Reaction mass of sodium 3-{[3-(diethylamino)propyl]carbamoyl}-2-(dodecylamino)propanoate and sodium 3-{[3-(diethylamino)propyl]carbamoyl}-3-(dodecylamino)propanoate

Acute Toxicity: oral

Administrative data

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

01 March - 19 April 2006

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: see 'Remark'

Remarks:

GLP study conducted in compliance with OECD guideline 420 with a minor deviation that does not affect study reliability: no rationale was reported for testing additional animals at 2000 mg/kg bw, despite the mortality noted with the first animal in the sighting test.

Cross-reference

Cross-reference 1

Reason / purpose for cross-reference:

reference to same study

Cross-reference 2

Reason / purpose for cross-reference:

reference to other study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2006

Report date:

2006

Materials and methods

Test guideline

Test guideline 1

Qualifier:

according to guideline

Guideline:

OECD Guideline 420 (Acute Oral Toxicity - Fixed Dose Method)

Deviations:

yes

Remarks:

no rationale was provided to test other animals at 2000 mg/kg bw, despite the death of the animal tested in the sighting test at this dose.

Test guideline 2

Qualifier:

according to guideline

Guideline:

EU Method B.1 bis (Acute Oral Toxicity - Fixed Dose Procedure)

Deviations:

yes

Remarks:

no rationale was provided to test other animals at 2000 mg/kg bw, despite the death of the animal tested in the sighting test at this dose.

Principles of method if other than guideline:

Not applicable

GLP compliance:

yes

Test type:

fixed dose procedure

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Reaction mass of sodium 3-{[3-(diethylamino)propyl]carbamoyl}-2-(dodecylamino)propanoate and sodium 3-{[3-(diethylamino)propyl]carbamoyl}-3-(dodecylamino)propanoate

EC Number:

939-579-8

Molecular formula:

Empirical Formula : C11H21N3O3Na C2nH4n+1 (n=4 – 9), C11H21N3O3NaC18H35, C11H21N3O3NaC18H33 Molecular formula of the two main constituents : C23H46N3O3Na

IUPAC Name:

Reaction mass of sodium 3-{[3-(diethylamino)propyl]carbamoyl}-2-(dodecylamino)propanoate and sodium 3-{[3-(diethylamino)propyl]carbamoyl}-3-(dodecylamino)propanoate

Details on test material:

- Name of test material (as cited in study report): CHIMEXANE HB
- Physical state: Yellowish thick gel
- Analytical purity: 55.9 %
- Lot/batch No.: 0126344
- Date of receipt: 21 February 2006
- Expiration date of the lot/batch: March 2007
- Storage condition of test material: At room temperature

Test animals

Species:

rat

Strain:

Sprague-Dawley

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Janvier, Le Genest-Saint-Isle, France
- Age at study initiation: 8 weeks
- Weight at study initiation: 198 ± 8 g
- Fasting period before study: Animals were fasted for an overnight period of approximately 18 h before dosing, but had free access to water. Food was given back approximately 4 h after administration of the test item.
- Housing: Animals were housed in polycarbonate cages with stainless steel lid. Each cage contained 1-7 rats/sex during the acclimation period and 1 rat (sighting test) and 3 or 5 rats/sex/group (main test) during the treatment period.
- Diet (e.g. ad libitum): SsniffR/M-H pelleted diet (SSNIFF Spezialdiäten GmbH, Soest, Germany), ad libitum
- Water (e.g. ad libitum): Drinking water filtered by a FG Millipore membrane (0.22 µ), ad libitum
- Acclimation period: At least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature: 22 ± 2 °C
- Humidity: 30-70 %
- Air changes: Approximately 12 cycles/h of filtered, non-recycled air
- Photoperiod: 12 h dark / 12 h light

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

water

Details on oral exposure:

- Amount of vehicle (if gavage): 10 mL/kg bw
- Rationale for the selection of the starting dose: A preliminary test (sighting test) preceded the main test in which the test item was administered at the dose level of 2000 mg/kg bw to one female. Despite the mortality noted with this first animal, a second female was treated at the concentration of 2000 mg/kg bw. As no mortality occurred, the test item was administered at 2000 mg/kg bw in the main test to three additional females.

