Registration Dossier

Administrative data

Description of key information

Repeated dose toxicity: via oral route;

The No Observed Adverse Effect Level (NOAEL) for the test chemical for repeated dose toxicity was considered to be in a dose range of 1000-1200 mg/Kg/day in test chemical.

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 3H,3'H-2,2'-bi-1-benzothiophene-3,3'-dione; Thioindigo (522-75-8 ) which is reported as 6.788058e-45 mmHg at 25 C. Also considering the particle size distribution of the substance the majority of the particles was found to be in the size of 150 micron to 53 micron which is much larger size range compared to the inhalable particulate matter .Thus, exposure to inhalable dust, mist and vapour of the chemical 3H,3'H-2,2'-bi-1-benzothiophene-3,3'-dione; Thioindigo (522-75-8 )is highly unlikely. Therefore this study is considered for waiver.

Repeated dermal study;

The acute toxicity value for 3H,3'H-2,2'-bi-1-benzothiophene-3,3'-dione; Thioindigo (522-75-8 ) (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 3H,3'H-2,2'-bi-1-benzothiophene-3,3'-dione; Thioindigo shall not exhibit 28 day repeated dose toxicity by the dermal route. In addition, there is no data available that suggests that 3H,3'H-2,2'-bi-1-benzothiophene-3,3'-dione 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 is from test chemical.
Reason / purpose:
read-across source
Related information:
Composition 1
Reason / purpose:
read-across source
Related information:
Composition 1
Reference:
Composition 0
Qualifier:
according to
Guideline:
other: Refer below principle
Principles of method if other than guideline:
WoE report is based on two reproductive toxicity studies on rats
1.Chronic repeated dose oral toxicity study was performed to evaluate the toxic nature of the test chemical .
2.Chronic repeated dose toxicity study of test chemical was conducted orally in rats to evaluate its toxic potential.
GLP compliance:
not specified
Limit test:
no
Test material information:
Composition 1
Species:
rat
Strain:
other: 1,Albino 2,Charles River CD
Details on species / strain selection:
No data
Sex:
male/female
Details on test animals and environmental conditions:
1,No data
2,Details on test animal
TEST ANIMALS
- Source: Charles River Breeding Laboratories, Wilmington,
MA
- Age at study initiation: 63-70 days old
- Weight at study initiation:No data available
- Fasting period before study: No data available
- Housing: Animals were housed individually in stainless steel
Cages in an environmentally controlled room.
- Diet (e.g. ad libitum): basal diet ad libitum
- Water (e.g. ad libitum): No data available
- Acclimation period: No data available

ENVIRONMENTAL CONDITIONS
- Temperature (°C):20-21 deg C
- Humidity (%):40-60%
- Air changes (per hr):No data available
- Photoperiod (hrs dark / hrs light):12 h light/dark cycle

IN-LIFE DATES: From: To: No data available
Route of administration:
oral: feed
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,Details on oral exposure
PREPARATION OF DOSING SOLUTIONS:

DIET PREPARATION
- Rate of preparation of diet (frequency):diet were prepared weekly
- Mixing appropriate amounts with (Type of food): Diets were blended in bulk in a twin shell blender. Assays of the homogeneity and stability of test chemical in the prepared diets were carried out before the start of the study.
- Storage temperature of food: test compound was stored in sealed containers in a locked closet in an environmentally controlled room with limited access.

VEHICLE
- Justification for use and choice of vehicle (if other than water):
- Concentration in vehicle:No data available
- Amount of vehicle (if gavage): No data available
- Lot/batch no. (if required): No data available
- Purity: No data available
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
2,29 months in males and 30 months in females.
Frequency of treatment:
Daily
Remarks:
0, 0.25, 1.0 or 3.0 % (0, 100, 400, 1200 mg/kg/day)
Remarks:
0.5%-250 mg/kg bw,
1.0%-500 mg/kg bw
2.0%-1000 mg/kg bw

For F1 generation:
Males-304mg/kg/day (0.5%), 632mg/kg/day (1.0%) and 1282 mg/kg/day (2.0%).
Females- 363, 775 and 1592 mg/kg/day.
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

2,70 rats of each sex in each group
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,Observations and examinations performed & frequency
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Twice daily, with
at least 5 hr between observations.
- Cage side observations checked in table [No.?] were included.: No

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Weekly

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

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- 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:

OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: once during the F0 generation, and at initiation and months 3, 6, 12, 18 and 24 of the chronic phase.
- Dose groups that were examined:

HAEMATOLOGY: Yes
- Time schedule for collection of blood:
- Anaesthetic used for blood collection: No data
- Animals fasted: No data
- How many animals: Ten animals of each sex from each group
- Parameters checked in table [No.?] were examined: haemoglobin and haematocrit values, erythrocyte and total and differential leucocyte
counts, and erythrocyte morphology.


CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood:No data
- Animals fasted: No data
- How many animals: Ten animals of each sex from each group
- Parameters checked in table [No.?] were examined. Glutamic-oxalacetic and glutamic-pyruvic transaminases,
alkaline phosphatase, blood urea nitrogen,fasting glucose, total protein and creatinine were determined in serum.

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. Urine was examined for gross and microscopic appearance, specific gravity, pH and the presence of protein, glucose, ketones, bilirubin and occult blood.
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,Sacrifice and pathology
GROSS PATHOLOGY: Yes (no table)
Gross necropsies were conducted on all animalsdying spontaneously, killed in a moribund condition or killed on schedule. Ten rats of each sex from each group were randomly selected for an interim kill at month 12.
HISTOPATHOLOGY: Yes (no table)
histopathology was conducted
on all animals from the two control groups and from the high-dose group
Tissues examined included:
adrenals (two), aorta (abdominal),
bone and marrow (femur), blood smear, brain (three sections: frontal cortex and basal ganglia, parietal cortex and thalamus, and cerebellum and pons), oesophagus, eyes (two, with optic nerve), heart (with coronary vessels), intestine (caecum, colon, duodenum and ileum), kidneys (two), liver, lung and mainstem bronchi (lungs inflated with formalin), lymph nodes (mesenteric and mediastinal), mammary gland (inguinal), nerve (sciatic), ovaries, pancreas, pituitary, prostate, salivary gland (mandibular), seminal vesicles (two), skeletal muscle (biceps femoris),skin, spinal cord (cervical), spleen, stomach, testeswith epididymides, thymus, thyroid with parathyroid, trachea, urinary bladder (inflated with formalin), uterus
Other examinations:
No data
Statistics:
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.
2There were no compound-related effects on the numbers of pregnant females per group or in pup viability at birth, although pup mortality in the high-dose group was increased during the lactation period. Mean pup weight was reduced for all treated groups.
Mortality:
no mortality observed
Description (incidence):
1,No mortality was observed in the treated rats.
2,No mortality were noted during pre-mating exposure.There were no deaths among the parental rats.
Body weight and weight changes:
not specified
Description (incidence and severity):
2,F0 group:
No effects on body weight was observed

F1 generation:
Mean body weights for the mid-dose and high-dose rats were slightly lower than those of the control animals at the start of the study
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,F0 group:
Food consumption showed a dose-related increase in the treated rats.

F1 generation:
Food consumption values for all treated rats were elevated in a dose-related fashion when compared to control values. The increased food consumption was probably due to the influence of the non-nutritive character of the test compound at these high concentrations.
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Description (incidence and severity):
2,F1 generation:
focal and diffuse retinopathy, conjunctivitis, uveitis and cataracts. None of these changes was related to compound administration.
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,F1 generation:
No compound related effects were seen
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,F1 generation:
Fasting glucose levels for all treated males and for high-dose females
were lower than the control values at months 6 and 12. At month 24, the high-dose males and all treated
females had lower fasting glucose values when compared to controls.
Urinalysis findings:
no effects observed
Description (incidence and severity):
2,F1 generation:
No compound related effect were observed.
Behaviour (functional findings):
not specified
Immunological findings:
not specified
Organ weight findings including organ / body weight ratios:
no effects observed
Description (incidence and severity):
2,F1 generation:
At the month 12 interim kill, the mean relative weights of the thyroids of low-dose and high-dose females and the mean relative kidney weights in the
high-dose females were lower than control values.
Increased mean relative spleen and liver weights were noted in all treated males and in the high-dose females at the terminal kill.
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,F1 generation:
Blue discoloration of the gastro-intestinal tract was noted in the treated groups.
An increased incidence of grossly visible abnormalities was noted in the urinary bladders of the high-dose male rats only.
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,F1 generation:
Chronic interstitial pneumonia
was equally common in control and treated animals.

Several control and treated rats that died spontaneously showed evidence of purulent bronchopneumonia consistent with infection by Corynebacterium kutcheri
An age-related chronic nephropathy was observed in all groups.

Periarteritis nodosa, characterized
by fibrinoid necrosis of the arterial walls, occurred most commonly in the arteries of the pancreas, mesentery and testes. Age-related testicular
atrophy of the seminiferous tubules, accompanied by oligospermia or aspermia, was present in male rats of
all groups.

