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

Repeated dose toxicity: oral

Administrative data

Endpoint:

short-term repeated dose toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

28 days

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

guideline study with acceptable restrictions

Justification for type of information:

Guideline study, but fails to provide good clinical and necropsy observations relating to colour changes in the animals, including colours of organs and GI tract.

Data source

Reference

Reference Type:

other company data

Title:

Unnamed

Year:

2017

Report date:

2017

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)

GLP compliance:

yes

Limit test:

no

Test material

Test material information

Constituent 1

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

Remarks:

migrated information: 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

Specific details on test material used for the study:

Purity ca 78%, but results expressed as material as supplied and not adjusted for purity

Test animals

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

- Source: BioLASCO Taiwan Co., Ltd.
- Age at study initiation: about 4-week old
- Housing: Male and female rats were fed, respectively. Two rats per cage in an autoclaved polyethylene cage.
- Acclimation period: 1 week
- Temperature (°C): 22 ± 3 °C
- Humidity (%): 55 ± 15%
- Photoperiod: 12-hrs dark / 12-hrs light

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

water

Analytical verification of doses or concentrations:

no

Details on analytical verification of doses or concentrations:

Samples prepared daily.
Material soluble in water and homogeneous

Duration of treatment / exposure:

28 days

Frequency of treatment:

Everyday

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

62.5 mg/kg bw/day (nominal)

Remarks:

Low dose group

Doses / concentrations 2

Dose / conc.:

250 mg/kg bw/day (nominal)

Remarks:

Medium dose group

Doses / concentrations 3

Dose / conc.:

1 000 mg/kg bw/day (nominal)

Remarks:

High dose group

No. of animals per sex per dose:

Six male and six female

Control animals:

yes, concurrent vehicle

Examinations

Observations and examinations performed and frequency:

Basic clincial observations performed according to guidelines

Results and discussion

Results of examinations

Clinical signs:

no effects observed

Mortality:

no mortality observed

Body weight and weight changes:

effects observed, non-treatment-related

Description (incidence and severity):

For male rats:
The body weight of low dose group was significantly lower than control group at week 3 (ρ<0.05), but this is not considered to be of toxicological relevance

Food efficiency:

effects observed, non-treatment-related

Description (incidence and severity):

For male rats:
The feed efficiency of medium dose group was significantly lower than control group during at week 2 (ρ<0.05).
For female rats:
The feed efficiency of low dose group was significantly higher than control group at week 4 (ρ<0.05). The feed efficiency of medium and high does group were significantly higher than control group at week 3 and 4 (ρ<0.05).

Ophthalmological findings:

no effects observed

Haematological findings:

effects observed, non-treatment-related

Description (incidence and severity):

For male rats:
The WBC of low, medium and high dose group and mean corpuscular hemoglobin concentration (MCHC) of medium and high dose group were lower than control group (ρ<0.05).
For female rats:
The mean corpuscular hemoglobin concentration (MCHC) and basophil of medium dose group and prothrombin time (PT) of medium and high dose group were significantly higher than control group (ρ<0.05).

Clinical biochemistry findings:

effects observed, non-treatment-related

Description (incidence and severity):

For male rats:
The total protein of medium dose group, triglyceride (TG) of high dose group and globulin of all treatment groups were lower than control group (ρ<0.05). The P of high dose group was higher than control group (ρ<0.05).
For female rats:
The glucose and TG of medium dose group was lower than control group (ρ<0.05). The Ca and P of high dose group were higher than control group (ρ<0.05).

Urinalysis findings:

no effects observed

Organ weight findings including organ / body weight ratios:

effects observed, non-treatment-related

Description (incidence and severity):

For male rats:
The absolute weight of epididymis in medium dose groups was significantly heavier than control group (ρ<0.05). The relative organ weight of testis in low and medium dose group were significantly heavier than control group (ρ<0.05). The relative organ weight of liver in low and medium dose group was significantly lower than control group (ρ<0.05). The relative organ weight of thymus in high dose group was significantly lower than control group (ρ<0.05).
For female rats:
The relative organ weight of heart in medium dose group was significantly lower than control group (ρ<0.05).

Gross pathological findings:

no effects observed

Description (incidence and severity):

Althopugh no adverse effects are reported, the laboratory nly examined for lesions and colour changes (if any) are not reported.

Histopathological findings: non-neoplastic:

effects observed, non-treatment-related

Description (incidence and severity):

Only one female rat in the high dose group showed a focal, slight tubular cyst in the kidney. One female rat in the control and one male and one female rat in the high dose groups showed focal, slight tubular infarct in the kidney.
These are not considered relevant

Histopathological findings: neoplastic:

no effects observed

Effect levels

Dose descriptor:

NOAEL

Effect level:

> 1 000 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

clinical biochemistry

clinical signs

food efficiency

haematology

histopathology: non-neoplastic

mortality

ophthalmological examination

organ weights and organ / body weight ratios

urinalysis

Target system / organ toxicity

Critical effects observed:

not specified

Applicant's summary and conclusion

Conclusions:

According to OECD 407 test method, the NOAEL was > 1000 mg/kg B.W..

Executive summary:

This test followed OECD 407 (OECD, 2008). The test article was administered to the three treatment groups by oral gavage in a dose of 62.5, 250 and 1000 mg/kg B.W. for 28 consecutive days. There were six male and six female Sprague-Dawley rat in each group. Clinical observation of the rats was carried out daily and the body weight and feed intake of the rats were recorded once a week. Results of the study indicated that rats in all group gained weight normally and did not show any abnormal clinical signs and ophthalmological examination during the study period. At end of the study, there were no significant abnormalities of the urinalysis, haematologyand clinical biochemistry parameters between the treatment and control groups. Necropsy and histopathological examination indicated that no treatment-related change was found. On the basis of the test results given above, the NOAEL was greater than 1000 mg/kg B.W..