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Description of key information

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 between 300 -2000 mg/kg bw, for acute oral toxicity. Thus, comparing this value with the criteria of CLP regulation, the given test chemical can be classified for acute oral toxicity category 4.

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:
28/08/1986 to 16/10/1986
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)
Qualifier:
according to
Guideline:
other: EWG Directive 84/449/EWG
Principles of method if other than guideline:
Acute oral toxicity study with test chemical in rats.
GLP compliance:
not specified
Test type:
other: No data
Limit test:
no
Species:
rat
Strain:
other: KFM-Han. Wistar
Remarks:
(outbred, SPF-Quality)
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Kleintierfarm Madoerin AG,
CH 4414 Fuellinsdorf / Switzerland
- Age at study initiation: 9 to 13 weeks old
- Weight at study initiation: Animals were weighed as follows - Males: 190 - 263 g; Females: 179 - 222 g
- Fasting period before study: The rats were fasted for 12 to 18 hours.
- Housing: Groups of 5 in Makrolon type-3 cages with standard softwood bedding
- Diet (e.g. ad libitum): Pelleted standard Kuba 343, Batch 50/86 rat maintenance diet, ad libitum.
- Water (e.g. ad libitum): Community tap water from Itingen, ad libitum.
- Acclimation period: At least one week under laboratory conditions, after veterinary examination.
ENVIRONMENTAL CONDITIONS
- Temperature (°C):22±3°C
- Humidity (%):relative humidity 40-70 %
- Air changes (per hr): Air-conditioned with 10-15 air changes per hour.
- Photoperiod (hrs dark / hrs light): 12 hours artificial fluorescent light/12 hours dark, music/light period.
IN-LIFE DATES: From: August 21, 1986 To: October 16, 1986
Route of administration:
oral: gavage
Vehicle:
CMC (carboxymethyl cellulose)
Remarks:
4 % solution of CMC carboxymethylcellulose sodium salt in distilled water
Details on oral exposure:
VEHICLE
- Concentration in vehicle: Group 1: 10 ml at 100 mg/kg; Group 2: 10 ml at 400 mg/kg;
Group 3: 10 ml at 1000 mg/kg; Group 4: 20 ml at 5000 mg/kg.
DOSAGE PREPARATION (if unusual): The test article was placed into a glass beaker on a tared Mettler PK 4800 balance, and the vehicle (4 % solution of CMC, carboxymethylcellulose sodium salt in distilled water) was added. A weight by volume dilution was prepared using a homogenizer.
Doses:
100, 400, 1000 and 5000 mg/kg
No. of animals per sex per dose:
Total = 40 (sex/dose)
Control animals:
not specified
Details on study design:
- Duration of observation period following administration: 15 days
- Frequency of observations and weighing: Mortality was observed 4 times during test day 1, and daily during days 2-15; and weighing: Test days 1 (pre-administration), 8 and 15 day.
- Necropsy of survivors performed: yes, all animals surviving to the end of the observation period were killed by intraperitoneal injection of sodium pentobarbitone.
- Other examinations performed: Each animal was examined for changes in appearance and behavior 4 times during day 1, and daily during days 2-15. All abnormalities were recorded. The animals were checked for the symptoms like - General Behavior, respiration, body posture, motor susceptibility, motility, etc.
Statistics:
The LOGIT-Model was applied to estimate the toxicity value. Additionally, the 90, 95 and 99% confidence intervals for the toxicity for each sex and the slope of the dose response line were estimated.
Preliminary study:
No data
Sex:
male/female
Dose descriptor:
LD50
Effect level:
473 mg/kg bw
Based on:
test mat.
95% CL:
>= 311 - <= 889
Remarks on result:
other: 50% mortality was observed
Sex:
male
Dose descriptor:
LD50
Effect level:
454 mg/kg bw
Based on:
test mat.
95% CL:
>= 227 - <= 1 582
Remarks on result:
other: 50% mortality was observed
Sex:
female
Dose descriptor:
LD50
Effect level:
454 mg/kg bw
Based on:
test mat.
95% CL:
>= 227 - <= 1 582
Remarks on result:
other: 50% mortality was observed
Mortality:
Mortality was observed as follows – In males – At 400 mg/kg: 1 animal was died.
At 1000 mg/kg: All animals were died.
At 5000 mg/kg: All animals were died.
In Females – At 400 mg/kg: 1 animal was died. At 1000 mg/kg: All animals were died. At 5000 mg/kg: All animals were died.
Clinical signs:
The following symptoms were observed: At 100 mg/kg: sedation, ataxia, curved body position, ruffled fur;
At 400 mg/kg: sedation, chromodacryorrhea, ataxia, curved body position, ruffled fur;
At 1000 mg/kg: sedation, dyspnea, ataxia, curved body position, ruffled fur;
At 5000 mg/kg: sedation, somnolence, rales, chromodacryorrhea, ataxia, latero-abdominal, position, curved body position, ruffled furventral body position (females).
All surviving rats had recovered within 4 to 5 observation days.
Body weight:
Body weight changes were observed in treated rats.
Gross pathology:
The following macroscopic organ changes were observed: At 100 mg/kg: no pathologic changes (10).
At 400 mg/kg: lung - discolored, dark-red (1); thymus - discolored, dark-red (1); stomach - meteorism, totally filled (1); p1eura1 cavity - watery, clear fluid (1ml) (1); skin, abdominal cavity - red to brown, yellowish, partly exfoliation, diameter 7mm (1); cannibalism - whole animal (1); no pathologic changes (8).
At 1000 mg/kg: lung - pale (1); dark-red (7); foam excretion (1); several foci, diameter 2mm (2); liver - dark-red (2); stomach - meteorism (2); intestines - meteorism (1);
no pathologic changes (2).
At 5000 mg/kg: lung - dark-red, black foci (1); reddish (6); right, dark-red foci (1); dark-red (1); liver - black (5); spleen - black (5); stomach - meteorism (1); pleural cavity - watery, clear, fluid, (1ml).
Other findings:
No data
Interpretation of results:
Category 4 based on GHS criteria
Conclusions:
The LD50 was considered to be 473 mg/kg bw in both Males/Females with a 95 % confidence interval of 311 - 889 mg/kg bw; 454 mg/kg with 95 % confidence interval of 227 - 1582 mg/kg in males; and 454 mg/kg ith 95 % confidence interval of 227 - 1582 mg/kg in females, when KFM-Han. Wistar rats were treated with test chemical via oral gavage route.
Executive summary:

