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Registration Dossier
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EC number: 264-267-7 | CAS number: 63484-12-8
Endpoint summary
Administrative data
Description of key information
Key study : Acute oral toxicity study in accordance with the OECD 423 Guideline. GLP study. The LD50 of the test item is higher than 2000 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:
- October 18, 2016 - November 3, 2016
- 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)
- Deviations:
- no
- Qualifier:
- according to guideline
- Guideline:
- EU Method B.1 tris (Acute Oral Toxicity - Acute Toxic Class Method)
- Deviations:
- no
- GLP compliance:
- yes (incl. QA statement)
- Test type:
- acute toxic class method
- Limit test:
- yes
- Specific details on test material used for the study:
- STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material:room temperature - Species:
- rat
- Strain:
- Sprague-Dawley
- 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-week old
- Weight at study initiation: mean 201.5g
- Fasting period before study: yes
- Housing: rats were housed by group of three in solid-bottomed clear polycarbonate cages with a stainle ss 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: foodstuff (ENVIGO - 2016) ad libitum
- Water (e.g. ad libitum): tap-water from public distribution system ad libitum
- Acclimation period:at least 5 days prior to dosing.
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19-25ºC
- Humidity (%): 30-70%
- Air changes (per hr): 10 changes per hour
- Photoperiod (hrs dark / hrs light): twelve hours continuous light (07.00 to 19.00) and twelve hours darkness
IN-LIFE DATES: From: 19 October 2016 To: 02 November 2016 - Route of administration:
- oral: gavage
- Vehicle:
- DMSO
- Details on oral exposure:
- VEHICLE
- Concentration of vehicle :2.0015g/ 10ml bw (fist step),, 2.0030g/10ml bw (second step).
- Amount of vehicle (if gavage): Administrated by gavage under volume of 10mL/kg of teh test item using a suitable graduated syringe fitted with and oesophageal metal canula.
- Justification for choice of vehicle: the most suitable formulation at the requested concentration.
MAXIMUM DOSE VOLUME APPLIED: 10mL/kg body weight
DOSAGE PREPARATION: Test item was weighted and dimethyl sulfoxide was added to two 10 mL volumetric flasks. The preparations were stirred by vortex to obtain colorless solutions just before the admi
nistration.
CLASS METHOD (if applicable) :
- Rationale for the selection of the starting dose: Without preliminary information. The selected starting dose is 2000 mg/kg body weight because it is a limit test.
- Doses:
- 2000 mg/kg body weight of test item
- No. of animals per sex per dose:
- 6
- Control animals:
- yes
- Remarks:
- historical data, Study No. TAO423-2016-006
- Details on study design:
- - Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Observations = Systemic observations at 30 min,1h, 3h, 4h, 24h, 48h after administration and daily during 14 days.
Weighing = D0 (just before administering the test item) then on D2, D7 and D14.
- Necropsy of survivors performed: yes. On D14, the animals were anesthetised with sodium pentobarbital and administration continued to fatal levels. Macroscopic observations were recorded. Only those organs likely to be modified in cases of acute toxicity were examined.
Clinical signs: 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.
Gross pathology: On D14, the animals were anaesthetised with sodium pentobarbital and administration continued to fatal levels. Macroscopic observations were entered on individual autopsy sheets.Only those organs likely to be modified in cases of acute toxicity were examined. Parameters examined:Oesophagus, Stomach, Duodenum, Jejunum, Ileon, Caecum, Colon, Rectum, Spleen, Liver, Thymus,Trachea, Lungs, Heart, Kidneys, Urinary Bladder, Ovaries, Uterus, Treatment Area, Adrenals and Pancreas. Only those organ likely to be modified in cases of acute toxicity were examined. - Key result
- Sex:
- female
- Dose descriptor:
- LD50
- Effect level:
- > 2 000 mg/kg bw
- Based on:
- test mat.
- Mortality:
- No mortality occurred during the study.
- Clinical signs:
- other: A decrease of spontaneous activity (3/6), an increase of salivation (2/6). myosis (3/6) were noted during the first hours of the test. The animals recovered a normal behaviour at 48 hours post dose.