Histopathological examination revealed non-neoplastic findings.
Histopathological findings: neoplastic:
not specified
Dose descriptor:
NOAEL
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
Remarks on result:
other: No toxic effect were observed
Dose descriptor:
NOAEL
Effect level:
1 000 other: mg/kg/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: Gross pathology,organ weight,body weight change,Histopatholgy,mortality,haematlogy,Clinical signs and urinalysis.
Remarks on result:
other: No toxic effects were observed
Critical effects observed:
not specified
Conclusions:
The No Observed Adverse Effect Level (NOAEL) for the test chemical for repeated dose toxicity was considered to be in a dose range of 1000-1200 mg/Kg/day in test chemical.
Executive summary:

The data available for the test chemical was reviewed to determine the toxic nature of 3H,3'H-2,2'-bi-1-benzothiophene-3,3'-dione; Thioindigo (522-75-8 )repeated exposure by oral route. The study is 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.

In a chronic toxicity study, chales river CD male and female rats treated with test chemical in dose concentration of 250 mg/kg bw, 500 mg/kg bw and 1000 mg/kg bw for F0 generation and 304mg/kg/day (0.5%), 632mg/kg/day (1.0%) and 1282 mg/kg/day (2.0%) and 363, 775 and 1592 mg/kg/day male and female For F1 generation respectively. The study was conducted in two phase utero phase and Chronic feeding phase .No effects were observed on survival, body weight, and haematology and organ weights of treated male and female rats. In addition, no gross pathological and histopathological effect was observed in treated rats as compared to control. Hence, NOAEL was considered to be be 1000 mg/kg For F0 generation and 1282 mg/kg/day ,1592 mg/kg/day For male and female F1 generation respectively when Charles river male and female rats were treated with test chemical orally in diet for 30 months.

Based on the data available from the test chemical 3H,3'H-2,2'-bi-1-benzothiophene-3,3'-dione; Thioindigo (522-75-8 )does not exhibit repeated dose oral toxicity in the range of 1000-1200 mg/kg bw. Hence the test chemical is not likely to classify as a repeated dose oral toxicity as per the criteria mentioned in CLP regulation.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
1 000 mg/kg bw/day
Study duration:
chronic
Species:
rat
Quality of whole database:
Weight of evidence prepared from qualified publication

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

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

Repeated dose toxicity: dermal - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Mode of Action Analysis / Human Relevance Framework

Additional information

Repeated dose toxicity: via oral route;

The data available for the test chemical was reviewed to determine the toxic nature of 3H,3'H-2,2'-bi-1-benzothiophene-3,3'-dione; Thioindigo (522-75-8 )repeated exposure by oral route. The study is 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.

In a chronic toxicity study, chales river CD male and female rats treated with test chemical in dose concentration of 250 mg/kg bw, 500 mg/kg bw and 1000 mg/kg bw for F0 generation and 304mg/kg/day (0.5%), 632mg/kg/day (1.0%) and 1282 mg/kg/day (2.0%) and 363, 775 and 1592 mg/kg/day male and female For F1 generation respectively. The study was conducted in two phase utero phase and Chronic feeding phase .No effects were observed on survival, body weight, and haematology and organ weights of treated male and female rats. In addition, no gross pathological and histopathological effect was observed in treated rats as compared to control. Hence, NOAEL was considered to be be 1000 mg/kg For F0 generation and 1282 mg/kg/day ,1592 mg/kg/day For male and female F1 generation respectively when Charles river male and female rats were treated with test chemical orally in diet for 30 months.

Based on the data available from the test chemical 3H,3'H-2,2'-bi-1-benzothiophene-3,3'-dione; Thioindigo (522-75-8 )does not exhibit repeated dose oral toxicity in the range of 1000-1200 mg/kg bw. Hence the test chemical is not likely to classify as a repeated dose oral toxicity as per the criteria mentioned in CLP regulation.

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 3H,3'H-2,2'-bi-1-benzothiophene-3,3'-dione; Thioindigo (522-75-8 ) which is reported as 6.788058e-45 mmHg at 25 C. Also considering the particle size distribution of the substance the majority of the particles was found to be in the size of 150 micron to 53 micron which is much larger size range compared to the inhalable particulate matter .Thus, exposure to inhalable dust, mist and vapour of the chemical 3H,3'H-2,2'-bi-1-benzothiophene -3,3'-dione; Thioindigo (522-75-8 )is highly unlikely. Therefore this study is considered for waiver.

Repeated dermal study;

The acute toxicity value for 3H,3'H-2,2'-bi-1-benzothiophene-3,3'-dione; Thioindigo (522-75-8 ) (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 3H,3'H-2,2'-bi-1-benzothiophene-3,3'-dione; Thioindigo shall not exhibit 28 day repeated dose toxicity by the dermal route. In addition, there is no data available that suggests that 3H,3'H-2,2'-bi-1-benzothiophene-3,3'-dione 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 3H,3'H-2,2'-bi-1-benzothiophene-3,3'-dione; Thioindigo (522-75-8 ) does not 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 3H,3'H-2,2'-bi-1-benzothiophene-3,3'-dione; Thioindigo (522-75-8 ) does not 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.