Fatty acids, C8-10, diesters with 1,4:3,6-dianhydro-D-glucitol

Acute Toxicity: oral

Administrative data

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

from August 07,2007 to August 21,2007

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: in compliance with OECD guideline No. 423; GLP conditions

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2008

Report date:

2008

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

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

Deviations:

yes

Remarks:

Test system, subsection 1.8.1, page 15: weight: body weights of females were between 215 g and 251.8 g instead of between 150 g and 250 g. Reason: body weights were higher than expected

GLP compliance:

yes (incl. QA statement)

Test type:

acute toxic class method

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Isosorbide Diesters

EC Number:

700-073-5

Cas Number:

1215036-04-6

Molecular formula:

As it is an UVCB, we can not provide the exact molecular formula.

IUPAC Name:

Isosorbide Diesters

Details on test material:

Name: LAB 3822.
Supplier: ROQUETTE FRERES.
Batch Number: FAL 07/25.
Galenic form: slightly yellowish liquid.
Molecular weight (salt form): not applicable.
Molecular weight (base form): about 426 g/mol.
Salt/Base ratio: not applicable.
Expiry date: March 2009.
On 17.Jul.2007, 26.2 kg samples of test item were received, in vial labelled ”LAB 3822, batch No.FAL 07/25”. The Sponsor confirmed that ”LAB 3822 - Di-ester-isosorbide” in the certificate of analysis corresponds to ”LAB 3822”, name used throughout the study plan.
Storage condition: Immediately upon receipt, LAB 3822 was registered, then stored at ambient temperature in accordance with the Sponsor's instructions.

Test animals

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Laboratories - Domaines des Oncins, BP 0109, 69592 L'Arbresle Cedex, France.

- Age at study initiation: 8-9 weeks on the day of randomisation.

- Weight at study initiation:
• Between 215 g and 251.8 g on the day of randomisation with a maximum range of 36.8 g for females.
• Between 275.4 g and 310.9 g on the day of randomisation with a maximum range of 35.5 g for males.

- Fasting period before study: Animals were fasted during the night before treatment and were remained deprived of food 3 to 4 hours post-dose.

- Housing:Observations were performed at the time of delivery of the animals and daily during the period of acclimatisation. Animals were housed in cages of standard dimensions with sawdust bedding (SAFE, Reference B8/20). Cages were cleaned according to CERB internal SOPs.

- Diet (e.g. ad libitum): RM1 (E)-SQC SDS/DIETEX feed (quality controlled/radiation sterilized) was available ad libitum except during the fasting experimental period. The criteria for acceptable levels of contaminants in the feed supplied were within the limits of the analytical specifications established by the diet manufacturer.

- Water (e.g. ad libitum):Drinking water was available ad libitum in polycarbonate feeder bottles with a stainless steel nipple. A specimen of water is obtained every 6 months and sent to the Laboratoire Départemental d'Analyse du Cher - 216, Rue Louis Mallet - 18014 Bourges Cedex, France, for analysis.
The criteria for acceptable levels of contaminants in the water supplied were within the limits of the analytical specifications.

- Acclimation period:Minimum of five days before treatment in the laboratory animal house where the experiment took place. Only animals without any visible sign of illness were used for the study.


ENVIRONMENTAL CONDITIONS
- Temperature (°C): in an air-conditioned 20-24°C
- Humidity (%): between 45% and 65%
- Air changes (per hr): 10 times per hour.
- Photoperiod (hrs dark / hrs light): 12 hours light and 12 hours darkness

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

water

Details on oral exposure:

VEHICLE

LAB 3822 and sterile water were administered to animals by the oral route by gavage. The density of LAB 3822 is 1.02, thus the volume of administration depended on the dose. For each animal, the exact amount of LAB 3822 (in mg) was recorded (by weighing the syringe before and after the administration). Control animals were given sterile water at the highest volume administered to the treated animals (i.e. 2.35 mL/kg).
The test item was supplied as a ready-to-use solution. Therefore, no formulation analysis was performed.

