Registration Dossier

Acute oral toxicity:

The acute oral toxicity dose (LD50) was considered based on different studies conducted on rats and mice for the test chemical. The LD50 value is 65 mg/kg bw. The study concluded that the LD50 value is between 50-300 mg/kg bw, for acute oral toxicity. Thus, comparing this value with the criteria of CLP regulation, the given test chemical can be classified in “Category 3” for acute oral toxicity.

Acute Inhalation Toxicity:

The acute inhalation toxicity study need not be conducted because exposure to humans via inhalation route is not likely taking into account due to very low vapour pressure of the test chemical, which is reported to be 1.235E-19 Pa (9.26E-22 mm Hg) at 25 °C and particle size of the test chemical which is determined to be in the range of 147 micron to 52 micron and which is much larger size range compared to the inhalable particulate matter. Thus, exposure to inhalable dust, mist and vapour of the chemical is highly unlikely. Therefore this study is considered for waiver.

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 >5000 mg/kg bw. The study concluded that 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.

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 Authoritative database

Qualifier:

according to guideline

Guideline:

other: as mentioned below

Principles of method if other than guideline:

Acute oral toxicity study of test chemical was performed in rats.

GLP compliance:

not specified

Test type:

other: not specified

Limit test:

no

Species:

rat

Strain:

not specified

Sex:

not specified

Details on test animals or test system and environmental conditions:

not specified

Route of administration:

oral: unspecified

Vehicle:

not specified

Details on oral exposure:

not specified

Doses:

65 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:

65 mg/kg bw

Based on:

test mat.

Remarks on result:

other: 50% mortality was observed

Mortality:

50% mortality was observed at 65 mg/kg bw.

Clinical signs:

other: not specified

Gross pathology:

not specified

Other findings:

not specified

Interpretation of results:

Category 3 based on GHS criteria

Conclusions:

The lethal concentration (LD50) value for acute oral toxicity test was considered to be 65 mg/kg bw, when rats were treated with the given test chemical orally.

Executive summary:

Acute oral toxicity study was performed in rats using the given test chemical at the dose concentration of 65 mg/kg bw.

Animals were observed for mortality. 50% mortality was observed at dose 65 mg/kg bw.

Hence, the LD50 value was considered to be 65 mg/kg bw, when rats were treated with the given test chemical orally.

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LD50

Value:

65 mg/kg bw

Quality of whole database:

Data is Klimisch 2 and from authoritative database

Reference

Endpoint:: acute toxicity: inhalation
Data waiving:: other justification
Justification for data waiving:: other:

Quality of whole database:

Waiver

Reference

Endpoint:

acute toxicity: dermal

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 from various test chemicals

Justification for type of information:

Data is summarized based on the available information from various test chemicals.

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across source

Qualifier:

according to guideline

Guideline:

other: As mentioned below

Principles of method if other than guideline:

WoE report is based on 2 acute dermal toxicity studies as- WoE 2 and WoE 3.
Acute dermal toxicity test was carried out to study the effects of the test chemicals on rodents.

GLP compliance:

not specified

Test type:

other: not specified

Limit test:

no

Species:

other: 2. rat 3. rabbit

Strain:

other: 2. not specified 3. White Russian

Sex:

male/female

Details on test animals or test system and environmental conditions:

2. not specified
3. TEST ANIMALS
- Source: Asta Pharma AG.
- Weight at study initiation: weight males 2.38-2.95 kg, females 2.48-2.93 kg.
- Fasting period before study: feed was withheld 16 h prior to dosing.
- Diet (e.g. ad libitum): feed was given

Type of coverage:

other: 2. Dermal 3. occlusive

Vehicle:

other: 2. not specified 3. water

Details on dermal exposure:

2. not specified
3. not specified

Duration of exposure:

2. not specified
3. 24 h

Doses:

2. 5000 mg/kg
3. 2000 mg/kg

No. of animals per sex per dose:

2. not specified
3. 5/sex/treatment

Control animals:

not specified

Details on study design:

2. not specified
3. - Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Mortality and clinical signs was observed from 0-6 hrs, and daily thereafter for 14 days. Body weight on day 0, 7 and 14.
- Necropsy of survivors performed: yes, on day 14.

Statistics:

2. not specified
3. not specified

Preliminary study:

2. not specified
3. not specified

Sex:

not specified

Dose descriptor:

LD50

Effect level:

> 5 000 mg/kg bw

Based on:

test mat.

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Mortality:

2. No mortality was observed at 5000 mg/kg bw in treated animals.
3. No mortality was observed at 2000 mg/kg bw in treated animals.

Clinical signs:

other: 2. not specified 3. A slight reddening was observed immediately after removal of the patches in all animals. In some animals the reddening was present till the end of the observation period.

Gross pathology:

2. not specified
3. No treatment-related effects were observed in necropsy.

Other findings:

2. not specified
3. not specified

Interpretation of results:

other: Not classified

Conclusions:

According to CLP regulation, the given test chemical cannot be classified for acute dermal toxicity, as the LD50 value is >5000 mg/kg bw.

