D-Glucitol, 1-deoxy-1-(methylamino)-, N-[C8-16 (even numbered) and C18 unsaturated acyl] derivs.

Acute Toxicity: oral

Administrative data

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

2015-03-17 to 2015-06-17

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: GLP guideline study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2015

Report date:

2015

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 (incl. QA statement)

Remarks:

(Bayerisches Landesamt für Gesundheit und Lebensmittelsicherheit, München, Germany)

Test type:

acute toxic class method

Test material

Test material information

Constituent 1

Reference substance name:

D-Glucitol, 1-deoxy-1-(methylamino)-, N-[C8-16 (even numbered) and C18 unsaturated acyl] derivs.

EC Number:

940-422-0

Cas Number:

1591783-13-9

Molecular formula:

C15H31NO6 (C8 derivative) C17H35NO6 (C10 derivative) C19H39NO6 (C12 derivative) C21H43NO6 (C14 derivative) C23H47NO6 (C16 derivative) C25H51NO6 (C18 derivative) C25H49NO6 (C18 unsatd. derivative)

IUPAC Name:

D-Glucitol, 1-deoxy-1-(methylamino)-, N-[C8-16 (even numbered) and C18 unsaturated acyl] derivs.

Constituent 2

Reference substance name:

Glucamide CC

IUPAC Name:

Glucamide CC

Test material form:

other: solid

Details on test material:

Chemical Name: D-Glucitol, 1-deoxy-1-(methylamino)-, N-coco acyl derivs.
CAS No.: 1591783-13-9
Physical State at Room Temperature: waxy solid
Colour: white to slightly yellowish
Storage Conditions: at room temperature
Safety Precautions: The routine hygienic procedures were sufficient to assure personnel health and safety.

Test animals

Species:

rat

Strain:

Wistar

Sex:

female

Details on test animals or test system and environmental conditions:

Housing and Feeding Conditions
- Full barrier in an air-conditioned room
- Temperature: 22 +/- 3 °C
- Relative humidity: 55 +/- 10%
- Artificial light, sequence being 12 hours light, 12 hours dark
- Air change: 10 x / hour
- Free access to Altromin 1324 maintenance diet for rats and mice (lot no. 1239)
- Free access to tap water, sulphur acidified to a pH value of approximately 2.8 (drinking water, municipal residue control, microbiological controls at regular intervals)
- The animals were kept in groups / individually in IVC cages, type III H, polysulphone cages on Altromin saw fibre bedding (lot no. 02102141114)
- Certificates of food, water and bedding are filed at BSL BIOSERVICE
- Adequate acclimatisation period (at least five days) under laboratory conditions

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

other: sterile water

Details on oral exposure:

The animals were marked for individual identification by tail painting.
Prior to the administration a detailed clinical observation was made of all animals.
Prior to the administration food was withheld from the test animals for 16 to 19 hours (access to water was permitted). Following the period of fasting the animals were weighed and the test item was administered. Food was provided again approximately 4 hours post dosing.
The test item was administered at a single dose by gavage using a feeding tube.
The test item was administered at a dose volume of 10 mL/kg body weight.

Doses:

The starting dose was selected to be 2000 mg/kg body weight. No compound related mortality was recorded for any animal of step 1. Based on these results and according to the acute toxic class method regime, a second step was performed at a dose of 2000 mg/kg body weight. Compound related mortality was recorded for one animal of step 2. Based on these results and according to the acute toxic class method regime no further testing was required.

No. of animals per sex per dose:

3 animals per step (2 steps performed)

Control animals:

no

Details on study design:

Observation Period
The surviving animals were observed for 14 days after dosing for general clinical signs, morbidity and mortality.

Weight Assessment
The animals were weighed on day 1 (prior to the administration) and on days 8 and 15.

Clinical Examination
A careful clinical examination was made several times on the day of dosing (at least once during the first 30 minutes and with special attention
given during the first 4 hours post-dose). As soon as symptoms were noticed they were recorded. Thereafter, the animals were observed for
clinical signs once daily until the end of the observation period. All abnormalities were recorded.
Cageside observations included changes in the skin and fur, eyes and mucous membranes. Also respiratory, circulatory, autonomic and central
nervous systems and somatomotor activity and behaviour pattern were examined. Particular attention was directed to observations of tremor,
convulsions, salivation, diarrhoea, lethargy, sleep and coma.

