Registration Dossier

Administrative data

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
25 Feb to 22 April 2008 in life
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
Follows existing guidelines, GLP requirements, and well documented. The initial dose given the first animal was selected as specified in the Acute Oral Toxicity-Fixed Dose method in error. All subsequent doses were chosen by the AOT425 Statistical program. This error was not considered to affect the purpose or integrity of the study.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2008
Report Date:
2008

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
OECD Guideline 425 (Acute Oral Toxicity: Up-and-Down Procedure)
Version / remarks:
US EPA OPPTS 870.1100 Acute Oral Toxicity, 2002
Deviations:
yes
Remarks:
Initial dose was chosed as per Acute Oral Toxicity - Fixed Dose method. Subsequent doses chosen by AOT425 Statistical program.
GLP compliance:
yes (incl. certificate)
Test type:
up-and-down procedure

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): SD10
- Physical state: Clear, colorless liquid
- Analytical purity: 97.17%
- Purity test date: 2007/05/03
- Lot/batch No.: 9147-192-3a
- Storage condition of test material: room temperature in dark

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: 8 to 12 weeks of age
- Weight at study initiation: 222 grams to 258 grams
- Fasting period before study: overnight
- Housing: individually in suspended solid floor polypropylene cages with woodflakes
- Diet (e.g. ad libitum): Certified Rat and Mouse Diet ad libitum
- Water (e.g. ad libitum): mains drinking water ad libitum
- Acclimation period: 5 days minimum

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19 to 25 degrees C
- Humidity (%): 30 to 70%
- Air changes (per hr): at least 15 changes per hour
- Photoperiod (hrs dark / hrs light): 12 hours dark/ 12 hours light

IN-LIFE DATES: From: 2008/02/25 To: 2008/04/22

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
arachis oil
Details on oral exposure:
Maximum dose of 2000 mg/kg used undiluted material. . Other dose levels used dilutions of test material in arachis oil. The test article did not dissolve or suspend in distilled water.

Concentrations and dose volumes:
175 mg/kg - 17.5 mg/ml - 10 ml
300 mg/kg - 30 mg/ml - 10 ml
550 mg/kg - 55 mg/ml - 10 ml
2000 mg/kg - as supplied, specific gravity 0.824 - 2.43 ml

CLASS METHOD (if applicable)
- Rationale for the selection of the starting dose: Initial dose was chosen as per Acute Toxicity - Fixed Dose method by error. Subsequent doses chosen by AOT425 Statistical program with the slope of the dose-response curve set to default (sigma = 0.5). The statistical program gave a recommended progression of 2000, 550, 175, 55.0, 17.5, 5.5 and 1.75 mg/kg.

Doses:
175 mg/kg, 300 mg/kg, 550 mg/kg, 2000 mg/kg
No. of animals per sex per dose:
8 total female animals; 1 at 175 mg/kg, 1 at 300 mg/kg, 4 at 550 mg/kg, 2 at 2000 mg/kg
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Observed at 1/2, 1, 2, and 4 hours after dosing, then daily for up to 14 days. Weighed prior to dosing and at 7 and 14 days or at death
- Necropsy of survivors performed: yes - gross observation
- Other examinations performed: clinical signs, body weights
Statistics:
The Oral LD50 was calculated by the maximum likelihood method. Using the mortality data obtained, an estimate of the acute oral median lethal dose was obtained. (LD50), with 95% confidence limits. An assumed sigma of 0.5 was used.

Results and discussion

Effect levels
Sex:
female
Dose descriptor:
LD50
Effect level:
ca. 550 mg/kg bw
Based on:
test mat.
95% CL:
>= 232.9 - <= 1 560
Mortality:
All animals at 2000 mg/kg and two of the animals treated at 550 mg/kg were found dead the day of dosing or within two or three days of dosing.
Clinical signs:
Signs of systemic toxicity noted were hunched posture, lethargy, ataxia, decreased respiratory rate, labored respiration, pilo-erection and pallor of the extremities. Surviving animals appeared normal 6 to 11 days after dosing.
Body weight:
Surviving animals showed expected gains in bodyweight over the study period except for one animal at a dose level of 550 mg/kg which showed bodyweight loss during the first week, but expected gain in bodyweight during the second week.
Gross pathology:
Abnormalities noted in deceased animals during the study were hemorhagic or abnormally red lungs, dark liver, dark kidneys, and slight hemorrhage of the gastric mucosa. No abnormalities were seen at necropsy of animals that survived to the end of the study.

Any other information on results incl. tables

  Mortality Data
 Dose level (mg/kg)  Number survived  Number died  Total animals  Day/time of Death
 175  1  0  1  
 300  1  0  1  
 550  2  2  4  Day 2, Day 3
 2000  0  2 2 Dosing day (1 hr, 2 hr)
 All doses  4  4  8  Dosing day, Day 2 or Day 3

Applicant's summary and conclusion

Conclusions:
The acute oral median lethal dose (LD50) and 95% confidence limits of the test material in the female Sprague-Dawley CD strain rat were calculated to be 550 (232.9-1560) mg/kg bodyweight (based on an assumed sigma of 0.5).
Executive summary:

The acute oral median lethal dose (LD50) and 95% confidence limits of the test material in the female Sprague-Dawley CD strain rat were calculated to be 550 (232.9-1560) mg/kg bodyweight (based on an assumed sigma of 0.5). An up and down method (OECD 425 - Acute Oral Toxicity - Up-and-down procedure) was used. Test article was administered once by gavage either undiluted (2000 mg/kg) or diluted with arachis oil (175, 300, or 550 mg/kg). Animals were observed at 1/2, 1, or 2 hours after dosing, and for 14 days thereafter. All animals at the high dose level died (1 to 2 hours post dose) and 2 of the animals treated at 550 mg/kg (days 2 and 3 post dosing). Signs of systemic toxicity observed during the study were hunched posture, lethargy, ataxia, decreased respiratory rate, labored breathing, pilo-erection and pallor of the extremities. Surviving animals appeared normal 6 to 11 days after dosing. No abnormalities were seen at gross necropsy at day 14 in surviving animals. Findings in animals that died during the study included hemorrhagic or abnormally red lugs, dark liver, dark kidneys, and slight hemorrhage of the gastric mucosa.