Registration Dossier

Administrative data

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
September 9, 1981 - December 3, 1981
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Conducted equivalent to OECD 401. The dosing volume is not according to this Guideline; no purity information provided; non-GLP.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1981
Report Date:
1981

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Deviations:
yes
Remarks:
; dosing volume: not constant at all dose levels and up to 25 mL/kg has been dosed (Guideline: max. 10 ml/kg)
GLP compliance:
no
Test type:
standard acute method
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): XDI (Takemate 500)
- Analytical purity: no data

Test animals

Species:
rat
Strain:
other: CD (Sprague-Dawley derived)
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River U.K. Limited, Margate, Kent, England
- Age at study initiation: approximately 4 to 6 weeks of age
- Weight at study initiation: 95 to 130 g
- Fasting period before study: approximately 18 +/- 2 hours prior to dosing
- Housing: metal cages with wire mesh floors (randomly allocated per dose group)
- Diet (e.g. ad libitum): ad libitum (standard laboratory diet)
- Water (e.g. ad libitum): ad libitum
- Acclimation period: minimum period of 6 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22.5 +/- 2.5 degrees Celsius
- Humidity (%): not controlled but remained within a range of 31-57%
- Air changes (per hr): approximately 15 per hr
- Photoperiod (hrs dark / hrs light): 12/12 hrs

IN-LIFE DATES: no data

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
corn oil
Details on oral exposure:
VEHICLE
- Concentration in vehicle: 20% w/v
- Amount of vehicle (if gavage): varied, depending on the dose

MAXIMUM DOSE VOLUME APPLIED: 25 mL/kg bw
Doses:
Preliminary study: 0.5; 2.0; 5.0 and 8.0 g/kg bw
Main study: 0; 2.5; 3.2; 4.0; 5.0 g/kg bw
No. of animals per sex per dose:
Preliminary study: 2 males + 2 females per dose
Main study: 5 males + 5 females per dose
Control animals:
yes
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing:
Day 1: Animals were observed soon after dosing; then at frequent intervals for the remainder of Day 1.
Day 2-14: On subsequent days the animals were observed at least once. Clinical signs were recorded at each observation.
During the observation period the following were recorded:
-Approximate time of death
-The nature, severity, approximate time of onset and duration of each toxic sign
-Individual bodyweights on days: 1, 8 and 15
- Necropsy of survivors performed: yes
Statistics:
The acute oral median LD50 to rats was calculated using the method of Finney (1971) Probit Analysis (3rd edition) Cambridge University Press

Results and discussion

Preliminary study:
See the table mentioned under the section "Any other information on results inc. tables" for the results of the preliminary study.
Effect levels
Sex:
male/female
Dose descriptor:
LD50
Effect level:
3 200 mg/kg bw
Based on:
test mat.
95% CL:
2 500 - 3 900
Mortality:
See the tables in the section "Any other information on results incl. tables"
Clinical signs:
See the table in the section "Any other information on results incl. tables"
Body weight:
See the tables in the section "Any other information on results incl. tables". Depressed bodyweight gains were recorded in all surviving treated rats during the first week of observation only, compared to the control.
Gross pathology:
Autopsy of died rats revealed congestion or haemorrhage of the lungs, pallor of the liver, spleen and kidneys and in rats dying overnight, an apparent brittleness of the stomage. These findings were accompanied by congestion of the blood vessels of the stomach in one male and two females at 3.2 g/kg; one male at 4.0 g/kg and two males and one female at 5.0 g/kg. Gaseous contents of the stomach were observed in one male and one female at 3.2 g/kg, one male at 4.0 g/kg and one male and one female at 5.0 g/kg.
Survivors showed no abnormalities.

