7	5.6
48-96 hours	0.4	< 0.1
Subtotal	97.5	95.2
Urine
0-96 hours	< 0.1	< 0.1
Expired CO2
0-48 hours	< 0.01	< 0.01
Cage wash	< 0.1	< 0.1
Total recovery	97.5 ± 1.8	95.2 ± 1

Applicant's summary and conclusion

Conclusions:

Interpretation of results (migrated information): no bioaccumulation potential based on study results
The faeces proved to be practically the only route of elimination (half life ranging from 7-13 hours).

Executive summary:

Method

The behaviour of three water-soluble fluorescent whitening agents (FWAs - including the test item) was studied in rats using ¹⁴C-labelled compounds. The fate of ¹⁴C-labeled test substance was followed in the rat. The animals dosed with 5.97 ± 0.33 mg/kg (actual dose) and faeces, urine and expired CO2 were monitored. After 96 hours animals were killed and tissues analized.

Results

Following oral doses of 5 mg/kg to rats rapid and complete excretion of radioactive material was observed with an excretion half life ranging from 7-13 hours. Faeces were practically the only route of excretion indicating, in combination with the short half life times, that no significant amounts of whitener were absorbed from the digestive tract. No radioactive residues were found in blood, liver, kidney, brain, muscle, or fat 96 hours after dosing (limit of quantitative determination 0.005-0.01 ppm FWA equivalents).