Doses:

0.25 g/kg -0.5g/kg - 1g/kg - 2g/kg of isosorbide diesters

No. of animals per sex per dose:

5 groups of 10 rats (each of 5 males and 5 females)

Control animals:

yes

Details on study design:

- Duration of observation period following administration: Animals were examined clinically in the home cage before the first dosing and twice on the day of treatment (at 60 minutes ± 30 minutes post-dose and then again between 3 and 4 hours post-dose). Thereafter they were examined clinically at least once a day for 14 days.
- Frequency of observations and weighing:Animals were weighed on the following days:
• on day of randomisation (D-1),
• on days D7 and D14,
• on D15, day of euthanasia (exsanguinated).

- Necropsy of survivors performed: yes

- Other examinations performed: clinical signs

Results and discussion

Effect levels

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 300 mg/kg bw

Mortality:

no mortality was seen in animal dosed with LAB 3822 whatever the dose

Clinical signs:

other: Under the experimental conditions adopted, males dosed with LAB 3822 at 0.25, 0.5 and 1 g/kg of DEI had a decrease in abdominal tone on D1. One female dosed with LAB 3822 at 1 g/kg of DEI also had a decrease in abdominal tone on D1. Since the decrease in

Gross pathology:

No gross lesion was seen in organs examined at necropsy in males and females dosed with LAB 3822, whatever the dose

Applicant's summary and conclusion

Interpretation of results:

practically nontoxic

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

Under the experimental conditions adopted, LAB 3822 administered once by the oral route in the male and female Sprague-Dawley rat did not induce any mortality or sign of toxicity up to the dose of 2 g/kg of DEI (2.3 g/kg of LAB 3822)

Executive summary:

Toxicity of the test item LAB 3822 (batch FAL 07/25) was evaluated after a single administration by the oral route in the rat.

Qualitative and/or quantitative evaluation of toxic effects seen following a single oral administration of LAB 3822 took place in male and female rats inspired by general requirements of the OECD guideline No.423 (December 17,2001).

The study involved 5 groups of 10 SPF Sprague-Dawley rats (each of 5 males and 5 females), 8 to 9 weeks old and weighing between 275.4 g and 310.9 g for males and between 215.0 g and 251.8 g for females on the day of randomisation. Animals were purchased from Charles River Laboratories France (Domaine des Oncins - 69592 L0Arbresle Cedex, France).

Groups were as follows:

• Group 1: control group dosed with sterile water.

• Group 2: dosed with LAB 3822 at the dose of 0.25 g/kg of DEI (0.29 g/kg of LAB 3822).

• Group 3: dosed with LAB 3822 at the dose of 0.5 g/kg of DEI (0.575 g/kg of LAB 3822).

• Group 4: dosed with LAB 3822 at the dose of 1 g/kg of DEI (1.15 g/kg of LAB 3822).

• Group 5: dosed with LAB 3822 at the dose of 2 g/kg of DEI (2.3 g/kg of LAB 3822).

LAB 3822 or sterile water were administered by the oral route at the volume below:

• Group 1: 2.35 mL/kg.

• Group 2: 0.30 mL/kg.

• Group 3: 0.59 mL/kg.

• Group 4: 1.17 mL/kg.

• Group 5: 2.35 mL/kg.

Experimental procedure:

Animals were weighed on the day of randomisation (D-1), on D7, D14 and D15. Mortality was recorded twice a day for 14 days. General observations were performed on D1, 60 minutes ± 30 minutes after dosing, again between 3 and 4 hours post-dose and then once a day for 14 days. Functional and neurobehavioural tests were also assessed on D1 60 minutes ±30 minutes after dosing and then on D7. All animals surviving at the end of the 14-day period were submitted to gross necropsy.

Results:

No mortality was seen in animals dosed with sterile water.

No effect on body weight gain, no clinical sign and no abnormality in organs examined at necropsy was seen in animals dosed with sterile water.

No mortality was seen in animals dosed with LAB 3822 by the oral route.

No effect on body weight gain was seen in animals dosed with LAB 3822, whatever the dose, when compared with the control group.

No relevant clinical sign was observed in animals dosed with LAB 3822, whatever the dose.

No gross lesion was seen in organs examined at necropsy .

Under the experimental conditions adopted, LAB 3822 (batch FAL 07/25) administered once by the oral route in the male and female Sprague-Dawley rat did not induce any mortality or sign of toxicity up to the dose of 2 g/kg of DEI (2.3 g/kg of LAB 3822).