Registration Dossier

Administrative data

Description of key information

Acute oral toxicity: 

Acute oral toxicity dose (LD50) was considered based on different studies conducted on rats and mice for the given test chemical. The LD50 value was considered to be 2400 mg/kg bw. The study concluded that the LD50 value is >2000 mg/kg bw. Thus, comparing this value with the criteria of CLP regulation, the given test chemical cannot be classified for acute oral toxicity.

Acute Inhalation toxicity: 

Acute Inhalation toxicity dose (LC50) was considered based on different studies conducted on mice and rats for the test chemical. The LC50 value was considered to be 527 mg/L (527000 mg/m3). The study concluded that the LC50 value is >5 mg/L air. Thus, comparing this value with the criteria of CLP regulation, the given test chemical cannot be classified for acute Inhalation toxicity.

Acute Dermal toxicity: 

The acute dermal toxicity dose (LD50) was considered based on different studies conducted on rats and rabbits for the test chemical. The LD50 value is 2190 mg/kg bw. The study concluded that the LD50 value is >2000 mg/kg bw, for acute dermal toxicity. Thus, comparing this value with the criteria of CLP regulation, the given test chemical cannot be classified for acute dermal toxicity.

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records
Reference
Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
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 publication.
Qualifier:
according to
Guideline:
other: As mentioned below
Principles of method if other than guideline:
Acute oral toxicity study of the given test chemical in rat.
GLP compliance:
not specified
Test type:
other: not specified
Limit test:
no
Species:
rat
Strain:
other: CFY strain
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Weight at study initiation: weight range 90-122 g
- Fasting period before study: The animals were starved overnight before treatment.
Route of administration:
oral: unspecified
Vehicle:
other: Aqueous solution or suspension in 0.5% aqueous gum tragacanth
Details on oral exposure:
VEHICLE
- Concentration in vehicle: 40%
- DOSAGE PREPARATION (if unusual): The test material was prepared as aqueous solution or suspension in 0.5% aqueous gum tragacanth containing 0.05% Na2SO3.
Doses:
Range of 2000 - 3000 mg/kg bw
No. of animals per sex per dose:
five males and five females per groups of rats
Control animals:
yes
Remarks:
Rats treated with the vehicle alone served as controls
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: During the observation period of 14 days, a record was kept of all deaths and signs of toxicity.
- Necropsy of survivors performed: yes, all rats that died were examined macroscopically in an attempt to identify the target organs, and animals surviving to the end of the experiment were similarly examined at that time to detect any possible residual damage. There was no microscopic examination of the various tissues and organ systems.
Statistics:
The LD50 and its 95% confidence limits were calculated from the mortality data either by the method of Litchfield & Wilcoxon (1949) or by that of Weil (1952).
Preliminary study:
In a preliminary range finding study, the freshly prepared solutions or suspensions were administered to groups of two male and two female rats by oral intubation in a range of dosage volumes, in order to find the approximate median lethal oral dose (LD50).
Sex:
male/female
Dose descriptor:
LD50
Effect level:
2 400 mg/kg bw
Based on:
test mat.
95% CL:
2 000 - 3 000
Mortality:
50% mortality was observed at 2400 mg/kg bw in treated animals.
Clinical signs:
Signs of reaction to treatment, observed shortly after dosing with the compound, included lethargy and piloerection. Other reactions included increased salivation, ataxia, fine body tremors, changes in respiratory rate, dieresis and diarrhea. Also, produced orange-stained urine. These signs were not considered to be indicative of any specific target-organ toxicity.
Body weight:
not specified
Gross pathology:
Autopsy of the animals that died as a result of treatment revealed changes which, in many cases, included darkening of the liver and kidneys, darkening or pallor of the spleen, hemorrhage of the lungs and intestines, and injection of the intestinal and mesenteric blood vessels. Also, the rats showed orange staining of the peritoneal wall.
Autopsy of the survivors at the end of each experiment did not reveal any abnormalities indicative of residual systemic effects.
Other findings:
not specified
Interpretation of results:
other: Not classified
Conclusions:
The acute oral LD50 value was considered to be 2400 mg/kg bw, with 95% confidence limit of 2000 - 3000 mg/kg bw, when groups of rats (five males and five females) were treated with the given test chemical via oral route.
Executive summary:

Acute oral toxicity study of the given test chemical was conducted in groups of rats (five males and five females) at the dose concentration range of 2000 - 3000 mg/kg bw.

