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Toxicological information

Acute Toxicity: oral

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Administrative data

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

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2000

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to
Guideline:
OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)
Deviations:
no
Qualifier:
according to
Guideline:
EU Method B.1 tris (Acute Oral Toxicity - Acute Toxic Class Method)
Deviations:
no
GLP compliance:
yes (incl. certificate)
Test type:
acute toxic class method
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Male and female Sprague Dawley CD strain rats were supplied by Charles River UK Ltd.
- Age at study initiation: Eight to twelve weeks of age
- Weight at study initiation: males 230 - 265g and females 209 - 241g. The bodyweights fell within an interval of ±20% of the mean initial bodyweight of the first treated group.
- Fasting period before study: Overnight fast immediately before dosing and for approximately three to four hours after dosing
- Housing: The animals were housed in groups of three by sex in suspended solid floor polypropylene cages furnished with woodflakes.
- Diet (e.g. ad libitum): Food (Rat and mouse expandd diet No. 1, Special Diets Services LTD) was allowed throughout the study.
- Water (e.g. ad libitum): Free access to mains drinking water was allowed throughout the study.
- Acclimation period: At least five days.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): Set to achieve limits of 19 to 25°C
- Humidity (%): Set to achieve limits of 30 to 70%
- Air changes (per hr): At least fifteen changes per hour
- Photoperiod (hrs dark / hrs light): lighting was controlled by a time switch to give twelve hours continuous light (06:00 to 18:00) and twelve hours darkness.

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
arachis oil
Details on oral exposure:
VEHICLE
- Concentration in vehicle: 200mg/ml for 2000 mg/kg dose level, 20mg/ml for 200 mg/kg dose level

DOSE VOLUME APPLIED:
10ml/kg

DOSAGE PREPARATION:
For the purpose of the study the test material was freshly prepared, as required as a suspension at the appropriate concentration in dried arachis. Preparation was aided by the use of a vortex mixer and homogeneity was assured by the use of a Silverson homogeniser.

All animals were dosed once only by gavage, using a metal cannula attached to a graduated syringe. The volume administered to each animal was calculated according to the fasted bodyweight at the time of dosing. Treatment of animals was sequential. Sufficient time was allowed between each dose level to confirm the survival of the previously dosed animals.
Doses:
200 mg/kg and 2000 mg/kg
No. of animals per sex per dose:
3 females and 3 males at 2000 mg/kg
3 females and 3 males at 200 mg/kg
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days

- Frequency of observations and weighing: The animals were observed for deaths or overt signs of toxicity ½, 1, 2 and 4 hours after dosing and subsequently once daily for up to fourteen days.

Individual bodyweights were recorded prior to dosing and seven and fourteen days after treatment or at death.

- Necropsy of survivors performed: yes; At the end of the observation period 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.

Results and discussion

Effect levels
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 200 - <= 2 000 mg/kg bw
Based on:
test mat.
Remarks on result:
other: Mortalities were observed at 2000mg/kg bw, no mortalities were observed at 200 mg/kg bw
Mortality:
Individual mortality data are given the attached background material.
Three animals treated with 2000 mg/kg (one female and two males) were found dead either on the day of dosing or one day after the day of dosing. There were no deaths observed at the dose level of 200 mg/kg.
Clinical signs:
Individual clinical observations are given in the attached background information.
Signs of toxicity observed at a dose level of 2000 mg/kg were ataxia, hunched posture and lethargy with additional signs of elevated tail, ptosis decreased respiratory rate, laboured respiration, occasional body tremors and splayed gait. Surviving animals treated with 2000 mg/kg recovered two or four days after dosing

There were no cinical signs of toxicity observed at a dose level of 200mg/kg.
Body weight:
Individual bodyweights and weekly bodyweight changes are given in the attached background information.
Surviving animals showed expected gains in bodyweight over the study period.
Gross pathology:
Individual necropsy findings are given in the attached background information.
Abnormalities observed at necropsy of animals that died during the study were haemorrhagic lungs, dark liver, dark kidneys, haemorrhagic gastric mucosa and haemorhagic small and large intestine.
No abnormalities were noted at necropsy of animals that were killed at the end of the study.

Applicant's summary and conclusion

Interpretation of results:
Category 4 based on GHS criteria
Conclusions:
The acute oral median lethal dose (LD50) of the test item in the male and female Sprague Dawley strain rat was estimated to be 200 - 2000 mg/kg bodyweight (Globally Harmonised Classification System – Category 4).
Executive summary:

Introduction.

The study was performed to assess the acute oral toxicity of the test item following a single oral administration in the Sprague Dawley strain rat. The method was designed to be compatible with the following

- OECD Guidelines for the Testing of Chemicals No. 423 “Acute Oral Toxicity – Acute Toxic Class Method” (adopted 22 March 1996)

- Method B1trisAcute Toxicity (Oral) of Commission Directive 96/54/EC

Method.

A group of three fasted females was treated with the test item at a starting dose of 2000 mg/kg bodyweight. This was followed by a group of three fasted males at the same dose level. Based on the results from this dose level further groups of fasted animals were treated at a dose level of 200 mg/kg bodyweight. Dosing was performed sequentially.

The test item was administered orally as a suspension in dried arachis oil BP. The animals were observed ½, 1, 2 and 4 hours after dosing and once daily for upto fourteen days. Clinical signs and bodyweight development were monitored during the study. All animals were subjected to gross necropsy.

Mortality. 

One female and two males treated with 2000 mg/kg died during the study.

Clinical Observations. 

The following signs of systemic toxicity were observed at a dose level of 2000 mg/kg,ataxia, hunched posture and lethargy with additional signs of elevated tail, ptosis decreased respiratory rate, laboured respiration, occasional body tremors and splayed gait.

Bodyweight. 

All surviving animals showed expected gains in bodyweight over the study period.

Necropsy. 

Abnormalities observed at necropsy of animals that died during the study were haemorrhagic lungs, dark liver, dark kidneys, haemorrhagic gastric mucosa and haemorhagic small and large intestine.

No abnormalities were noted at necropsy of animals that were killed at the end of the study.

Conclusion.

The acute oral median lethal dose (LD50) of the test item in the male and female Sprague Dawley strain rat was estimated to be 200 - 2000 mg/kg bodyweight (Globally Harmonised Classification System – Category 4).