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Description of key information

Acute Toxicity: Oral, van Sas (2018)

Under the conditions of this study, the acute oral LD50 of the test material was established to exceed 2 000 mg/kg bodyweight.

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:
10 September 2018 to 09 October 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:
2001
Deviations:
no
Qualifier:
according to guideline
Guideline:
EU Method B.1 tris (Acute Oral Toxicity - Acute Toxic Class Method)
Version / remarks:
2008
Deviations:
no
Qualifier:
according to guideline
Guideline:
EPA OPPTS 870.1100 (Acute Oral Toxicity)
Version / remarks:
2002
Deviations:
no
Qualifier:
according to guideline
Guideline:
other: Appendix to Director General Notification, No. 12-Nousan-8147. Agricultural Production Bureau, Ministry of Agriculture, Forestry and Fisheries of Japan (JMAFF)
Version / remarks:
November 2000, including the most recent revisions.
Deviations:
no
GLP compliance:
yes
Test type:
acute toxic class method
Limit test:
yes
Species:
rat
Strain:
Wistar
Remarks:
Crl: WI(Han)
Sex:
female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Females nulliparous and non-pregnant: Yes
- Age at study initiation: Approximately 9-12 weeks old
- Weight at study initiation: 160 to 205 g
- Fasting period before study: Animals were deprived of food overnight (for a maximum of 20 hours) prior to dosing and until 3-4 hours after administration of the test item. Water was available.
- Housing: On arrival and following assignment to the study, animals were group housed (up to 3 animals of the same sex and same dosing group together) in polycarbonate cages (height 18 cm.) containing sterilised sawdust as bedding material equipped with water bottles. Animals were separated during designated procedures/activities.
- For psychological/environmental enrichment, animals were provided with paper, except when interrupted by study procedures/activities.
- Diet: Ad libitum
- Water: Ad libitum
- Acclimation period: The animals were allowed to acclimate to the Test Facility toxicology accommodation for at least 5 days before the commencement of dosing.

ENVIRONMENTAL CONDITIONS
- Temperature: daily mean 21 °C
- Humidity: 37 to 69 %
- Air changes: Ten or greater air changes per hour with 100 % fresh air (no air recirculation) were maintained in the animal rooms.
- Photoperiod: A 12 hour light/12 hour dark cycle was maintained.
Route of administration:
oral: gavage
Vehicle:
unchanged (no vehicle)
Details on oral exposure:
MAXIMUM DOSE VOLUME APPLIED:
The dose volume for each animal was based on the body weight measurement prior to dosing. Dose volume (mL/kg body weight) was calculated as follows:
Dose level (g/kg) / density (g/cm^3).

DOSAGE PREPARATION
- The test material was administered as received.
- The dosing formulations were stirred continuously during dose administration

