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Toxicological information

Acute Toxicity: oral

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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: Study conducted following the current relevant guideline and fully GLP compliant documentation.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2007
Report Date:
2007

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:
EU Method B.1 tris (Acute Oral Toxicity - Acute Toxic Class Method)
Deviations:
no
GLP compliance:
yes (incl. certificate)
Test type:
acute toxic class method
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
Batch number 25557

Test animals

Species:
rat
Strain:
other: CD (Crl:CD BR)
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS
- Age at study initiation: 8-12 weeks (at test item administration)
- Weight at study initiation: 180-202 g
- Fasting period before study: overnight and approximately 4 hours after dosing
- Housing: 3 animals/cage
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19-23°C
- Humidity (%): 40-70%
- Photoperiod (hrs dark / hrs light): 12/12


Administration / exposure

Route of administration:
oral: gavage
Vehicle:
other: 1% w/v aqueous methylcellulose
Details on oral exposure:
Vehicle: 1% w/v aqueous methylcellulose
The test substance was formulated at a concentration of 30 and 200 mg/ml in the vehicle and administered at a volume of 10 ml/kg bodyweight
Doses:
300 and 2000 mg/kg b.w.
No. of animals per sex per dose:
3
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations: at 60 min after dosing and once daily thereafter
- Frequency of weighing: day 0 (prior to dosing), day 8 and day 15
- Necropsy of survivors performed: yes
- Other examinations performed: gross examination of organs at necropsy, organ weights, histopathology

Results and discussion

Effect levels
Sex:
female
Dose descriptor:
LD50
Effect level:
>= 300 - <= 2 000 mg/kg bw
Based on:
test mat.
Mortality:
One female dosed at 2000 mg/kg was found dead approximately 60 minutes after dosing. The remaining two animals dosed at 2000 mg/kg were
found dead on Day 2. Clinical signs prior to death comprised partially closed eyelids (both) and flat posture seen in all animals. In addition,
piloerection, hunched posture, underactivity, reduced body temperature, post dose salivation, abnormal gait (uncoordination), tremors,
convulsions and irregular respiration were seen in two females. Abnormal gait (unsteady), dark extremities, lacrimation and salivation were seen in
one female. These signs were first observed from approximately seventeen minutes after dosing. A loss in bodyweight was recorded for two
decedents. Macroscopic examination ofthe decedents treated at 2000 mg/kg revealed congestion (characterised by darkened tissues/organs or
blood vessels injected) of the brain, liver, stomach, duodenum, caecum, small and large intestines were found in all animals, subcutaneous tissue,
heart, lungs and spleen was seen in two animals. In addition, small (atrophy) spleen in one animal, pallor of the kidneys in two animals and white/
yellow contents of the stomach, duodenum and small intestines, seen in all animals. White/yellow contents were also observed in the large intestine in one animal
Clinical signs:
Clinical signs of reaction to treatment in animals which were dosed at 300 mg/kg comprised hunched posture, piloerection, abnormal gait
(unsteady), seen in all six females. In addition, underactivity, poor righting reflex, fast respiration, and reduced body temperature, were seen in
four females. Fasciculation’s were seen in three females, lacrimation, tremors (tremors only during handling) and partially closed eyelids (both)
were seen in two animals, dark extremities and salivation were seen in one female. These signs were first observed approximately 30 minutes after dosing and recovery, as judged by external appearance and behaviour, by Day 2.
Body weight:
All surviving animals were considered to have achieved satisfactory bodyweight gains throughout the study
Gross pathology:
No abnormalities were seen in the surviving animals at the macroscopic examination at study termination on Day 15

Applicant's summary and conclusion

Interpretation of results:
Category 4 based on GHS criteria
Remarks:
Migrated information
Conclusions:
The acute median lethal oral dose (LD50) to rats of VRT-126017 dcha- was demonstrated to be between 300 and 2000 mg/kg bodyweight
Executive summary:

Two groups of three fasted female rats received a single oral gavage dose of the test substance,

formulated in 1% w/v aqueous methylcellulose, at a dose level of 300 mg/kg bodyweight. As

results at this dose level indicated the acute lethal oral dose of the test substance to be greater

than 300 mg/kg bodyweight, in compliance with the study guidelines, a further group of

three fasted female rats was similarly dosed at 2000 mg/kg. As all three females at this dosage

died, no further animals were dosed.

The acute median lethal oral dose (LD50) to rats of Z-L-tert.-Leucine * DCHA (called VRT-126017 dcha in the respective report) was demonstrated to be between 300 and 2000 mg/kg bodyweight (included in category 4 according to GHS).