Registration Dossier

Administrative data

Description of key information

Acute oral toxicity: 

The acute oral toxicity dose (LD50) was considered based on different studies conducted on rats for the test chemical.The study concluded that the LD50 value is >2000 mg/kg bw, for acute oral toxicity.Thus, comparing this value with the criteria of CLP regulation, the given test chemical cannot be classified 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 the low vapour pressure of the test chemical, which is reported to be 0.0147 Pa = 0.00011 mmHg. 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 studies 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
Study period:
September 2002 - October 2003
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Justification for type of information:
Data is from study report.
Qualifier:
according to
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Deviations:
not specified
Principles of method if other than guideline:
The purpose of this study was to assess the Toxicological profile of test item to a single administration via oral route to rats.
GLP compliance:
yes
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Females (if applicable) nulliparous and non-pregnant: yes
- Age at study initiation: healthy rats
- Weight at study initiation: The pretest body weight range was 316- 350 grams for males and 243- 276 grams for females. The weight variation of the animals used did not exceed +/- 20% of the mean weight.
- Fasting period before study: 16-20 hours
- Housing/Identification/Bedding: The animals were identified by cage notation and indelible body marks, and housed 5/sex/cage in suspended wire cages. Bedding was placed beneath the cages and changed at least three times/week.
- Diet (e.g. ad libitum): Fresh PMI Rat Chow was freely available except for 16-20 hours prior to dosing.
- Water (e.g. ad libitum): Water was freely available at all times.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): temperature controlled
- Air changes (per hr): was kept clean and vermin free.
- Photoperiod (hrs dark / hrs light): a 12 hour light/dark cycle

Route of administration:
oral: gavage
Vehicle:
unchanged (no vehicle)
Details on oral exposure:
not specified
Doses:
2000 mg/kg b.w.
No. of animals per sex per dose:
5 males and 5 females
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Animals were observed 1, 2 and 4 hours postdose and once daily for 14 days for toxicity effects. The animals were observed twice daily for mortality. Body weights were recorded immediately pretest, weekly and at termination.
- Necropsy of survivors performed: yes, All animals were humanely sacrificed using CO2 and examined for gross pathology. Abnormal tissues were preserved in 10% buffered formalin for possible future microscopic examination.
Statistics:
An estimate of the LD50 was made based on the results.
Preliminary study:
not specified
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
No mortality was observed at 2000 mg/kg bw.
Clinical signs:
Instances of lethargy, wet anogenital area, ataxia, soiled anogenital area and diarrhea were noted on the day of dosing. All animals appeared normal from day 1 to day 14.
Body weight:
Body weight changes were normal.
Gross pathology:
Necropsy results were normal in 9/10 animals. One animal had mottled kidneys.
Other findings:
None
Interpretation of results:
other: Not classified
Conclusions:
The lethal concentration (LD50) value for acute oral toxicity test was considered to be >2000 mg/kgbw, when male and female wistar rats were treated with test chemical orally via gavage according to OECD Guideline 401 (Acute Oral Toxicity).
Executive summary:

The acute oral toxicity profile of the given test chemical was conducted according to OECD Guideline 401 (Acute Oral Toxicity) in Wistar rats.

10 Healthy male and female wistar rats were used for the study. The given test chemical was administered via oral gavage route with the dose concentration of 2000 mg/kg b.w.

Animals were observed 1, 2 and 4 hours postdose and once daily for 14 days for toxicity effects. The animals were observed twice daily for mortality. Body weights were recorded immediately pretest, weekly and at termination. All animals were humanely sacrificed using CO2 and examined for gross pathology. Abnormal tissues were preserved in 10% buffered formalin for possible future microscopic examination. An estimate of the LD50 was made based on the results.

No mortality was observed at 2000 mg/kg bw. Instances of lethargy, wet anogenital area, ataxia, soiled anogenital area and diarrhea were noted on the day of dosing. All animals appeared normal from day 1 to day 14. Body weight changes were normal. Necropsy results were normal in 9/10 animals. One animal had mottled kidneys.

Under the condition of the study, the lethal concentration (LD50) value for acute oral toxicity test was considered to be >2000 mg/kgbw,  when male and female wistar rats were treated with test chemical orally via gavage according to OECD Guideline 401 (Acute Oral Toxicity).

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
2 000 mg/kg bw
Quality of whole database:
Data is Klimisch 1 and from study report.

