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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
Reference
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.

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

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.

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.

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