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Description of key information

Acute oral toxicity (1996), GLP, ACUTE ORAL TOXICITY (LIMIT TEST) IN THE RAT (GERMAN WATER HAZARDS CLASSIFICATION SCHEME), gavage, 2000 mg/kg, LD50 >2000 mg/kg bw.

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:
16 April - 16 May 1996
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP - guideline study
Qualifier:
no guideline followed
Principles of method if other than guideline:
Following a range-finding study, a group of ten fasted animals (five males and five females) was given a single oral dose of test material as a solution in distilled water at a dose level of 2000 mg/kg bodyweight. The animals were observed for fourteen days after the day of dosing and were then killed and subjected to gross pathological examination.
GLP compliance:
yes (incl. QA statement)
Remarks:
(The Department of Health of the Government of the United Kingdom)
Limit test:
yes
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River (UK) Ltd. , Margate , Kent , UK
- Age at study initiation: 5 - 8 weeks
- Weight at study initiation: 157-173g (males) and 133-148g (females)
- Fasting period before study: overnight fast immediately before dosing and for approximately two hours after dosing
- Housing: animals were housed in groups of up to five by sex in solid-floor polypropylene cages furnished with woodflakes
- Diet : Rat and Mouse Expanded Diet No.1 (Special Diets Services Limited , Witham , Essex , UK) , ad libitum
- Water : mains drinking water , ad libitum
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19-23
- Humidity (%): 43-62
- Air changes (per hr): approximately 15
- Photoperiod (hrs dark / hrs light): 12/12
Route of administration:
oral: gavage
Vehicle:
other: distilled water
Details on oral exposure:
VEHICLE
- Concentration in vehicle: 200 mg/ml
- Amount of vehicle (if gavage): 10 ml/kg bw
Doses:
2000 mg/kg bw
No. of animals per sex per dose:
5
Control animals:
no
Details on study design:
Range-finding Study
A range-finding study was performed to establish a dosing regime with undiluted test material at a dose level of 2000 mg/kg and formulations of 2000 mg/kg and 200 mg/kg in distilled water. The animals were observed for deaths or overt signs of toxicity 1/2, 1, 2 and 4 hours after dosing and subsequently once daily for five days. Individual bodyweights were recorded on the day of dosing to allow calculation of individual treatment volumes. No necropsies were performed.
Main study
Based on the results of the range-finding study, a group of ten fasted animals (five males and five females) was given a single oral dose of test material as a solution in distilled water at a dose level of 2000 mg/kg bodyweight. The animals were observed for deaths or overt signs of toxicity 1/2, 1, 2 and 4 hours after dosing and subsequently once daily for fourteen days. Individual bodyweights were recorded prior to dosing on Day 0 and on Days 7 and 14 or at death. At the end of the study the surviving animals were killed by cervical dislocation. All animals were subjected to gross pathological examination. This consisted of an external examination and opening of the abdominal and thoracic cavities for examination of major organs. The appearance of any macroscopic abnormalities was recorded. No tissues were retained.
Statistics:
Using the mortality data obtained, an estimate of the acute oral median lethal dose (LD50) of the test material was made.
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
Range-finding study :
The two animals treated with the undiluted test material at a dose level of 2000 mg/kg were found dead 30 minutes after dosing. When the test material was administered as a formulation there were no deaths.
Main study :
One female was found dead 30 minutes after dosing.
Clinical signs:
Range-finding study :
Clinical signs of toxicity noted in the female treated with 2000 mg/kg were ataxia, hunched posture and decreased respiratory rate. There were no signs of toxicity noted in the male treated with 2000 mg/kg or the animals treated with 200 mg/kg.
Main study :
Clinical signs of toxicity noted in one male during Days 4 to 13 included distended abdomen, dehydration, emaciation, hunched posture, decreased respiratory rate, gasping, laboured and noisy respiration and tiptoe gait. No other clinical signs of toxicity were noted during the study.
Body weight:
Surviving animals showed an expected gain in bodyweight during the study except for one male which showed bodyweight loss during the first week and expected gain during the second week of the study.
Gross pathology:
Abnormalities noted at necropsy of the female that died during the study were abnormally red lungs, dark liver, dark kidneys, severe haemorrhage of the gastric mucosa and severe haemorrhage of the small and large intestines. No abnormalities were noted at necropsy of animals that were killed at the end of the study.

TABLE 1 :

INDIVIDUAL CLINICAL OBSERVATIONS AND MORTALITY DATA IN THE RANGE-FINDING STUDY

Dose Level
mg/kg
Animal No.
and sex
Effects noted after dosing (Hours) Effects noted during period after dosing (Days)
½ 1 2 4 1 2 3 4 5
2000 * 1-0 Male X                
2-0 Female X                
2000 3-0 Male 0 0 0 0 0 0 0 0 0
5-0 Female 0 0 0 0 HARd 0 0 0 0
200 3-1 Male 0 0 0 0 0 0 0 0 0
4-1 Female 0 0 0 0 0 0 0 0 0

* = test material administered undiluted as supplied

A = ataxia

H = hunched posture

Rd = decreased respiratory rate

X = animal dead

0 = no signs of systemic toxicity

TABLE 2 :

