1,4:3,6-dianhydro-2,5-di-O-octanoyl-D-glucitol

Repeated dose toxicity: oral

Administrative data

Endpoint:

sub-chronic toxicity: oral

Type of information:

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

Adequacy of study:

key study

Study period:

2008-2009

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: (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:

2010

Report date:

2010

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)

GLP compliance:

yes (incl. QA statement)

Test material

Test material information

Constituent 1

Reference substance name:

Automatically generated during migration to IUCLID 6, no data available

IUPAC Name:

Automatically generated during migration to IUCLID 6, no data available

Details on test material:

Name: LAB 3822
Batch Number: FAL 07/25,
Galenic form: Slightly yellowish liquid,
Molecular weight (base form): about 426 g/mol,
Expiry date: Mar 2009 extended to Mar 2010, according to the last analysis. On 17 Jul 2007, a 26.2 kg sample of test item was received, in vials labelled "LAB 3822, batchNo. FAL 07/25".
Storage conditions: Immediately upon receipt, the test item was registered, then stored at ambient temperature .
Handling instructions for LAB 3822: General safety procedures as appropriate for handling of chemicals of unknown hazard potential must be applied.

Test animals

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
Origin: Charles River Laboratoires France - Domaine des Oncins - 69592 L0Arbresle Cedex - France.
Identification: Animals were identified individually, using labelling by ear clips.
Age: 6 to 10 weeks on the day of the first administration.
Weight:
• Between 249.2 g and 273.1 g for the males of the main groups.
• Between 248.8 g and 268 g for the males of the withdrawal groups.
• Between 237.1 g and 273.8 g for the males of the toxicokinetics groups.
• Between 148.8 g and 183 g for the females of the main groups.
• Between 156.6 g and 182 g for the females of the withdrawal groups.
• Between 142.9 g and 182 g for the females of the toxicokinetics groups.
Acclimatisation:
Minimum of five days in the laboratory animal house where the experiment took place.
Housing:
Daily observations were undertaken at the time of delivery of the animals and during the period of acclimatisation. Animals were housed in groups (separated by sex) in cages of standard dimensions with sawdust bedding (or equivalent). The animals were placed in an air-conditioned (20-24°C)
animal house kept at relative humidity between 45% and 65% (except during the cleaning slot) in which non-recycled filtered air was changed approximately 10 times per hour. Any deviations outside of the temperature or hygrometry ranges were stated by the Study Director according to the SOP 5.36. The artificial day/night cycle involved 12 hours light and 12 hours darkness with light on at 7.30 a.m. (except on 21 Feb 2009 and 29 Mar 2009).
Feeding:
RM1 (E)-SQC SDS/DIETEX feed (quality controlled/irridiation sterilised) was available ad libitum except during fasting experimental periods. The criteria for acceptable levels of contaminants in the feed supplied were within the limits of the analytical specifications established by the diet manufacturer.
Drinking water:
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 Laboratoire LAEASE Région Sud Est - 5, avenue Achille Maureau - B.P. 95 - 84703 Sorgues Cedex - France, for analysis.
The criteria for acceptable levels of contaminants in the water supplied were within the limits of the analytical specifications.

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

unchanged (no vehicle)

Analytical verification of doses or concentrations:

yes

Duration of treatment / exposure:

13 weeks

Frequency of treatment:

daily

Doses / concentrations

Doses / concentrations 1

Remarks:

Doses / Concentrations:
0.59 ml/kg
Basis:

Doses / concentrations 2

Remarks:

Doses / Concentrations:
1.17 ml/kg
Basis:

Doses / concentrations 3

Remarks:

Doses / Concentrations:
2.35 ml/kg
Basis:

No. of animals per sex per dose:

15

Control animals:

yes

Details on study design:

The study involved:
• 120 animals in the main groups,
• 40 animals in the drug withdrawal groups,
• 60 animals in the satellite groups for toxicokinetics assessment, only

Choice of doses
Proposed doses selected are based on previous studies (Repeated dose 28-day toxicity study in the rat by the oral route followed by a 14-day drug withdrawal period, CERB REPORT No. 20070263TRB) and on the presumed effective pharmacological dose. The highest dose should reveal signs of toxicity and the lowest dose should represent a no-observed-adverse effect level.

