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Administrative data

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2015-2017
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2017

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to guideline
Guideline:
OECD Guideline 420 (Acute Oral Toxicity - Fixed Dose Method)
Version / remarks:
first addendum, 2001
Deviations:
yes
Remarks:
3 animals were between 7-8 weeks old because of limited availability of animals but this deviation did not influence the quality or integrity of the results.
Qualifier:
according to guideline
Guideline:
EPA OPPTS 870.1100 (Acute Oral Toxicity)
Version / remarks:
2002
Deviations:
yes
Remarks:
3 animals were between 7-8 weeks old because of limited availability of animals but this deviation did not influence the quality or integrity of the results.
Qualifier:
according to guideline
Guideline:
EU Method B.1 bis (Acute Oral Toxicity - Fixed Dose Procedure)
Deviations:
yes
Remarks:
3 animals were between 7-8 weeks old because of limited availability of animals but this deviation did not influence the quality or integrity of the results.
GLP compliance:
yes
Test type:
fixed dose procedure
Limit test:
yes

Test material

Constituent 1
Test material form:
solid: particulate/powder
Specific details on test material used for the study:
- Source and lot/batch No.of test material:040802#
- Expiration date of the lot/batch: 06.08.2016
- Purity test date:08/01/2015
- purity: 99.17%

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: room temperature
- Stability under test conditions: stable in water, instable after repeated contact to air
- Solubility and stability of the test substance in the solvent/vehicle: 100% - table in water, instable after repeated contact to air
- Reactivity of the test substance with the solvent/vehicle of the cell culture medium: no

TREATMENT OF TEST MATERIAL PRIOR TO TESTING
- Treatment of test material prior to testing: dilution in aqua ad injectabilia
- Preliminary purification step (if any): a correction factor of 1.008 was applied

FORM AS APPLIED IN THE TEST (if different from that of starting material): liquid

OTHER SPECIFICS:

Test animals

Species:
rat
Strain:
Wistar
Sex:
female
Details on test animals or test system and environmental conditions:
- Source:
- Females (if applicable) nulliparous and non-pregnant: yes
- Age at study initiation: animal n°1 and 2: 8-9 weeks
Animal n° 3-5 : 7-8 weeks
- Weight at study initiation: Animal n°1: 154 g
Animal n°2: 165 g
Animal n°3: 146 g
Animal n°4: 146 g
Animal n°5: 136 g
- Fasting period before study: between 16 and 19 hours prior testing (access to water permitted)
- Housing: The animals were kept in groups in IVC cages, type III H, polysulphone cages on Altromin saw fibre bedding (lot no. 02102151120)
- Diet (e.g. ad libitum): Altromin 1324 maintenance diet for rats and mice (lot no. 0922) ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 +/- 3°C
- Humidity (%): 55 +/- 10%
- Air changes (per hr): 10 x / hour
- Photoperiod (hrs dark / hrs light): 12 hr dark / 12 hr light

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
water
Details on oral exposure:
VEHICLE
- Concentration in vehicle: 2000 mg/kg
- Amount of vehicle (if gavage): Animals n° 1/2: 2.5 ml
Animals 3/4/5: 10 ml
- Justification for choice of vehicle: chosen due to its non-toxic characteristics
- Lot/batch no. (if required): 511535 (AlleMan Pharma)

MAXIMUM DOSE VOLUME APPLIED: 10 ml/kg bw

DOSAGE PREPARATION (if unusual):
Animal 1/2: 0.504g test item into vehicle (final volume 2.5 ml)
Animal 3/4/5: 2.016g test item into vehicle (final volume 10 ml)
Doses:
2000 mg/kg body weight
No. of animals per sex per dose:
5
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: at least once during the first 30 min and with special attention during the first 4 hours post-dose. Animals were weighed on day 1 prior to the administration, day 8 and 15.
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight other:gross pathological changes

Results and discussion

Preliminary study:
1 animal at 2000 mg/kg body weight: no signs
Effect levels
Key result
Sex:
female
Dose descriptor:
LD50 cut-off
Effect level:
> 2 000 mg/kg bw
Based on:
test mat. (total fraction)
Remarks on result:
not determinable due to absence of adverse toxic effects
Mortality:
none
Clinical signs:
2 animals showed slight piloerection the first day, between 120 and 180 min post-administration, but it is not considered to be related to the test item but to the administration procedure and the possible stress induced. No specific findings during the rest of the observation period for these 2 animals nor for the 3 3 others during all the observation duration.
Body weight:
None animals showed weight loss during the observation period.
Gross pathology:
None animals showed specific gross pathological changes during the observation period.

Any other information on results incl. tables

Clinical signs - Individual data :

     
 Animal No./Sex Time of observation post-dose  Observations
       Dose level 2000 mg/kg Body Weight

 1/ female

2/ female

 0 min - 60 min  no specific findings
  

 1/ female

2/ female

 120 min - 180 min  slight piloerection
  

 1/ female

2/ female

 240 min - 15 days  no specific findings 
 3/ female  0 min - 15 days   no specific findings 
 4/ female   0 min - 15 days   no specific findings 
 5/ female   0 min - 15 days   no specific findings 

Based on these results and according to the acute toxic class method regime no further testing was required.

Absolute body weights in grams and body weight gain in %:

 Animal No. / sex Starting dose (mg/kg bw)  Body Weight (g) - Day 1   Body Weight (g) - Day 8   Body Weight (g) - Day 15  Body Weight Change in comparison to day 1 (%)
 1/Female  2000  154  164  183  19
 2/Female  2000  165  181  186  13
 3/Female  2000  146  167  174  19
 4/Female  2000  146  171  185  27
 5/Female 2000  136  165  175  29

Applicant's summary and conclusion