- Gross pathology:
- Macroscopic examination of the animals at the end of the study did not reveal treatment related changes.
- Interpretation of results:
- GHS criteria not met
- Conclusions:
- The LD50 of the test item is higher than 2000 mg/kg body weight by oral route in the rat.
- Executive summary:
An acute toxic class method test on rats was performed according to OECD Guideline 423 and test method B.1 tris. The test item was administered, as supplied, to a group of 6 female Sprague Dawley rats (8 weeks old, 3 per group) at the dose of 2000 mg/kg body weight by oral gavage. No mortality occurred during the study. A decrease in spontaneous activity (3/6), an increase of salivation (2/6), and myosis (3/6), was noted during the first hours of the test. The animals recovered a normal behaviour at 48 hours post dose. Body weight evolution and macroscopic examinations were normal. In conclusion, the LD50 of the test item is higher than 2000 mg/ kg body weight by oral route in the rat. In accordance with the O.E.C.D. Test Guideline No. 423, the LD50 cut-off of the test item may be considered to be higher than 5000 mg/ kg body weight by oral route in the rat.
Reference
Lexicon:
Spontaneous activity |
D-decreased |
N -normal |
|
Preyer's reflex (noise) |
N-normal |
0-none |
|
Respiratory rate |
N-normal |
D-dyspnea B-bradypnea P-Polypnea |
|
Convulsions |
N-none |
T-tonic C-clonic |
|
Body temperature |
N-normal |
D-hypothermia A-hyperthermia |
|
Muscle tone |
N-normal |
D-decreased A-Increased 0-None |
|
Palpebral opnening |
N-normal |
Pc-Eyes partly closed Cc-Eyes completely closed |
|
Pupil appearance |
N-normal |
Md-Mydriasis Ms-Myosis |
|
Salivation |
N-normal |
A-Increased |
|
Lachrymation |
N-normal |
A-Increased |
|
Righting reflex |
N-normal |
D-limited 0-None |
|
Back hair appearance |
N-normal |
Pi-piloerection |
|
Tremors |
N-none |
Tr-tremors |
|
MORTALITY |
0 |
0 |
|
OBSERVATIONS:
TABLE 1:
OBSERVATIONS |
FEMALES |
FEMALES |
||||||
T0 + 30 minutes |
Rf |
Rf |
Rf |
Rf |
Rf |
Rf |
||
0523 |
0524 |
0525 |
0536 |
0537 |
0538 |
|||
Spontaneous activity |
N |
D |
N |
N |
N |
N |
||
Preyer's reflex (noise) |
N |
N |
N |
N |
N |
N |
||
Respiratory rate |
N |
N |
N |
N |
N |
N |
||
Convulsions |
N |
N |
N |
N |
N |
N |
||
Body temperature |
N |
N |
N |
N |
N |
N |
||
Muscle tone |
N |
N |
N |
N |
N |
N |
||
Palpebral opnening |
N |
N |
N |
N |
N |
N |
||
Pupil appearance |
Ms |
Ms |
Ms |
N |
N |
N |
||
Salivation |
N |
N |
N |
N |
N |
N |
||
Lachrymation |
N |
N |
N |
N |
N |
N |
||
Righting reflex |
N |
N |
N |
N |
N |
N |
||
Back hair appearance |
N |
N |
N |
N |
N |
N |
||
Tremors |
N |
N |
N |
N |
N |
N |
||
MORTALITY |
0 |
0 |
0 |
0 |
0 |
0 |
||
TABLE 2:
OBSERVATIONS |
FEMALES |
FEMALES |
||||||
T0 + 1 hour |
Rf |
Rf |
Rf |
Rf |
Rf |
Rf |
||
0523 |
0524 |
0525 |
0536 |
0537 |
0538 |
|||
Spontaneous activity |
N |
D |
N |
N |
N |
N |
||
Preyer's reflex (noise) |
N |
N |
