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

Acute Toxicity: dermal

Administrative data

Endpoint:

acute toxicity: dermal

Type of information:

experimental study

Adequacy of study:

key study

Study period:

2013-09-20 to 2013-11-25

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 402 (Acute Dermal Toxicity)

Deviations:

no

Test guideline 2

Qualifier:

according to guideline

Guideline:

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

Deviations:

no

Test guideline 3

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

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:

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. 801)
- 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. 60613)
- Certificates of food, water and bedding are filed at BSL BIOSERVICE
- Adequate acclimatisation period (at least five days) under laboratory conditions

Administration / exposure

Type of coverage:

semiocclusive

Vehicle:

water

Details on dermal exposure:

Preparation of the Animals:
The animals were marked for individual identification by tail painting.
Approximately 24 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 aqua ad injectionem (AlleMan Pharma, lot no. 26210s1-2, expiry date: 30/09/2013).

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; lot no. 231073; expiry date: 31/07/2013) at the dosage of approximately 5 mL/kg bw.
All animals were subjected to gross necropsy. All gross pathological changes were recorded.


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.
With few exceptions, toxicology and pathology data were captured, using the validated departmental computerized system E-Workbook (version 9.1.1.1, ID Business Solutions Ltd).
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.

Results and discussion

Effect levels

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

act. ingr.

Mortality:

No mortality was observed.

Clinical signs:

other: No treatment-related effects were observed.

Gross pathology:

No treatment-related effects were observed.

Other findings:

Reversible signs of dermal irritation were observed at the treated skin sites.

Applicant's summary and conclusion

Interpretation of results:

study cannot be used for classification

Remarks:

Migrated information

Conclusions:

Under the conditions of the present study, single dermal application of the test item C8/10-Glucamide AC93/13 to rats at a dose of 2000 mg/kg body weight was associated with no mortality and neither signs of toxicity but signs of irritation. The dermal LD50 was determined to be > 2000 mg C8/10-Glucamide AC93/13 / kg body weight.
In conformity with the criteria given in Annex VI to Commission Directive 2001/59/EC the test item C8/10-Glucamide AC93/13 has no
obligatory labelling requirement for percutaneous toxicity.
According to Annex I of Regulation (EC) 1272/2008 the test item C8/10-Glucamide AC93/13 has no obligatory labelling requirement
for percutaneous toxicity and is unclassified.
According to GHS (Globally Harmonized Classification System) the test item C8/10-Glucamide AC93/13 has no obligatory labelling
requirement for percutaneous toxicity and is unclassified.

Executive summary:

With regard to acute dermal toxicity, single administration of 2000 mg Glucamide 810 per kg body weight to rats according OECD TG 402 was not associated with mortality or with any clinical signs of toxicity. Reversible signs of dermal irritation were observed at the treated skin sites. The acute systemic toxicity (LD50) of Glucamide 810 (Test material GA AC93/13, 93.9%) following dermal application in rats is thus greater 2000 mg/kg body weight. The absence of toxicity following dermal exposure is supported by the read-across compound Glucamide 24 (Test material, E-4194.01, 98.8%), which revealed also a LD50 value greater than 2000 mg/kg body weight via the dermal route when tested in male and female New Zealand White rabbits.