Registration Dossier

Administrative data

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2005-08-23 to 2005-11-17
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: well documented study according to OECD guideline and GLP

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2005
Report Date:
2005

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:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent
Type:
Constituent
Test material form:
solid: particulate/powder
Remarks:
migrated information: powder
Details on test material:
- Name of test material (as cited in study report): PM-6976
- Substance type: light yellow powder
- Physical state: solid
- Analytical purity: 99.3%
- Lot/batch No.: ISJO7-003
- Expiry date: 2006-08-09
- Storage condition of test material: at room temperature in the dark (stability: substance stable under these conditions)
- Soluble in methyl ethyl ketone and acetone

Test animals

Species:
rat
Strain:
Wistar
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Deutschland, Sulzfeld Germany
- Age at study initiation: approx. 8 weeks
- Weight at study initiation: 192 - 214 g (body weight did not exceed +/- 20% of mean)
- Fasting period before study: max. 20h prior dosing until 3-4 hours after administration of the test substance
- Housing: three animals per cage in labelled Macrolon cages (MIV type; height 18 cm) containing sterilised sawdust as bedding material and paper as cage-enrichment
- Diet: ad libitum standard pelleted laboratory animal diet (from Altromin, Lage, Germany)
- Water: ad libitum tap water
- Acclimation period: 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21.0 +/- 3.0 °C
- Humidity (%): 39 - 81 % (only temporary fluctuations above 70% due to cleaning procedures, with no effect on test validity)
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
propylene glycol
Details on oral exposure:
VEHICLE

- Justification for choice of vehicle: selected based on trial formulations performed at the test facility NOTOX and on test substance data supplied by the sponsor
- purchased from Merck, Darmstadt, Germany (specific gravity 1.036)
- preparation: 4 hours prior to dosing; homogeneity accomplished to visually acceptable level
Doses:
2000 mg/kg (10 ml/kg) b.w., single dosis on day 1
No. of animals per sex per dose:
3 females per group, two groups of 2000 mg/kg dose
Control animals:
no
Details on study design:
- Duration of observation period following administration: 15 days
- Frequency of observations and weighing:
Mortality/viability: twice daily
Body weights: days 1 (pre-administration), 8 and 15
- Necropsy of survivors performed: yes, at the end of observation period by oxygen/carbon dioxide procedure
Statistics:
No statistical analysis was performed for a LD50 estimation.

Results and discussion

Effect levels
Sex:
female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Remarks on result:
other: up to 2000 mg/kg no mortality occured
Mortality:
All rats survived.
Clinical signs:
Hunched posture in all animals and lethargy in one animal were observed on day 1 after dosing.
Body weight:
The body weight gain shown by the animals over the study period was considered to be normal (see Table 1)
Gross pathology:
No abnormalities were found.

Any other information on results incl. tables

Table 1: Body weights of all treated rats measured before dosing (day 1) and after dosing (day 8 and day 15)

 Animal  day 1  day 8  day 15
 1 (group 1)  194  215  233
 2 (group 1)  209  231  254
 3 (group 1)  192  224  241
 4 (group 2)  203  223  233
 5 (group 2)  214  240  247
 6 (group 2)  211  241  249

Applicant's summary and conclusion

Interpretation of results:
practically nontoxic
Remarks:
Migrated information Criteria used for interpretation of results: other: GHS/ CLP
Conclusions:
The oral LD50 value of PM-6976 in female Wistar rats was determined to exceed the limit dose of 2000 mg/kg b.w.
Executive summary:

The acute oral toxicity of the test item PM-6976 was determined by the acute toxic class method according to the OECD guideline 423 (2001) ‘Acute Toxicity-Oral, Acute Toxic Class Method” and GLP using female rats. Two groups of three animals each were treated with the limit single dose of 2000 mg/kg b.w. and observed for 15 days. All rats survived and clinical signs such as hunched posture were only observed on day 1 after dosing. No effects in body weights or abnormalities after macroscopic examination after terminal sacrifice were observed. Hence, the LD5O value of PM-6976 in Wistar rats was found to exceed 2000 mg/kg b.w.. The study is considered valid and reliable without restrictions.