Acute oral toxicity test was conducted according to OECD Guidelines No. 401 “Acute Oral Toxicity" and EWG Directive 84/449/EWG, using test chemical in 40 male and female KFM-Han. Wistar (outbred, SPF-Quality) rats at the concentration of 100, 400, 1000 and 5000 mg/kg bw. The test substance (Purity >96%) was placed into a glass beaker on a tared Mettler PK 4800 balance, and the vehicle (4 % solution of CMC, carboxymethylcellulose sodium salt in distilled water) was added. A weight by volume dilution was prepared using a homogenizer and administered by oral gavage route at the concentration in vehicle as: Group 1: 10 ml at 100 mg/kg; Group 2: 10 ml at 400 mg/kg; Group 3: 10 ml at 1000 mg/kg; Group 4: 20 ml at 5000 mg/kg. Mortality was observed 4 times during test day 1, and daily during days 2-15; and weighing: Test days 1 (pre-administration), 8 and 15 day. All animals surviving to the end of the observation period were killed by intraperitoneal injection of sodium pentobarbitone. Each animal was examined for changes in appearance and behavior 4 times during day 1, and daily during days 2-15. All abnormalities were recorded. The animals were checked for the symptoms like - General Behavior, respiration, body posture, motor susceptibility, motility, etc.The LOGIT-Model was applied to estimate the toxicity value. Additionally, the 90, 95 and 99% confidence intervals for the toxicity for each sex and the slope of the dose response line were estimated.Mortality was observed as - In males – At 400 mg/kg: 1 animal was died. At 1000 mg/kg: All animals were died. At 5000 mg/kg: All animals were died. In Females – At 400 mg/kg: 1 animal was died. At 1000 mg/kg: All animals were died. At 5000 mg/kg: All animals were died. The symptoms were observed in animals as: At 100 mg/kg: sedation, ataxia, curved body position, ruffled fur; At 400 mg/kg: sedation, chromodacryorrhea, ataxia, curved body position, ruffled fur; At 1000 mg/kg: sedation, dyspnea, ataxia, curved body position, ruffled fur; At 5000 mg/kg: sedation, somnolence, rales, chromodacryorrhea, ataxia, latero-abdominal, position, curved body position, ruffled furventral body position (females). All surviving rats had recovered within 4 to 5 observation days. Therefore, LD50 was considered to be 473 mg/kg bw in both Males/Females with a 95 % confidence interval of 311 - 889 mg/kg bw; 454 mg/kg with 95 % confidence interval of 227 - 1582 mg/kg in males; and 454 mg/kg ith 95 % confidence interval of 227 - 1582 mg/kg in females, when KFM-Han. Wistar rats were treated with test chemical via oral gavage route.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LD50
Value:
473 mg/kg bw
Quality of whole database:
Data is K1 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 and mice for test chemical. The studies are summarized as below –

