Carbamic acid, N-[[5-[[[2-[2-(dimethylamino)ethoxy]ethoxy]carbonyl]amino]-1,3,3-trimethylcyclohexyl]methyl]-, 2-[2-(dimethylamino)ethoxy]ethyl ester

Acute Toxicity: oral

Administrative data

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

05 Apr - 21 Jun 2011

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: GLP-Guideline study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2011

Report date:

2011

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

Test guideline 3

Qualifier:

according to guideline

Guideline:

EPA OPPTS 870.1100 (Acute Oral Toxicity)

Deviations:

no

GLP compliance:

yes

Test type:

acute toxic class method

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

-

EC Number:

441-100-8

EC Name:

-

Cas Number:

351197-46-1

Molecular formula:

Hill formula: C24 H48 N4 O6 CAS formula: C24 H48 O6 N4

IUPAC Name:

2-[2-(dimethylamino)ethoxy]ethyl N-{[1,3,3-trimethyl-5-(9-methyl-2-oxo-3,6-dioxa-1,9-diazadecan-1-yl)cyclohexyl]methyl}carbamate

Details on test material:

- Name of test material (as cited in study report): UAX-1179
- Molecular formula (if other than submission substance): Amber liquid
- Analytical purity: 98.6%
- Lot/batch No.: D07Q028
- Expiration date of the lot/batch: 27 Jul 2012
- Stability under test conditions: Unknown; excluded from the statement of compliance
- Storage condition of test material: At room temperature (range of 20 ± 5°C, provided by Harlan Laboratories Ltd.), light protected
- Safety precautions: Routine hygienic procedures (gloves, goggles, face mask)

Test animals

Species:

rat

Strain:

other: RccHan: WIST (SPF)

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Harlan Laboratories B.V., Kreuzelweg 53, 5961 NM Horst / The Netherlands
- Age at study initiation: 9 - 10 weeks
- Weight at study initiation: 178.0 g - 199.7 g
- Housing: In groups of three per sex in Makrolon type-4 cages with wire mesh tops and standardized softwood bedding ('Lignocel', J. Rettenmaier&Söhne GmbH&CoKG, 73494 Rosenberg / Germany).
- Diet: Pellet standard Teklad Rat-Mouse Diet 2914C, batch no. 85/10 (Provimi Kliba AG, 4303 Kaiseraugst / Switzerland) ad libitum (except for the overnight fasting period prior to intubation and approximately 3 - 4 hours post dose). Results of analyses for contaminants are archived at Harlan Laboratories Ltd.
- Water: Community tap-water, from ltingen ad libitum. Results of bacteriological, chemical and contaminant analyses are archived at Harlan Ltd, Itingen.
- Acclimation period: 5 to 9 days under laboratory conditions, after health examination. Only animals without any visible signs of illness were used for the study.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 3
- Humidity (%): 30 - 70
- Air changes (per hr): 10 - 15
- Photoperiod (hrs dark / hrs light): 12 / 12

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

water

Details on oral exposure:

VEHICLE
- Concentration in vehicle: A preparation of 20% (w/w) in purified water was selected
- Justification for choice of vehicle: Non-GLP solubility trial performed before the study initiation date

MAXIMUM DOSE VOLUME APPLIED: 10 mL/kg bw

Doses:

300, 2000 mg/kg bw

No. of animals per sex per dose:

3 females

Control animals:

no

Details on study design:

-Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Daily during acclimatization, prior to treatment, within the first 30 minutes and approximately 1, 2, 3 and 5 hours after treatment on Test day 1 (with the clinical signs) and twice daily during Test days 2 - 15 (Mortality / Viability); on Test days 1 (pre-administration), 8 and 15 (Body weights)
- Frequency of observations: Clinical signs: Daily during acclimatization, prior to treatment, within the first 30 minutes and approximately 1, 2, 3 and 5 hours after treatment on Test day 1. Once daily during Test days 2 -15
- Necropsy of survivors performed: Yes, on all animals treated with 2000 mg/kg bw (Group 2) which died within 1 hour after treatment, a macroscopic examination was performed as soon as they were found dead. All animals treated with 300 mg/kg bw (Groups 1 and 3) were killed at the end of the observation period by carbon dioxide asphyxiation and discarded after macroscopic examinations were performed. An external examination and opening of the abdominal and thoracic cavities for examinations of major organs was performed. The appearance of any macroscopic abnormalities was recorded. No organs or tissues were retained.
- Other examinations performed: clinical signs, body weights, organ weights

Results and discussion

Effect levels

Sex:

female

Dose descriptor:

LD50

Effect level:

> 300 - < 2 000 mg/kg bw

Based on:

test mat.

Mortality:

Female: 300 mg/kg bw; Number of animals: 3; Number of deaths: 0
Female: 2000 mg/kg bw; Number of animals: 3; Number of deaths: 3
Female: 300 mg/kg bw; Number of animals: 3; Number of deaths: 0

All animals treated with 2000 mg/kg body weight of the test item died after treatment on Test day 1. All animals treated with 300 mg/kg survived until the end of the study period.

Clinical signs:

other: All animals treated with 2000 mg/kg bw (Group 2) showed marked shivering, muscle twitching, markedly decreased activity, prostration and marked dyspnea prior to their death within one hour after treatment. Slightly to moderately ruffled fur on Test days 1

Gross pathology:

No macroscopic findings were observed at necropsy.

Applicant's summary and conclusion

Interpretation of results:

harmful

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

harmful, if swallowed

Executive summary:

In an acute oral toxicity GLP study according to OECD 423, three groups, each consisting of 3 female RccHan:WIST (SPF) rats, were treated by oral gavage with UAX-1179 at 300 (2 groups) and 2000 mg/kg body weight (1 group). The test item was applied in a volume of 10 mL/kg bw. The animals were examined for clinical signs daily during the acclimatization period, five times during Test day 1 and once daily during Test days 2 – 15. Mortality and viability were recorded daily during the acclimatization period and together with clinical signs at the same time intervals on Test day 1 and at least twice daily on Test days 2 – 15. Body weights were recorded on day 1 (prior to administration) and on Days 8 and 15. All animals were necropsied and examined macroscopically. All animals treated with 300 mg/kg bw (Groups 1 and 3) survived the observation period. All animals treated with 2000 mg/kg bw (Group 2) died after treatment on Test day 1. All animals of the highest dose group (2000 mg/kg bw) showed marked shivering, muscle twitching, markedly decreased activity, prostration and marked dyspnea prior to their death within 1 hour after treatment. Animals in Group 1 treated with 300 mg/kg body weight showed slightly to moderately ruffled fur on Test days 1-2. Otherwise, no clinical signs were observed during the course of the study. The body weight of the animals was within the range commonly recorded for this strain and age. No macroscopic findings were observed at necropsy.

The oral LD50 value of UAX-1179 after single administration to female rats, observed over a period of 14 days is considered to be between 300 and 2000 mg/kg body weight.