INDIVIDUAL CLINICAL OBSERVATIONS AND MORTALITY DATA IN THE MAIN STUDY

Dose Level
mg/kg
Animal No.
and sex
Effects noted after dosing (Hours) Effects noted during period after dosing (Days)
½ 1 2 4 1 2 3 4 5 6 7 8 9 10 11 12 13 14
2000 6-0 Male 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
6-1 Male 0 0 0 0 0 0 0 HRdRIRg
RnDhEm
DaWt
HRdRI
RgRnDh
EmDaWt
HRdRI
RnEmDa
DhWt
HRdRI
RnEm
DaDh
EmH
RdRI
HRdRI
Em
HRdRI
Em
EmRIH
Rd
HRdRI H 0
6-2 Male 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
6-3 Male 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
6-4 Male 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
7-0 Female 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
7-1 Female X                                  
7-2 Female 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
7-3 Female 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
7-4 Female 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0

H = hunched posture

Rn = noisy respiration

Wt = tiptope gait

Rd = decreased respiratory rate

Da = distended abdomen

X = animal dead

RI = laboured respiration

Em = emiciation

0 = no signs of systemic toxicity

Rg = gasping respiration

Dh = dehydration

TABLE 3 :

INDIVIDUAL BODYWEIGHTS AND WEEKLY CHANGES IN THE MAIN STUDY

Dose Level
mg/kg
Animal Number
and Sex
Bodyweight (g) at Day Bodyweight (g) at
Death
Bodyweight Gain (g) During Week
0 7 14 1 2
 2000 6-0 Male 161 181 249   20 68
 2000 6-1 Male 165 131 201   -34 70
 2000 6-2 Male 173 203 231   30 28
 2000 6-3 Male 157 193 232   36 39
2000 6-4 Male 159 199 251   40 52
 2000 7-0 Female 148 191 213   43 22
 2000 7-1 Female 133 - - 133 - -
 2000 7-2 Female 141 169 199   28 30
 2000 7-3 Female 146 177 212   31 35
 2000 7-4 Female 140 190 209   50 19

- = animal dead

TABLE 4 :

INDIVIDUAL NECROPSY FINDINGS IN THE MAIN STUDY

Dose Level
mg/kg
Animal Number
and Sex
Time of Death Macroscopic Observations
2000 6-0 Male Killed Day 14 No abnormalities detected
6-1 Male Killed Day 14 No abnormalities detected
6-2 Male Killed Day 14 No abnormalities detected
6-3 Male Killed Day 14 No abnormalities detected
6-4 Male Killed Day 14 No abnormalities detected
7-0 Female Killed Day 14 No abnormalities detected
7-1 Female Found dead Day 0 Abnormally red lungs, dark liver, dark kidneys, severe haemorrhage of the gastric mucosa,
severe haemorrhage of the small and large intestines
7-2 Female Killed Day 14 No abnormalities detected
7-3 Female Killed Day 14 No abnormalities detected
7-4 Female Killed Day 14 No abnormalities detected
Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
A study in 5 male and 5 female rats revealed that acute oral LD50 for the test material was > 2000 mg/kg bw. The study was performed according to the general guidelines for acute oral toxicity under GLP conditions.
Executive summary:

A study was performed to assess the acute oral toxicity of the test material in the Sprague-Dawley CD strain rat.

The results were used as a basis for classification under the German Water Hazards Classification Scheme. Following a range-finding study, a group of ten fasted animals (five males and five females) was given a single oral dose of test material as a solution in distilled water at a dose level of 2000 mg/kg bodyweight. The animals were observed for fourteen days after the day of dosing and were then killed and subjected to gross pathological examination. One female was found dead 30 minutes after dosing. Clinical signs of toxicity noted in one male during Days 4 to 13 included distended abdomen, dehydration, emaciation, hunched posture, decreased respiratory rate, gasping, laboured and noisy respiration and tiptoe gait. Surviving animals showed an expected gain in bodyweight during the study except for one male which showed bodyweight loss during the first week and expected gain during the second week of the study. Abnormalities noted at necropsy of the female that died during the study were abnormally red lungs, dark liver, dark kidneys, severe haemorrhage of the gastric mucosa and severe haemorrhage of the small and large intestines. No abnormalities were noted at necropsy of animals that were killed at the end of the study.

The acute oral median lethal dose (LD50) of the test material in the Sprague-Dawley CD strain rat was found to be greater than 2000 mg/kg bodyweight. The test material was assigned the numerical value 1 according to the German Water Hazards Classification Scheme.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
2 000 mg/kg bw

Additional information

Acute oral toxicity:

A study was performed to assess the acute oral toxicity of the test material in the Sprague-Dawley CD strain rat.

The results were used as a basis for classification under the German Water Hazards Classification Scheme. Following a range-finding study, a group of ten fasted animals (five males and five females) was given a single oral dose of test material as a solution in distilled water at a dose level of 2000 mg/kg bodyweight. The animals were observed for fourteen days after the day of dosing and were then killed and subjected to gross pathological examination. One female was found dead 30 minutes after dosing. Clinical signs of toxicity noted in one male during Days 4 to 13 included distended abdomen, dehydration, emaciation, hunched posture, decreased respiratory rate, gasping, laboured and noisy respiration and tiptoe gait. Surviving animals showed an expected gain in bodyweight during the study except for one male which showed bodyweight loss during the first week and expected gain during the second week of the study. Abnormalities noted at necropsy of the female that died during the study were abnormally red lungs, dark liver, dark kidneys, severe haemorrhage of the gastric mucosa and severe haemorrhage of the small and large intestines. No abnormalities were noted at necropsy of animals that were killed at the end of the study.

The acute oral median lethal dose (LD50) of the test material in the Sprague-DawleyCD strain rat was found to be greater than 2000 mg/kg bodyweight. The test material was assigned the numerical value 1 according to the German Water Hazards Classification Scheme.


Justification for selection of acute toxicity – oral endpoint
Only one study available.

Justification for classification or non-classification