The given test chemical was prepared as aqueous solution or suspension in 0.5% aqueous gum tragacanth, containing 0.05% Na2SO3 and administered via oral route. Rats treated with the vehicle alone served as control.

In a preliminary range finding study, the freshly prepared solutions or suspensions were administered to groups of two male and two female rats by oral intubation in a range of dosage volumes, in order to find the approximate median lethal oral dose (LD50).

After these preliminary range-finding tests had given a rough approximation of the LD50, larger groups of rats (five males and five females) were used in order to locate the median lethal dose more precisely. A logarithmic dosage interval of 1.6 was used for material.

During the observation period of 14 days, a record was kept of all deaths and signs of toxicity. Necropsy of survivors performed. All rats that died were examined macroscopically in an attempt to identify the target organs, and animals surviving to the end of the experiment were similarly examined at that time to detect any possible residual damage. There was no microscopic examination of the various tissues and organ systems.

The LD50 and its 95% confidence limits were calculated from the mortality data either by the method of Litchfield & Wilcoxon (1949) or by that of Weil (1952).

50% mortality was observed at 2400 mg/kg bw in treated animals. Signs of reaction to treatment, observed shortly after dosing with the compound, included lethargy and piloerection. Other reactions included increased salivation, ataxia, fine body tremors, and changes in respiratory rate, dieresis and diarrhea. Also, produced orange-stained urine. These signs were not considered to be indicative of any specific target-organ toxicity.

Autopsy of the animals that died as a result of treatment revealed changes which, in many cases, included darkening of the liver and kidneys, darkening or pallor of the spleen, hemorrhage of the lungs and intestines, and injection of the intestinal and mesenteric blood vessels. Also, the rats showed orange staining of the peritoneal wall. Autopsy of the survivors at the end of each experiment did not reveal any abnormalities indicative of residual systemic effects.

Under the condition of the study, the LD50 value was considered to be 2400 mg/kg bw, with 95% confidence limit of 2000 - 3000 mg/kg bw, when groups of rats (five males and five females) were treated with the given test chemical via oral route.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
2 400 mg/kg bw
Quality of whole database:
Data is Klimisch 2 and from publication.

Acute toxicity: via inhalation route

Link to relevant study records
Reference
Endpoint:
acute toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
key study
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 authoritative database.
Qualifier:
according to
Guideline:
other: As mentioned below
Principles of method if other than guideline:
Acute inhalation toxicity study of the given test chemical in rat.
GLP compliance:
not specified
Test type:
other: not specified
Limit test:
no
Species:
rat
Strain:
not specified
Sex:
not specified
Details on test animals and environmental conditions:
not specified
Route of administration:
inhalation
Type of inhalation exposure:
not specified
Vehicle:
not specified
Remark on MMAD/GSD:
not specified
Details on inhalation exposure:
not specified
Analytical verification of test atmosphere concentrations:
not specified
Duration of exposure:
4 h
Concentrations:
527 mg/L (527000 mg/m3)
No. of animals per sex per dose:
not specified
Control animals:
not specified
Details on study design:
- Other examinations performed: Animals were observed for mortality and clinical signs.
Statistics:
not specified
Preliminary study:
not specified
Sex:
not specified
Dose descriptor:
LC50
Effect level:
527 000 mg/m³ air
Based on:
test mat.
Exp. duration:
4 h
Mortality:
50% mortality was observed at 527 mg/L in treated animals.
Clinical signs:
Data on the symptoms triggered by the substance inhalation are lacking. The substance must be assumed to trigger irritations of the respiratory tract.
After massive exposures, systemic effects must at least be considered to occur.
Body weight:
not specified
Gross pathology:
not specified
Other findings:
not specified
Interpretation of results:
other: Not classified
Conclusions:
The acute inhalation toxicity dose (LC50) was considered to be 527 mg/L (527000 mg/m3), when rats were exposed to the given test chemical via inhalation route for 4 hour exposure.
Executive summary:

The acute inhalation toxicity study was conducted by using the given test chemical in rats at the concentration of 527 mg/L (527000 mg/m3).

Animals were observed for mortality and clinical signs. 50% mortality was observed at 527 mg/L in treated animals. Data on the symptoms triggered by the substance inhalation are lacking. The substance must be assumed to trigger irritations of the respiratory tract. After massive exposures, systemic effects must at least be considered to occur.

Hence, the LC50 value was considered to be 527 mg/L (527000 mg/m3), when rats were exposed to the given test chemical via inhalation route for 4 hour exposure.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LC50
527 000 mg/m³
Quality of whole database:
Data is Klimisch 2 and from authoritative database.