Acute toxicity: via inhalation route

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

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
Study period:
October 2002 - October 2003
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Justification for type of information:
Data is from study report.
Qualifier:
according to
Guideline:
other: 16 CFR 1500.40
Deviations:
not specified
Principles of method if other than guideline:
The purpose of this study was to assess the Toxicological profile of test item to a single administration via dermal route to rabbits.
GLP compliance:
yes
Test type:
standard acute method
Limit test:
yes
Species:
rabbit
Strain:
New Zealand White
Sex:
male/female
Type of coverage:
semiocclusive
Vehicle:
unchanged (no vehicle)
Details on dermal exposure:
TEST SITE
- Area of exposure: A single dose of the test article was applied to the prepared site, under a 4 ply porous gauze dressing measuring 10 x 15 cm
- Type of wrap if used: The torso was wrapped with plastic which was secured with non-irritating tape.

REMOVAL OF TEST SUBSTANCE
- Washing (if done): The sites were wiped (not washed) prior to making dermal evaluations.
- Time after start of exposure:24 hours

TEST MATERIAL
- Concentration (if solution): The dose was based on the sample weight as calculated from the specific gravity.
Duration of exposure:
24 hrs
Doses:
2000 mg/kg b.w.
No. of animals per sex per dose:
5 males and 5 females
Control animals:
not required
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Dermal responses were recorded 24 hours postdose and on days 7 and 14. Animals were observed for mortality, toxicity and pharmacological effects once daily for 14 days. Body weights were recorded pretest and at termination. The general health of the animals was monitored at each observation time.
- Necropsy of survivors performed: yes, All animals were humanely sacrificed using CO2 following study termination.
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
All animals survived at the 2000 mg/kg dermal application.
Clinical signs:
Dermal responses were absent to slight at 24 hours and absent on days 7 and 14. There were no abnormal physical signs noted during the observation period.
Body weight:
Body weight changes were normal.
Gross pathology:
Not examined

Dose level: 2000 mg/kg bw

Time periods

G1965 M

G1966 M

G1967 M

G1968 M

G1969 M

G1994 F

G1995 F

G1996 F

G1997 F

G1998 F

Day 0

 

 

 

 

 

 

 

 

 

 

Day 1

 

 

 

 

 

 

 

 

 

 

Day 2

 

 

 

 

 

 

 

 

 

 

Day 3

 

 

 

 

 

 

 

 

 

 

Day 4

 

 

 

 

 

 

 

 

 

 

Day 5

 

 

 

 

 

 

 

 

 

 

Day 6

 

 

 

 

 

 

 

 

 

 

Day 7

 

 

 

 

 

 

 

 

 

 

Day 8

 

 

 

 

 

 

 

 

 

 

Day 9

 

 

 

 

 

 

 

 

 

 

Day 10

 

 

 

 

 

 

 

 

 

 

Day 11

 

 

 

 

 

 

 

 

 

 

Day 12

 

 

 

 

 

 

 

 

 

 

Day 13

 

 

 

 

 

 

 

 

 

 

Day 14

 

 

 

 

 

 

 

 

 

 

No entry indicates animal appeared normal at that observation period.

Interpretation of results:
other: Not classified
Conclusions:
The lethal concentration (LD50) value for acute dermal toxicity test was considered to be >2000 mg/kg bw, when male and female New Zealand White rabbits were treated with test chemical to the dermal application semiocclusively according to 16 CFR 1500.40.
Executive summary:

The acute dermal toxicity profile of the given test chemical was conducted according to 16 CFR 1500.40 in male and female New Zealand White rabbits.

A single dose of the test chemical was applied to the prepared site, under a 4 ply porous gauze dressing measuring 10 x 15 cm at a dose level of 2000 mg/kg. The dose was based on the sample weight as calculated from the specific gravity. Gentle pressure was applied to the gauze to aid in the distribution of the test substance over the prepared site. The torso was wrapped with plastic which was secured with non-irritating tape. The test chemical remained in contact with the skin for 24 hours at which time the wrappings were removed and an estimate of the amount of test article remaining was made. The sites were wiped (not washed) prior to making dermal evaluations.

Dermal responses were recorded 24 hours postdose and on days 7 and 14. Animals were observed for mortality, toxicity and pharmacological effects once daily for 14 days. Body weights were recorded pretest and at termination. The general health of the animals was monitored at each observation time. All animals were humanely sacrificed using CO2 following study termination.