N |
N |
N |
N |
||
Respiratory rate |
N |
N |
N |
N |
N |
N |
||
Convulsions |
N |
N |
N |
N |
N |
N |
||
Body temperature |
N |
N |
N |
N |
N |
N |
||
Muscle tone |
N |
N |
N |
N |
N |
N |
||
Palpebral opnening |
N |
N |
N |
N |
N |
N |
||
Pupil appearance |
Ms |
Ms |
Ms |
N |
N |
N |
||
Salivation |
N |
N |
N |
N |
N |
N |
||
Lachrymation |
N |
N |
N |
N |
N |
N |
||
Righting reflex |
N |
N |
N |
N |
N |
N |
||
Back hair appearance |
N |
N |
N |
N |
N |
N |
||
Tremors |
N |
N |
N |
N |
N |
N |
||
MORTALITY |
0 |
0 |
0 |
0 |
0 |
0 |
||
TABLE 3
OBSERVATIONS |
FEMALES |
FEMALES |
||||||
T0 + 3 hours |
Rf |
Rf |
Rf |
Rf |
Rf |
Rf |
||
0523 |
0524 |
0525 |
0536 |
0537 |
0538 |
|||
Spontaneous activity |
N |
D |
N |
N |
N |
N |
||
Preyer's reflex (noise) |
N |
N |
N |
N |
N |
N |
||
Respiratory rate |
N |
N |
N |
N |
N |
N |
||
Convulsions |
N |
N |
N |
N |
N |
N |
||
Body temperature |
N |
N |
N |
N |
N |
N |
||
Muscle tone |
N |
N |
N |
N |
N |
N |
||
Palpebral opnening |
N |
N |
N |
N |
N |
N |
||
Pupil appearance |
N |
Ms |
Ms |
N |
N |
N |
||
Salivation |
N |
N |
N |
N |
N |
N |
||
Lachrymation |
N |
N |
N |
N |
N |
N |
||
Righting reflex |
N |
N |
N |
N |
N |
N |
||
Back hair appearance |
N |
N |
N |
N |
N |
N |
||
Tremors |
N |
N |
N |
N |
N |
N |
||
MORTALITY |
0 |
0 |
0 |
0 |
0 |
0 |
||
TABLE 4:
OBSERVATIONS |
FEMALES |
FEMALES |
||||||
T0 + 4 hours |
Rf |
Rf |
Rf |
Rf |
Rf |
Rf |
||
0523 |
0524 |
0525 |
0536 |
0537 |
0538 |
|||
Spontaneous activity |
N |
D |
N |
N |
N |
N |
||
Preyer's reflex (noise) |
N |
N |
N |
N |
N |
N |
||
Respiratory rate |
N |
N |
N |
N |
N |
N |
||
Convulsions |
N |
N |
N |
N |
N |
N |
||
Body temperature |
N |
N |
N |
N |
N |
N |
||
Muscle tone |
N |
N |
N |
N |
N |
N |
||
Palpebral opnening |
N |
N |
N |
N |
N |
N |
||
Pupil appearance |
N |
N |
Ms |
N |
N |
N |
||
Salivation |
N |
N |
N |
N |
N |
N |
||
Lachrymation |
N |
N |
N |
N |
N |
N |
||
Righting reflex |
N |
N |
N |
N |
N |
N |
||
Back hair appearance |
N |
N |
N |
N |
N |
N |
||
Tremors |
N |
N |
N |
N |
N |
N |
||
MORTALITY |
0 |
0 |
0 |
0 |
0 |
0 |
||
TABLE 5:
OBSERVATIONS |
FEMALES |
FEMALES |
||||||
D1 |
Rf |
Rf |
Rf |
Rf |
Rf |
Rf |
||
0523 |
0524 |
0525 |
0536 |
0537 |
0538 |
|||
Spontaneous activity |
D |
D |
D |
N |
N |
N |
||
Preyer's reflex (noise) |
N |
N |
N |
N |
N |
N |
||
Respiratory rate |
N |
N |
N |
N |
N |
N |
||
Convulsions |
N |
N |
N |
N |
N |
N |
||
Body temperature |
N |
N |
N |
N |
N |
N |
||
Muscle tone |
N |
N |
N |
N |
N |
N |
||
Palpebral opnening |
N |
N |
N |
N |
N |
N |
||
Pupil appearance |
N |
N |
N |
N |
N |
N |
||
Salivation |
N |
N |
N |
N |
N |
N |
||
Lachrymation |
N |
N |
N |
N |
N |
N |
||
Righting reflex |
N |
N |
N |
N |
N |
N |
||
Back hair appearance |
N |
N |
N |
N |
N |
N |
||
Tremors |
N |
N |
N |
N |
N |
N |
||
MORTALITY |
0 |
0 |
0 |
0 |
0 |
0 |
||
TABLE 6:
OBSERVATIONS |
FEMALES |
FEMALES |
||||||
D2 to D14 |
Rf |
Rf |
Rf |
Rf |
Rf |
