Registration Dossier

Administrative data

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
10th October 2002 - 04 November 2002
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Study conducted 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:
2003
Report Date:
2003

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)
Deviations:
yes
Remarks:
The sequence of dosing may not always follow the Test Guideline as shown in the schematic diagram in attachment 1. It is Company Policy to minimise the number of animals used on each study in accordance with UK Government Home Office guidelines.
GLP compliance:
yes (incl. certificate)
Test type:
acute toxic class method

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): DEATES

The client has requested that the test material name be amended due to differences between the protocol and the test material data sheet.

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River (UK) Ltd, Margate, Kent, UK

- Age at study initiation: At the start of the study the animals were eight to twelve weeks of age.

- Weight at study initiation: Weights not recorded, however, the bodyweights fell within an interval of +/- 20% of the mean initial bodyweight of the first group.

- Fasting period before study: Overnight fasting immediately before dosing and for approximately three to four hours after dosing.

- Housing: The animals were housed in groups of three in suspended solid-floor polypropylene cages furnished with woodflakes.

- Diet (e.g. ad libitum): Certified Rat and Mouse Diet (Code 5LF2) supplied by International Products Supplies Limited, Wellingborough, Northants, UK. The diet was routinely analysed and were considered not to contain any contaminants that would reasonably be expected to affect the purpose or integrity of the study.

- Water (e.g. ad libitum): Free access to mains drinking water. The water was routinely analysed and were considered not to contain any contaminants that would reasonably be expected to affect the purpose or integrity of the study.

- Acclimation period: At least five days.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): Set to achieve limits of 19 deg C to 25 deg C.

- Humidity (%): Set to achieve limits of 30 to 70%.

- Air changes (per hr): The rate of air exchanges was at least fifteen changes per hour.

- Photoperiod (hrs dark / hrs light): Light controlled by a time switch to give twelve hours continuous light (06:00 to 18:00 and twelve hours darkness.

IN-LIFE DATES: From: 10th October 2002 To: 24th October 2002

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
arachis oil
Details on oral exposure:
VEHICLE
- Concentration in vehicle: The substance was present at levels of 30 mg/ml in the vehicle.

- Amount of vehicle (if gavage): Test material was made into a solution with the vehicle at a dose level of 300 mg/kg.

- Justification for choice of vehicle: Arachis oil BP was used because the test material did not dissolve in distilled water.

- Lot/batch no. (if required): Not recorded.

- Purity: Not recorded.


MAXIMUM DOSE VOLUME APPLIED:
10 ml/kg

The test material was administered orally undiluted at a dose level of 2000 mg/kg, and as a solution in arachis oil BP at a dose level of 300 mg/kg.

Dosing was performed sequentially.

DOSAGE PREPARATION (if unusual):
In the absence of data regarding the toxicity of the test material, 300 mg/kg was chosen as the starting dose.

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 group and each dose level to confirm the survival of the previously dosed animals.


CLASS METHOD (if applicable)
- Rationale for the selection of the starting dose:
In the absence of data regarding the toxicity of the test material, 300 mg/kg was chosen as the starting dose.
Doses:
300 (with vehicle) and 2000 (undiluted) mg/kg.
No. of animals per sex per dose:
3 animals per dose, 3 dose groups.
Control animals:
no
Details on study design:
- Duration of observation period following administration:
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 up to fourteen days.

- Frequency of observations and weighing:
Individual bodyweights were recorded prior to dosing and seven and fourteen days after treatment or at death.

- Necropsy of survivors performed: yes

- Other examinations performed: clinical signs, body weight, necropsy.
Statistics:
None recorded.

Results and discussion

Preliminary study:
Not applicable.
Effect levels
Sex:
female
Dose descriptor:
LD50
Effect level:
> 500 - < 1 000 mg/kg bw
Mortality:
Individual mortality data are given in Attachment 2 - Table 1.

Two animals treated with 2000 mg/kg were found dead one day after dosing. There were no deaths noted at a dose level of 300 mg/kg,
Clinical signs:
Individual clinical observations are given in Attachment 2 - Table 2 and Table 3.

Signs of systemic toxicty noted in animals treated with 2000 mg/kg were hunched posture, lethargy, ataxia, decreased respiratory rate, diarrhoea, ptosis and pilo-erection. There were no signs of systemic toxicity noted at a dose level of 300 mg/kg.
Body weight:
Individual bodyweights and weekly bodyweight changes are given in Attachment 2 Table4 and Table 5.

The surviving animals showed expected gains in bodyweight over the study period.
Gross pathology:
Individual necropsy findings are given in Attachment 2 Table 6 and Table 7.

Abnormalities noted at necropsy of animals that died during the study were haemorrhagic lungs, dark liver, dark kidneys, haemorrhage of the gastric mucosa, non-glandular epithelium of the stomach and small intestine. Stomach adhering to the liver was noted in the animal treated with 2000 mg/kg that was killed at the end of the study. No abnormalities were noted at necropsy of animals treated with 300 mg/kg.
Other findings:
No other findings recorded.

Applicant's summary and conclusion

Interpretation of results:
harmful
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
The acute oral median lethal dose (LD50) of the test material in the female Sprague-Dawley CD strain rat was estimated to be in the range of 500 - 1000 mg/kg bodyweight.
Executive summary:

In an acute oral toxicity study, groups of 8-12 week old, Sprague-Dawley CD (Crl: CD (SD) IGS BR) stain rat (3 females per dose group) were given a single oral dose of U-donor in arachis oil BP at doses of 300 mg/kg bw and undiluted at doses of 2000 mg/kg bw and observed for 14 days.

Oral LD50Females = 500-1000 mg/kg bw

 

U-donor is of MODERATE Toxicity based on the LD50 in females. The test material was classified as HARMFUL and the symbol “Xn” and risk phrase R22 “HARMFUL IF SWALLOWED” are required according to EU labelling regulations Commission Directive 2001/59/EC.