All animals survived at the 2000 mg/kg dermal application. Dermal responses were absent to slight at 24 hours and absent on days 7 and 14. There were no abnormal physical signs noted during the observation period. Body weight changes were normal.

Under the condition of the study, the lethal concentration (LD50) value for acute dermal toxicity test was considered to be >2000 mg/kg bw, when male and female New Zealand White rabbits were treated with test chemical to the dermal application semiocclusively according to 16 CFR 1500.40.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
2 000 mg/kg bw
Quality of whole database:
Data is Klimisch 1 and from study report.

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 for test chemical. The studies are summarized as below:

 

The acute oral toxicity profile of the given test chemical was mentioned in study report and conducted according to OECD Guideline 401 (Acute Oral Toxicity) in Wistar rats. 10 Healthy male and female wistar rats were used for the study. The given test chemical was administered via oral gavage route with the dose concentration of 2000 mg/kg b.w. Animals were observed 1, 2 and 4 hours post dose and once daily for 14 days for toxicity effects. The animals were observed twice daily for mortality. Body weights were recorded immediately pre-test, weekly and at termination. All animals were humanely sacrificed using CO2 and examined for gross pathology. Abnormal tissues were preserved in 10% buffered formalin for possible future microscopic examination. An estimate of the LD50 was made based on the results.

No mortality was observed at 2000 mg/kg bw. Instances of lethargy, wet anogenital area, ataxia, soiled anogenital area and diarrhoea were noted on the day of dosing. All animals appeared normal from day 1 to day 14. Body weight changes were normal. Necropsy results were normal in 9/10 animals. One animal had mottled kidneys.

Under the condition of the study, the lethal concentration (LD50) value for acute oral toxicity test was considered to be >2000 mg/kg bw, when male and female wistar rats were treated with test chemical orally via gavage according to OECD Guideline 401 (Acute Oral Toxicity).

 

The above study report is supported with another study mentioned in experimental report for the given test chemical and was conducted according to Federal Hazardous Substances Act, 16 CFR Part 1500.3(c)(2)(i)(A) in 10 male Wistar rats.

A single dose of 5000 mg/kg b.w. was administered orally by syringe and dosing needle. Animals were observed 3-4 hours post dose and once daily thereafter for 14 days for mortality and other toxicity effects. Body weights were recorded pre-test. The general health of the animals was monitored at each observation time. All animals were humanely sacrificed using C02 following study termination and were not examined for gross pathology.

Six animals died after administration of dose 5000 mg/kg b.w. (4 animals died on 1st day of observation period, 2 animals died on 2nd day of observation period). Wetness of the anogenital area, lethargy, coma, negative righting reflex was observed.

Under the condition of the study, the lethal concentration (LD50) value for acute oral toxicity test was considered to be <5000 mg/kg bw, when male wistar rats were treated with test chemical orally via gavage according to Federal Hazardous Substances Act, 16 CFR Part 1500.3(c)(2)(i)(A).

 

These studies are further supported with the study mentioned in peer-reviewed journal, handbook and different databases to determine the acute oral toxicity profile of the given test chemical in rats at the dose concentration of 5000 mg/kg bw. Animals were observed for mortality. 50% mortality was observed at 5000 mg/kg bw in treated animals. Hence, the LD50 value was considered to be 5000 mg/kg bw, when rats was treated with the given test chemical via oral gavage route.

 

This study is supported with the study mentioned in report for the test chemical. The acute oral toxicity study of test chemical was performed as per OECD No. 423 in six female Wistar rats.

The animals were fasted for minimum 16-18 hours prior to dosing and for 4 hours post dosing, food was withheld but drinking water provided ad libitum. The time intervals between dosing were determined by the onset, duration and severity of toxic signs. Three rats of first group were dosed with starting dose of 2000 mg/kg body weight and the animals did not show any mortality so another three animals of the same group were dosed with 2000 mg/kg body weight and no mortality was observed. Hence, further dosing was stopped.

Body weights were recorded on day 0 (prior to dosing) 7 and 14. Mean body weight of all the animals treated with 2000 mg/kg body weight was observed with gain on day 7 and 14, as compared to day 0. At 2000 mg/kg, all the animals were normal throughout the experimental period. No external and internal gross pathological changes were seen in all the six animals treated with 2000 mg/kg body weight during terminal sacrifice. No mortality was observed at dose 2000mg/kg bw in treated rats.

