Registration Dossier

Administrative data

Description of key information

Repeated dose toxicity: Oral

The No Observed Adverse Effect Level (NOAEL) for the test chemical  using male and female rats is considered to be in a dose range of 968- 1200 mg/Kg/day.

Repeated dose toxicity: Inhalation

According to Annex IX of the REACH regulation, testing by the inhalation route is appropriate only if exposure of humans via inhalation is likely. Taking into account the low vapour pressure of the substance of 2-({4-[ethyl(2-hydroxyethyl)amino]phenyl}diazenyl)-6-methoxy-3-methyl-1,3-benzothiazol-3-ium acetate(84051-87-6) which is reported as 7.15E-15 mm Hg at 25 C. Thus, exposure to inhalable dust, mist and vapour of the chemical of 2-({4-[ethyl(2-hydroxyethyl)amino]phenyl}diazenyl)-6-methoxy-3-methyl-1,3-benzothiazol-3-ium acetate is highly unlikely. Therefore this study is considered for waiver.

Repeated dose toxicity: Dermal

The acute toxicity value for 2-({4-[ethyl(2-hydroxyethyl)amino]phenyl}diazenyl)-6-methoxy-3-methyl-1,3-benzothiazol-3-ium acetate(84051-87-6)  (as provided in section 7.2.3) is >2000 mg/kg body weight. Also, given the use of the chemical; repeated exposure by the dermal route is unlikely since the use of gloves is common practice in industries. Thus, it is expected that 2-({4-[ethyl(2-hydroxyethyl)amino]phenyl}diazenyl)-6-methoxy-3-methyl-1,3-benzothiazol-3-ium acetate shall not exhibit 28 day repeated dose toxicity by the dermal route. In addition, there is no data available that suggests that 2-({4-[ethyl(2-hydroxyethyl)amino]phenyl}diazenyl)-6-methoxy-3-methyl-1,3-benzothiazol-3-ium acetate shall exhibit repeated dose toxicity by the dermal route. Hence this end point was considered for waiver.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records
Reference
Endpoint:
chronic toxicity: oral
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
data from handbook or collection of data
Justification for type of information:
data from handbook or collection of data
Reason / purpose:
read-across source
Reason / purpose:
read-across source
Qualifier:
according to
Guideline:
other: Refer below principle
Principles of method if other than guideline:
WoE preapared from various publication mention below
1,Chronic repeated dose oral toxicity study was performed to evaluate the toxic nature of the test chemical.
2,Subacute repeated dose oral toxicity study was performed to evaluate the toxic nature of the test chemical
GLP compliance:
not specified
Limit test:
no
Species:
rat
Strain:
other: 1. Albino 2. No data
Details on species / strain selection:
No data
Sex:
male/female
Details on test animals and environmental conditions:
1. No data
2. No data
Route of administration:
other: 1. Feed 2. No data
Details on route of administration:
No data
Vehicle:
other: Feed
Details on oral exposure:
1. PREPARATION OF DOSING SOLUTIONS: The test chemical was mixed with diet at dose levels of 0, 0.25, 1.0 or 3.0 % (0, 100, 400, 1200 mg/kg/day)

DIET PREPARATION
- Rate of preparation of diet (frequency): No data
- Mixing appropriate amounts with (Type of food): No data
- Storage temperature of food: No data

VEHICLE
- Justification for use and choice of vehicle (if other than water): Diet
- Concentration in vehicle: 0, 0.25, 1.0 or 3.0 % (0, 100, 400, 1200 mg/kg/day)
- Amount of vehicle (if gavage): No data
- Lot/batch no. (if required): No data
- Purity: No data

2. No data
Analytical verification of doses or concentrations:
not specified
Details on analytical verification of doses or concentrations:
No data
Duration of treatment / exposure:
1. 2 years
2. No data
Frequency of treatment:
Daily
Remarks:
0, 0.25, 1.0 or 3.0 % (0, 100, 400, 1200 mg/kg/day) / 1
Remarks:
No data/ 2
No. of animals per sex per dose:
1. Total: 160 males and 160 females
0 mg/Kg/day: 80 males and 80 females
100 mg/Kg/day: 25 males and 25 females
400 mg/Kg/day: 25 males and 25 females
1200 mg/Kg/day: 25 males and 25 females