Any other information on results incl. tables

Results of the preliminary study:

Dosage (g/kg)

Mortality ratio

Time of death after dosing (hours)

Male

Female

Combined

0.5

1 / 2

0 / 2

1 / 4

<4 days

2.0

0 / 2

0 / 2

0 / 4

-

5.0

2 / 2

2 / 2

4 / 4

<22 - <70

8.0

2 / 2

2 / 2

4 / 4

<4 - <22

Results of the main study:

Sex

Dosage (g/kg)

Average bodyweight (g) at:

Mortality ratio

Time of death after dosing (hours)

Dosing

1 week

2 weeks

Male

0

112

193

255

0 / 5

-

2.5

117

181

247

2 / 5

<70

3.2

122

181

248

2 / 5

<22 - <46

4.0

122

157

215

3 / 5

<22 - <46

5.0

125

171

235

4 / 5

<22 - <70

Female

0

104

166

194

0 / 5

-

2.5

107

154

186

1 / 5

<46

3.2

103

146

184

2 / 5

<22 - <27

4.0

106

138

175

4 / 5

<22 - <70

5.0

105

-

-

5 / 5

<22 - <46

Recovery of the survivors, as judged by external appearance and behaviour, was apparently complete by Day 10. Clinical signs:

Signs

Signs of reaction ratio

Dosage (g/kg)

0

2.5

3.2

4.0

5.0

Pilo-erection

10 / 10

10 / 10

10 / 10

10 / 10

10 / 10

Abnormal body carriage (hunched posture)

0 / 10

10 / 10

10 / 10

10 / 10

10 / 10

Abnormal gait (waddling)

0 / 10

10 / 10

10 / 10

10 / 10

10 / 10

Lethargy

0 / 10

10 / 10

10 / 10

10 / 10

10 / 10

Decreased respiratory rate

0 / 10

10 / 10

10 / 10

10 / 10

10 / 10

Diarrhoea

7 / 10

10 / 10

10 / 10

10 / 10

10 / 10

Pallor of extremities

0 / 10

10 / 10

10 / 10

10 / 10

10 / 10

Ptosis

0 / 10

6 / 10

9 / 10

10 / 10

10 / 10

Diuresis

0 / 10

2 / 10

2 / 10

2 / 10

0 / 10

Increased salivation

0 / 10

5 / 10

6 / 10

10 / 10

10 / 10

Gasping respiration

0 / 10

2 / 10

1 / 10

1 / 10

2 / 10

Râles

0 / 10

5 / 10

2 / 10

6 / 10

5 / 10

Abnormal gait (walking on toes)

0 / 10

0 / 10

0 / 10

2 / 10

1 / 10

Increased lacrimation

0 / 10

3 / 10

6 / 10

7 / 10

5 / 10

Bloodstained muzzle

0 / 10

2 / 10

2 / 10

4 / 10

3 / 10

Body tremors

0 / 10

0 / 10

4 / 10

2 / 10

4 / 10

Applicant's summary and conclusion

Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
In a study conducted similar to OECD 401, the LD50 oral in rats was shown to be 3200 mg/kg (95% confidence limits: 2500 to 3900 mg/kg).
Executive summary:

The acute oral toxicity in rats has been studied similar to OECD 401. The only deviation from the OECD Guideline were the used dosing volumes, which were not constant at all dose levels and up to 25 mL/kg (Guideline: max. 10 ml/kg). The substance was dosed in corn oil at 0, 2.5, 3.2, 4.0 and 5.0 g/kg bw in 5 male and 5 female rats (doses based on the results from the preliminary study). Signs of reaction to treatment observed shortly after dosing in all treated rats included pilo-erection, an abnormal body carriage (hunched posture), abnormal gait (waddling), lethargy, decreased respiratory rate, pallor of the extremities and diarrhoea. Mortalities occurred amongst rats treated at 2.5 g/kg and above from within 22 hours to 70 hours of dosing. Autopsy of died rats revealed congestion or haemorrhage of the lungs, pallor of the liver, spleen and kidneys and in rats dying overnight, an apparent brittleness of the stomage.

Terminal autopsy findings were within normal limits. Depressed bodyweight gains were recorded in all surviving treated rats during the first week of observation only, compared to the control. The acute oral toxicity was determined to be 3200 mg/kg (95% confidence limits: 2500 to 3900 mg/kg). Based on this result, the substance does not need to be classified for acute toxicity by the oral route.