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Description of key information

An acute oral toxicity study was conducted with 5 female Crl:WI rats according to the OECD Guideline 425. Under the conditions of this study, the estimated acute oral median lethal dose (LD50) of the test item was found to be greater than 2000 mg/kg bw in female Crl:WI rats.

An acute dermal toxicity study was performed according to OECD Guideline 402. The median lethal dose (LD50) of the test substance after a single dermal administration was greater than 2000 mg/kg bw in male and female CRL:(WI) rats.

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:
18 May 2016 to 14 June 2016
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 425 (Acute Oral Toxicity: Up-and-Down Procedure)
Deviations:
no
GLP compliance:
yes
Test type:
up-and-down procedure
Limit test:
no
Species:
rat
Strain:
other: Crl:WI Wistar rats
Sex:
female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories, Research Models and Services, Germany GmbH, Sandhofer Weg 7, D-97633 Sulzfeld, Germany.
- Females (if applicable) nulliparous and non-pregnant: Yes
- Age at study initiation: 8 - 10 weeks old
- Weight at study initiation: 201 - 218g
- Fasting period before study: Overnight prior to dosing
- Housing: Animals were housed individually in Type II polypropylene/polycarbonate cages. Animals were housed with deep wood sawdust bedding to allow digging and other normal rodent activities.
- Diet (e.g. ad libitum): Yes
- Water (e.g. ad libitum): Yes
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19.9 - 25.0°C
- Humidity (%): 32 - 70%
- Air changes (per hr): 15 - 20 air changes per hour
- Photoperiod (hrs dark / hrs light): 12 hours light from 6:00am to 6:00pm
Route of administration:
oral: gavage
Vehicle:
CMC (carboxymethyl cellulose)
Details on oral exposure:
VEHICLE
- Concentration in vehicle: 17.5 mg/L, 55 mg/L and 200 mg/L for 175, 500 and 2000 mg/kg bw doses respectively.
- Amount of vehicle (if gavage): 1% Carboxymethyl cellulose (CMC)

MAXIMUM DOSE VOLUME APPLIED: 10 mL/kg bw

Doses:
175, 550 and 2000 mg/kg body weight
No. of animals per sex per dose:
175 mg/kg bw = 1 animal
550 mg/kg bw = 1 animal
2000 mg/kg bw = 3 animals
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: animals were observed for clinical signs 30 minutes after dosing, then at approximately 1, 2, 3, 4 and 6 hours after dosing and once each day for 14 days thereafter. Body weights were recorded on days -1, 0 (before treatment), 7 and 14.
- Necropsy of survivors performed: yes
- Other examinations performed: All animals were necropsied and subject to gross macroscopic examination.
Statistics:
The LD50 was calculated using the AOT425StatPgm program. This program was prepared for the US Environmental Protection Agency by Westat, May 2001 and updated by the US EPA June 2003. This programme was constructed using the most appropriate method to estimate the LD50.
Key result
Sex:
female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Remarks on result:
not determinable due to absence of adverse toxic effects
Mortality:
There was no mortality during the study
Clinical signs:
At dose level 175 mg/kg bw, hunched back was observed only on the day of treatment in 1/1 animals.
At dose level 550 mg/kg bw, hunched back and decreased activity were observed only on the day of treatment in 1/1 animals.
At dose level 2000 mg/kg bw, hunched back in 3/3 animals, decreased activity in 2/3 animals, incoordination in 1/3 animals and piloerection in 1/3 animals on the day of treatment.
There were no further clinical signs after Day 0 at any dose level.
Body weight:
There were no treatment related effects on body weight or body weight gain
Gross pathology:
At necropsy there were no observations to be reported at any dose level
Interpretation of results:
GHS criteria not met
Conclusions:
An acute oral toxicity study was conducted with 5 female Crl:WI rats according to the OECD guideline 425. Under the conditions of this study, the estimated acute oral median lethal dose (LD50) of the test item was found to be greater than 2000 mg/kg bw in female Crl:WI rats.
Executive summary:

An acute oral toxicity (up and down procedure) study was conducted with 5 female Crl:WI rats according to the OECD guideline 425.  

Animals were treated with a single oral (gavage) dose of the test substance at dose levels of 175, 550 or 2000 mg/kg body weight (bw) followed by a 14-day observation period. The animals were fasted overnight prior to treatment and food was returned 3 hours after dosing. Animals were observed individually after dosing at 30 minutes, then 1, 2, 3, 4 and 6 hours post treatment and once each day for 14 days thereafter. Body weight was measured on Day -1, just before dosing and weekly thereafter. All animals were examined macroscopically at the end of the observation period.

There was no mortality during the study. At dose level 175 mg/kg bw, hunched back was observed only on the day of treatment in 1/1 animals. At dose level 550 mg/kg bw, hunched back and decreased activity were observed only on the day of treatment in 1/1 animals. At dose level 2000 mg/kg bw, hunched back in 3/3 animals, decreased activity in 2/3 animals, incoordination in 1/3 animals and piloerection in 1/3 animals on the day of treatment.

