D-Glucitol, 1-deoxy-1-(methylamino)-, N-[C18-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:

2013-11-04 to 2013-11-29

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: GLP guideline study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2013

Report date:

2013

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

Limit test:

yes

Test material

Test material information

Constituent 1

Reference substance name:

(6E)-N-[(2R,3S,4S,5S)-6-hydroxy-2,3,4,5-tetramethylhexyl]-N-methyloctadec-6-enamide; N-[(2R,3S,4S,5S)-6-hydroxy-2,3,4,5-tetramethylhexyl]-N-methyloctadecanamide

EC Number:

940-373-5

Cas Number:

1591782-99-8

Molecular formula:

C25H49NO6 (C18 unsatd.) C25H51NO6 (C18 satd.)

IUPAC Name:

(6E)-N-[(2R,3S,4S,5S)-6-hydroxy-2,3,4,5-tetramethylhexyl]-N-methyloctadec-6-enamide; N-[(2R,3S,4S,5S)-6-hydroxy-2,3,4,5-tetramethylhexyl]-N-methyloctadecanamide

Test material form:

other: Waxy solid

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. 0801)
- 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 in IVC cages, type III H, polysulphone cages on Altromin saw fibre bedding (lot no. 060613)
- Certificates of food, water and bedding are filed at BSL BIOSERVICE
- Adequate acclimatisation period (at ieast five days) under laboratory conditions

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

corn oil

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 or 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:

6

Control animals:

no

Details on study design:

Observation Period
All 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
At the end of the observation period the animals were sacrificed with an overdosage of sodium pentobarbital injected intraperitoneally (Narcoren®, Merial; lot no. 231073, expiry date: 31/07/2016) at a dosage of approximately 8 mL/kg bw.
All animals were subjected to gross necropsy and findings recorded.

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

Effect level:

5 000 mg/kg bw

Based on:

test mat.

Mortality:

Under the conditions of the present study, a single oral application of the test item C18/C18 unsatd.-Glucamide to rats at a dose of
2000 mg/kg body weight was associated with signs of toxicity but not mortality.

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, wasp waist, piloerection and hunched posture. The animals recovered from all symptoms by day 3 of treatment.

Gross pathology:

No changes recorded for any animal.

Applicant's summary and conclusion

Interpretation of results:

practically nontoxic

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 C18/C18 unsatd.-Glucamide to rats at a dose of 2000 mg/kg
body weight was associated with unspecific signs of toxicity but not mortality.
The median lethal dose of C18/C18 unsatd.-Glucamide after a single oral administration to female rats, observed over a period of 14 days is:
LD50 cut-off (rat): 5000 mg/ kg bw

Executive summary:

The acute oral toxicity of C18/C18 unsatd.-Glucamide was investigated in a GLP compliant study according to OECD TG 423. 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 suspended 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 after their entrance at BSL 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.

Results per Step

Step		Sex / No.		Starting Dose (mg/kg bw)		Number of Animals		Number of Intercurrent Deaths
Step1		Female / 1 - 3		2000		3		0
Step2		Female / 4 - 6		2000		3		0

bw = body weight

All animals survived until the end of the study showing signs of toxicity. Throughout the 14-day observation period, the body weight gain of the test animals was within the normal range of variation for this strain. At necropsy, no treatment-related macroscopic findings were observed in any animal of any step. 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, wasp waist, piloerection and hunched posture. The animals recovered from all symptoms by day 3 of treatment. Under the conditions of the present study, a single oral application of the test item C18/C18 unsatd.-Glucamide to rats at a dose of 2000 mg/kg body weight was associated with signs of toxicity but not mortality.

The median lethal dose of C18/C18 unsatd.-Glucamide after a single oral administration to female rats, observed over a period of 14 days is: LD₅₀cut-off (rat): 5000 mg/ kg body weight