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Administrative data

Endpoint:
basic toxicokinetics, other
Type of information:
other: data review and expert estimation
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
data from handbook or collection of data
Justification for type of information:
Review of available data. Intense colour of the substance means that existing data provides evidence for absorption, distribution and excretion.

Data source

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

Materials and methods

Objective of study:
absorption
distribution
excretion
metabolism
Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
The toxicokinetic assessment is prepared by evaluating the available physical, environmental and toxicological properties.
GLP compliance:
no
Remarks:
Paper assessment

Test material

Constituent 1
Chemical structure
Reference substance name:
Pyridinium, 1,1'-[(6,13-dichloro-4,11-disulfo-3,10-triphenodioxazinediyl)bis[imino-2,1-ethanediylimino[6-[(2,5-disulfophenyl)amino]-1,3,5-triazine-4,2-diyl]]]bis[3-carboxy-, dihydroxide, bis(inner salt), hexasodium salt
EC Number:
279-256-2
EC Name:
Pyridinium, 1,1'-[(6,13-dichloro-4,11-disulfo-3,10-triphenodioxazinediyl)bis[imino-2,1-ethanediylimino[6-[(2,5-disulfophenyl)amino]-1,3,5-triazine-4,2-diyl]]]bis[3-carboxy-, dihydroxide, bis(inner salt), hexasodium salt
Cas Number:
79771-28-1
Molecular formula:
C52H38Cl2N16O24S6.6Na
IUPAC Name:
Pyridinium, 1,1'-[(6,13-dichloro-4,11-disulfo-3,10-triphenodioxazinediyl)bis[imino-2,1-ethanediylimino[6-[(2,5-disulfophenyl)amino]-1,3,5-triazine-4,2-diyl]]]bis[3-carboxy-, dihydroxide, bis(inner salt), hexasodium salt
Test material form:
solid: particulate/powder
Details on test material:
- Name of test material (as cited in study report): Everzol SB26
- Substance type: Powder
- Composition of test material, percentage of components: 78.12%
- Lot/batch No.: 3540
- Storage condition of test material: Ambient
Radiolabelling:
no

Results and discussion

Preliminary studies:
Genetic toxicological information:
Bacterial reverse mutation test: Negative; 5 mg/plate was the highest concentration (according to the SuperLab Final Report M62-151100132).
In vitro mammalian chromosomal aberration test: Negative; 2.0 mg/mL was the highest concentration treated with or without S9 Mix (according to the SuperLab Final Report (M62-151100133).
In vitro mammalian cell gene mutation test: Negative; 2.0 mg/mL was the highest concentration treated with or without S9 Mix (according to the SuperLab Final Report M62-151100141).

General toxicological information:
Subacute oral toxicity: NOAEL > 1,000 mg/kg B.W. (according to the SuperLab Final Report M62-151100131).
Acute dermal toxicity: LD50 > 2,000 mg/kg B.W. (according to the SuperLab Final Report M62-151100129).
Skin irritation: Negative (test dosage: 0.5 g) (according to the SuperLab Final Report M62-151100139).
Skin sensitization: Negative (test concentration: 10%) (according to the SuperLab Final Report M62-151100130).
Eye irritation: Negative (test dosage: 0.1 g) (according to the SuperLab Final Report M62-151100140).

Ecological toxicological information:
Adsorption coefficient test: sludge Koc < 28.84; soil Koc < 18.20 (according to the SuperLab Final Report M62-151100137).
Activated sludge respiration inhibition test: EC50 > 1,000 mg/L (according to the SuperLab Final Report M62-151100136).
Alga growth inhibition test: ErC50 > 100.00 mg/L; EyC50 = 24.56 mg/L (according to the SuperLab Final Report M62-151100134)
Daphnia sp., Acute immobilisation test: EC50 > 100.00 mg/L (according to the SuperLab Final Report M62-151100135).
Ready biodegradability: Up to ca 20% over 60 days (according to the SuperLab Final Report M62-151100138).
Main ADME resultsopen allclose all
Type:
absorption
Results:
Evidence of some absorption from oral exposure
Type:
distribution
Results:
Discolouration of organs (eg kindeys) is a good indicator that there is distribution. However, no target organ was identified.
Type:
metabolism
Results:
No specific evidence of metabolic activity. Slow biodegradartion reported, so metabolim considred likely to be slow, if any
Type:
excretion
Results:
Significant excretion via faeces (likley non-absorbed),b ut also discoloured urine and discoloured kidneys suggesting exctretion route

Toxicokinetic / pharmacokinetic studies

Details on absorption:
There was no evidence of systemic effects reported for oral or dermal toxicity studies, with the repeat oral study and reproduction toxicity screening tests conclude that there was no adverse effect at the top dose of 1000 mg/kg/day.

