Registration Dossier
Registration Dossier
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EC number: 600-496-4 | CAS number: 103877-51-6
Endpoint summary
Administrative data
Description of key information
Acute oral toxicity: Key study. Test method according to OECD 420, GLP study. The LD50 of the test item is higher than 50 mg/ kg body weight and lower than 300 mg/kg body weight by oral route in the rat.
Key value for chemical safety assessment
Acute toxicity: via oral route
Link to relevant study records
- Endpoint:
- acute toxicity: oral
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 30 June 2020 - 18 August 2020
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 420 (Acute Oral Toxicity - Fixed Dose Method)
- Deviations:
- yes
- Remarks:
- A relative humidity higher than 70% was registered on 15 and 16 August 2020. The maximum value measured was 72%. As no effect was noted on the health of the animals, this deviation is considered as without impact on the conclusion of the study.
- GLP compliance:
- yes (incl. QA statement)
- Test type:
- fixed dose procedure
- Limit test:
- yes
- Species:
- rat
- Strain:
- Sprague-Dawley
- Remarks:
- (SPF Caw)
- Sex:
- female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Elevage JANVIER LABS (53940 Le Genest St Isle – France)
- Females nulliparous and non-pregnant: yes
- Age at study initiation: 8 or 9 weeks
- Weight at study initiation: 197.6 g (average in steps 1 & 2, SD = 10.1 g), 208 g (step 3), and 194.6 g (average in steps 4 & 5, SD = 8.6 g)
- Fasting period before study: Food was removed on D-1 and then redistributed 4 hours after the test item administration.
- Housing: Rats were housed by group of three in solid-bottomed clear polycarbonate cages with a stainless steel mesh lid. Each cage contains sawdust bedding which was changed at least 2 times a week. Each cage was installed in conventional air conditioned animal husbandry.
- Diet (e.g. ad libitum): Ad libitum. Teklad Global 16% Protein Rodent Diet (ENVIGO 2016).
- Water (e.g. ad libitum): Ad libitum. Drinking water (tap-water from public distribution system). Microbiological and chemical analyses of the water were carried out once every six months by Bureau Veritas – Eurofins (FRANCE).
- Acclimation period: the animals were acclimatized for at least 5 days before treatment.
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19ºC to 25ºC
- Humidity (%): 30 to 70%
- Air changes (per hr): ≥ 10 air changes/hour
- Photoperiod (hrs dark / hrs light): 12 hours light (07.00 to 19.00) and 12 hours dark cycle.
- Route of administration:
- oral: gavage
- Vehicle:
- DMSO
- Details on oral exposure:
- VEHICLE
- Concentration in vehicle: 200, 30 and 5 mg/mL.
- Amount of vehicle (if gavage): 10 mL/kg bw
- Justification for choice of vehicle: Dimethyl sulfoxide (DMSO) was chosen as it produced the most suitable formulation at the requested concentration.
MAXIMUM DOSE VOLUME APPLIED: 10 mL/kg bw
DOSAGE PREPARATION (if unusual): The preparations were stirred using a vortex to obtain pink homogeneous suspensions (Step 1 to Step 3), a white homogeneous suspension (Step 4) or a colourless solution (Step 5) just before the administration.
- Doses:
- 2000 mg/kg bw
- No. of animals per sex per dose:
- Step 1 (2000 mg/kg bw): 1 animal
Step 2 (2000 mg/kg bw): 4 animals
Step 3 (300 mg/kg bw): 1 animal
Step 4 (50 mg/kg bw): 1 animal
Step 5 (50 mg/kg bw): 4 animals. - Control animals:
- yes
- Remarks:
- (study performed on three animals receiving DMSO under requirements of OECD Guideline 423)
- Details on study design:
- - Duration of observation period following administration: 14 days
- Frequency of observations and weighing: At each step, the animals were observed four times on test day 0 (day of administration), i.e. at T0+30 min, T0+1h, T0+3h and T0+4h, and once daily during days 1 to 14 post administration. The body weights were recorded on test day 0 (just before administration) then on D2, D7, and D14.
- Necropsy of survivors performed: yes.
- Clinical signs including body weight: spontaneous activity, Preyer’s reflex (noise), respiratory rate, convulsions, tremors, body temperature, muscle tone, palpebral opening, pupil appearance, salivation, lachrymation, righting reflex, back hair appearance. The body weight evolution of animals treated with the test item was compared with the body weight evolution of the control group.
