Registration Dossier

Administrative data

Description of key information

Repeated dose toxicity: Oral

The No Observed Adverse Effect Level (NOAEL) for the test chemical Reaction mass of 3H-Indolium, 2-[2-[4-[(2-cyanoethyl)methylamino]phenyl]ethenyl]-1,3,3-trimethyl- & acetate using male and female rats is considered to be 1200 mg/Kg/day.

Repeated dose toxicity: Inhalation

Reaction mass of 3H-Indolium, 2-[2-[4-[(2-cyanoethyl)methylamino]phenyl]ethenyl]-1,3,3-trimethyl- & acetate has very low vapor pressure (2.3E-013 Pa.), so the potential for the generation of inhalable vapours is very low. Also the normal conditions of use of this substance will not result in aerosols, particles or droplets of an inhalable size, so exposure to humans via the inhalatory route will be highly unlikely and therefore this end point was considered for waiver.

Repeated dose toxicity: Dermal

The acute dermal toxicity value for Reaction mass of 3H-Indolium, 2-[2-[4-[(2-cyanoethyl)methylamino]phenyl]ethenyl]-1,3,3-trimethyl- & acetate (as provided in section 7.2.3) is >2000 mg/kg body weight. The substance was also found to be not irritating and not sensitizing to the skin.  Considering this, the end point for repeated dermal toxicity is considered as 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
Remarks:
experimental data of read across substances
Justification for type of information:
Data for the target chemical is summarized based on the structurally similar read across chemicals
Reason / purpose for cross-reference:
read-across source
Reason / purpose for cross-reference:
read-across source
Qualifier:
according to guideline
Guideline:
other: Refer below principle
Principles of method if other than guideline:
WoE derived based on the experimental data from structurally and functionally similar read across chemicals
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 or test system and environmental conditions:
1. No data2. 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 dataVEHICLE- 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 data2. 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 years2. 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 females0 mg/Kg/day: 80 males and 80 females100 mg/Kg/day: 25 males and 25 females400 mg/Kg/day: 25 males and 25 females1200 mg/Kg/day: 25 males and 25 females2. 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, mortalityDETAILED CLINICAL OBSERVATIONS: Yes- Time schedule: No dataBODY WEIGHT: Yes- Time schedule for examinations: No dataFOOD 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 dataFOOD 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 dataWATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No data- Time schedule for examinations: No dataOPHTHALMOSCOPIC EXAMINATION: No data- Time schedule for examinations: No data- Dose groups that were examined: No dataHAEMATOLOGY: 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 valuesCLINICAL 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. BilirubunuriaURINALYSIS: 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 dataNEUROBEHAVIOURAL 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 dataOTHER: No data2. CAGE SIDE OBSERVATIONS: No data- Time schedule: No data- Cage side observations checked in table [No.?] were included. No dataDETAILED CLINICAL OBSERVATIONS: No data- Time schedule: No dataBODY WEIGHT: No data- Time schedule for examinations: No dataFOOD 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 dataFOOD 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 dataWATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No data- Time schedule for examinations: No dataOPHTHALMOSCOPIC EXAMINATION: No data - Time schedule for examinations: No data- Dose groups that were examined: No dataHAEMATOLOGY: 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 dataCLINICAL 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 impairedURINALYSIS: 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 dataNEUROBEHAVIOURAL 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 dataOTHER: No data
Sacrifice and pathology:
1. GROSS PATHOLOGY: Yes, any gross changes in the organs or viscera attributable to the test material were notedHISTOPATHOLOGY: Yes2. No data
Other examinations:
1. No data
Statistics:
1. No data2. 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 rats2. 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 study2. 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 Reaction mass of 3H-Indolium, 2-[2-[4-[(2-cyanoethyl)methylamino]phenyl]ethenyl]-1,3,3-trimethyl- & acetate using male and female rats is considered to be 1200 mg/Kg/day.
Executive summary:

Data available for the test chemicals was reviewed to determine the toxic nature of Reaction mass of 3H-Indolium, 2-[2-[4-[(2-cyanoethyl)methylamino]phenyl]ethenyl]-1,3,3-trimethyl- & acetate. 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 3-(N-Ethylanilino)propionitrile. 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.

Based on the data available for the test chemical, the No Observed Adverse Effect Level (NOAEL) for the test chemical using male and female rats is considered to be 1200 mg/Kg/day. Reaction mass of 3H-Indolium, 2-[2-[4-[(2-cyanoethyl)methylamino]phenyl]ethenyl]-1,3,3-trimethyl- & acetate is ttherefore not likely to be toxic as per the criteria mentioned in CLP regulation.

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

Link to relevant study records
Reference
Endpoint:
repeated dose toxicity: inhalation, other
Data waiving:
other justification
Justification for data waiving:
other:
Endpoint conclusion
Quality of whole database:
Waiver

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - systemic effects

Link to relevant study records
Reference
Endpoint:
repeated dose toxicity: dermal, other
Data waiving:
other justification
Justification for data waiving:
other:
Endpoint conclusion
Quality of whole database:
Waiver

Repeated dose toxicity: dermal - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Repeated dose toxicity: Oral

Data available for the test chemicals was reviewed to determine the toxic nature of Reaction mass of 3H-Indolium, 2-[2-[4-[(2-cyanoethyl)methylamino]phenyl]ethenyl]-1,3,3-trimethyl- & acetate. 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 3-(N-Ethylanilino)propionitrile. 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.

Based on the data available for the test chemical, the No Observed Adverse Effect Level (NOAEL) for the test chemical using male and female rats is considered to be 1200 mg/Kg/day. Reaction mass of 3H-Indolium, 2-[2-[4-[(2-cyanoethyl)methylamino]phenyl]ethenyl]-1,3,3-trimethyl- & acetate is ttherefore not likely to be toxic upon repeated exposure by oral route as per the criteria mentioned in CLP regulation.

Repeated dose toxicity: Inhalation

Reaction mass of 3H-Indolium, 2-[2-[4-[(2-cyanoethyl)methylamino]phenyl]ethenyl]-1,3,3-trimethyl- & acetate has very low vapor pressure (2.3E-013 Pa.), so the potential for the generation of inhalable vapours is very low. Also the normal conditions of use of this substance will not result in aerosols, particles or droplets of an inhalable size, so exposure to humans via the inhalatory route will be highly unlikely and therefore this end point was considered for waiver.

Repeated dose toxicity: Dermal

The acute dermal toxicity value for Reaction mass of 3H-Indolium, 2-[2-[4-[(2-cyanoethyl)methylamino]phenyl]ethenyl]-1,3,3-trimethyl- & acetate (as provided in section 7.2.3) is >2000 mg/kg body weight. The substance was also found to be not irritating and not sensitizing to the skin.  Considering this, the end point for repeated dermal toxicity is considered as waiver.

Justification for classification or non-classification

Based on the data available for the test chemical, Reaction mass of 3H-Indolium, 2-[2-[4-[(2-cyanoethyl)methylamino]phenyl]ethenyl]-1,3,3-trimethyl- & acetate is not likely to be toxic upon repeated exposure by oral route as per the criteria mentioned in CLP regulation.