D-Glucitol, 1-deoxy-1-(methylamino)-, N-[C18-C18 (unsaturated) acyl] derivs.

Endpoint summary

Description of key information

With regard to the acute toxicity of the registered substance, key studies for the oral and dermal exposure routes are available. Using the acute toxic class method according OECD test TG 423, a single oral application of Glucamide OL to rats at a dose of 2000 mg/kg body weight was associated with unspecific signs of toxicity but not mortality. Based on the results, the LD50 cut-off value of Glucamide OL is 5000 mg/kg body weight.

The acute dermal toxicity of the registered substance was evaluated in an OECD 402 study according to GLP. After topical treatment with the limit dose of 2000 mg/kg body weight neither mortality nor significant clinical symptoms of intoxication were observed. The LD50 after dermal treatment was established to be greater 2000 mg/kg body weight.

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Reference

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

Qualifier:

according to guideline

Guideline:

OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)

Deviations:

no

Qualifier:

according to guideline

Guideline:

EU Method B.1 tris (Acute Oral Toxicity - Acute Toxic Class Method)

Deviations:

no

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

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

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.

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.

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

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

2 000 mg/kg bw

Quality of whole database:

Data reliable and meet criteria for classification & labelling requirements.

Acute toxicity: via inhalation route

Link to relevant study records

Reference

Endpoint:

acute toxicity: inhalation

Data waiving:

study scientifically not necessary / other information available

Justification for data waiving:

the study does not need to be conducted because exposure of humans via inhalation is not likely taking into account the vapour pressure of the substance and/or the possibility of exposure to aerosols, particles or droplets of an inhalable size

Endpoint conclusion

Endpoint conclusion:

no study available

Acute toxicity: via dermal route

Link to relevant study records

Reference

Endpoint:

acute toxicity: dermal

Type of information:

experimental study

Adequacy of study:

key study

Study period:

2013-11-27 to 2013-11-04

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: GLP guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

Deviations:

no

Qualifier:

according to guideline

Guideline:

EU Method B.3 (Acute Toxicity (Dermal))

Deviations:

no

Qualifier:

according to guideline

Guideline:

EPA OPPTS 870.1200 (Acute Dermal Toxicity)

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Remarks:

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

Test type:

standard acute method

Limit test:

yes

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental 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 individually 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 (five days) under laboratory conditions

Type of coverage:

semiocclusive

Details on dermal exposure:

Preparation of the Animals
The animals were marked for individual identification by tail painting.
Approximately 25 hours before the test, the fur was removed from the dorsal area of the trunk using an electric clipper.
Care was taken to avoid abrading the skin, and only animals with healthy intact skin were used.
No less than 10% of the body surface was cleared for the application.
Prior to the application a detailed clinical observation was made of all animals.

Application
The test item was applied at a single dose, uniformly over an area which was approximately 10% of the total body surface.
The test item was held in contact with the skin by a dressing throughout a 24-hour period. The dressing consisted of a gauze-dressing
and non-irritating tape and was fixed with an additional dressing in a suitable manner.

Duration of exposure:

The test item was held in contact with the skin throughout a 24-hour period. At the end of the exposure period the residual test item was removed using corn oil.

Doses:

The test item was applied at a single dose of 2000 mg/kg body weight to each animal.

No. of animals per sex per dose:

5 male and 5 female

Control animals:

not required

Details on study design:

Observation period:
All animals were observed for 14 days after dosing

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

Clinical Examination:
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. Attention was directed to observations of tremors, convulsions, salivation, diarrhoea, lethargy, sleep and coma.

Pathology:
At the end of the observation period the surviving animals were sacrificed with an overdosage of pentobarbital injected intraperitoneally (Narcoren®, Merial) at the 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.