- Other examinations performed: Macroscopic observations were entered on individual autopsy sheets. No organ was removed and preserved in view to microscopic examinations. - Key result
- Sex:
- female
- Dose descriptor:
- LD50
- Effect level:
- > 50 - <= 300 mg/kg bw
- Based on:
- test mat.
- Mortality:
- Steps 1 and 2: One mortality (1/5) was noted in animals treated at the dose of 2000 mg/kg bw at 48 hours post-dose. Due to the severity of the clinical signs noted in the surviving animals, three rats (3/4) were euthanized in accordance with the principles of animal welfare (two on day 5 and one on day 6). Because of these adverse effects a new sighting study was initiated with the dose of 300 mg/kg bw (step 3).
The animal treated at the dose of 300 mg/kg bw was found dead on day 5.
No mortality was noted in animals treated at the dose of 50 mg/kg body weight (steps 4 and 5). - Clinical signs:
- other: Steps 1 and 2: The mortality and the euthanasia were preceded by a decrease in spontaneous activity (4/4) associated with hypothermia (3/4), piloerection (3/4), swollen leg, red spots and scab (3/4) and injured abdomen (3/4). One animal had a missing fing
- Gross pathology:
- Steps 1 and 2: The macroscopic examinations of the dead and euthanized animals revealed air inside intestines (3/4), cellular lysis of intestine (1/4), a thinning of forestomach and corpus with red spots (3/4). The macroscopic examination of the surviving animal at the end of the study did not reveal treatment related changes.
Step 3: The macroscopic examination of the animal revealed a thinning of forestomach and corpus and black spot on the corpus.
Steps 4 and 5: The macroscopic examination of the animals at the end of the study revealed air inside digestive system and stomach (4/5) and whitish thickening between corpus and forestomach (1/5). - Interpretation of results:
- other: Category 3 (CLP Regulation EC no. 1272/2008)
- Conclusions:
- The LD50 of the test item is higher than 50 mg/ kg body weight and lower than 300 mg/kg body weight by oral route in the rat.
- Executive summary:
The acute oral toxicity of the test item has been tested in accordance with OECD Test Guideline 420, following GLP. Female Sprague-Dawley rats were administered by oral gavage with test item diluted in vehicle DMSO. The sighting study was performed at the dose of 2000 mg/kg bw in one animal. As no effects were observed in the first few days, 4 more females were administered at the same dose of 2000 mg/kg bw. Afterwards, one mortality (1/5) was noted at 48 hours post-dose. Due to the severity of the clinical signs noted in the surviving animals, three rats (3/4) were euthanized (two on day 5 and one on day 6). Because of these adverse effects a new sighting study was initiated with the dose of 300 mg/kg bw (step 3). The animal treated at this dose was found dead on day 5, thus, one more animal was dosed with 50 mg/kg bw (step 4). As this animal survived until the end of the study, the definitive main study was performed with 4 more animals treated at the dose of 50 mg/kg bw (step 5). No mortality was noted in animals treated at the dose of 50 mg/kg bw. A decrease in spontaneous activity (4/5) and Preyer’s reflex (4/5) were noted in the first hours (T0 + 1 hour & T0 + 3 hours) of the test. A noisy breathing (1/5) was noted from 48 hours post-dose and associated with swollen stomach between days 10 and 14. A decrease of body weight (1/5) was noted between days 2 and 14 versus day 0 (-27.09%). The body weight evolution of the other animals (4/5) was normal during the study. The macroscopic examination of the animals at the end of the study revealed air inside digestive system and stomach (4/5) and whitish thickening between corpus and forestomach (1/5). Based on these results, the LD50 of the test item was determined to be higher than 50 mg/ kg bw and lower than 300 mg/kg bw by oral route in the rat.