2. No data
Control animals:
yes, concurrent vehicle
Details on study design:
No data
Positive control:
No data
Observations and examinations performed and frequency:
1. CAGE SIDE OBSERVATIONS: Yes
- Time schedule: No data
- Cage side observations checked in table [No.?] were included. Appearance and behavior of test rats, mortality

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: No data

BODY WEIGHT: Yes
- Time schedule for examinations: No data

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: No data
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: No data

FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: No data

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No data
- Time schedule for examinations: No data

OPHTHALMOSCOPIC EXAMINATION: No data
- Time schedule for examinations: No data
- Dose groups that were examined: No data

HAEMATOLOGY: Yes
- Time schedule for collection of blood: No data
- Anaesthetic used for blood collection: No data
- Animals fasted: No data
- How many animals: No data
- Parameters checked in table [No.?] were examined. Hematocrit and hemoglobin values

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: No data
- Animals fasted: No data
- How many animals: No data
- Parameters checked in table [No.?] were examined. Bilirubunuria

URINALYSIS: Yes
- Time schedule for collection of urine: No data
- Metabolism cages used for collection of urine: No data
- Animals fasted: No data
- Parameters checked in table [No.?] were examined. No data

NEUROBEHAVIOURAL EXAMINATION: No data
- Time schedule for examinations: No data
- Dose groups that were examined: No data
- Battery of functions tested: sensory activity / grip strength / motor activity / other: No data

OTHER: No data

2. CAGE SIDE OBSERVATIONS: No data
- Time schedule: No data
- Cage side observations checked in table [No.?] were included. No data

DETAILED CLINICAL OBSERVATIONS: No data
- Time schedule: No data

BODY WEIGHT: No data
- Time schedule for examinations: No data

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): No data
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: No data
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: No data

FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: No data

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No data
- Time schedule for examinations: No data

OPHTHALMOSCOPIC EXAMINATION: No data
- Time schedule for examinations: No data
- Dose groups that were examined: No data

HAEMATOLOGY: Yes
- Time schedule for collection of blood: No data
- Anaesthetic used for blood collection: No data
- Animals fasted: No data
- How many animals: No data
- Parameters checked in table [No.?] were examined. No data

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: No data
- Animals fasted: No data
- How many animals: No data
- Parameters checked in table [No.?] were examined. Liver function tests were impaired

URINALYSIS: Yes
- Time schedule for collection of urine: No data
- Metabolism cages used for collection of urine: No data
- Animals fasted: No data
- Parameters checked in table [No.?] were examined. No data

NEUROBEHAVIOURAL EXAMINATION: No data
- Time schedule for examinations: No data
- Dose groups that were examined: No data
- Battery of functions tested: sensory activity / grip strength / motor activity / other: No data

OTHER: No data
Sacrifice and pathology:
1. GROSS PATHOLOGY: Yes, any gross changes in the organs or viscera attributable to the test material were noted