However, the intense colour of the test material allowed visual observations to confirm absorption.

Blue faeces were observed through the test period for the repeated dose toxicity studies suggesting that a significant proportion of the substance passes through without absorption. The intestines were observed to be blue, but otherwise non-affected by the test material in the oral reproduction toxicity study.

However, blue discolouration of various organs confirms that some absorption does occur.

There is no evidence of dermal absorption and from the high molecular weight and lack of surface active properties, it is likely to have a low rate of dermal absorption. Guidance suggests that a default of 10% can be used in such cases.

Discolouration of skin and fur was seen in many animals in the reproductive toxicity screening test, but this is often due to grooming activities where faeces and urine are discoloured.
Details on distribution in tissues:
Discolouration of organs was noted, but no other adverse effects reported and in the absence of toxicological findings, no target organ has been identified.

The 28 day toxicity study test report failed to indicate any discolouration of the GI tract, kidneys or bladder and only ‘lesions’ were looked for. The absence of reported findings is considered to be a deficiency in the reporting and does not mean that these changes in colour took place.

In the oral reproduction toxicity study, discolouration was noted in mesenteric lymph nodes, lungs, uterus, kidneys all suggesting distribution of absorbed materials. The substance is very water soluble and if absorbed in the GI tract, transport through the blood would be expected.
Details on excretion:
The discoloured kidneys and urine suggest excretion of absorbed material in the urine. However, the intense dark blue of the faeces suggests that a significant proportion is excreted unchanged following oral exposure.

In the oral reproduction toxicity screening test, blue faeces were seen shortly after administration and were present typically on day 2 of dosing representing normal passage through the GI tract.

Colouration of urine was typically observed from day 7 or 8 and then continued for the duration of the study. This suggested either that there is a time delay of approximately 7 days from absorption to excretion or that the rate of absorption is slow and it was only after continued dosing for up to 8 days that sufficient had been absorbed to be observed in the urine.

Since the discolouration was noted in all treatment groups to start at approximately the same time, it is unlikely to be due to accumulation (build up to a critical levels would be dose related) so it appears that there is some delay between adsorption and excretion.

Metabolite characterisation studies

Metabolites identified:
no
Details on metabolites:
The low rate of biodegradation from eukaryotic microbial cells would suggest only a limited rate of metabolic activity in animals. During in-vitro mutagenicity testing performed on the salts, differences between replicates with and without metabolic activation were not seen. However, none of the replicates showed any significant toxicity or mutagenic potential.

Especially in view of water solubility, it is considered likely that accumulation will not occur and that the substance will be excreted or ultimately metabolise. The urine was not analysed and although assumed excreted unchanged (blue), some metabolic processes could have led to biotransformation to other blue compounds.

Any other information on results incl. tables

Estimated dermal adsorption factor 10% based on structure and molecular weight

Low bioaccumulation potential based on solubilty in water

Applicant's summary and conclusion

Conclusions:
The intense colour of the test material means it is possible to identify absorption, distribution and excretion. In the absence of specific toxicokinetic data from animal testing it is not possible to make firm conclusions concerning metabolism, but the limited biodegradation will indicate that some slow metabolism is likely.

There is no indication of accumulation.

It is not considered appropriate to perform further animal studies on this substance.
Executive summary:

The substances has been extensively tested for REACH Registration and animal test work failed to indicate any adverse effect up to accepted limits of exposure. Likewise, the in-vtro mutagenicity testing failed to lead to any relevant findings.

 

The intense colour of the test material means it is possible to identify absorption, distribution and excretion through direct observation of animals during dosing and from necropsy findings.

 

In the absence of specific toxicokinetic data from animal testing it is not possible to make firm conclusions concerning metabolism, but the limited biodegradation will indicate that some slow metabolism is likely.  There is no indication of accumulation.  

 

It is not considered appropriate to perform further animal studies on this substance.

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