Reference
Table 1: Observation data sheet. Steps 1 & 2 (2000 mg/kg bw)
OBSERVATIONS: |
FEMALES |
||||
D1 |
Rf 4996 |
Rf 4999 |
Rf 5000 |
Rf 5001 |
Rf 5002 |
Spontaneous activity |
N |
N |
N |
D |
N |
Preyer’s reflex (noise) |
N |
N |
N |
N |
N |
Respiratory rate |
N |
N |
N |
N |
N |
Convulsions |
N |
N |
N |
N |
N |
Tremors |
N |
N |
N |
N |
N |
Body temperature |
N |
N |
N |
N |
N |
Muscle tone |
N |
N |
N |
N |
N |
Palpebral opening |
N |
N |
N |
N |
N |
Pupil appearance |
N |
N |
N |
N |
N |
Salivation |
N |
N |
N |
N |
N |
Lachrymation |
N |
N |
N |
N |
N |
Righting reflex |
N |
N |
N |
N |
N |
Back hair appearance |
N |
N |
N |
N |
N |
MORTALITY |
0 |
0 |
0 |
0 |
0 |
Remarks |
None
|
||||
OBSERVATIONS: |
FEMALES |
||||
D2 |
Rf 4996 |
Rf 4999 |
Rf 5000 |
Rf 5001 |
Rf 5002 |
Spontaneous activity |
N |
N |
N |
|
N |
Preyer’s reflex (noise) |
N |
N |
N |
N |
|
Respiratory rate |
N |
N |
N |
N |
|
Convulsions |
N |
N |
N |
N |
|
Tremors |
N |
N |
N |
N |
|
Body temperature |
N |
N |
N |
N |
|
Muscle tone |
N |
N |
N |
N |
|
Palpebral opening |
N |
N |
N |
N |
|
Pupil appearance |
N |
N |
N |
N |
|
Salivation |
N |
N |
N |
N |
|
Lachrymation |
N |
N |
N |
N |
|
Righting reflex |
N |
N |
N |
N |
|
Back hair appearance |
N |
N |
N |
N |
|
MORTALITY |
0 |
0 |
0 |
1 |
0 |
Remarks |
Animal Rf5001 found dead on day 2 |
||||
OBSERVATIONS: |
FEMALES |
||||
D3 |
Rf 4996 |
Rf 4999 |
Rf 5000 |
Rf 5001 |
Rf 5002 |
Spontaneous activity |
N |
N |
N |
|
N |
Preyer’s reflex (noise) |
N |
N |
N |
N |
|
Respiratory rate |
N |
N |
N |
N |
|
Convulsions |
N |
N |
N |
N |
|
Tremors |
N |
N |
N |
N |
|
Body temperature |
N |
N |
N |
N |
|
Muscle tone |
N |
N |
N |
N |
|
Palpebral opening |
N |
N |
N |
N |
|
Pupil appearance |
N |
N |
N |
N |
|
Salivation |
N |
N |
N |
N |
|
Lachrymation |
N |
N |
N |
N |
|
Righting reflex |
N |
N |
N |
N |
|
Back hair appearance |
N |
N |
N |
N |
|
MORTALITY |
0 |
0 |
0 |
- |
0 |
Remarks |
None |
||||
OBSERVATIONS: |
FEMALES |
||||
D4 |
Rf 4996 |
Rf 4999 |
Rf 5000 |
Rf 5001 |
Rf 5002 |
Spontaneous activity |
N |
D |
D |
|
N |
Preyer’s reflex (noise) |
N |
N |
N |
N |
|
Respiratory rate |
N |
N |
N |
N |
|
Convulsions |
N |
N |
N |
N |
|
Tremors |
N |
N |
N |
N |
|
Body temperature |
N |
D |
D |
N |
|
Muscle tone |
N |
N |
N |
N |
|
Palpebral opening |
N |
N |
N |
N |
|
Pupil appearance |
N |
N |
N |
N |
|
Salivation |
N |
N |
N |
N |
|
Lachrymation |
N |
N |
N |
N |
|
Righting reflex |
N |
N |
N |
N |
|
Back hair appearance |
N |
Pi |
Pi |
N |
|
MORTALITY |
0 |
0 |
0 |
- |
0 |
Remarks |
Rf4999 & Rf5000: swollen right front leg, scab, red spots, open ventral area. Rf5000: missing finger |
||||
OBSERVATIONS: |
FEMALES |
||||
D5 |
Rf 4996 |
Rf 4999 |
Rf 5000 |
Rf 5001 |
Rf 5002 |
Spontaneous activity |
D |
D |
D |
|
N |
Preyer’s reflex (noise) |
N |
N |
N |
N |
|
Respiratory rate |
N |
N |
N |
N |
|
Convulsions |
N |
N |
N |
N |
|
Tremors |
N |
N |
N |
N |
|
Body temperature |
D |
D |
D |
N |
|
Muscle tone |
N |
N |
N |
N |
|
Palpebral opening |
N |
N |
N |
N |
|
Pupil appearance |
N |
N |
N |
N |
|
Salivation |
N |
N |
N |
N |
|
Lachrymation |
N |
N |
N |
N |
|
