Ethyl 2-(dimethylamino)-1-phenylcyclohex-3-ene-1-carboxylate

Acute Toxicity: oral

Administrative data

Endpoint:

acute toxicity: oral

Type of information:

migrated information: read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: GLP complaint guideline study, available as unpublished report, no restrictions, fully adequate for assessment

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2010

Report date:

2010

Materials and methods

Test guideline

Test guideline 1

Qualifier:

according to guideline

Guideline:

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

Test guideline 2

Qualifier:

according to guideline

Guideline:

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

Test guideline 3

Qualifier:

according to guideline

Guideline:

EPA OPPTS 870.1100 (Acute Oral Toxicity)

Test guideline 4

Qualifier:

according to guideline

Guideline:

other: Japan MAFF Testing Guideline of 12 Nosan No.8147

GLP compliance:

yes (incl. QA statement)

Remarks:

Bioassay, Labor für biologische Analytik GmbH, INF 515, 69120 Heidelberg

Test type:

acute toxic class method

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

41524-32-7

Cas Number:

41524-32-7

IUPAC Name:

41524-32-7

Constituent 2

Reference substance name:

3-Cyclohexene-1-carboxylic acid, 2-(dimethylamino)-1-phenyl-, ethyl ester, trans-, ethanedioate (1:1)

IUPAC Name:

3-Cyclohexene-1-carboxylic acid, 2-(dimethylamino)-1-phenyl-, ethyl ester, trans-, ethanedioate (1:1)

Details on test material:

- Name of test material (as cited in study report): trans-tilidin- Oxalat, Erstabtrennung
- Storage: room temperature
- Physical state: white solid

Test animals

Species:

rat

Strain:

Wistar

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Wiga GmbH, Sandhofer Weg 7, 97633 Sulzgeld, Germany
- Age at study initiation: 9 - 11 weeks
- Weight at study initiation: 2000mg/kg group: 193.3g (SD: 4.16g); 300mg/kg group 1: 169.3g (SD: 6.66g); 300mg/kg group 2: 186.3g (SD: 4.04g);
- Fasting period before study: at least 16 hours (water was available ad libitum)
- Housing: single housing, Makrolon cage type III; H 15005-29 bedding, Ssniff, Spezialitäten GmbH (Experimental Animal Diets Inc. 59494 Soest, Germany); NGM E-022 enrichment, ABEDD® LAB&VET Service GmbH, Hasnerstrasse 84/6, 1160 Wien - Austria
- Diet: VRG1(P); SDS Special Diets Services, 67122 Altrip, Germany
- Water: ad libitum, tap water
- Acclimation period: at least 5 days
- Animals were nulliparous and non-pregnant

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 3
- Humidity (%): 30 - 70
- Air: fully air-conditioned rooms
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

water

Remarks:

deionized

Details on oral exposure:

VEHICLE
- Concentration in vehicle: 3 and 20 g/100 mL
- Administration volume: 10 mL/kg bw
- Justification for choice of vehicle: Aqueous formulation corresponds to the physiological medium

CLASS METHOD
- Rationale for the selection of the starting dose: 300 mg/kg bw was chosen as the 1st step. As no animals died, 2000 mg/kg bw were administered to 3 female animals in the 2nd step. Because all animals died at the 2nd step, 300 mg/kg bw were adminsterd to another group of 3 female animals in the 3rd step.

Doses:

300 and 2000 mg/kg bw

No. of animals per sex per dose:

- 300 mg/kg bw: 6 female animals
- 2000 mg/kg bw: 3 female animals

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Recording of clinical signs several times on the day of administration, and at least once daily thereafter each workday for the individual animals. Individual body weights shortly before administration (day 0), weekly thereafter and on the last day of observation. Additionally, at day of death in animals that died or were sacrificed moribund starting with study day 1. A check for any dead or moribund animals was made at least once each workday.
- Necropsy of survivors performed: yes, but no histological examinations were performed.

Results and discussion

Effect levels

Sex:

female

Dose descriptor:

LD50

Effect level:

> 300 - < 2 000 mg/kg bw

Based on:

test mat.

Mortality:

- No mortality was observed in animals exposed to 300 mg/kg bw.
- All animals exposed to 2000 mg/kg bw died.

Clinical signs:

- An impaired and poor general state, dyspnoea, staggering, abdominal position, ataxia, twitching, chromodacryorrhea, exophthalmos, flat respiration, high stepping gait and salivation from hour 0 up to hour 5 after administration were observed in animals exposed to 2000 mg/kg bw.
- In the first 300 mg/kg bw test group impaired general state, dyspnoea, staggering and exophthalmos were observed from hour 1 up to day 1 in all three animals at the latest. Furthermore, piloerection, exsiccosis and reduced feces were observed in one animal at study day 1 after administration.
- In the second 300 mg/kg bw test group impaired and poor general state, dyspnoea, ataxia, staggering, abdominal position, exophthalmos, piloerection, reduced feces, exsiccosis and salivation was observed from hour 0 until study day 2 at the latest.

Body weight:

The mean body weight of the surviving animals increased throughout the study period within the normal range.

Gross pathology:

- At necropsy two animals that died in the 2000 mg/kg bw test group showed dark red spotted discoloration in all lobes of the lung. Two animals showed gaseous stomach, filled with liquid content and two animals were found to have red discoloration of content in the small intestine and red discoloration of the small intestine.
- There were no macroscopic pathological findings in the animals sacrificed at the end of the observation period.

Applicant's summary and conclusion

Interpretation of results:

harmful

Remarks:

Migrated information

Conclusions:

Under the conditions of this study the test substance was found to be greater than 300 mg/kg bw and less than 2000 mg/kg bw in rats.

Executive summary:

In an acute toxic class method test (OECD 423 guideline study, GLP compliant) the test substance was administered to female Wistar rats by oral gavage. One group of three female rats were exposed to 300 mg/kg bw, followed by a group of three female rats exposed to 2000 mg/kg bw and another group of three female rats exposed to 300 mg/kg bw. After an observation period of 14 days surviving animals were necropsied. All animals exposed to 2000 mg/kg bw died within one day after administration. No mortality was observed in animals exposed to 300 mg/kg bw. Clinical observation in the 2000 mg/kg bw test group revealed impaired and poor general state, dyspnoea, staggering, abdominal position, ataxia, twitching, chromodacryorrhea, exophthalmos, flat respiration, high stepping gait and salivation from hour 0 up to hour 5 after administration. In the two 300 mg/kg bw test groups impaired and poor general state, dyspnoea, ataxia, staggering, abdominal position, exophthalmos, piloerection, reduced feces, exsiccosis and salivation was observed from hour 0 until study day 2 after administration. The mean body weight of the surviving animals increased throughout the study period within the normal range. Dark spotted discoloration in all lobs of the lung was observed in two animals that died in the 2000 mg/kg bw group. Two animals showed gaseous stomach, filled with liquid content and two animals were found to have red discoloration of content in the small intestine and red discoloration of the small intestine. No pathological findings were observed in animals exposed to 300 mg/kg bw. The LD50 was therefore determined to be greater than 300 mg/kg bw and less than 2000 mg/kg bw.