Pathology
The animal which was found dead during the observation period was necropsied as soon as it was killed.
At the end of the observation period the surviving animals were sacrificed with an overdosage of pentobarbital injected intraperitoneally
(Narcoren, Merial; lot no.: 242074; expiry date: 31/07/2017) at a dosage of 250-400 mg/kg bw.
All animals were subjected to gross necropsy. All gross pathological changes were recorded and the tissues were preserved for a possible
histopathological evaluation. The preserved tissues of which no histopathological evaluation was made will be discarded 3 months after the release of the final report unless otherwise agreed upon with the sponsor.

Statistics:

According to OECD guidelines, the biological relevance of the results is the criterion for the interpretation of results, a statistical evaluation of the
results is not regarded as necessary.

Results and discussion

Effect levels

Sex:

female

Dose descriptor:

other: LD50 cut-off (rat)

Effect level:

ca. 2 500 mg/kg bw

Based on:

test mat.

Mortality:

One animal treated with the test item at a dose of 2000 mg/kg was found dead on test day 2. All remaining animals survived until the end of the study showing signs of toxicity.

Clinical signs:

other: The most relevant clinical findings in the animals treated with the test item at a dose of 2000 mg/kg bw were reduced spontaneous activity, moving the bedding, irregular slowness in motions in combination with reduced spontaneous activity, stilted gait,

Gross pathology:

Macroscopic findings of surviving animals:
At necropsy, no treatment-related macroscopic findings were observed in any animal of any step.
Macroscopic findings of animals not having survived until the end of the observation period:
Necropsy revealed a stomach filled with fluid consisting of residual test item solution.

Applicant's summary and conclusion

Interpretation of results:

not classified

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

Under the conditions of the present study, a single oral application of the test item Glucamide CC to rats at a dose of 2000 mg/kg body weight was associated with signs of toxicity and mortality.The median lethal dose of Glucamide CC after a single oral administration to female rats, observed over a period of 14 days is: LD50 cut-off (rat): 2500 mg/ kg bw

Executive summary:

Summary Results

Two groups, each of three female WISTAR Crl: WI(Han) rats, were treated with the test item by oral gavage administration at a dosage of

2000 mg/kg body weight. The test item was dissolved in the vehicle aqua ad injectionem (sterile water) at a concentration of 0.2 g/mL and administered at a dose volume of 10 mL/kg.

All animals used in the study were allowed to acclimatise to the laboratory conditions for at least 5 days. The animals were observed on delivery, on inclusion in the study and before administration for mortality/morbidity and other clinical signs. All animals were examined for clinical signs several times on the day of dosing and once daily until the end of the observation period. Their body weights were recorded on day 1 (prior to the administration) and on days 8 and 15. All animals were necropsied and examined macroscopically.

One animal treated with the test item at a dose of 2000 mg/kg was found dead on test day 2. All remaining animals survived until the end of the study showing signs of toxicity. The most relevant clinical findings in the animals treated with the test item at a dose of 2000 mg/kg bw were reduced spontaneous activity, moving the bedding, irregular slowness in motions in combination with reduced spontaneous activity, stilted gait, hunched posture, prone position, pinched flanks, piloerection and eyes half closed. All symptoms recovered within up to 3 days post-dose.

Throughout the 14-day observation period, the weight gain of the surviving animals was within the normal range of variation for this strain.

At necropsy, no treatment-related macroscopic findings were observed in any surviving animal of any step. Macroscopic findings of the animal not having survived until the end of the observation period were restricted to a stomach filled with fluid consisting of residual test item solution.

Based on the results it was concluded that under the conditions of the present study, a single oral application of the test item Glucamide CC to rats at a dose of 2000 mg/kg body weight was associated with signs of toxicity and mortality. The median lethal dose (LD₅₀ cut-off) of Glucamide CC after a single oral administration to female rats, obeserved over a period of 14 days is 2500 mg/kg body weight.