Registration Dossier

Administrative data

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: According to the OECD Guideline and GLP

Data source

Referenceopen allclose all

Reference Type:
study report
Title:
Unnamed
Year:
1998
Report Date:
1998
Reference Type:
other: abstract
Title:
Unnamed
Year:
1999
Report Date:
1999

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to
Guideline:
OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)
Deviations:
no
Qualifier:
according to
Guideline:
other: EC-guideline 93/21
Deviations:
no
Principles of method if other than guideline:
Method: OECD Guide-line 423
GLP compliance:
yes (incl. certificate)
Test type:
acute toxic class method
Limit test:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent
Type:
Constituent
Details on test material:
Ro 1525 corresponds to Colipa A 155
RO 1525
SAT 980375
Batch-Nr.: Ro-Rn 6567-083

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
water
Details on oral exposure:
A peroral administration was performed once in the morning by stomach intubation using a
meta1 gavage within 20 minutes after the preparation of the test substance solutions.
The dose volume was 20 ml per kg body weight. The individual dose volume was calculated
using the body weight determined at the day of the administration.
Doses:
2000 mg "RO 1525" per kg body weight to male rats.
200 mg "RO 1525" per kg body weight to male rats.
25 mg "RO 1525" per kg body weight to male rats.
25 mg "RO 1525" per kg body weight to female rats.
The dose volume was 20 ml per kg body weight for all groups
No. of animals per sex per dose:
3
Control animals:
not specified

Results and discussion

Effect levels
Sex:
male/female
Dose descriptor:
LD50
Effect level:
25 - 200 mg/kg bw
Mortality:
2000 mg/kg bw, males: 3/3 rats died spontaneously within 1 hour after the administration of
the test substance.
200 mg/kg bw, males: 3/3 rats died spontaneously 2 to 4 days after the administration of the
test substance.
25 mg/kg bw, males: 3/3 rats survived until the scheduled termination.
25 mg/kg bw, females: 3/3 rats survived until the scheduled termination.
Clinical signs:
Observations were performed within the periods 0 - 0.5,0.5 - 1, 1 - 2,2 - 4 and 4 - 6 hours
after administration (p.a.) of the test substance and then at least once a day for a total of 2
weeks. Observations included but were not limited to changes in skin, fur, eyes, the occurrence
of secretions and excretions, autonomic activity, changes in gait, posture and the presence of
convulsions.
Body weight:
Body weight was determined
before administration.
of early deaths as soon as possible after finding (exception: spontaneous death on the day
of adrninistration).
7 days p.a.
14 days p.a.
Body weight gain was calculated for each week of the study, i.e. between
0 and 7 d p.a.
7 and 14 d p.a
Gross pathology:
Spontaneously died animals were dissected and examined macroscopically in an attempt to
identify the target Organs.
Surviving animals were killed by CO:! 14 days p.a. and subjected to a necropsy including a
gross pathological examination.

Any other information on results incl. tables

The LD50 of "RO 1525" is estimated to be higher than 25 and less than 200 mg/kg body weight in rats.

The test substance caused gastric ulceration and pulmonary haemorrhages with secondary circulatory problems and signs of general malaise at doses of 200 mg/kg body weight and above, which led to a 100 % mortality. A dose of 25 mg/kg body weight was survived with only a few signs of reduced well-being.

Applicant's summary and conclusion

Interpretation of results:
toxic
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
The test substance caused gastric ulceration and pulmonary haemorrhages with secondary
circulatory problems and signs of general malaise at doses of 200 mg per kg b.w. and above,
which led to a 100 % mortality. All the signs noted in life and the post mortem findings may be
directly or indirectly related to this main effects.
A dose of 25 mgkg b.w. was survived with only a few signs of reduced well-being.
Therefore the test substance "Ro1525" is toxic according to the EC-guideline 93/21.
Executive summary:

Aim of the study

It was the aim of the study to investigate acute toxic effects of the test substance after a single

peroral administration.

Methods

The OECD-Guideline 423, "Acute Oral Toxicity - Acute Toxic Class Method" of 22 March

1996 was applied.

Administration

"RO 1525", freshly dissolved in deionised water, was administered once oraily by stomach

intubation to Him:OFA Sprague Dawley rats. The dosing was performed sequentially to

groups of 3 animals each using a starting dose of 2000 mg per kg body weight.

Sequence of dosing:

2000 mg "RO 1525" per kg body weight to male rats.

200 mg "RO 1525" per kg body weight to male rats.

25 mg "RO 1525" per kg body weight to male rats.

25 mg "RO 1525" per kg body weight to female rats.

The dose volume was 20 ml per kg body weight for all groups.

Investigations

Body weight: before administration, 7 and 14 days p.a., dead animals.

Clinical observations: at least once per day.

Necropsy: Surviving animals were sacrificed and necropsied 14 days p.a.

Spontaneously died animals were necropsied as soon as possible.

Resuits

Mortality

2000 mgkg, males: 313 animals died within 1 hour p.a.

200 mgkg, males: 313 animals died within 3 days p.a.

25 mgkg, males: 313 animals survived until the scheduled termination.

25 mgikg, females: 313 animals survived until the scheduled termination.

Body weights

Males and females: Body weight and body weight gain of the surviving animals were

inconspicuous.

Clinical observations

All animals were affected in any way. The findings were:

Piloerection, closed eyes, chromodacryorrhoea, pale skin, retention of faeces, dis coloured

urine and hunched posture. These signs of general appearance were mainly Seen in the 200

and in the 25 mgkg groups. The high dosed group (2000 mgkg) died rapidly. Probably

therefore some of the signs were not observed in this group.

Tremor in the 200 mgkg group.

Sedation and unconsciousness in the 2000 mgkg group; sedation in the 200 mgkg group.

Dyspnoea in the 200 mgkg group.

The toxic signs were observed on the day of administration of the test substance and lasted in

the surviving animals until a maximum of 4 d p.a. No toxic effects were noted at later times .

Necropsy findings

Test substance related changes were noted only in the 200 mgkg group: exsiccosis; small

spleen; gastric ulcers; gastric, intestinal and pulmonary haemorrhages; clear liquids in the

thoracic cavity were observed.

Animals of the 25 and 2000 mgkg groups were normal at the post mortem examination.

Sex differentes

The response to the test substance at 25 mgkg body weight did not indicate a Sex difference.