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Description of key information

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:
November 1, 2017 - March 12, 2018
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)
Version / remarks:
adopted on December 17, 2001
Deviations:
no
Qualifier:
according to guideline
Guideline:
EU Method B.1 (Acute Toxicity (Oral))
Version / remarks:
Council Regulation (EC) No. 440/2008 laying down test methods pursuant to Regulation (EC) No. 1907/2006 of the European Parliament and the council on the Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH).
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Test type:
acute toxic class method
Limit test:
no
Specific details on test material used for the study:
TREATMENT OF TEST MATERIAL PRIOR TO TESTING
- Final preparation of a solid: The test item preparation was made directly before administration. Appropriate amounts of the test item were suspended in the vehicle using a spatula, a mini shaker (Vortex Genie 2®, Scientific Industries Inc, New York, USA), Ultra-Turrax device (Ultra-Turrax T25, IKA®-Werke GmbH & Co. KG, Staufen, Germany) and a magnetic stirrer. The test item preparation was administered within less than 1 hour after preparation. The stability of the test item in the vehicle was not investigated.
Species:
rat
Strain:
Wistar
Sex:
female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Wiga GmbH, Sulzfeld, Germany
- Females (if applicable) nulliparous and non-pregnant: yes
- Age at start of study: 9 weeks
- Weight at study initiation: 154 - 178g
- Fasting period before study: 17 hours before until up to 4 hours after treatment
- Housing: separately in type III Makrolon cages
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: at least 7 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22.3 - 23.0°C
- Humidity (%): 44.5 - 58.0%
- Photoperiod (hrs dark / hrs light): 12 hour light - 12 hour dark regime

IN-LIFE DATES: From: day 1 To: day 15
Route of administration:
oral: gavage
Vehicle:
methylcellulose
Remarks:
Methocel K4M Premium solution
Details on oral exposure:
VEHICLE
- Concentration in vehicle: 200 g/L and 30 g/L
- Amount of vehicle (if gavage): 10 mL/kg
- Justification for choice of vehicle: well tolerated and established standard vehicle

Doses:
2000 mg/kg bw and 300 mg/kg bw
No. of animals per sex per dose:
300 mg/kg bw: 6 (f)
2000 mg/kg bw: 3 (f)
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations: daily
- Frequency of weighing: day 1, 2, 4, 6, 8, 11, 13 and 15
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight, gross pathology
Statistics:
Standard statistical methods have been applied for data processing.
Key result
Sex:
female
Dose descriptor:
LD50
Effect level:
> 300 - <= 2 000 mg/kg bw
Based on:
test mat.
Mortality:
The rats treated with 300 mg/kg survived the observation period. One rat treated with
2000 mg/kg died on day 5 of the experimental phase. The other two rats treated with 2000 mg/kg were killed in moribund condition on day 6 of the experimental phase.
Clinical signs:
No clinical signs of toxicity were observed in all rats treated with 300 mg/kg. The rat treated with 2000 mg/kg which died on day 5 showed locomotor disturbance on day 2 up to day 4 and sunken flanks on day 5. The two rats treated with 2000 mg/kg which were killed in moribund on day 6 condition showed sunken flanks on day 5 and 6.
Body weight:
Three rats treated with 300 mg/kg showed clear reduction of body weight only on day 4 of the experimental phase. The body weight development of all other the rats treated with 300 mg/kg was inconspicuous throughout the study. The body weight of the rats treated with 2000 mg/kg increased the first day after treatment and then declined continuously until they died or were killed in moribund condition. .
Gross pathology:
The gross pathological examination revealed no treatment-related organ alterations in rats dosed with 300 mg/kg. Animal no. 4 showed findings in the reproduction tract, that were considered incidental and spontaneous in nature. In rats dosed with 2000 mg/kg, animal no. 7 was found dead on study day 5 and animals no. 8, 9 were killed in moribund state on day 6. No organ alterations were identified during the gross pathological examination that could be related to treatment. For clarification of possible causes of death and moribund status, liver, spleen, stomach, intestines, and kidney were further examined. Histopathology revealed no findings in the organs examined.

Objective

The objective of the present study was to identify potential toxic effects of the test item after single oral administration to rats in a stepwise procedure.

Study Design

The study was started with 300 mg/kg in 6 female rats and continued with further 3 females treated with 2000 mg/kg.

Mortality and clinical signs were monitored for at least 6 hours after administration and then daily. All animals were weighed before treatment (day 1) and on days 2, 4, 6, 8, 11, 13, and 15. At the end of the observation period, all surviving rats were sacrificed and subjected to a detailed necropsy.

Results

The rats treated with 300 mg/kg survived the observation period. One rat treated with
2000 mg/kg died on day 5 of the experimental phase. The other two rats treated with 2000 mg/kg were killed in moribund condition on day 6 of the experimental phase.

No clinical signs of toxicity were observed in all rats treated with 300 mg/kg. The rat treated with 2000 mg/kg which died on day 5 showed locomotor disturbance on day 2 up to day 4 and sunken flanks on day 5. The two rats treated with 2000 mg/kg which were killed in moribund on day 6 condition showed sunken flanks on day 5 and 6.

Three rats treated with 300 mg/kg showed clear reduction of body weight only on day 4 of the experimental phase. The body weight development of all other the rats treated with 300 mg/kg was inconspicuous throughout the study. The body weight of the rats treated with 2000 mg/kg increased the first day after treatment and then declined continuously until they died or were killed in moribund condition.

The gross pathological examination revealed no treatment-related organ alterations in rats dosed with 300 mg/kg. Animal no. 4 showed findings in the reproduction tract, that were considered incidental and spontaneous in nature. In rats dosed with 2000 mg/kg, animal no. 7 was found dead on study day 5 and animals no. 8, 9 were killed in moribund state on day 6. No organ alterations were identified during the gross pathological examination that could be related to treatment. For clarification of possible causes of death and moribund status, liver, spleen, stomach, intestines, and kidney were further examined. Histopathology revealed no findings in the organs examined.

Conclusion

Under the conditions of the present study, the LD50 value for the test item is expected to be greater than 300 and smaller than or equal 2000 mg/kg bw after single oral administration in rats.

Interpretation of results:
Category 4 based on GHS criteria
Conclusions:
The test item has no acute toxic potential under the conditions of the present study, and the LD50 value is expected to be > 300 <= 2000 mg/kg bw after single oral administration in rats.
Executive summary:

This study was performed according to GLP and is fully compliant with OECD TG 423. The test item has no acute toxic potential under the conditions of the present study, and the LD50 value is expected to be > 300 <= 2000 mg/kg after single oral administration in rats.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
discriminating dose
Value:
300 mg/kg bw
Quality of whole database:
Guideline study under GLP conditions

Acute toxicity: via inhalation route

Endpoint conclusion
Endpoint conclusion:
no study available

Acute toxicity: via dermal route

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Acute oral toxicity

The LD50 of the test item was determined to be > 300 <= 2000 mg/kg bw after single oral administration in rats.

Justification for classification or non-classification

Based on the data provided, the test item is classified for acute oral toxicity cat. 4 and labelled with H302 according to Regulation (EC) No 1272/2008.