Positive control:

Control animal was given sterile water under the same conditions than animals dosed with LAB 3822

Examinations

Observations and examinations performed and frequency:

Body weight assessment, food consumption and full clinical examination were performed once a week.
Water consumption was assessed daily. General observations were performed before the first treatment and between 30 and 90 minutes post-dose at least, daily. Mortality was recorded twice a day. Functional and neurobehavioural tests and measurement of body temperature were performed before the first dosing, during the fourth week between 30 and 90 minutes post-dose and during the second week of the recovery period for animals from the reversibility study.
Ophthalmologic examinations were performed at pre-treatment, at the end of the study and at the end of the recovery period for animals from the reversibility study.
Blood sampling for haematology, coagulation parameters and clinical chemistry analysis were performed on D29 and D92 for all animals and
on D120 from the drug withdrawal groups. Urine sampling was performed on D92 for all animals and on D120 from the drug withdrawal groups.
Blood samples for toxicokinetics were taken on D1 (at predose and at 30 min, 1h, 2h, 4h and 8h postdose), on D28 at predose and on D91 (predose and at 30 min, 1h, 2h, 4h and 8h post-dose).

Sacrifice and pathology:

On the day of necropsy and after overnight (about 16 hours) fast, all surviving animals were euthanased by subtotal exsanguination following anaesthesia by isoflurane inhalation.
Moribund animals were euthanased in the same way in agreement with the Study Director or the veterinarian staff with the concurrence of the Study Director.

Results and discussion

Results of examinations

Clinical signs:

effects observed, treatment-related

Mortality:

mortality observed, treatment-related

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

Lower for male animals, no effects for female animals.

Food consumption and compound intake (if feeding study):

no effects observed

Description (incidence and severity):

Slight decrease was observed in males from week 4 onwards, mainly in groups dosed with LAB 3822 at 1 and 2 g of DEI/kg

Food efficiency:

not specified

Ophthalmological findings:

no effects observed

Haematological findings:

no effects observed

Clinical biochemistry findings:

no effects observed

Urinalysis findings:

no effects observed

Behaviour (functional findings):

not specified

Organ weight findings including organ / body weight ratios:

no effects observed

Gross pathological findings:

no effects observed

Histopathological findings: non-neoplastic:

no effects observed

Histopathological findings: neoplastic:

no effects observed

Details on results:

No relevant toxicological clinical signs were observed whatever the dose of LAB 3822.
No relevant changes on body temperature were noted.
In male animals, LAB 3822 administered at all doses had a tendency to increase triglycerides, statistically significant on D29 and D92 at the dose of 2 g of DEI/kg. In females, triglycerides were also increased at the dose of 2 g of DEI/kg on D29 only.
No relevant toxicological changes in biochemical chemistry, haematology, coagulation parameters or urinalysis were noted. All statistically significant variations are presented in the Table 1 (Any other information on results).
Toxicokinetics results confirmed that all treated animals were exposed to LAB 3822 for both gender on D1 and D91.
No relevant abnormality was seen at macroscopic examination and no relevant change was noted in organ weight.
A decrease in mobile spermatozoa and in the total number of spermatozoa was noted with LAB 3822 administered at the dose of 2 g of DEI/kg.
Treatment with LAB 3822 administered at 2 g of DEI/kg, for 13 weeks was without treatment related change.

Effect levels

Dose descriptor:

NOAEL

Effect level:

>= 2 000 mg/kg bw/day (nominal)

Sex:

male/female

Basis for effect level:

other: LAB 3822 administered at the doses of 0.5, 1 and 2 g of DEI/kg for 13 weeks did not induce any sign of toxicity.

Target system / organ toxicity

Critical effects observed:

not specified

Any other information on results incl. tables

Table 1 - Statistically significant variations in chemical parameters

	Chemical parameters	Group	Sex	Day	Statistically significant variation
	Cholesterol	2	M	29	-19%
	Triglycerides	4	M	29	+31%
	Amylase	4	M	29	+12%
	Triglycerides	4	F	29	+27%
	Creatinin	4	F	29	+12%
	Cholesterol	2	M	92	-18%
	Triglycerides	4	M	92	+39%
	Creatinin	2	M	92	+16%
	Urea	4	M	92	-9%
	Albumin	4	M	120	+3%
	Urea	4	M	120	-12%
	Glucose	4	F	120	+16%
	Calcium	4	F	120	-3%

Applicant's summary and conclusion

Conclusions:

Under the experimental conditions adopted, LAB 3822 administered at the doses of 0.5, 1 and 2 g of DEI/kg for 13 weeks did not induce any sign of toxicity. Therefore, the No-Observed-Adverse Effect Level (NOAEL) of LAB 3822 corresponds to at least 2 g of DEI/kg.