Executive summary:

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 reported study was mentioned in authoritative database and conducted to determine acute dermal toxicity profile of the given test chemical. The study was performed in rats at the concentration of 5000 mg/kg bw. Animals were observed for mortality. No mortality was observed at 5000 mg/kg bw in treated animals. Therefore, the LD50 value was considered to be >5000 mg/kg bw, when rats were treated with the given test chemical by dermal application.

The above study is supported with another study available in authoritative database and secondary report and conducted in male and female rabbits at the concentration of 2000 mg/kg bw.

The given test chemical (purity 99.8%) was dissolved in water and applied to the skin of rabbits by occlusive patch for 24 hours. Mortality and clinical signs was observed from 0-6 hours and daily thereafter for 14 days. Body weight was observed on day 0, 7 and 14. Necropsy of survivors performed on day 14.

No mortality was observed at 2000 mg/kg bw in treated animals. A slight reddening was observed immediately after removal of the patches in all animals. In some animals the reddening was present till the end of the observation period. No treatment-related effects were observed in body weight. No treatment-related effects were observed in necropsy.

Hence, the LD50 value was considered to be >2000 mg/kg bw, when male and female White Russian rabbits were treated with the given test chemical by dermal application occlusively.

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.

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

5 000 mg/kg bw

Quality of whole database:

Data is Klimisch 2 and from authoritative database.

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 reported study was mentioned in different authoritative databases and handbooks and designed to determine the acute oral toxicity profile of the given test chemical in rats at the dose concentration of 65 mg/kg bw. Animals were observed for mortality. 50% mortality was observed at dose 65 mg/kg bw. Hence, the LD50 value was considered to be 65 mg/kg bw, when rats were treated with the given test chemical orally.

The above study is supported with another study mentioned in different authoritative databases and handbook for the given test chemical. The acute oral toxicity study was performed in mouse at the dose concentration of 65 mg/kg bw. Animals were observed for mortality. 50% mortality was observed at dose 65 mg/kg bw. Hence, the LD50 value was considered to be 65 mg/kg bw, when mouse were treated with the given test chemical orally.

Both the above studies are further supported with the study mentioned in authoritative database for the given test chemical. The acute oral toxicity study was performed in rats at the dose concentration of 150 mg/kg bw. Animals were observed for mortality and clinical signs. 50% mortality was observed at dose 150 mg/kg bw. In clinical signs observations, increased urine volume, behavioural rigidity and tremor were seen. Hence, the LD50 value was considered to be 150 mg/kg bw, when rats were treated with test chemical orally.

Thus, based on the above summarised studies on test chemical, it can be concluded that LD50 value is between 50-300 mg/kg bw. Thus, comparing this value with the criteria of CLP regulation, the given test chemical can be classified in “Category 3” for acute oral toxicity.

Acute Inhalation Toxicity:

The acute inhalation toxicity study need not be conducted because exposure to humans via inhalation route is not likely taking into account due to very low vapour pressure of the test chemical, which is reported to be 1.235E-19 Pa (9.26E-22 mm Hg) at 25 °C and particle size of the test chemical which is determined to be in the range of 147 micron to 52 micron and which is much larger size range compared to the inhalable particulate matter. Thus, exposure to inhalable dust, mist and vapour of the chemical is highly unlikely. Therefore this study is considered for waiver.

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 reported study was mentioned in authoritative database and conducted to determine acute dermal toxicity profile of the given test chemical. The study was performed in rats at the concentration of 5000 mg/kg bw. Animals were observed for mortality. No mortality was observed at 5000 mg/kg bw in treated animals. Therefore, the LD50 value was considered to be >5000 mg/kg bw, when rats were treated with the given test chemical by dermal application.

The above study is supported with another study available in authoritative database and secondary report and conducted in male and female rabbits at the concentration of 2000 mg/kg bw.

The given test chemical (purity 99.8%) was dissolved in water and applied to the skin of rabbits by occlusive patch for 24 hours. Mortality and clinical signs was observed from 0-6 hours and daily thereafter for 14 days. Body weight was observed on day 0, 7 and 14. Necropsy of survivors performed on day 14.

No mortality was observed at 2000 mg/kg bw in treated animals. A slight reddening was observed immediately after removal of the patches in all animals. In some animals the reddening was present till the end of the observation period. No treatment-related effects were observed in body weight. No treatment-related effects were observed in necropsy.

Hence, the LD50 value was considered to be >2000 mg/kg bw, when male and female White Russian rabbits were treated with the given test chemical by dermal application occlusively.

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.

Based on the above studies on test chemical, it can be concluded that LD50 value is between 50-300 mg/kg bw, for acute oral toxicity and LD50 value is >2000 mg/kg bw, for acute dermal toxicity. Thus, comparing this range and value with the criteria of CLP regulation, the given test chemical can be classified in “Category 3” for acute oral toxicity and cannot be classified for acute dermal toxicity. For acute inhalation toxicity wavier was added so, not possible to classify.