Registration Dossier

Administrative data

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
June - September 1992
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study with acceptable restrictions

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1992
Report Date:
1992

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Deviations:
no
GLP compliance:
yes
Remarks:
This study has been performed in compliance with GLP in Switzerland, Procedures and Principles, March 1986, issued by the Swiss federal Department of the Interior and the Intercantonal Office for the Control of Medicaments.
Test type:
standard acute method
Limit test:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
solid: bulk

Test animals

Species:
rat
Strain:
other: Tif: RAI f (SPF)
Sex:
male/female

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
other: 0.5% (w/v) carboxymethylcellulose in 0.1% (w/v) aqueous polysorbate 80
Doses:
1000 mg/kg, males and females
2000 mg/kg, males and females
No. of animals per sex per dose:
5 animals per sex per dose (total number of animals: 20)
Control animals:
no

Results and discussion

Effect levelsopen allclose all
Sex:
male
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Sex:
female
Dose descriptor:
LD50
Effect level:
> 1 000 mg/kg bw
Remarks on result:
other: approx. 2000 mg/kg bw
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw

Any other information on results incl. tables

In-life observations

 

Animal No.

Observations

Admin. day

Days after administration

1h

3h

5h

1

2

3

4

5

6

7

8

1000 mg/kg, males

1-5

Piloerection

+

+

+

+

+

+

 

 

 

 

 

1-5

Hunched post

+

++

++

+

+

 

 

 

 

 

 

1-5

Dyspnea

++

++

++

+

 

 

 

 

 

 

 

1-5

red. locom. act

 

+

+

 

 

 

 

 

 

 

 

1000 mg/kg, females

1, 3-5

Piloerection

+

+

+

+

++

+

+

+

 

 

 

2

Piloerection

+

+

+

 

 

 

 

 

 

 

 

1, 3-5

Hunched post

++

++

++

++

++

+

+

 

 

 

 

2

Hunched post

++

++

++

 

 

 

 

 

 

 

 

1, 3-5

Dyspnea

++

++

++

++

+

+

 

 

 

 

 

2

Dyspnea

++

++

++

 

 

 

 

 

 

 

 

1, 3-5

red. locom. act

+

++

++

+

+

 

 

 

 

 

 

2

red. locom. act

+

++

++

 

 

 

 

 

 

 

 

1, 3-5

tremor

 

 

+

+

 

 

 

 

 

 

 

2

tremor

 

 

+

 

 

 

 

 

 

 

 

1-5

ataxia

 

 

+

 

 

 

 

 

 

 

 

2000 mg/kg, males

1-4

Piloerection

+

+

++

++

++

++

+

+

 

 

 

5

Piloerection

+

+

++

 

 

 

 

 

 

 

 

1-4

Hunched post

+

++

++

++

+

+

+

 

 

 

 

5

Hunched post

+

++

++

 

 

 

 

 

 

 

 

1-4

Dyspnea

++

++

++

++

+

+

 

 

 

 

 

5

Dyspnea

++

++

++

 

 

 

 

 

 

 

 

1-5

red. locom. act

+

+

+

 

 

 

 

 

 

 

 

2000 mg/kg, females

1,2,5

Piloerection

+

+

+

+

+

+

+

+

+

 

 

3

Piloerection

+

+

+

 

 

 

 

 

 

 

 

4

Piloerection

+

+

+

+

 

 

 

 

 

 

 

1,2,5

Hunched post

+

++

++

++

++

+

+

+

 

 

 

3

Hunched post

+

++

++

 

 

 

 

 

 

 

 

4

Hunched post

+

++

++

++

 

 

 

 

 

 

 

1,2,5

Dyspnea

++

++

++

++

+

+

+

 

 

 

 

3

Dyspnea

++

++

++

 

 

 

 

 

 

 

 

4

Dyspnea

++

++

++

++

 

 

 

 

 

 

 

1-5

red. locom. act

+

+

+

 

 

 

 

 

 

 

 

3

Tonic spasm

 

 

+

 

 

 

 

 

 

 

 


+ = slight; ++ = moderate, +++ = severe

hunched post = hunched posture

red. locom. act. = reduced locomotor activity

 

Applicant's summary and conclusion

Interpretation of results:
GHS criteria not met
Conclusions:
LD50 in male rats: > 2000 mg/kg body weight
LD50 in female rats: > 1000, approx. 2000 mg/kg body weight
LD50 in rats of both sexes: > 2000 mg/kg body weight
Executive summary:

In an acute oral toxicity study (performed according to the OECD guideline 401), groups of young adult albino rats (Tif: RAI f (SPF)) of both sexes were given a single oral dose by gastric intubation of CA 1139 A in 0.5% (w/v) carboxymethylcellulose (in 0.1% (w/v) aqueous polysorbate 80) at doses of 1000 and 2000 mg/kg bw and observed for 14 days.

The following LD50 was determined for CA 1139 A:

LD50 in male rats: > 2000 mg/kg body weight

LD50 in female rats: > 1000, approx. 2000 mg/kg body weight

LD50 in rats of both sexes: > 2000 mg/kg body weight

Piloerection, hunched posture, and dyspnea were seen, being common symptoms in acute tests. Additionally, reduced locomotor activity was observed in all animals. In the females dosed 1000 mg/kg tremor, ataxia and respiratory sounds were noticed. In one female dosed with 2000 mg/kg tonic spasms were observed.

One female dosed with 1000 and one male and two females dosed with 2000 mg/kg died spontaneously within two days after administration.

The animals recovered within 4 to 7 days.

At necropsy, a spotted thymus was found in one female dosed with 2000 mg/kg. No deviations from normal morphology were found in the remaining animals.