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Acute Toxicity: oral

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Administrative data

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
From 2018-01-03 to 2018-01-31
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2018
Report date:
2018

Materials and methods

Test guidelineopen allclose all
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
Test type:
acute toxic class method
Limit test:
no

Test material

1
Chemical structure
Reference substance name:
Bis and tris and tetra{N-[(2-ethylanilino) or 2,4(or 2,5 or 2,6)-dimethylanilino]-N’-[(2-ethylanilino) or 2,4(or 2,5 or 2,6)-dimethylanilino] methaniminium} [phthalocyanine(bis and tris and tetra)sulfonato-κ4N29,N30,N31,N32]cuprate(II)
EC Number:
946-424-8
Molecular formula:
C32H16-τN8Cu(SO3C17H22N3) (where τ = 2.80 to 3.04)
IUPAC Name:
Bis and tris and tetra{N-[(2-ethylanilino) or 2,4(or 2,5 or 2,6)-dimethylanilino]-N’-[(2-ethylanilino) or 2,4(or 2,5 or 2,6)-dimethylanilino] methaniminium} [phthalocyanine(bis and tris and tetra)sulfonato-κ4N29,N30,N31,N32]cuprate(II)
Test material form:
solid: particulate/powder
Specific details on test material used for the study:
STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: room temperature

Test animals

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 (if applicable) nulliparous and non-pregnant: yes

- Age at study initiation: 8 weeks old

- Weight at study initiation: 191- 210 g (mean 201.2 g)

- Fasting period before study: Drinking water (tap-water from public distribution system) and foodstuff (ENVIGO - 2016) were supplied ad libitum. Food was removed on day -1 and then redistributed 4 hours after the test item administration.

- Housing:
* Housed by group of three in solid-bottomed clear polycarbonate cages with a stainless steel mesh lid.
* Each cage contained sawdust bedding which was changed at least 2 times a week
* cages installed in conventional air conditioned animal husbandry.

- Diet (e.g. ad libitum): foodstuff (ENVIGO – 2016), ad libitum

- Water (e.g. ad libitum): tap-water from public distribution system, ad libitum

- Acclimation period: at least five days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19-25°C
- Humidity (%): 30-70%
- Air changes (per hr): at least ten times
- Photoperiod (hrs dark / hrs light):

IN-LIFE DATES:

Step 1:
From: 2018-01-03 To: 2018-01-03

Step 2:
From: 2018-01-15 To: 2018-01-30


Step 3:
From: 2018-01-16 To:2018-01-31

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
DMSO
Details on oral exposure:
VEHICLE
- Concentration in vehicle:
* First step: 2.0000 g of test item in a 10 mL volumetric flask and filled up with DMSO
* Second and third steps: 0.3006 g and 0.3000 g of test item in two 10 mL volumetric flasks and filled up with DMSO

- Amount of vehicle (if gavage):10mL /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: 10mL /kg bw

Doses:
* Step 1: 2000 mg of test item /kg bw
* Step 2 and 3 : 300 mg of test item /kg bw
No. of animals per sex per dose:
3 female rats per dose
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days

- Frequency of observations and weighing:
* Observations: performed daily
* Weighing : at day 0 (just before administration of the test item), day 2, day 7 and day 14

- Necropsy of survivors performed: yes. were euthanized with sodium pentobarbital (Dolethal®).
Only those organs likely to be modified in cases of acute toxicity were examined. No organ was removed and preserved in view to microscopic examinations.

- Other examinations performed: clinical signs, body weight,organ weights, histopathology, other:
Macroscopic examinations at the end of the study (after euthanisia) with the examination of organs
likely to be modified in cases of acute toxicity (i.e. oesophagus, stomach, the entire digestif tract, spleen, liver, thymus, trachea, lungs, heart, kidneys, urinary bladder, ovaries, uterus, treatment area,adrenals, pancreas).

Results and discussion

Effect levels
Key result
Sex:
female
Dose descriptor:
LD50
Effect level:
> 300 - < 2 000 mg/kg bw
Based on:
test mat.
Mortality:
- Step 1: 3 mortalities in animals treated at 2000 mg test item /kg bw (between 1 and 3 hours post dose)


- Step 2 and 3: No mortality in animals treated at 300 mg test item /kg bw


Clinical signs:
At 2000 mg test item /kg bw :
- a decrease in spontaneous activity (3/3)
- righting reflex (1/3)
- muscle tones (1/3)
- an increase of muscle tones (1/3) associated with mydriasis (1/3)
- eyes partly closed (3/3)
- tremors (2/3)
- tonic convulsions (1/3).

At 300 mg test item /kg bw: No clinical signs related to the administration of the test item were observed during the study.
Body weight:
The body weight evolution of the animals treated at the dose of 300 mg/kg body weight remained normal during the study.
Other findings:
- Other observations:

* Step 1: At 2000 mg test item /kg bw :

Macroscopic examination :
- thinning of corpus (3/3),
- blue stomach contents (3/3).


* Steps 2 and 3 : At 300 mg test item /kg bw:
Macroscopic examination :
- red forestomach (1/6).

Applicant's summary and conclusion

Interpretation of results:
Category 4 based on GHS criteria
Conclusions:
The LD50 of the test item is higher than 300 mg/kg body weight and lower than 2000 mg/kg 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 as 500 mg/kg body weight by oral route in the rat.

According to the criteria for classification, packaging and labelling of dangerous substances and preparations in accordance with the Regulation EC No. 1272/2008, the test item has to be classified in category 4.

The signal word “Warning” and hazard statement H302 “Harmful if swallowed” are required.
Executive summary:

The test item was administered to a group of 3 female Sprague Dawley rats at the dose of 2000 mg/kg body weight and then to a group of 6 female Sprague Dawley rats at the dose of 300 mg/kg body weight.

The experimental protocol was established according to O.E.C.D. Test Guideline No. 423 dated 17 December 2001 concerning acute oral toxicity and the test method B.1tris of Council regulation No.440/2008 dated 30 May 2008.

Three mortalities were noted in animals treated at the dose of 2000 mg/kg body weight between 1 and 3 hours post-dose.

The mortalities were preceded by a decrease in spontaneous activity (3/3), righting reflex (1/3), a decrease of muscle tones (2/3), an increase of muscle tones (1/3) associated with mydriasis (1/3), eyes partly closed (3/3), tremors (2/3) and tonic convulsions (1/3).

The macroscopic examination of the animals revealed a thinning of corpus (3/3), and blue stomach contents (3/3).

No mortality was noted in animals treated at the dose of 300 mg/kg body weight.

No clinical signs related to the administration of the test item were observed during the study.

The body weight evolution of the animals treated at the dose of 300 mg/kg body weight remained normal during the study.

The macroscopic examination of the animals at the end of the study revealed a red forestomach (1/6).

In conclusion, the LD50 of the test item is higher than 300 mg/kg body weight and lower than 2000 mg/kg 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 as 500 mg/kg body weight by oral route in the rat.

According to the criteria for classification, packaging and labelling of dangerous substances and preparations in accordance with the Regulation EC No. 1272/2008, the test item has to be classified in category 4. The signal word “Warning” and hazard statement H302 “Harmful if swallowed” are required.