Registration Dossier

Administrative data

Description of key information

Oral (OECD 423), rat: LD50 cut-off value = 500 mg/kg bw
Dermal (OECD 402), rat: LD50 > 5000 mg/kg bw

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:
5 Apr - 6 May 2016
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Reference:
Composition 1
Qualifier:
according to
Guideline:
OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)
Version / remarks:
adopted 17 December 2001
Deviations:
no
GLP compliance:
yes
Test type:
acute toxic class method
Limit test:
no
Test material information:
Composition 1
Species:
rat
Strain:
other: Crl:CD(SD), SPF
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS
- Age at study initiation: 8 weeks
- Weight at study initiation: 172.8 - 195.7 g
- Fasting period before study: overnight, approx. 16 h prior and 4 h after dosing
- Housing: 1 animal per cage in stainless wire mech cages (260W x 350D x 210H mm)
- Diet: Teklad Certified Irradiated Global 18% Protein Rodent Diet 2918C (Envigo RMS. Ltd., USA), ad libitum
- Water: public tap water filtered and irradiated by ultraviolet light, ad libitum
- Acclimation period: 4 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21.2 - 23.1
- Humidity (%): 45.1 - 54.5
- Air changes (per hr): 10 - 15
- Photoperiod (hrs dark / hrs light): 12/12
Route of administration:
oral: gavage
Vehicle:
corn oil
Details on oral exposure:
MAXIMUM DOSE VOLUME APPLIED: 5 mL/kg bw

CLASS METHOD
- Rationale for the selection of the starting dose: Due to the low expected toxicity of the test substance 2000 mg/kg bw was selected as the starting dose.
Doses:
2000 mg/kg bw (step 1)
300 mg/kg bw (step 2 and 3)
No. of animals per sex per dose:
6 (300 mg/kg bw); 3 (2000 mg/kg bw)
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Animals were observed 30 min and 1, 2, 4 and 6 h after dosing and thereafter once daily for 14 days. Individual body weights were recorded prior to dosing on Day 0 and on Days 1, 3, 7 and on the day of necropsy, Day 14. The body weights of animals found dead during the observation period were recorded prior to necropsy.
- Necropsy of survivors performed: yes
- Other examinations performed: Histopathological examination was performed on animals with gross findings in the thoracic cavity, stomach and/or liver at 2000 mg/kg bw.
Key result
Sex:
female
Dose descriptor:
LD50
Effect level:
500 mg/kg bw
Based on:
test mat.
Remarks on result:
other: LD50 cut-off according to OECD 423
Mortality:
All animals dosed at 2000 mg/kg were found dead on Days 1, 2 and 3 after dosing, respectively.
No mortality was observed at 300 mg/kg bw.
Clinical signs:
Salivation and/or lacrimation were observed in two animals at 2000 mg/kg bw from 0.5 and 1 h after dosing. Abnormal gait, salivation, staining around mouth, decrease in locomotor activity, decrease of fecal volume and/or lacrimation were observed on Days 1, 2 and 3 after dosing. Three animals were found dead in a state of lying on side, dorsal position, prone position or staining around mouth on Days 1, 2 and 3 after dosing, respectively. These clinical signs were considered to be test substance-related.
During the observation period, no clinical abnormalities were observed in any animal at 300 mg/kg bw.
Body weight:
A tendency to suppressed body weight gain was observed in two animals at 2000 mg/kg bw on Day 1. These changes were considered to be test substance-related.
Normal body weight gains were observed in all animals at 300 mg/kg bw.
Gross pathology:
Macroscopic examination of dead animals revealed gross findings in the thoracic cavity, stomach and/or liver.
No grossly visible evidence of morphological abnormalities was observed in any animal at 300 mg/kg bw.
Other findings:
- Histopathology: Histopathological examination of the liver revealed granular and eosinophilic hepatocellular degeneration, single cell necrosis of hepatocytes and perivenular mononuclear cell infiltration. These findings showed centrilobular distribution. In the forestomach, epithelial necrosis with submucosal hemorrhage and edema were observed. The hepatic and gastric findings were considered to be associated with gross findings in the liver and forestomach, respectively. These necropsy findings were considered to be test substance-related.
Interpretation of results:
other: Acute Tox. Cat. 4
Remarks:
according to Regulation (EC) 1272/2008
Conclusions:
In this acute oral toxicity study in rats a LD50 cut-off value of 500 mg/kg bw was found.
Executive summary:

Three animals dosed at 2000 mg/kg died on Days 1, 2 and 3 after dosing.

There were no deaths of any of the six animals at 300 mg/kg. No test substance-related effects were observed in clinical signs, body weight data or necropsy findings in any animal at 300 mg/kg.