HISTOPATHOLOGY: Yes

2. No data
Other examinations:
1. No data
Statistics:
1. No data
2. No data
Clinical signs:
no effects observed
Description (incidence and severity):
1. Appearance and behavior of the test rats were generally comparable to those of the controls.
2. No data
Mortality:
no mortality observed
Description (incidence):
1. No mortality was observed in the treated rats
2. No data
Body weight and weight changes:
not specified
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
1. At the 3% level (1200 mg/Kg/day), food consumption was significant lower than controls for the first six months but comparable to controls during the remainder of the study
2. No data
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Haematological findings:
effects observed, treatment-related
Description (incidence and severity):
1. Significantly lower hematocrit and hemoglobin values in comparison with controls were obtained at all time intervals except 24 months for the males fed 3%. No such effect was noted in the females.
2. Normocytic anemia was noted at the highest dose level
Clinical biochemistry findings:
effects observed, treatment-related
Description (incidence and severity):
1. Bilirubinuria was observed at 24 months in male and female at 1% and females at 3%.
2. Liver function tests impaired
Urinalysis findings:
not specified
Description (incidence and severity):
2. Proteinuria was observed
Behaviour (functional findings):
not specified
Immunological findings:
not specified
Organ weight findings including organ / body weight ratios:
not specified
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
1. The test animals sacrificed at 52 weeks did not present any gross changes in the organs or viscera attributable to the test material. Autopsies performed on the animals which died during the second year of the study did not reveal any consistent gross changes.
2. No data
Neuropathological findings:
not specified
Histopathological findings: non-neoplastic:
no effects observed
Description (incidence and severity):
1. Microscopic findings at two years revealed no compound related effects on the kidneys or other tissues in either sex.
2. No data
Histopathological findings: neoplastic:
not specified
Dose descriptor:
NOAEL
Remarks:
1
Effect level:
1 200 other: mg/Kg/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No adverse effects were noted at the mentioned dose level
Dose descriptor:
NOAEL
Remarks:
2
Effect level:
968 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
not specified
Basis for effect level:
other: No adverse effects were noted at the mentioned dose level
Critical effects observed:
not specified
Conclusions:
The No Observed Adverse Effect Level (NOAEL) for the test chemical using male and female rats is considered to be in a dose range of 968- 1200 mg/Kg/day.
Executive summary:

Data available for the test chemicals was reviewed to determine the toxic nature of test chemical . The studies are as mentioned below:

Chronic repeated dose oral toxicity study was performed to evaluate the toxic nature of the test chemical. Male and female albino rats were used in the study. The test compound was mixed with diet and used at dose levels of 0, 0.25, 1.0 or 3.0 % (0, 100, 400, 1200 mg/kg/day). The rats were treated for 2 years. The treated animals were noted for clinical signs, mortality, chenges in food consumption, hematology, blood chemistry, gross pathology and histopathology. Appearance and behavior of the test rats were generally comparable to those of the controls. No mortality was observed in the treated rats. At the 3% level (1200 mg/Kg/day), food consumption was significant lower than controls for the first six months but comparable to controls during the remainder of the study. Significantly lower hematocrit and hemoglobin values in comparison with controls were obtained at all time intervals except 24 months for the males fed 3%. No such effect was noted in the females. Bilirubinuria was observed at 24 months in male and female at 1% and females at 3%. The test animals sacrificed at 52 weeks did not present any gross changes in the organs or viscera attributable to the test material. Autopsies performed on the animals which died during the second year of the study did not reveal any consistent gross changes. Microscopic findings at two years revealed no compound related effects on the kidneys or other tissues in either sex. Based on the observations made, the No Observed Adverse Effect Level (NOAEL) for the test chemical using male and female Albino rats is considered to be 1200 mg/Kg/day.

Subacute repeated dose oral toxicity study was performed to evaluate the toxic nature of the test chemical. The study was performed using rats for 30 days. During the study period,Normocytic anemia was noted at the highest dose level. Liver function tests impaired and proteinuria was observed. Based on the observations made, No Observed Adverse Effect Level (NOAEL) for the test chemical using rats is considered to be 968 mg/Kg/day.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
1 200 mg/kg bw/day
Study duration:
chronic
Species:
rat
Quality of whole database:
Data is from K2 source

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available
Quality of whole database:
Waiver

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available
Quality of whole database:
Waiver

Repeated dose toxicity: dermal - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

The data available for the test chemical was reviewed to determine the toxic nature of 2-({4-[ethyl(2-hydroxyethyl)amino]phenyl}diazenyl) -6-methoxy-3-methyl -1,3-benzothiazol -3-ium acetate(84051-87-6) repeated exposure by oral route. The study is as mentioned below:

 

 Repeated oral study:

Chronic repeated dose oral toxicity study was performed to evaluate the toxic nature of the test chemical. Male and female albino rats were used in the study. The test compound was mixed with diet and used at dose levels of 0, 0.25, 1.0 or 3.0 % (0, 100, 400, 1200 mg/kg/day). The rats were treated for 2 years. The treated animals were noted for clinical signs, mortality, and changes in food consumption, hematology, blood chemistry, gross pathology and histopathology. Appearance and behavior of the test rats were generally comparable to those of the controls. No mortality was observed in the treated rats. At the 3% level (1200 mg/Kg/day), food consumption was significant lower than controls for the first six months but comparable to controls during the remainder of the study. Significantly lower hematocrit and hemoglobin values in comparison with controls were obtained at all time intervals except 24 months for the males fed 3%. No such effect was noted in the females. Bilirubinuria was observed at 24 months in male and female at 1% and females at 3%. The test animals sacrificed at 52 weeks did not present any gross changes in the organs or viscera attributable to the test material. Autopsies performed on the animals which died during the second year of the study did not reveal any consistent gross changes. Microscopic findings at two years revealed no compound related effects on the kidneys or other tissues in either sex. Based on the observations made, the No Observed Adverse Effect Level (NOAEL) for the test chemical using male and female Albino rats is considered to be 1200 mg/Kg/day.

 

Subacute repeated dose oral toxicity study was performed to evaluate the toxic nature of the test chemical. The study was performed using rats for 30 days. During the study period,Normocytic anemia was noted at the highest dose level. Liver function tests impaired and proteinuria was observed. Based on the observations made, No Observed Adverse Effect Level (NOAEL) for the test chemical using rats is considered to be 968 mg/Kg/day.

 

 Repeated inhalation study:

According to Annex IX of the REACH regulation, testing by the inhalation route is appropriate only if exposure of humans via inhalation is likely. Taking into account the low vapour pressure of the substance of 2-({4-[ethyl(2-hydroxyethyl)amino]phenyl}diazenyl)-6-methoxy-3-methyl-1,3-benzothiazol-3-ium acetate(84051-87-6) which is reported as 7.15E-15 mm Hg at 25 C. Thus, exposure to inhalable dust, mist and vapour of the chemical of 2-({4-[ethyl(2-hydroxyethyl)amino]phenyl}diazenyl) -6-methoxy-3- methyl-1,3-benzothiazol-3-ium acetate is highly unlikely. Therefore this study is considered for waiver.

Repeated dermal study;

The acute toxicity value for 2-({4-[ethyl(2-hydroxyethyl)amino]phenyl}diazenyl)-6-methoxy-3-methyl-1,3-benzothiazol-3-ium acetate(84051-87-6)  (as provided in section 7.2.3) is >2000 mg/kg body weight. Also, given the use of the chemical; repeated exposure by the dermal route is unlikely since the use of gloves is common practice in industries. Thus, it is expected that 2-({4-[ethyl(2-hydroxyethyl)amino]phenyl}diazenyl)-6-methoxy-3-methyl-1,3-benzothiazol-3-ium acetate shall not exhibit 28 day repeated dose toxicity by the dermal route. In addition, there is no data available that suggests that 2-({4-[ethyl(2-hydroxyethyl)amino]phenyl}diazenyl)-6-methoxy-3-methyl-1,3-benzothiazol-3-ium acetate shall exhibit repeated dose toxicity by the dermal route. Hence this end point was considered for waiver.

Based on the data available for the test chemical 2-({4-[ethyl(2-hydroxyethyl)amino]phenyl}diazenyl)-6-methoxy-3-methyl-1,3-benzothiazol-3-ium acetate(84051-87-6) not likely to exhibit toxic nature upon repeated exposure by oral, inhalation and dermal route of exposure and hence is not likely to classify as per the criteria mentioned in CLP regulation.

Justification for classification or non-classification

Based on the data available for the test chemical 2-({4-[ethyl(2-hydroxyethyl)amino]phenyl}diazenyl)-6-methoxy-3-methyl-1,3-benzothiazol-3-ium acetate(84051-87-6) not likely to exhibit toxic nature upon repeated exposure by oral, inhalation and dermal route of exposure and hence is not likely to classify as per the criteria mentioned in CLP regulation.