Acute oral toxicity test was conducted according to OECD Guidelines No. 401 “Acute Oral Toxicity" and EWG Directive 84/449/EWG, using test chemical in 40 male and female KFM-Han. Wistar (outbred, SPF-Quality) rats at the concentration of 100, 400, 1000 and 5000 mg/kg bw. The test substance (Purity >96%) was placed into a glass beaker on a tared Mettler PK 4800 balance, and the vehicle (4 % solution of CMC, carboxymethylcellulose sodium salt in distilled water) was added. A weight by volume dilution was prepared using a homogenizer and administered by oral gavage route at the concentration in vehicle as: Group 1: 10 ml at 100 mg/kg; Group 2: 10 ml at 400 mg/kg; Group 3: 10 ml at 1000 mg/kg; Group 4: 20 ml at 5000 mg/kg. Mortality was observed 4 times during test day 1, and daily during days 2-15; and weighing: Test days 1 (pre-administration), 8 and 15 day. All animals surviving to the end of the observation period were killed by intraperitoneal injection of sodium pentobarbitone. Each animal was examined for changes in appearance and behavior 4 times during day 1, and daily during days 2-15. All abnormalities were recorded. The animals were checked for the symptoms like - General Behavior, respiration, body posture, motor susceptibility, motility, etc.The LOGIT-Model was applied to estimate the toxicity value. Additionally, the 90, 95 and 99% confidence intervals for the toxicity for each sex and the slope of the dose response line were estimated.Mortality was observed as - In males – At 400 mg/kg: 1 animal was died. At 1000 mg/kg: All animals were died. At 5000 mg/kg: All animals were died. In Females – At 400 mg/kg: 1 animal was died. At 1000 mg/kg: All animals were died. At 5000 mg/kg: All animals were died. The symptoms were observed in animals as: At 100 mg/kg: sedation, ataxia, curved body position, ruffled fur; At 400 mg/kg: sedation, chromodacryorrhea, ataxia, curved body position, ruffled fur; At 1000 mg/kg: sedation, dyspnea, ataxia, curved body position, ruffled fur; At 5000 mg/kg: sedation, somnolence, rales, chromodacryorrhea, ataxia, latero-abdominal, position, curved body position, ruffled furventral body position (females). All surviving rats had recovered within 4 to 5 observation days. Therefore, LD50 was considered to be 473 mg/kg bw in both Males/Females with a 95 % confidence interval of 311 - 889 mg/kg bw; 454 mg/kg with 95 % confidence interval of 227 - 1582 mg/kg in males; and 454 mg/kg ith 95 % confidence interval of 227 - 1582 mg/kg in females, when KFM-Han. Wistar rats were treated with test chemical via oral gavage route.

In a Single dose acute oral toxicity study, Crj:CD(SD)IGS male and female rats were treated with test chemical in the concentration of 0, 500, 800, 1300, 2000 mg/kg for male and 0, 800, 1300 mg/kg for female orally by gavage in Corn oil. All the male and female rats died at 1300 and 2000 mg/ kg bw as compared to control. Salivation, decrease in locomotor activity, a prone position and ataxic gait were observed in treated rats as compared to control. Decreased body weight gain and/or depressed body weight was observed on the second day in 800 mg/ kg bw treated male and female rats as compared to control. Insufficient retraction and dark red areas in the lung and pale discoloration of the spleen were observed in dead animals and Pulmonary edema and atrophy of the spleen were observed in treated rats. Therefore,LD50 was considered to be between 1300 and 2000 mg/kg for male and between 800 and 1300 mg/kg for female rats when Crj:CD(SD)IGS male and female rats were treated with test chemical orally by gavage.

In a acute oral toxicity study,Crj:CD(SD)IGS male and female rats were treated with test chemical in the concentration of 0, 300, 500, 900, 1500 mg/kg orally by gavage in corn oil. Deaths were observed between days 1 and 3 after administration in male and female rats at 900 and 1500 mg/kg and in female rats 500 mg/kg, at as compared to control. Salivation in all treated groups and lacrimation in the 500, 900 and 1500 mg/kg were observed in both sexes. In addition, decreased spontaneous movement, abnormal gait, adoption of a prone or lateral position and oligopnea were also evident in some animals which died of either sex. All clinical signs observed in the survivors disappeared by day 1 after the administration.When treated with Suppression of gain or decrease of body weights was observed in both sexes in 500, 900 and 1500 mg/kg, mg/kw, but this had disappeared by day 10 after administration in males and day 3 after administration in female. Therefore,LD50 was considered to be 734 mg/kg bw for male and 671 mg/kg bw for female when Crj:CD(SD)IGS male and female rats were treated with test chemical orally by gavage in corn oil.

Thus, based on the above summarised studies on test chemical, it can be concluded that LD50 value is is between 300-2000 mg/kg bw. Thus, comparing this value with the criteria of CLP regulation, the given test chemical can be classified as "Acute oral toxicity Category 4" according to CLP regulation.

Justification for classification or non-classification

Based on the above studies on test chemical, it can be concluded that LD50 value is between 300 -2000 mg/kg bw, for acute oral toxicity. Thus, comparing this value with the criteria of CLP regulation, the given test chemical can be classified for acute oral toxicity and comes under "Category 4".