D-Glucitol, 1-deoxy-1-(methylamino)-, N-C8-10 acyl derivs.

Acute Toxicity: oral

Administrative data

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

2013-09-16 to 2013-12-10

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:

no

Test material

Test material information

Constituent 1

Reference substance name:

D-Glucitol, 1-deoxy-1-(methylamino)-, N-[C8-10(even numbered) acyl] derivs.

EC Number:

940-284-1

Cas Number:

1591782-62-5

Molecular formula:

C15H31NO6 C17H35NO6

IUPAC Name:

D-Glucitol, 1-deoxy-1-(methylamino)-, N-[C8-10(even numbered) acyl] derivs.

Test material form:

solid: particulate/powder

Remarks:

migrated information: powder

Details on test material:

Chemical Name : D-Glucitol, 1-deoxy-1-(methylamino)-, N-C8-10 acyl derivs.
Cas No.: 85316-98-9 and 85261-20-7 (related to main C-chain lengths of the active material)
Physical State: solid, powder
Colour: colourless
Molecular Weight: 321.42 – 349.47 g/mol
pH: 8-10 (20°C, 10 g/l)
Storage Conditions: room temperature
Safety Precautions: The routine hygienic procedures are 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:

Test System
Species/strain: healthy rats, WISTAR rats Crl: WI(Han) (full barrier)
Source: Charles River, 97633 Sulzfeld, Germany
Sex: female, non-pregnant, nulliparous
Number of animals: 3 per step
Age at the beginning of the study: 8 - 13 weeks old
Body weight on the day of administration:
Step1: animals no. 4 - 6 : 187 – 205g
Step2: animals no. 4 - 6 : 151 - 160 g
Step3: animals no. 7 - 9 : 145 - 163 g
The animals were derived from a controlled full-barrier maintained breeding system (SPF). According to Art. 9.2, No. 7 of the German Act
on Animal Welfare the animals were bred for experimental purposes.

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 / individually in IVC cages, type III H, polysulphone cages on Altromin saw fibre bedding (lot no. 240113)
- 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:

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. Compound-related mortality was recorded for all animals 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 300 mg/kg body weight.
No compound-related mortality was recorded for any animal of step 2. Based on these results and according to the acute toxic class method regime, a third step was performed at a dose of 300 mg/kg body weight. No compound-related mortality was recorded for any animal of step 3.
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 per step

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 animals which were found dead on the day of administration were necropsied upon retrieval.
At the end of the observation period the surviving animals were sacrificed with an overdosage of pentobarbital injected intraperitoneally
(Narcoren®, Merial; lot no. 231073, expiry date: 31/07/2013) at a dosage of approximately 8 mL/kg bw.
All animals were subjected to gross necropsy. All gross pathological changes were recorded and in case of findings 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

Effect level:

500 mg/kg bw

Based on:

test mat.

Mortality:

All 3 animals of the first step treated with the test item at a dose of 2000 mg/kg bw were found dead 4 to 6 hours after treatment.
All remaining animals dosed with 300 mg/kg bw survived until the end of the study.

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 prone position, increased spontaneous activity and afterwards reduced spontaneous activity, salivation, moving the bedding, wasp waist, eyes hal

Gross pathology:

Macroscopic findings of animals not having survived until the end of the observation period:
Necropsy revealed fluid content in the stomach, large size and abnormal content (gaseous distension, fluid filled) in duodenum,
jejunum and ileum, discoloured and pale lungs with smooth consistency and red or uncoloured nasal discharge.
Macroscopic findings of surviving animals:
At necropsy, no treatment-related macroscopic findings were observed in any animal of any step.

Applicant's summary and conclusion

Interpretation of results:

Toxicity Category IV

Remarks:

Migrated information Based on CLP / GHS Criteria used for interpretation of results: EU

Conclusions:

Based on the results from the study, the LD50 cut-off value of the test material is 500 mg/kg body weight.

Executive summary:

Summary Results

One group of three female WISTAR Crl: WI(Han) rats was 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. 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 300 mg/kg body weight. The test item was dissolved in the vehicle aqua ad injectionem (sterile water) at a concentration of 0.03 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.

All animals of the first step treated with the test item at a dose of 2000 mg/kg bw were found dead 4 to 6 hours after treatment. All remaining animals survived until the end of the study. The most relevant clinical findings in the animals treated with the test item at a dose of 2000 mg/kg bw were prone position, increased spontaneous activity and afterwards reduced spontaneous activity, salivation, moving the bedding, wasp waist, eyes half closed, piloerection, respiratory sounds, tremor, lacrimation and clonic convulsions. The most relevant clinical findings in the animals treated with the test item at a dose of 300 mg/kg bw were reduced spontaneous activity and piloerection. All animals of step 2 and 3 recovered from all symptoms by up to day 2 of treatment. Throughout the 14-day observation period, the weight gain of the surviving animals was within the normal range of variation for this strain. Macroscopic findings of animals not having survived until the end of the observation period: Necropsy revealed fluid content in the stomach, large size and abnormal content (gaseous distension, fluid filled) in duodenum, jejunum and ileum, discoloured and pale lungs with smooth consistency and red or uncoloured nasal discharge. Macroscopic findings of surviving animals: At necropsy, no treatment-related macroscopic findings were observed in any animal of any step.

 

Conclusion

Under the conditions of the present study, a single oral administration of the test item Glucamide 810 to rats at a dose of 2000 mg/kg body weight

was associated with signs of toxicity and mortality.

Under the conditions of the present study, a single oral administration of the test item Glucamide 810 to rats at a dose of 300 mg/kg body weight

was associated with only slight and transient signs of toxicity but no mortality.

The median lethal dose of Glucamide 810 after a single oral administration to female rats, observed over a period of 14 days is:

LD50 cut-off (rat): 500 mg/ kg bw

In conformity with the criteria given in Annex VI to Commission Directive 2001/59/EC the test item C8/10-Glucamide AC93/13 has obligatory labelling

requirement for toxicity.

According to Annex I of Regulation (EC) 1272/2008 the test item Glucamide 810 has obligatory labelling requirement for toxicity and is classified into Category 4.

According to GHS (Globally Harmonized Classification System) the test item Glucamide 810 has obligatory labelling requirement for toxicity and is classified into Category 4.