Based on the result of the acute oral toxicity study in Sprague-Dawley rats the test item was classified to be Category 4

The LD50 cut-off is 500 mg/kg bw.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LD50
500 mg/kg bw
Quality of whole database:
The available information comprises an adequate and reliable study (Klimisch score 1), and is thus sufficient to fulfil the standard information requirements set out in Annex VII, 8.5, of Regulation (EC) No 1907/2006.

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:
11 - 25 Nov 1985
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study with acceptable restrictions
Remarks:
No information on purity was given and reduced number of test animals per sex.
Reference:
Composition 1
Qualifier:
according to
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Version / remarks:
1981
Deviations:
yes
Remarks:
no data on purity of test substance, only 2 animals per sex instead of 5 animals per sex
GLP compliance:
yes
Test type:
standard acute method
Limit test:
no
Test material information:
Composition 1
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Age at study initiation: approx. 10-12 weeks
- Weight at study initiation: 228-293 g (males), 197-234 g (females)
- Housing: individually during the 24 h exposure period and subsequently up to 4 animals of the same sex per cage in polypropylene cages, bedding sawdust
- Diet: Rat and Mouse Expanded Diet No.1 (Special Diets Services Limited, Witham, UK), ad libitum
- Water: mains tap water, ad libitum
- Acclimation period: minimum 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19-21
- Humidity (%): 45-65
- Air changes (per hr): approx. 10
- Photoperiod (hrs dark / hrs light): 12/12
Type of coverage:
semiocclusive
Vehicle:
unchanged (no vehicle)
Details on dermal exposure:
TEST SITE
- Area of exposure: skin of the dorsal, lateral and ventral regions (6 cm x 12 cm)
- % coverage: 10%
- Type of wrap if used: The treated skin was covered with a surgical gauze patch (7 cm x 4 cm) which was held in place with a strip of elastic adhesive bandage (7.5 cm wide and 25-30 cm long) wrapped around the trunk.

REMOVAL OF TEST SUBSTANCE
- Washing: The skin and surrounding hair were sponged thoroughly with warm water, rinsed and dried using absorbant paper.
- Time after start of exposure: 24 h

TEST MATERIAL
- Amounts applied: 0.06, 0.47, 2.33 and 5.82 mL/kg bw
- Constant concentration used: yes
Duration of exposure:
24 h
Doses:
50, 400, 2000 and 5000 mg/kg bw
No. of animals per sex per dose:
2
Control animals:
not required
Details on study design:
- Duration of observation period following administration: 14 days
Frequency of observations and weighing: Animals were observed 1 and 4 h after administration and subsequently once daily for 14 days. Mortality and evidence of overt toxicity was recorded at each observation. Individual body weights were determined on Days 0, 7 and 14.
- Necropsy of survivors performed: yes
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 5 000 mg/kg bw
Based on:
test mat.
Mortality:
No mortality occurred during the study period.
Clinical signs:
No clinical signs of toxicity were noted during the 14-day observation period.
Body weight:
All treated animals showed normal bodyweight gains during the study period.
Gross pathology:
No abnormalities were noted at necropsy.
Interpretation of results:
other: CLP/EU GHS criteria not met, no classification required according to Regulation (EC) No 1272/2008
Conclusions:
In this acute dermal toxicity study a LD50 value > 5000 mg/kg bw in male and female rats was found.
Executive summary:

An acute dermal toxicity study in rats was performed according to OECD 402 with 50, 400, 2000 and 5000 mg/kg bw of the test substance with 2 animals per sex and dose. No mortality was observed and the animals showed no signs of toxicity. Due to these results it was concluded that the dermal LD50 was > 5000 mg/kg bw in rats.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Quality of whole database:
The available information comprises an adequate and reliable study (Klimisch score 2). This study is not a standard information requirement set out in Annex VII of Regulation (EC) No 1907/2006 and is thus considered as additional information.

Additional information

Oral

The acute oral toxicity of the test substance was assessed in a study according to OECD Guideline 423 and in compliance with GLP (2016). In this acute oral toxicity study in rats a LD50 cut-off value of 500 mg/kg bw was found.

Dermal

The acute dermal toxicity of the test substance was assessed in a study according to OECD Guideline 402 and in compliance with GLP (1985). In this acute dermal toxicity study a LD50 value > 5000 mg/kg bw in male and female rats was found.

Justification for classification or non-classification

The available data on acute oral toxicity of the test substance meet the criteria for Acute Tox. Cat. 4 (H302) according to Regulation (EC) 1272/2008.

The available data on acute dermal toxicity do not meet the criteria for classification according to Regulation (EC) 1272/2008, and are therefore conclusive but not sufficient for classification.