Righting reflex |
N |
N |
N |
N |
|
Back hair appearance |
Pi |
Pi |
Pi |
N |
|
MORTALITY |
0 |
0 |
0 |
- |
0 |
Remarks |
Rf4996: swollen left front leg, scab, red spots, open ventral area. Rf4999 & Rf5000: swollen right front leg, scab, red spots, open ventral area. Rf5000: missing finger animals Rf4999 & Rf5000 euthanized on day 5 due to apparent suffering |
||||
OBSERVATIONS: |
FEMALES |
||||
D6 |
Rf 4996 |
Rf 4999 |
Rf 5000 |
Rf 5001 |
Rf 5002 |
Spontaneous activity |
D |
|
N |
||
Preyer’s reflex (noise) |
N |
N |
|||
Respiratory rate |
N |
N |
|||
Convulsions |
N |
N |
|||
Tremors |
N |
N |
|||
Body temperature |
D |
N |
|||
Muscle tone |
N |
N |
|||
Palpebral opening |
N |
N |
|||
Pupil appearance |
N |
N |
|||
Salivation |
N |
N |
|||
Lachrymation |
N |
N |
|||
Righting reflex |
N |
N |
|||
Back hair appearance |
Pi |
N |
|||
MORTALITY |
0 |
- |
- |
- |
0 |
Remarks |
Rf4996: swollen left front leg, scab, red spots, open ventral area. animal euthanized on day 6 due to apparent suffering |
||||
OBSERVATIONS: |
FEMALES |
||||
D7 to D14 |
Rf 4996 |
Rf 4999 |
Rf 5000 |
Rf 5001 |
Rf 5002 |
Spontaneous activity |
|
|
N |
||
Preyer’s reflex (noise) |
N |
||||
Respiratory rate |
N |
||||
Convulsions |
N |
||||
Tremors |
N |
||||
Body temperature |
N |
||||
Muscle tone |
N |
||||
Palpebral opening |
N |
||||
Pupil appearance |
N |
||||
Salivation |
N |
||||
Lachrymation |
N |
||||
Righting reflex |
N |
||||
Back hair appearance |
N |
||||
MORTALITY |
1 |
- |
- |
- |
0 |
Remarks |
Rf4996: swollen left front leg, scab, red spots, open ventral area. The animal was euthanized on day 6 due to apparent suffering |
||||
D: decreased
Pi: Piloerection
Table 2: Observation data sheet. Step 3 (300 mg/kg bw)
OBSERVATIONS |
|
D1 to D4 |
Rf5050 |
Spontaneous activity |
N |
Preyer’s reflex (noise) |
N |
Respiratory rate |
N |
Convulsions |
N |
Tremors |
N |
Body temperature |
N |
Muscle tone |
N |
Palpebral opening |
N |
Pupil appearance |
N |
Salivation |
N |
Lachrymation |
N |
Righting reflex |
N |
Back hair appearance |
N |
MORTALITY |
0 |
Remarks |
None |
OBSERVATIONS |
|
D5 |
Rf5050 |
Spontaneous activity Preyer’s reflex (noise) Respiratory rate Convulsions Tremors Body temperature Muscle tone Palpebral opening Pupil appearance Salivation Lachrymation Righting reflex Back hair appearance |
|
MORTALITY |
1 |
Remarks |
Animal found dead on day 5 |
Table 3: Observation data sheet. Steps 4 & 5 (50 mg/kg bw)
OBSERVATIONS: |
FEMALES |
||||
T0 + 1 hour T0 + 3 hours |
Rf 5054 |
Rf 5083 |
Rf 5084 |
Rf 5085 |
Rf 5086 |
Spontaneous activity |
N |
D |
D |
D |
D |
Preyer’s reflex (noise) |
N |
D |
D |
D |
D |
Respiratory rate |
N |
N |
N |
N |
N |
Convulsions |
N |
N |
N |
N |
N |
Tremors |
N |
N |
N |
N |
N |
Body temperature |
N |
N |
N |
N |
N |
Muscle tone |
N |
N |
N |
N |
N |
Palpebral opening |
N |
N |
N |
N |
N |
Pupil appearance |
N |
N |
N |
N |
N |
Salivation |
N |
N |
N |
N |
N |
Lachrymation |
N |
N |
N |
N |
N |
Righting reflex |
N |
N |
N |
N |
N |
Back hair appearance |
N |
N |
N |
N |
N |
MORTALITY |
0 |
0 |
0 |
0 |
0 |
Remarks |
None |
||||
OBSERVATIONS: |
FEMALES |
||||
D1 to D9 |
Rf 5054 |