CLASS METHOD
- Rationale for the selection of the starting dose: The oral route was selected as it is a possible route of human exposure during manufacture, handling or use of the test material.
- The dose levels were based on the OECD test guidelines and were selected from the series 5 (lowest dose level), 50, 300 and 2 000 (highest dose level) mg/kg body weight. The starting dose level should be the one that is likely to produce mortality in at least some of the animals and was selected based on available toxicity data of the test material.
- The toxicity of the test material was assessed by stepwise treatment of groups of 3 females. The absence or presence of mortality of animals dosed at one step determined the next step, based on the test procedure defined in the guidelines. The onset, duration and severity of the signs of toxicity were taken into account for determination of the time interval between the dose groups. The first group was treated at a dose level of 2 000 mg/kg. Based on the results, one additional group was dosed at 2 000 mg/kg.
Doses:
2 000 mg/kg body weight
No. of animals per sex per dose:
6 females
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Throughout the study, animals were observed for general health/mortality and moribundity twice daily, in the morning and at the end of the working day. Animals were not removed from cage during observation, unless necessary for identification or confirmation of possible findings. Post-dose observations were performed at periodic intervals on the day of dosing (at least three times) and once daily thereafter. The observation period was 14 days. All the animals were examined for reaction to dosing. The onset, intensity and duration of these signs was recorded (if appropriate). Signs were graded for severity and the maximum grade was predefined at 3 or 4. Grades were coded as slight (grade 1), moderate (grade 2), severe (grade 3) and very severe (grade 4). For certain signs, only its presence (grade 1) or absence (grade 0) was scored.
Animals were weighed individually on Day 1 (pre-dose), 8 and 15. A fasted weight was recorded on the day of dosing.
- Necropsy of survivors performed: Yes. All animals were sacrificed by oxygen/carbon dioxide procedure at the end of the observation period. All animals assigned to the study were subjected to necropsy and descriptions of all internal macroscopic abnormalities were recorded.
Statistics:
All results presented in the tables of the report are calculated using values as per the raw data rounding procedure and may not be exactly reproduced from the individual data presented.
The oral LD50 value of the test item was ranked within the following ranges: 0-5, 5-50, 50-300 or 300-2 000 mg/kg b.w. or as exceeding 2 000 mg/kg b.w. The LD50 cut-off value was established based on OECD guideline 423. No statistical analysis was performed (The method used is not intended to allow the calculation of a precise LD50 value).
The results were evaluated according to:
- Globally Harmonised System of Classification and Labelling of Chemicals (GHS) of the United Nations (2017) (including all amendments).
- Regulation (EC) No 1272/2008 of the European Parliament and of the Council of 16 December 2008 on classification, labelling and packaging of items and mixtures (including all amendments).
Key result
Sex:
female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
No mortality occurred.
Clinical signs:
Hunched posture, uncoordinated movements and/or piloerection were noted for the animals on Day 1.
Body weight:
The mean body weight gain shown by the animals over the study period was considered to be similar to that expected for normal untreated animals of the same age and strain.
Gross pathology:
No abnormalities were found at macroscopic post mortem examination of the animals.
Interpretation of results:
other: Not classified in accordance with EU criteria
Conclusions:
Under the conditions of this study, the acute oral LD50 of the test material was established to exceed 2 000 mg/kg bodyweight.
Executive summary:

The acute oral toxicity of the test material was investigated in accordance with the standardised guidelines OECD 423, EU Method B1.tris, OPPTS 870.1100 and Japanese guidelines, under GLP conditions.

The test material was administered by oral gavage to two consecutive groups of three female Wistar Han rats at 2 000 mg/kg body weight. Animals were subjected to daily observations and weekly determination of body weight. Macroscopic examination was performed after terminal sacrifice (Day 15).

No mortality occurred. Hunched posture, uncoordinated movements and/or piloerection were noted for the animals on Day 1. The mean body weight gain shown by the animals over the study period was considered to be similar to that expected for normal untreated animals of the same age and strain. No abnormalities were found at macroscopic post mortem examination of the animals.

Under the conditions of this study, the acute oral LD50 of the test material in Wistar Han rats was established to exceed 2 000 mg/kg bodyweight.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
2 000 mg/kg bw

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 Toxicity: Oral, van Sas (2018)

The acute oral toxicity of the test material was investigated in accordance with the standardised guidelines OECD 423, EU Method B1.tris, OPPTS 870.1100 and Japanese guidelines, under GLP conditions. The study was awarded a reliability score of 1 in accordance with the criteria set forth by Klimisch et al. (1997).

The test material was administered by oral gavage to two consecutive groups of three female Wistar Han rats at 2 000 mg/kg body weight. Animals were subjected to daily observations and weekly determination of body weight. Macroscopic examination was performed after terminal sacrifice (Day 15).

No mortality occurred. Hunched posture, uncoordinated movements and/or piloerection were noted for the animals on Day 1. The mean body weight gain shown by the animals over the study period was considered to be similar to that expected for normal untreated animals of the same age and strain. No abnormalities were found at macroscopic post mortem examination of the animals.

Under the conditions of this study, the acute oral LD50 of the test material in Wistar Han rats was established to exceed 2 000 mg/kg bodyweight.

Justification for classification or non-classification

In accordance with the criteria for classification as defined in Annex I, Regulation (EC) No 1272/2008, the substance does not require classification with respect to acute oral toxicity.