Registration Dossier

Administrative data

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
01 October 1992 to 29 October 1992
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Study conducted to GLP in compliance with agreed protocols, with no or minor deviations from standard test guidelines and/or minor methodological deficiencies, which do not affect the quality of the relevant results.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1992
Report Date:
1992

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Deviations:
yes
Remarks:
- Only two dose levels were used
Qualifier:
according to
Guideline:
EU Method B.1 (Acute Toxicity (Oral))
Deviations:
yes
Remarks:
- Of the two dose levels administered, one was not the standard value recommended in the guideline.
GLP compliance:
yes (incl. certificate)
Test type:
standard acute method
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
solid: particulate/powder
Remarks:
migrated information: powder
Details on test material:
- Appearance: Dark yellow powder
- Storage conditions of test material: Room temperature

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Age at study initiation: 5 to 8 weeks of age
- Weight at study initiation: Males weighed 143 to 189 g and the females weighed 143 to 159 g
- Fasting period before study: Yes, overnight and approximately 2 hours after dosing
- Housing: The animals were housed in groups of 5 by sex in solid floor polypropylene cages with sawdust bedding
- Diet: ad libitum access to diet
- Water: ad libitum access to mains drinking water
- Acclimation period: At least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature: 19 to 21 °C
- Humidity: 37 to 67 %
- Air changes: Approximately 15 per hour
- Photoperiod: Lighting was controlled by a time switch to give 12 hours of continuous light and 12 hours of darkness

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
arachis oil
Details on oral exposure:
VEHICLE
- Concentration in vehicle: The 2000 mg/kg dose level was formulated at a concentration of 200 mg/mL. The 200 mg/kg dose level was formulated at a concentration of 20 mg/mL.
- Amount of vehicle: The volume administered to each animal was calculated according to its fasted bodyweight at the time of dosing.

MAXIMUM DOSE VOLUME APPLIED: 10 mL/kg

RATIONALE FOR THE SELECTION OF THE STARTING DOSE: The starting dose was selected on the basis of a range-finding study; 2000 mg/kg was administered to 1 male and 1 female animal.
Doses:
200 and 2000 mg/kg bw
No. of animals per sex per dose:
5 animals per sex per dose
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Surviving animals were observed for deaths or overt signs of toxicity ½, 1, 2 and 4 hours after dosing and subsequently once daily for 14 days. Individual bodyweights were recorded prior to dosing on Day 0 and on Days 7 and 14 or at death.
- Necropsy of survivors performed: Yes. At the end of the study the surviving animals were killed by cervical dislocation. All animals, including those that died during the study, were subjected to gross pathological examination. This consisted of an external examination and opening of the abdominal and thoracic cavities. The appearance of any macroscopic abnormalities was recorded. No tissues were retained.

Results and discussion

Preliminary study:
The female animal was killed in extremis one day after dosing. Common signs of systemic toxicity noted were ataxia, hunched posture, lethargy, decreased respiratory rate and laboured respiration with additional or isolated incidents of chromodacryorrhoea, dehydration, hypothermia, ptosis, gasping respiration, loss of righting reflex and light brown-coloured staining around the mouth.
Light brown-coloured staining of the fur was commonly noted in the male.
Based on this information, dose levels were selected for the main study.
Effect levels
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 200 - < 2 000 mg/kg bw
Based on:
test mat.
Mortality:
At the 2000 mg/kg bw dose level, two females were found dead one day after dosing. Four animals (one male and three females) were killed ln extremis one or four days after dosing.
There were no deaths in the 200 mg/kg bw dose group.
Clinical signs:
At the 2000 mg/kg bw dose level, common signs of systemic toxicity noted were ataxia, hunched posture, lethargy, decreased respiratory rate and laboured respiration with additional signs of ptosis and loss of righting reflex. Isolated incidents of systemic toxicity noted were chromodacryorrhoea, dehydration, pallor of the extremities, emaciation, hypothermia, increased salivation and occasional body tremors. Yellow-coloured staining of the fur was also commonly noted. Surviving animals recovered three or ten days after dosing.
In the 200 mg/kg bw dose group, no signs of systemic toxicity were noted during the study.
Body weight:
In the 2000 mg/kg bw dose group, one male showed a slightly reduced gain in bodyweight during week one. All other surviving animals showed expected gain in bodyweight during the study.
In the 200 mg/kg bw dose group all animals showed the expected gain in bodyweight during the study.
Gross pathology:
In the 2000 mg/kg bw dose group, abnormalities noted at necropsy of animals that died or were killed in extremis during the study were haemorrhagic lungs, dark or pale liver, patchy pallor of the liver or red-coloured possible necrosis of the liver and haemorrhagic or pale gastric mucosa. No abnormalities were noted at necropsy of one female that was killed in extremis during the study and four males that were killed a t the end of the study.
In the 200 mg/kg bw dose group no abnormalities were noted at necropsy.

Any other information on results incl. tables

Table 1: Summary of Mortality data in the 2000 mg/kg bw Dose Group

Sex

Animal Number

Effect noted

Male

3-0

Survived until scheduled necropsy

3-1

Killed in extremis on day 4 after dosing

3-2

Survived until scheduled necropsy

3-3

Survived until scheduled necropsy

3-4

Survived until scheduled necropsy

Female

4-0

Killed in extremis on day 1 after dosing

4-1

Found dead on day 1 after dosing

4-2

Found dead on day 1 after dosing

4-3

Killed in extremis on day 1 after dosing

4-4

Killed in extremis on day 1 after dosing

Applicant's summary and conclusion

Interpretation of results:
other: Category 4
Remarks:
Criteria used for interpretation of results: EU
Conclusions:
Under the conditions of this study the LD50 was found to be greater than 200 mg/kg bw but less than 2000 mg/kg bw.
Executive summary:

The acute toxicity potential of the test material was investigated in a study conducted in accordance with the standardised guidelines OECD 401 and EU Method B.1 under GLP conditions.

A group of ten fasted Sprague-Dawley rats (five males and five females) was given a single oral dose of the test material as a suspension in arachis oil B.P. at a dose level of 2000 mg/kg bodyweight. An additional group of ten fasted animals was then treated with the test material administered as a suspension in arachis oil B.P. a t a dose level of 200 mg/kg bodyweight. The surviving animals were observed for fourteen days. All animals were subjected to a gross pathological examination.

Two females treated with 2000 mg/kg were found dead one day after dosing. Four animals (one male and three females) in this group were killed in extremis one or four days after dosing. Common signs of systemic toxicity noted in this group were ataxia, hunched posture, lethargy, decreased respiratory rate and laboured respiration with additional signs of ptosis and loss of righting reflex. Surviving animals in this group recovered three or ten days after dosing. There were no deaths or signs of systemic toxicity noted in animals treated with 200 mg/kg.

One male treated with 2000 mg/kg showed a slightly reduced gain in bodyweight during week one. All other surviving animals showed the expected gain in bodyweight during the study.

Abnormalities noted at necropsy of animals that died or were killed in extremis during the study were haemorrhagic lungs, dark or pale liver, patchy pallor of the liver or red-coloured possible necrosis of the liver and haemorrhagic or pale gastric mucosa. No abnormalities were noted at necropsy of one female treated with 2000 mg/kg that was killed in extremis during the study, four males treated with 2000 mg/kg and animals treated with 200 mg/kg that were sacrificed at the end of the study.

Under the conditions of this study the LD50 was found to be greater than 200 mg/kg bw but less than 2000 mg/kg bw.