Evaluation of Results:
Individual reactions of each animal were recorded at each time of observation.
Toxic response data were recorded by sex and dose level.
Nature, severity and duration of clinical observations were described.
The body weight changes were summarised in a tabular form.
Necropsy findings were described.
On the basis of the test results, the test item may be classified in one of the following classes in conformity with the criteria given in Annex VI to Commission Directive 2001/59/EC:
• Very toxic
Substances and preparations shall be classified as very toxic, and assigned the symbol “T+” and indication of danger “very toxic” in accordance with the criteria specified below:
R27 Very toxic in contact with skin
- LD50 dermal, rat or rabbit: <= 50 mg/kg
• Toxic
Substances and preparations shall be classified as toxic, and assigned the symbol “T” and indication of danger “toxic” in accordance with the criteria specified below. Risk phrases shall be assigned in accordance with the following criteria:
R24 Toxic in contact with skin
- LD50 dermal, rat or rabbit: 50 < LD50 <= 400 mg/kg
• Harmful
Substances and preparations shall be classified as harmful, and assigned the symbol “Xn” and indication of danger “harmful” in accordance with the criteria specified below. Risk phrases shall be assigned in accordance with the following criteria:
R21 Harmful in contact with skin
- LD50 dermal, rat or rabbit: 400 < LD50 <= 2000 mg/kg
On the basis of the test results, the following risk phrases may be assigned in conformity with the criteria given in Annex I of Regulation (EC) 1272/2008:
Category 1: LD50 <= 50 mg/kg. DANGER. Skull and crossbones in diamond. Fatal in contact with skin.
Category 2: LD50 > 50 mg/kg <= 200 mg/kg. DANGER. Skull and crossbones in diamond. Fatal in contact with skin.
Category 3: LD50 > 200 mg/kg <= 1000 mg/kg. DANGER. Skull and crossbones in diamond. Toxic in contact with skin.
Category 4: LD50 > 1000 mg/kg <= 2000 mg/kg. WARNING. Exclamation point in diamond. Harmful in contact with skin.
On the basis of the test results, the following risk phrases may be assigned in conformity with the criteria given in GHS - Globally Harmonized System of Classification and Labelling of Chemicals, third revised edition, July 2009:
Category 1: LD50 <= 50 mg/kg. DANGER. Skull and crossbones in diamond. Fatal in contact with skin.
Category 2: LD50 > 50 mg/kg <= 200 mg/kg. DANGER. Skull and crossbones in diamond. Fatal in contact with skin.
Category 3: LD50 > 200 mg/kg <= 1000 mg/kg. DANGER. Skull and crossbones in diamond. Toxic in contact with skin.
Category 4: LD50 > 1000 mg/kg <= 2000 mg/kg. WARNING. Exclamation point in diamond. Harmful in contact with skin.
Category 5: LD50 > 2000 mg/kg <= 5000 mg/kg. WARNING. No symbol. May be harmful in contact with skin.

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.

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Mortality:

No mortality was observed

Clinical signs:

other: No treatment-related effects were observed.

Gross pathology:

With the exception of acute injection of blood vessels in the abdominal region, which is due to the euthanasia injection, no specific gross pathological changes were recorded for any animal.

Other findings:

Erythema grade 1 were observed in 3 of 5 male and 3 of 5 female animals. Eschar was observed in 5 of 5 male and 4 of 5 female animals.
Scratches were observed in 2 of 5 male and 2 of 5 female animals.
No oedema was observed. All signs of irritation were reversible within the observation period.

Interpretation of results:

practically nontoxic

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

Under the conditions of the present study, single dermal application of the test item C18/C18 unsatd.-Glucamide to rats at a dose of 2000 mg/kg body weight was associated with neither mortality nor signs of toxicity but signs of local irritation at the application site.
The dermal LD50 was determined to be > 2000 mg C18/C18 unsatd.-Glucamide / kg body weight.

Executive summary:

The acute dermal toxicity of C18/C18 unsatd.-Glucamide was tested in a GLP compliant study according to OECD TG 402. Under the conditions of the present study, single dermal application of the test item C18/C18 unsatd.-Glucamide to rats at the limit dose of 2000 mg/kg body weight was associated with neither mortality nor signs of systemic toxicity. Based on the study results, the dermal LD50 was determined to be greater than 2000 mgC18/C18 unsatd.-Glucamide/ kg body weight.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

2 000 mg/kg bw

Quality of whole database:

Data reliable and meet criteria for classification & labelling requirements.

Justification for classification or non-classification

Based on the results from an OECD TG 423 guideline study which revealed a LD50 cut-off value of 5000 mg/kg body weight, no classification according to CLP of Glucamide OL is warranted with regard to acute oral toxicity.

Based on the results from an OECD 402 guideline study which revealed a LD50 greater 2000 mg/kg body weight, no classification of Glucamide OL according to CLP is warranted with regard to acute dermal toxicity.