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Toxicological information

Acute Toxicity: oral

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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
Study period:
From 8 August 2007 to 22 August 2007
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: in compliance with GLP and OECD guidelines (as the data is used in a read-across approach, a maximal reliability score of 2 was attributed).

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2008
Report Date:
2008

Materials and methods

Test guideline
Qualifier:
according to
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 males were between 32.0 g and 39.3 g instead of between 25 g and 35 g. Reason: Body weights were higher than expected.
GLP compliance:
yes (incl. certificate)
Test type:
acute toxic class method
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
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:
mouse
Strain:
Swiss
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories - Domaines des Oncins, BP 0109, 69592 L'Arbresle Cedex, France.
- Age at study initiation: 7-8 weeks on the day of randomisation.

- Weight at study initiation:
• Between 24.9 g and 28.3 g on the day of randomisation with a maximum range of 5.4 g for females.
• Between 32 g and 39.3 g on the day of randomisation with a maximum range of 7.3 g for males.

- Fasting period before study: Animals were fasted 3 to 4 hours before treatment and were remained deprived of food 25 min to 1h23 min 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:
LAB 3822 or sterile water was administered to animals by the oral route by gavage. The density of LAB 3822 was 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; 1.25; 0.5; 1 and 2 g/kg of Isosorbide diesters
No. of animals per sex per dose:
10 animals (5 males and 5 females)
Control animals:
yes
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing:at least once time a day
- 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:
Under the experimental conditions adopted, no mortality was seen in mice dosed with the sterile water by the oral route.
Under the experimental conditions adopted, no mortality was seen in mice dosed with LAB 3822 whatever the dose.
Clinical signs:
Under the experimental conditions adopted, one female dosed with LAB 3822 at 0.25 g/kg of DEI and one female dosed with LAB 3822 at 2 g/kg of DEI had a loss of the hind limb reflex on D1. Since the change was observed only on D1, is not dose related and not related to any other clinical signs, it is not deemed to be of toxicological relevance.
Body weight:
Under the experimental conditions adopted, no effect was seen on body weight gains of mice dosed with sterile water.
Under the experimental conditions adopted, no effect was seen on body weight gains of mice dosed with LAB 3822, whatever the dose, when compared to the control group.
Gross pathology:
No abnormality was seen in organs examined at necropsy in mice dosed with sterile water.
No abnormality was seen in organs examined at necropsy in mice 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 (batch FAL 07/25) administered once by the oral route in male and female swiss mice 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 mice 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 male and female Swiss mice 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).