Rf 5083 |
Rf 5084 |
Rf 5085 |
Rf 5086 |
Spontaneous activity |
N |
N |
N |
N |
N |
Preyer’s reflex (noise) |
N |
N |
N |
N |
N |
Respiratory rate |
N |
N |
N |
N |
N |
Convulsions |
N |
N |
N |
N |
N |
Tremors |
N |
N |
N |
N |
N |
Body temperature |
N |
N |
N |
N |
N |
Muscle tone |
N |
N |
N |
N |
N |
Palpebral opening |
N |
N |
N |
N |
N |
Pupil appearance |
N |
N |
N |
N |
N |
Salivation |
N |
N |
N |
N |
N |
Lachrymation |
N |
N |
N |
N |
N |
Righting reflex |
N |
N |
N |
N |
N |
Back hair appearance |
N |
N |
N |
N |
N |
MORTALITY |
0 |
0 |
0 |
0 |
0 |
Remarks |
Rf5086: noisy breathing on days 2, 7 & 8 decrease of body weight on day 9 |
||||
OBSERVATIONS: |
FEMALES |
||||
D10 to D14 |
Rf 5054 |
Rf 5083 |
Rf 5084 |
Rf 5085 |
Rf 5086 |
Spontaneous activity |
N |
N |
N |
N |
N |
Preyer’s reflex (noise) |
N |
N |
N |
N |
N |
Respiratory rate |
N |
N |
N |
N |
N |
Convulsions |
N |
N |
N |
N |
N |
Tremors |
N |
N |
N |
N |
N |
Body temperature |
N |
N |
N |
N |
N |
Muscle tone |
N |
N |
N |
N |
N |
Palpebral opening |
N |
N |
N |
N |
N |
Pupil appearance |
N |
N |
N |
N |
N |
Salivation |
N |
N |
N |
N |
N |
Lachrymation |
N |
N |
N |
N |
N |
Righting reflex |
N |
N |
N |
N |
N |
Back hair appearance |
N |
N |
N |
N |
N |
MORTALITY |
0 |
0 |
0 |
0 |
0 |
Remarks |
Rf5086: noisy breathing from D10 to D14. skinny animal, swollen stomach |
||||
D: decreased
Table 4: Body weight and weight gain in grams. Steps 1 & 2 (2000 mg/kg bw)
FEMALES |
D0 |
D2 |
D2-D0 |
D7 |
D7-D0 |
D14 |
D14-D0 |
Rf4996 |
196 |
189 |
-7 |
† |
|||
Rf4999 |
207 |
218 |
11 |
† |
|||
Rf5000 |
197 |
199 |
2 |
† |
|||
Rf5001 |
206 |
† |
|
|
|||
Rf5002 |
182 |
184 |
2 |
192 |
10 |
205 |
23 |
MEAN |
197.6 |
197.5 |
2.0 |
192.0 |
10.0 |
205.0 |
23.0 |
Standard deviation |
10.1 |
15.0 |
7.3 |
|
|||
Notes:
†: Rf5001 found dead on day 2 post dose
†: Rf4996, Rf4999 & Rf5000 euthanized on day 5 or 6 post dose
Table 5: Body weight and weight gain in grams. Step 3 (300 mg/kg bw)
FEMALES |
D0 |
D2 |
D2-D0 |
D7 D7-D0 D14 D14-D0 |
Rf 5050 |
208 |
158 |
-50 |
† |
MEAN
Standard deviation |
208.0 |
158.0 |
-50.0 |
|
|
|
|||
Notes:
†: Rf5050 found dead on day 5 post dose
Table 6: Body weight and weight gain in grams. Steps 4 & 5 (50 mg/kg bw)
FEMALES |
D0 |
D2 |
D2-D0 |
D7 |
D7-D0 |
D14 |
D14-D0 |
Rf5054 |
190 |
194 |
4 |
209 |
19 |
220 |
30 |
Rf5083 |
203 |
218 |
15 |
257 |
54 |
269 |
66 |
Rf5084 |
194 |
201 |
7 |
222 |
28 |
229 |
35 |
Rf5085 |
183 |
194 |
11 |
207 |
24 |
214 |
31 |
Rf5086 |
203 |
193 |
-10 |
151 |
-52 |
148 |
-55 |
MEAN |
194.6 |
200.0 |
5.4 |
209.2 |
14.6 |
216.0 |
21.4 |
Standard deviation |
8.6 |
10.6 |
9.6 |
38.2 |
39.6 |
43.7 |
45.2 |
Endpoint conclusion
- Endpoint conclusion:
- adverse effect observed
- Dose descriptor:
- LD50
- Value:
- 50 mg/kg bw
- Quality of whole database:
- Key study with Klimisch score = 1
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
Justification for classification or non-classification
Based on the available data, the substance is classified for acute oral toxicity (Category 3) according to CLP Regulation (EC) no. 1272/2008.
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