Registration Dossier

Administrative data

Endpoint:
basic toxicokinetics, other
Remarks:
Assessment
Type of information:
calculation (if not (Q)SAR)
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Justification for type of information:
Assessment based on toxicity studies and assessment of physico-chemical parameters. The colour of the substance means that some assessment is possible with relation to the discolouration of the animal and potential target organs.

Data source

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

Materials and methods

Objective of study:
toxicokinetics
Test guideline
Version / remarks:
no guideline. Assessment the toxicological and ecotoxicological properties of Everlan SL65.
GLP compliance:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
Sodium [4-[[dihydroxy[(2-hydroxy-3,5-dinitrophenyl)azo]phenyl]azo]benzenesulphonato(3-)]cuprate(1-)
EC Number:
305-729-0
EC Name:
Sodium [4-[[dihydroxy[(2-hydroxy-3,5-dinitrophenyl)azo]phenyl]azo]benzenesulphonato(3-)]cuprate(1-)
Cas Number:
95009-01-1
Molecular formula:
C18H9CuN6O10S.Na
IUPAC Name:
sodium [4-[[dihydroxy[(2-hydroxy-3,5-dinitrophenyl)azo]phenyl]azo]benzenesulphonato(3-)]cuprate(1-)
Test material form:
solid: particulate/powder
Details on test material:
- Name of test material (as cited in study report): Everlan SL65
- Substance type: Powder
- Composition of test material, percentage of components: 71.19%
- Lot/batch No.: 3010
- Storage condition of test material: Ambient
Specific details on test material used for the study:
- Name of test material (as cited in study report): Everlan SL65
- Synonym: Acid Brown 97
- Substance type: Powder
- Composition of test material, percentage of components: 71.19%
- Lot/batch No.: 3010
- Storage condition of test material: Refrigeration (5  3℃) and protect from light.
Radiolabelling:
no

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on absorption:
There was no evidence of systemic effects reported for acute oral or dermal toxicity studies, but over longer periods, the repeat oral study and reproduction toxicity screening tests conclude that there was slight adverse effect at the top dose of 1000 mg/kg/dad and at lower doses of 250 and 300 mg/kg/day respectively for each study.

Red-brown faeces were observed through the test period for the reproduction screening test suggesting that a significant proportion of the substance passes through without absorption. There was no obvious discolouration of organs and the only discolouration seen was to the cecum on some of the high dose animals.

Discoloured urine (only observed in the reproduction screening test) in the higher dose groups does imply absorption does occur, although followed by excretion of via the kidneys. No discolouration of the kidneys was reported.

There is no evidence of dermal absorption and although there was surface tension reduction in water, 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 not noted, but effects reported with blood chemistry changes in the high dose groups. There were no other toxicological findings (other than reduced weight gain in the reproduction toxicity screen) and no target organ has been identified.

Both of the repeated dose studies failed to indicate any discolouration of the kidneys or bladder.
The high water solubility would suggest that any absorbed material would be transported in the blood, although it is very likely that there would be dissociation of the sodium.
Details on excretion:
The discoloured urine suggest excretion of absorbed material in the urine. However, the red-brown colour of the faeces suggests that a significant proportion is excreted unchanged (or similar coloured transformation products) following oral exposure.

In the oral reproduction toxicity screening test, red-brown faeces were seen shortly after administration and were present typically on day 2 of dosing representing normal passage through the GI tract. This was only seen with the higher does groups, suggesting at lower doses, the colour change was less obvious.

Colouration of urine was typically observed from day 2, but a bit later in some animals.
Since the discolouration of the urine was noted mostly in the higher treatment groups to start at approximately the same time, it is unlikely to be due to accumulation. This is a relatively quick rate of excretion.

Metabolite characterisation studies

Metabolites identified:
not measured

Any other information on results incl. tables

1. Genetic toxicological information:

- Bacterial reverse mutation test: postive; 5 mg/plate was the highest concentration. (Reprot no.: M62 -151100105)

- In vitro mammalian chromosomal aberration test: postive. 2.0 mg/ml was the highest concentration treated with or without S9 Mix for 3 hours, and 1.0 mg/ml was the highest concentration treated without S9 Mix for 20 hours. (Report no.: M62 -151100106).

- In vitro mammalian cell gene mutation test: postive; 2.0 mg/ml was the highest concentration treated with or without S9 Mix. (Repoet no.: M62 -151100112)

2. General toxicological information:

- Subacute oral toxicity: NOAEL = 62.5 mg/kg BW (Repoet no.: M62 -151100104)

- Acute dermal toxicology: LD50 > 2,000 mg/kg BW (Repoet no.: M62 -151100100)

- Skin irritation: Negative (Repoet no.: M62 -151100101)

- Skin sensitization: Negative (Repoet no.: M62 -151100103)

- Eye irritation:(test dosage: 0.1 g) (Repoet no.: M62 -151100102)

3. Ecological toxicolgical information:

- Adsorption coefficient test: sludge Koc = 93.54; soli Koc = 205.13 (Repoet no.: M62 -151100110)

- Activated sludge respiration inhibition test: EC50 > 1,000 mg/L (Repoet no.: M62 -151100109)

- Alga growth inhibition test: ErC50 = 3.10 mg/L; EyC50 = 1.65 mg/L (Repoet no.: M62 -151100107)

- Daphnia sp., acute immobilisation test: EC50 = 2.57 mg/L (Repoet no.: M62 -151100108)

- Ready biodegradability: it was not the ready biodegradable article. (Repoet no.: M62 -151100111)

Applicant's summary and conclusion

Conclusions:
The colour of the test material will help absorption, distribution and excretion, but the only indication that some absorption occurs is from the discolouration of urine in high-doses following repeated dose administration. 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:

Metabolism

The low rate of biodegradation from eukaryotic microbial cells would suggest only a limited rate of metabolic activity in animals; however, there were flaws in the biodegradation study and there may be a higher rate of breakdown. It is possible that copper is released once organic components are broken down.

 

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, although were positive in terms of potential mutagenicity 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 for copper and although assumed excreted unchanged (red-brown), some metabolic processes could have led to biotransformation to other similar coloured compounds.