Rf |
||
0523 |
0524 |
0525 |
0536 |
0537 |
0538 |
|||
Spontaneous activity |
D |
N |
N |
N |
N |
N |
||
Preyer's reflex (noise) |
N |
N |
N |
N |
N |
N |
||
Respiratory rate |
N |
N |
N |
N |
N |
N |
||
Convulsions |
N |
N |
N |
N |
N |
N |
||
Body temperature |
N |
N |
N |
N |
N |
N |
||
Muscle tone |
N |
N |
N |
N |
N |
N |
||
Palpebral opnening |
N |
N |
N |
N |
N |
N |
||
Pupil appearance |
N |
N |
N |
N |
N |
N |
||
Salivation |
N |
N |
N |
N |
N |
N |
||
Lachrymation |
N |
N |
N |
N |
N |
N |
||
Righting reflex |
N |
N |
N |
N |
N |
N |
||
Back hair appearance |
N |
N |
N |
N |
N |
N |
||
Tremors |
N |
N |
N |
N |
N |
N |
||
MORTALITY |
0 |
0 |
0 |
0 |
0 |
0 |
||
TABLE 7
(Body weight and weight gain in grams)
|
D0 D2 D2-D0 |
D7 254 250 212 241 250 246 242.2
15.4 |
D7D0 42 40 20 41 49 52 40.7
11.2 |
D14 271 253 228 272 256 274 259.0
17.6 |
D14D0 59 43 36 72 55 80 27.5
16.7 |
Rf 0523 Rf 0524 Rf 0525 |
212 228 16 210 219 9 192 206 14 200 221 21 201 234 33 194 225 31 201.5 222.2 20.7
8.1 9.5 9.6 |
||||
Rf 0536 Rf 0537 Rf 0538 |
|||||
MEAN
Standart deviations |
Endpoint conclusion
- Endpoint conclusion:
- no adverse effect observed
- Dose descriptor:
- LD50
- Value:
- 2 000 mg/kg bw
- Quality of whole database:
- Klimisch score = 1. GLP study.
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
Key study: An acute toxic class method test on rats was performed according to OECD Guideline 423 and test method B.1 tris. The test item was administered, as supplied, to a group of 6 female Sprague Dawley rats (8 weeks old, 3 per group) at the dose of 2000 mg/kg body weight by oral gavage. No mortality occurred during the study. A decrease in spontaneous activity (3/6), an increase of salivation (2/6), and myosis (3/6), was noted during the first hours of the test. The animals recovered a normal behaviour at 48 hours post dose. Body weight evolution and macroscopic examinations were normal. In conclusion, the LD50 of the test item is higher than 2000 mg/ kg body weight by oral route in the rat. In accordance with the O.E.C.D. Test Guideline No. 423, the LD50 cut-off of the test item may be considered to be higher than 5000 mg/ kg body weight by oral route in the rat.
Justification for classification or non-classification
Based on the available information (LD50>2000 mg/kg bw), the substance is not classified for acute toxicity according to CLP Regulation (EC) no.1272/2008.
Information on Registered Substances comes from registration dossiers which have been assigned a registration number. The assignment of a registration number does however not guarantee that the information in the dossier is correct or that the dossier is compliant with Regulation (EC) No 1907/2006 (the REACH Regulation). This information has not been reviewed or verified by the Agency or any other authority. The content is subject to change without prior notice.
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