Hence, the LD50 value was considered to be >2000mg/kg bw, when rats were treated with test chemical orally. Based on the value the test chemical was considered to be not classified as per CLP regulation.

 

These studies are supported with the study mentioned in another study report for the test chemical. The acute oral toxicity study of test chemical was performed as per OECD No. 423 in six female Wistar rats.

The animals were fasted for minimum 16-18 hours prior to dosing and for 4 hours post dosing, food was withheld but drinking water provided ad libitum. The time intervals between dosing were determined by the onset, duration and severity of toxic signs. Three rats of first group were dosed with starting dose of 2000 mg/kg body weight and the animals did not show any mortality so another three animals of the same group were dosed with 2000 mg/kg body weight and no mortality was observed. Hence, further dosing was stopped.

Body weights were re­corded on day 0 (prior to dosing) 7 and 14. Mean body weight of all the animals treated with 2000 mg/kg body weight was observed with gain on day 7 and 14, as compared to day 0. At 2000 mg/kg, all the animals were normal throughout the experimental period. No external and internal gross pathological changes were seen in all the six animals treated with 2000 mg/kg body weight during terminal sacrifice.

Hence, the acute oral LD50 value of test chemical was considered to be >2000 mg/kg body weight. Based on the value the given test chemical cannot be considered for acute oral toxicity.

 

All the above studies are supported with the study mentioned in publication for the test chemical. The acute oral toxicity study was done in rat using test chemical at the dose concentration of 5000 mg/kg bw. Animals were observed for mortality. No mortality was observed at 5000 mg/kg bw. Hence, the LD50 value was considered to be >5000mg/kg body weight, when rats were treated with the given test chemical orally.

 

Thus, based on the above summarised experimental studies on test chemical, the LD50 value is >2000 mg/kg bw. Therefore, comparing this value with the criteria of CLP regulation, the given test chemical cannot be classified 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 the low vapour pressure of the test chemical, which is reported to be 0.0147 Pa = 0.00011 mmHg. 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 acute dermal toxicity profile of the given test chemical was conducted according to 16 CFR 1500.40 in male and female New Zealand White rabbits.

A single dose of the test chemical was applied to the prepared site, under 4 ply porous gauze dressing measuring 10 x 15 cm at a dose level of 2000 mg/kg. The dose was based on the sample weight as calculated from the specific gravity. Gentle pressure was applied to the gauze to aid in the distribution of the test substance over the prepared site. The torso was wrapped with plastic which was secured with non-irritating tape. The test chemical remained in contact with the skin for 24 hours at which time the wrappings were removed and an estimate of the amount of test article remaining was made. The sites were wiped (not washed) prior to making dermal evaluations.

Dermal responses were recorded 24 hours post dose and on days 7 and 14. Animals were observed for mortality, toxicity and pharmacological effects once daily for 14 days. Body weights were recorded pre-test and at termination. The general health of the animals was monitored at each observation time. All animals were humanely sacrificed using CO2 following study termination.

All animals survived at the 2000 mg/kg dermal application. Dermal responses were absent to slight at 24 hours and absent on days 7 and 14. There were no abnormal physical signs noted during the observation period. Body weight changes were normal.

Under the condition of the study, the lethal concentration (LD50) value for acute dermal toxicity test was considered to be >2000 mg/kg bw, when male and female New Zealand White rabbits were treated with test chemical to the dermal application semiocclusively according to 16 CFR 1500.40.

 

The above study is supported with another study mentioned in peer-reviewed journal and database to determine the acute dermal toxicity profile of the given test chemical in rabbits at the dose concentration of 5000 mg/kg bw. Animals were observed for mortality. No mortality was observed at 5000 mg/kg bw in treated animals. Hence, the LD50 value was considered to be >5000 mg/kg bw, when rabbits were treated with the given test chemical by dermal application.

 

These studies are supported with the study mentioned in report for the test chemical. The acute dermal toxicity study was conducted by using the given test chemical in Wistar Rats as per OECD No. 402.

Five male and five female healthy young adult rats were randomly selected and used for conducting acute dermal toxicity study. Rats free from injury and irritation of skin were selected for the study. Approximately, twenty four hours prior to dermal application of test item, greater than 10% of body surface area of each rat was clipped. A limit dose of 2000 mg/ kg body weight based on the test item density (1.07513) and latest body weight was applied by single dermal application and observed for 14 days after treatment.