Acute toxicity: via dermal route

Link to relevant study records
Reference
Endpoint:
acute toxicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
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 authoritative database.
Qualifier:
according to
Guideline:
other: As mentioned below
Principles of method if other than guideline:
Acute dermal toxicity study of the given test chemical in rabbit.
GLP compliance:
not specified
Test type:
other: not specified
Limit test:
no
Species:
rabbit
Strain:
not specified
Sex:
not specified
Details on test animals and environmental conditions:
not specified
Type of coverage:
other: Dermal
Vehicle:
not specified
Details on dermal exposure:
not specified
Duration of exposure:
not specified
Doses:
2190 mg/kg bw
No. of animals per sex per dose:
not specified
Control animals:
not specified
Details on study design:
not specified
Statistics:
not specified
Preliminary study:
not specified
Sex:
not specified
Dose descriptor:
LD50
Effect level:
2 190 mg/kg bw
Based on:
test mat.
Mortality:
50% mortality was observed at 2190 mg/kg bw in treated animals.
Clinical signs:
not specified
Body weight:
not specified
Gross pathology:
not specified
Other findings:
not specified
Interpretation of results:
other: Not classified
Conclusions:
The acute dermal LD50 value was considered to be 2190 mg/kg bw, when rabbits were treated with the given test chemical by dermal route.
Executive summary:

Acute dermal toxicity study of the given test chemical was conducted in rabbits at the dose concentration of 2190 mg/kg bw.

The animals were observed for mortality. 50% mortality was observed at 2190 mg/kg bw in treated animals.

Hence, the LD50 value was considered to be 2190 mg/kg bw, when rabbits were treated with the given test chemical by dermal route.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
2 190 mg/kg bw
Quality of whole database:
Data is Klimisch 2 and authoritative database.

Additional information

Acute oral toxicity:

In different studies, the given test chemical has been investigated for acute oral toxicity to a greater or lesser extent. Often are the studies based on in-vivo experiments in rodents,

i.e. most commonly in rats and mice for test chemical. The studies are summarized as below -

 

The experimental study mentioned in peer-reviewed journals, handbooks, authoritative databases and secondary report for the given test chemical was conducted in groups of rats (five males and five females) at the dose concentration range of 2000 - 3000 mg/kg bw.

The given test chemical was prepared as aqueous solution or suspension in 0.5% aqueous gum tragacanth, containing 0.05% Na2SO3 and administered via oral route. Rats treated with the vehicle alone served as control.

In a preliminary range finding study, the freshly prepared solutions or suspensions were administered to groups of two male and two female rats by oral intubation in a range of dosage volumes, in order to find the approximate median lethal oral dose (LD50).

After these preliminary range-finding tests had given a rough approximation of the LD50, larger groups of rats (five males and five females) were used in order to locate the median lethal dose more precisely. A logarithmic dosage interval of 1.6 was used for material.

During the observation period of 14 days, a record was kept of all deaths and signs of toxicity. Necropsy of survivors performed. All rats that died were examined macroscopically in an attempt to identify the target organs, and animals surviving to the end of the experiment were similarly examined at that time to detect any possible residual damage. There was no microscopic examination of the various tissues and organ systems.

The LD50 and its 95% confidence limits were calculated from the mortality data either by the method of Litchfield & Wilcoxon (1949) or by that of Weil (1952).

50% mortality was observed at 2400 mg/kg bw in treated animals. Signs of reaction to treatment, observed shortly after dosing with the compound, included lethargy and piloerection. Other reactions included increased salivation, ataxia, fine body tremors, and changes in respiratory rate, dieresis and diarrhea. Also, produced orange-stained urine. These signs were not considered to be indicative of any specific target-organ toxicity.

Autopsy of the animals that died as a result of treatment revealed changes which, in many cases, included darkening of the liver and kidneys, darkening or pallor of the spleen, hemorrhage of the lungs and intestines, and injection of the intestinal and mesenteric blood vessels. Also, the rats showed orange staining of the peritoneal wall. Autopsy of the survivors at the end of each experiment did not reveal any abnormalities indicative of residual systemic effects.

Under the condition of the study, the LD50 value was considered to be 2400 mg/kg bw, with 95% confidence limit of 2000 - 3000 mg/kg bw, when groups of rats (five males and five females) were treated with the given test chemical via oral route.

 

The above study is supported with the study mentioned in peer-reviewed journals and conducted on five males and five females CD rats for the test chemical at the dose concentration of 4000 mg/kg bw.