Doses:

- Sighting test: 2000 mg/kg bw
- Main test: 300 and 2000 mg/kg bw

No. of animals per sex per dose:

- Sighting test: 2 females
- Main test: 3 or 5 females

Control animals:

other: historical control data

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing:
Clinical signs: Animals were observed frequently during the hours following administration of the test item; subsequently once daily up to 14 days
Body weight was recorded on Days 1 (just before administration), 8 and 15.
- Necropsy of survivors performed: Yes, all surviving animals were killed by carbon dioxide asphyxiation on Day 15.
- All animals were subjected to a macroscopic examination which consisted of opening the thoracic and abdominal cavities. The macroscopic appearance of all examined organs was recorded.

Statistics:

None

Results and discussion

Preliminary study:

In the sighting test, the test item was first administered at the dose level of 2000 mg/kg bw to one female. Despite the mortality noted with this first animal, a second female was treated at the concentration of 2000 mg/kg bw. As no mortality occurred, the test item was administered at the dose-level of 2000 mg/kg bw in the main test to three additional females.

Effect levels

Sex:

female

Dose descriptor:

LD50

Effect level:

> 300 - < 2 000 mg/kg bw

Based on:

test mat.

Mortality:

- At 2000 mg/kg bw: 2/5 females were found dead on Day 2 or 3.
- At 300 mg/kg bw: No mortality was noted.

Clinical signs:

other: - At 2000 mg/kg bw: Hypoactivity, piloerection and dyspnea were noted in 2/5 females prior to the death, from Day 1. Soft faeces were also noted in one female on Day 1 only. Piloerection, concurrently with hypoactivity and/or dyspnea were observed in surv

Gross pathology:

- No macroscopic abnormalities were observed at necropsy.

Other findings:

None

Any other information on results incl. tables

None

Applicant's summary and conclusion

Interpretation of results:

Toxicity Category IV

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

The oral LD50 for CHIMEXANE HB is greater than 300 mg/kg bw and less than 2000 mg/kg bw in rats therefore it is classified as ‘R22 Harmful if swallowed’ according to the Annex VI to the Directive 67/548/EEC and ‘Category 4’ according to the CLP Regulation (EC) N° (1272-2008).

Executive summary:

In a GLP acute oral toxicity study performed according to OECD Guideline 420, groups of female Sprague Dawley [Rj: SD (IOPS Han)] rats were given a single oral dose of CHIMEXANE HB at 300 and 2000 mg/kg bw. A preliminary test (sighting test) preceded the main test in which the test item was administered at the dose level of 2000 mg/kg bw to one female. Despite the mortality noted with this first animal, a second female was treated at the concentration of 2000 mg/kg bw. As no mortality occurred, the test item was administered at 2000 mg/kg bw in the main test to three additional females. All animals were observed for mortality, clinical signs and bodyweights for 14 days and were all sacrificed for macroscopic examination.

 

At 2000 mg/kg bw, 2/5 females were found dead on Day 2 or 3. Hypoactivity, piloerection and dyspnea were noted prior to the death, from Day 1. Soft faeces were also noted in one of them on Day 1 only. Piloerection, concurrently with hypoactivity and/or dyspnea were observed in surviving animals between Days 1 and 3. At 300 mg/kg bw, no mortality and no clinical signs were observed. When compared to historical control animals, a slightly reduced body weight gain was noted in 1/5 and 2/5 females at 300 and 2000 mg/kg bw, respectively. The overall body weight gain of the other treated animals was not affected by treatment with the test item. No macroscopic abnormalities were observed at study termination on Day 15. In this study, the oral LD50 of CHIMEXANE HB was considered to be 300-2000 mg/kg bw in female rats.

 

The oral LD50 for CHIMEXANE HB is greater than 300 mg/kg bw and less than 2000 mg/kg bw in rats therefore it is classified as ‘R22 Harmful if swallowed’ according to the Annex VI to the Directive 67/548/EEC and ‘Category 4’ according to the CLP Regulation (EC) N° (1272-2008).