There were no further clinical signs after Day 0 at any dose level. There were no treatment related effects on body weight or body weight gain. Body weights were within the range commonly recorded for this strain and age. At necropsy, there were no observations to be reported at a dose level of 175, 550 or 2000 mg/kg bw.

Under the conditions of this study, the estimated acute oral median lethal dose (LD50) of the test item was found to be greater than 2000 mg/kg bw in female Crl:WI rats.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
2 000 mg/kg bw
Quality of whole database:
Klimisch 1 (reliable without restriction)

Acute toxicity: via inhalation route

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:
24 May 2016 to 09 June 2016
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Deviations:
yes
Remarks:
Due to technical reason, temperature values (3 occasions, maximum of 25.5°C) outside the expected range of 17-23°C were recorded. This deviation is not considered to impact the results or integrity of this study as confirmed by the site veterinarian.
GLP compliance:
yes
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
other: CRL:(WI)
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories, Research Models and Services, Germany GmbH, Sandhofer Weg 7, D-97633 Sulzfeld, Germany.
- Females (if applicable) nulliparous and non-pregnant: Yes
- Age at study initiation: Young adults (age range not given)
- Weight at study initiation: Between 221g and 254g (at dosing)
- Fasting period before study: Not reported
- Housing: Animals were housed individually in Type II. polypropylene/polycarbonate cages. Animals were housed with deep wood sawdust bedding to allow digging and other normal rodent activities.
- Diet (e.g. ad libitum): Yes
- Water (e.g. ad libitum): Yes
- Acclimation period: At least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21.0 – 25.5 °C
- Humidity (%): 30 – 68%
- Air changes (per hr): 15 - 20
- Photoperiod (hrs dark / hrs light): 12 hours light daily, from 6.00 a.m. to 6.00 p.m.
Type of coverage:
semiocclusive
Vehicle:
other: The test item was administered as supplied in a single dose. Sufficient water was used to dampen the test material to ensure good contact with the skin.
Details on dermal exposure:
TEST SITE
- Area of exposure: back of animal
- % coverage: Approximately 10% area of the toal body surface
- Type of wrap if used: Semi-occlusive plastic wrap

REMOVAL OF TEST SUBSTANCE
- Washing (if done): Yes, using water at body temperature
- Time after start of exposure: 24 hours

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 2000 mg/kg body weight
Duration of exposure:
24 hours
Doses:
2000 mg/kg body weight
No. of animals per sex per dose:
Five male and five female
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Necropsy of survivors performed: Yes
- Other examinations performed: clinical signs, skin irritation, body weight
- Frequency of observations and weighing: Clinical observations at 1 and 5 hours after treatment and then daily. Body weights recorded on day ) (just before treatment) and on days 7 and 14.
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
No mortality occured during the study
Clinical signs:
No adverse clinical signs or any type of local effect was observed after treatment with the test item or during the 14 day observation period
Body weight:
There were no treatment related changes in body weight. The body weights were within the range commonly recorded for the strain and animal age.
Gross pathology:
No macroscopic changes were observed
Other findings:
- Other observations: No treatment related skin irritation was observed in any animal throughout the study.
Interpretation of results:
GHS criteria not met
Conclusions:
An acute dermal toxicity study was performed according to OECD Guideline 402. The median lethal dose (LD50) of the test substance after a single dermal administration was greater than 2000 mg/kg bw in male and female CRL:(WI) rats.
Executive summary:

An acute dermal toxicity study was performed according to OECD Guideline 402. Five male and five female CRL:(WI) rats were treated with a single, semi occlusive dermal application of the test substance at the limit dose of 2000 mg/kg body weight (bw). Test item was administered as supplied without dilution. The application period was 24 hours, followed by a 14-day observation period. Clinical observations along with a check of viability and mortality were performed on all animals at 1 and 5 hours after dosing and daily for 14 days thereafter. Body weight was measured prior to dosing on Day 0 and on Days 7 and 14. All animals were euthanized and subjected to a gross macroscopic examination at the end of the 2 weeks observation period.

No mortality occurred during the study. No adverse clinical signs or any type of local effect was observed after treatment with the test item or during the 14 day observation period. There were no treatment related changes in body weight. The body weights were within the range commonly recorded for this strain and age. No macroscopic changes were seen.

The median lethal dose (LD50) of the test substance after a single dermal administration was greater than 2000 mg/kg bw in male and female CRL:(WI) rats.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
2 000 mg/kg bw
Quality of whole database:
Klimisch 1 (reliable without restriction)

Additional information

Justification for classification or non-classification

Based on the reliable and valid studies on acute oral toxicity (OECD TG 425) and acute dermal toxicity (OECD TG 402), the substance does not need to be classified for acute toxicity in accordance with Regulation (EC) No. 1272/2008.