The given test chemical was administered orally in an oil-in-water emulsion by stomach tube to groups of ten fasted Charles River CD rats weighing 200-300 g.

The animals were observed for mortality. The LD50's were calculated by the method of Weil (1952). No mortality was observed at 4000 mg/kg bw in treated animals.

Therefore, the LD50 value was considered to be >4000 mg/kg bw, when five males and five females CD rats were treated with the given test chemical via oral route.

 

These studies are contradicted with the study conducted on rats and mentioned in database and handbooks for the test chemical at the dose concentration of 1030 mg/kg bw via oral route. Animals were observed for mortality. 50% mortality was observed at 1030 mg/kg bw in treated animals. Hence, the LD50 value was considered to be 1030 mg/kg bw, when rats were treated with the given test chemical via oral route.

 

The above study is supported by the data mentioned in publication for the test chemical and conducted onmale rats at the dose concentration of two different groups as - Group I - 10, 100 and 1000 mg/kg bw; and Group II – 140, 225, 370, 600 and 1000 mg/kg bw.

Animals were observed for mortality. 50% mortality was observed at 700 mg/kg bw in treated animals. Hence, the LD50 value was considered to be 700 mg/kg bw, when male rats were treated with the given test chemical via oral route.

As this is a combination study and conducted for the investigation of the acute toxicity of an unknown chemical substance, this value will difficult to consider for the classification. The probabilities of synergistic effects from the other similar compounds over this chemical may cause the change in classification criteria. Thus, this study will not be considered for the classification.

 

The above study is supported by the study mentioned in secondary source on rats for the test chemical. The acute oral toxicity study was conducted at the dose concentration of 1840 mg/kg bw. The animals were observed for mortality. 50% mortality was observed at 1840 mg/kg bw in treated animals. Hence, the LD50 value was considered to be 1840 mg/kg bw, when rats were treated with the given test chemical via oral route.

 

All the above contradicted studies are further supported by the study available in handbooks and databases for the test chemical. The acute oral toxicity study of the given test chemical was conducted in mice at the dose concentration of 850 mg/kg bw. The animals were observed for mortality. 50% mortality was observed at 850 mg/kg bw in treated animals. Hence, the LD50 value was considered to be 850 mg/kg bw, when mice were treated with the given test chemical via oral route.

 

Thus, based on the above summarised studies on the given test chemical, the studies having contradicted results will not be considered for the classification because of inconclusive data for the test chemical. Hence, the LD50 value was considered to be >2000 mg/kg bw and comparing this value with the criteria of CLP regulation, the given test chemical cannot be classified for acute oral toxicity.

 

Acute Inhalation Toxicity:

In different studies, the given test chemical has been investigated for acute inhalation toxicity to a greater or lesser extent. Often are the studies based on in-vivo experiments in rodents, i.e. most commonly in rats and mice for test chemical. The studies are summarized as below -

 

The experimental study mentioned in authoritative database and was conducted to determine the acute inhalation toxicity dose by using the given test chemical in rats at the concentration of 527 mg/L (527000 mg/m3).

Animals were observed for mortality and clinical signs. 50% mortality was observed at 527 mg/L in treated animals. Data on the symptoms triggered by the substance inhalation are lacking. The substance must be assumed to trigger irritations of the respiratory tract. After massive exposures, systemic effects must at least be considered to occur.

Hence, the LC50 value was considered to be 527 mg/L (527000 mg/m3), when rats were exposed to the given test chemical via inhalation route for 4 hour exposure.

 

The above study is further supported with the study mentioned in authoritative database and secondary report for the test chemical. The acute inhalation toxicity study was conducted by using the given test chemical in group of 5 males and 5 females Spartan rats at the concentrations of 50000 mg/m3 and 185000 mg/m3 via inhalation (whole body) route for 4 hour exposure. Animals were observed for mortality and clinical signs during and immediately following exposure. Necropsy of survivors performed.

During exposure 2 females were died at 185000 mg/m3. Clinical signs were observed such as - At 50000 mg/m3, (all rats): increased /decreased motor activity, eye squint, erythema, lacrimation, salivation, clear nasal discharge, ocular and nasal porphyrin discharge, slight dispnoea. The symptoms disappeared in all rats 24 hours after exposure.

At 185000 mg/m3, (all rats): The same symptoms as at 50000 mg/m3, with addition of marked dispnoea, corneal opacity, ataxia, sedation and body jerking. The symptoms disappeared 72 hours after exposure (one rat exhibiting nasal porphyrin discharge at day 10). Congested lungs and liver, slight corneal opacity (in the animals that died) was observed at necropsy.

