Registration Dossier

Toxicological information

Acute Toxicity: oral

Currently viewing:

Administrative data

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1967
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Well-documented study comparable to recent guidelines. Although the study was done before GLP implementation and limited information, it was considered reliable, adequate and relevant for classification.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1967
Report Date:
1967

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Deviations:
yes
Remarks:
7 days instead of 14 days observation
Principles of method if other than guideline:
Single oral application to mice and calculation of 7 day LD50
Study performance before implementation of corresponding international guidelines, however study performance is comparable to recent guidelines to great extent.
GLP compliance:
no
Remarks:
study performance before implementation of GLP
Test type:
standard acute method
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
other: liquid

Test animals

Species:
mouse
Strain:
NMRI
Sex:
male
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Institut für industrielle und biologische Forschung, GmbH, Köln
- Age at study initiation: Not provided
- Weight at study initiation: Median weight of 23.7 g
- Fasting period before study: Approximately 17-20 hours
- Housing: Prior to the application in Plastibox cages (42x28x17 cm3) in groups of 35 animals on vermiculite. After application in Makrolon cages on wire roasting over vermiculite.
- Diet (e.g. ad libitum): Altromin R, pellet diameter 8-9mm, supplier: Altromin GmbH
- Water (e.g. ad libitum): Tap water, ad libitum
- Acclimation period: Not provided

ENVIRONMENTAL CONDITIONS
- Temperature (°C): ca. 21°C
- Humidity (%): ca. 70%
- Air changes (per hr): Not provided
- Photoperiod (hrs dark / hrs light): Not provided


Administration / exposure

Route of administration:
oral: gavage
Vehicle:
water
Details on oral exposure:
VEHICLE
- Concentration in vehicle: 0.0464, 0.215, 0.464, 1.00, 1.00 and 1.00 (mL/mL) at the dose levels of 1.00, 4.64, 10.0, 21.5, 31.6 and 46.4 mL/kg bw, respectively


MAXIMUM DOSE VOLUME APPLIED: 46.4 mL/kg bw or rather 1.10 mL/mouse

Doses:
1.00 mL/kg bw; 4.64 mL/kg bw ; 10.0 mL/kg bw ; 21.5 mL/kg bw ; 31.6 mL/kg bw and 46.4 mL/kg bw
No. of animals per sex per dose:
10 for the 1.00; 4.64; and 10.0 mL/kg dose
20 for the 21.5 and 46.4 mL/kg dose
16 for the 31.6 mL/kg dose
Control animals:
no
Details on study design:
- Duration of observation period following administration: 7 days
- Frequency of observations and weighing: The mice were observed after application about 8 hours long at short intervals. Further assessments were performed several times daily until 7 days after application.
- Necropsy of survivors performed: yes
- Other examinations performed: vitality, pain reflex, cyanosis, breathing, corneal reflex, lid wide, exophtalmus, sound sensitivity, shaky walking, abdominal position, side position, running motion, clonic-tonic convulsions, ophistotonos, defecation; necropsy of deceased animals
Statistics:
The quantitative evaluation of the lethality data was performed by graphical determination of the LD50 7 days after application, in the probability grid with logarithmic shared X-axis, when using confidence limits.

Results and discussion

Effect levelsopen allclose all
Sex:
male
Dose descriptor:
LD50
Effect level:
28.7 mL/kg bw
Based on:
test mat.
Remarks on result:
other: LD50 as reported in study report referring to the test substance as delivered by the sponsor
Sex:
male
Dose descriptor:
LD50
Effect level:
ca. 11 000 mg/kg bw
Remarks on result:
other: Recalculated LD50 referring to solid content of 39% (according to producer information) and an assumed density of roughly 1
Mortality:
Up to and including the dose level of 10.0 mL/kg bw no animal died.
In the dose group of 21.5 mL/kg bw 5% (1/20) of the animals was found death two days p.a.. In the dose groups of 31.6 and 46.4 mL/kg bw 88% (14/16) and 100% (20/20) of the animals died within 24 hours or 6 hours p.a. respectively.
Clinical signs:
Especially in the doses 21.5; 31.6 and 46.6 mL/kg quiet, apathetic behavior, closed eyes, diarrhea with soft faeces and decreased sound sensitivity were observed. Also in the 10.0 mL/kg dose group a number of animals showed diarrhea ( occurrence ca. 2 hours after application; this symptom was no longer observed after 1 day after application) . The behavior of the mice in the 1.00 and 4.64 mL/kg was normal active and unremarkable.
Body weight:
No data
Gross pathology:
In the stomach and small intestine of mice who died, dark reddish-brown slimy liquid was determined. The mucous membranes were dark red and translucent, and showed macroscopic signs of irritation, especially the main gastric membranes. Intubation injuries were not found.
Other findings:
- Organ weights: no data
- Histopathology: no data
- Potential target organs: no data
- Other observations: no data

Any other information on results incl. tables

Table 1. Lethality, chronological categorization (summed up, %)

Experimental Period

Dosis (mL/kg)

0 bis

1.00

4.64

10.0

21.5

31.6

46.4

20 min

 

 

 

 

6

 

40 min

 

 

 

 

13

35

60 min

 

 

 

 

19

60

2 h

 

 

 

 

44

70

4 h

 

 

 

 

50

90

6 h

 

 

 

 

 

100

24 h

0

0

0

0

88

100

2 d

 

 

 

5

 

 

3 d

 

 

 

 

 

 

4 d

 

 

 

 

 

 

5 d

 

 

 

 

 

 

6 d

 

 

 

 

 

 

7 d

0

0

0

5

88

100

Number of mice used

10

10

10

20

16

20

Applicant's summary and conclusion

Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
The LD50 at 7 days was 28.7mL/kg. The LD50 for an observation period of 24 hours did practically not differ from the previous value. Recalculated LD50 referring to solid content of 39% (according to producer information) and an assumed density of roughly 1 was calculated to be ca. 11000 mg/kg bw.
Executive summary:

Acute oral toxicity (LD50) of the test item was examined by gavage in male NMRI mice at doses of 1, 4.64, 10, 21.5, 31.6 and 46.4 mL/kg bw. There were no pronounced , specific toxic behavioral symptoms registered at the lower doses of 1 and 4.64 mL/kg bw. At doses ≥10 ml/kg diarrhea was seen. The died mice showed irritation of the mucous membranes of the stomach and small intestine. At the higher doses (21.5, 31.6 and 4.64 mL/kg bw/day), quiet apathetic behaviour, closed eyes and decreased sound activity were also observed.
The LD50
 at 7 days was 28.7 mL/kg. Recalculated LD50 referring to solid content of 39% (according to producer information) and an assumed density of roughly 1 was calculated to be ca. 11000 mg/kg bw.