On test day 0, calculated volume of test item was applied directly on the intact skin of clipped area of rats; the porous gauze dressing was put on to the intact skin of clipped area. This porous gauze dressing was covered with a non-irritating tape. After the 24-hour application period, the dressings were removed and the skin was gently wiped with distilled water. The skin reactions were assessed.

The animals were observed daily for mortality and clinical signs, during the acclimatization period and post dosing till the termination. All animals were observed for clinical signs at approximately 1, 2, 3 and 4 hours after treatment on day 0 and once daily during test days 1-14. Mortality was recorded after application on test day 0 and twice daily during days 1-14 (at least once on the day of sacrifice). Local signs / Skin reactions were observed daily from test days 1-14 (in common with clinical signs). Body weights were re­corded on day 0 (prior to application) and on day 7 and 14. All animals were necropsied and examined macroscopically.

No mortality was observed in any animal till the end of the experimental period. At 2000 mg/kg, all the animals were observed normal throughout the experimental period. Mean body weight was observed with gain on day 7 and 14 of male and female animals, as compared to day 0. The external and internal gross pathological observation of all terminally sacrificed animals did not show any pathological abnormality. Hence, the LD50 was considered to be >2000mg/kg bw, when rats were treated with test chemical by dermal application.

 

This study is supported with the data available from the study report for the test chemical. The reported study was designed and conducted to determine the acute dermal toxicity profile of the given test chemical as per OECD Guideline 402 (Acute Dermal Toxicity) in Sprague Dawley rats.

The test item was applied to shorn skin of 5 male and 5 female animals at 2000 mg/kg body weight. Administration of the test item at 2000 mg/kg did not result in any skin reaction at the site of application during the study period of 14 days.

Administration of the test item did not result in any signs of toxicity and mortality during the study period of 14 days. Animals exhibited normal body weight gain through the study period of 14 days. Gross pathological examination did not reveal any abnormalities attributable to the treatment. 

It was concluded that the acute dermal median lethal dose (LD50) of the given test chemical, when administered to male and female Sprague Dawley rats was considered to be >2000 mg/kg body weight. Thus, according to CLP criteria for acute toxicity rating for the chemicals, it infers that the given test chemical does not classify as an acute dermal toxicant. CLP Classification: “Not classified”.

 

All the above studies are further supported with the study mentioned in report for the test chemical. Acute dermal toxicity study was conducted by using the given test chemical as per OECD No.402 in 10 male and female healthy young adult Wistar rats. The rats free from injury and irritation of skin were randomly selected and used for conducting acute dermal toxicity study at the concentration of 2000 mg/kg bw. 24 hours prior to dermal application of test item, approximately 10% of body surface area of each rat was clipped. A limit dose of 2000 mg/ kg body weight of test item was applied by single dermal application and observed for 14 days after treatment.

On test day 0, as such amount of test item, calculated based on density (1.0016) and body weight was applied directly on the intact skin of clipped area of rats; the surgical gauze patch was put on to the intact skin of clipped area. This porous gauze dressing was covered with a non-irritating adhesive tape. The porous gauze dressing was wrapped around the abdomen and anchored with non-irritating adhesive tape. After the 24-hour application period, the dressings were removed and the skin was gently wiped with distilled water. The skin reactions were assessed.

The animals were observed daily for mortality and clinical signs, during the acclimatization period. All animals were observed for clinical signs at approximately 1, 2, 3 and 4 hours after treatment on day 0 and once daily during test days 1‑14. Mortality was recorded after application on test day 0 and twice daily during days 1-14 (at least once on the day of sacrifice). Local signs / Skin reactions were observed daily from test days 1-14 (in common with clinical signs). Body weights were re­corded on day 0 (prior to application) and on day 7 and 14. All animals were necropsied and examined macroscopically.

No mortality was observed in any animal till the end of the experimental period. No clinical signs and any skin reaction were observed throughout the experimental period in all treated animals. The male and female animals were observed with body weight gain throughout the experiment, except on day 7 male animals were observed with decline in mean body weight gain as compared to day 0. The external and internal gross pathological observation of all terminally sacrificed animals did not show any pathological abnormality.

Hence, the LD50 was considered to be >2000 mg/kg bw, when rats were treated with the given 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 the LD50 value is >2000 mg/kg bw, for acute oral and acute dermal toxicity. Thus, comparing this value with the criteria of CLP regulation, the given test chemical cannot be classified for acute oral and acute dermal toxicity. For acute inhalation toxicity wavier was added so, not possible to classify.