Under the condition of the study, the LC50 value was considered to be >185000 mg/m³, when group of 5 males and 5 females Spartan rats were exposed to the given test chemical via inhalation (whole body) route for 4 hour exposure.

 

Both the above studies are further supported with the study mentioned in publication and databases for the test chemical. The acute inhalation toxicity study was conducted by using test chemical in mice at the concentration range between 2,000 and 17,000 mg/m³. 

Animals were observed for mortality and clinical signs. Necropsy was performed.

50% mortality was observed in treated mice at 7570 mg/m³ when exposed for 2 hours. Initially all animals exhibited slight inflammations of the eyes and the respiratory tract as well as agitation, followed by a loss of activity. After exposures to values up to 4,000 mg/m³ these symptoms were reversible after the termination of the exposure. Higher concentrations caused further CNS and neuromuscular symptoms (weak reflexes, unsteady gait, respiratory disorders, and tonic-clonic spasms). The dissection revealed injuries in several organs (vascularisation, bleeding, dystrophic changes).

Therefore, LC50 was considered to be 7570 mg/m³, when mice were exposed to test chemical via inhalation by vapor for 2 hour exposure.

 

Thus, based on the above summarised studies on the test chemical, it can be concluded that LC50 value is >5 mg/L air. Thus, comparing this value with the criteria of CLP regulation, the given test chemical cannot be classified for acute inhalation toxicity.

 

Acute Dermal toxicity:

In different studies, the given test chemical has been investigated for acute dermal toxicity to a greater or lesser extent. Often are the studies based on in-vivo experiments in rodents, i.e. most commonly in rats and rabbits for test chemical. The studies are summarized as below –

 

The experimental study mentioned in database and secondary report and conducted on rabbits to determine acute dermal toxicity dose for the test chemical at the dose concentration of 2190 mg/kg bw. The animals were observed for mortality. 50% mortality was observed at 2190 mg/kg bw in treated animals. Hence, the LD50 value was considered to be 2190 mg/kg bw, when rabbits were treated with the given test chemical by dermal route.

 

The above study is supported with the study mentioned in publication for the test chemical. The acute dermal toxicity study was conducted by using the given test chemical in groups of four to eight New Zealand White rabbits at the dose concentration of 5000 mg/kg bw to the closely shaved skin.

The test material was applied in 10 ml of an oxidation-type hair dye base. The period of application was 24 hr. Animals were observed for mortality. No mortality was observed at the dose concentration of 5000 mg/kg bw in treated animals.

Hence, the LD50 value was considered to be >5000 mg/kg bw, when groups of four to eight New Zealand rabbits were treated with the given test chemical by dermal application for 24 hr exposure.

 

These studies are supported with the study mentioned in database and publication for the test chemical. The acute dermal toxicity study of test chemical was conducted in 6 male and 6 female New Zealand white rabbits at the dose concentration of 5000mg/kg bw.

The back of each rabbit was clipped free of hair and the animals were fitted with plastic collars to prevent oral ingestion of the compound. The test chemical was applied to the back of each rabbit with a gauze pad. The pads were left in place under semiocclusive conditions for 24 hr. The rabbits were observed for 7 days after patch removal. No mortality was observed at 5000 mg/kg bw.

Hence, the LD50 value was considered to be >5000 mg/kg bw, when 6 male and 6 female New Zealand white rabbits were treated with test chemical by dermal application semiocclusively for 24 hour.

 

All the above studies are further supported with the study mentioned in database for the test chemical. The acute dermal toxicity study of test chemical was conducted in rabbits at the dose concentration of 8112 mg/kg bw. Animals were observed for mortality. 50% mortality was observed at 8112 mg/kg bw. Hence, the LD50 value was considered to be 8112 mg/kg bw, when rabbits were treated with test chemical by dermal application.

 

Thus, based on the above summarised studies on test chemical, it can be concluded that LD50 value is >2000 mg/kg bw. Thus, comparing this value with the criteria of CLP regulation, the given test chemical cannot be classified for acute dermal toxicity.

 

Justification for classification or non-classification

Based on the above studies on test chemical, it can be concluded that LD50 value is >2000 mg/kg bw, for acute oral toxicity; LC50 value is >5 mg/L air, for acute inhalation toxicity; and LD50 value is >2000 mg/kg bw, for acute dermal toxicity. Thus, comparing these values with the criteria of CLP regulation, the given test chemical cannot be classified for acute oral, acute inhalation and acute dermal toxicity.