4-Oxazolidinone, 3-cyclohexyl-2-(cyclohexylimino)-5-[[4-(diethylamino)-2-methoxyphenyl]methylene]-

Acute Toxicity: oral

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 guideline

Test guideline 1

Qualifier:

according to guideline

Guideline:

OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)

Deviations:

no

Test guideline 2

Qualifier:

according to guideline

Guideline:

EU Method B.1 tris (Acute Oral Toxicity - Acute Toxic Class Method)

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Test type:

acute toxic class method

Limit test:

yes

Test material

Test material information

Constituent 1

Reference substance name:

C27H39N3O3

IUPAC Name:

C27H39N3O3

Constituent 2

Reference substance name:

structure formular is shown and is the same as for substance defined in section 1

IUPAC Name:

structure formular is shown and is the same as for substance defined in section 1

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 or test system 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:

other: Hunched posture in all animals and lethargy in one animal were observed on day 1 after dosing.

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.