Registration Dossier

Administrative data

Description of key information

Acute toxicity, oral, rat female LD50 > 2000 mg/kg (no mortality and no clinical signs at this dose) (CitoxLab, 2018)

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:
2018-01-31 - 2018-05-28
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)
Deviations:
no
Qualifier:
according to
Guideline:
EU Method B.1 tris (Acute Oral Toxicity - Acute Toxic Class Method)
Deviations:
no
GLP compliance:
yes (incl. certificate)
Test type:
acute toxic class method
Limit test:
yes
Species:
rat
Strain:
Wistar
Remarks:
Crl:WI
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories, Research Models and Services, Germany GmbH, Sandhofer Weg 7, D-97633 Sulzfeld, Germany
- Females (if applicable) nulliparous and non-pregnant: yes
- Age at study initiation: Young healthy adult rats, 8 weeks old
- Weight at study initiation: 191 - 202 g
- Fasting period before study: yes, On the night before treatment, the animals were fasted. The food but not water was withheld during an overnight period.
- Housing: 3 animals/cage. Cage type: Type II. polypropylene/polycarbonate. Animals were housed by group to allow social interaction and with deep wood sawdust bedding to allow digging and other normal rodent activities.
- Diet (e.g. ad libitum) / Water (e.g. ad libitum): Animals received ssniff® SM R/M "Autoclavable complete diet for rats and mice – breeding and maintenance" produced by ssniff Spezialdiäten GmbH, D-59494 Soest,
Germany (Batch number: 382 24962, Expiry date: 30 April 2018), ad libitum, and tap water from the municipal supply, as for human consumption from a 500 ml bottle, ad libitum.
- Acclimation period: 5 or 6 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20.0 – 23.7 °C
- Humidity (%): 33 – 53 %
- Air changes (per hr): 15-20 air exchanges/hour
- Photoperiod (hrs dark / hrs light): Lighting period: 12 hours daily, from 6.00 a.m. to 6.00 p.m.

IN-LIFE DATES: From: 08 february 2018 To: 28 february 2018
Route of administration:
oral: gavage
Vehicle:
other: distilled water
Details on oral exposure:
VEHICLE
- Concentration in vehicle: The test item was freshly formulated at a concentration of 796 mg/mL in the vehicle, in the Pharmacy of Citoxlab Hungary Ltd. on the day of administration. The formulation container was magnetic stirred continuously up to the end of dose administration procedures.
- Name: Distilled water
- Batch number: 8130917
- Manufacturer: Hungaro-Gal Kft.
- Expiry Date: 04 March 2018
- Storage condition: Room temperature


CLASS METHOD
- Rationale for the selection of the starting dose: The initial dose level was selected by the Study Director to be that which is most likely to produce mortality in some of the dosed animals. In the lack of any preliminary toxicological information, 2000 mg/kg bw was selected to be the starting dose.
Doses:
2000 mg/kg bw
No. of animals per sex per dose:
6 animals, 3 animals/group
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Clinical observations were performed on all animals at 30 minutes, 1, 2, 3, 4 and 6 hours after dosing and daily for 14 days thereafter. Individual observations were performed on the skin, fur, eyes, mucous membranes, respiratory, circulatory, autonomic and central nervous system, somatomotor activity and behaviour pattern. Particular attention was directed to observation of tremors, convulsions, salivation, diarrhoea, lethargy, sleep and coma. The body weight was recorded on the day before treatment (Day -1), on the day of the treatment (Day 0), weekly thereafter (Day 7) and at necropsy (Day 14).
- Necropsy of survivors performed: yes, Macroscopic examination was performed on all animals. The animals were sacrificed by exsanguination under pentobarbital anaesthesia (Euthanimal 40%; Lot No.: 1609291-03, Expiry date: 31 October 2019, produced by: Alfasan Nederland BV, Kuipersweg 9, Woerden, The Netherlands). After examination of the external appearance, the cranial, thoracic and the abdominal cavities were opened and the organs and the tissues were observed.
Statistics:
no data
Preliminary study:
no preliminary study
Key result
Sex:
female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
act. ingr.
Mortality:
Sopromine 1686 did not cause mortality at a dose level of 2000 mg/kg bw in any animal.
Clinical signs:
All animals were symptom-free during the observation period at a dose level of 2000 mg/kg bw.
Body weight:
There were no treatment related body weight changes. Body weights were within the range commonly recorded for this strain and age.
Gross pathology:
There was no evidence of the macroscopic changes at a dose level of 2000 mg/kg bw in any animal.
Other findings:
no data
Interpretation of results:
GHS criteria not met
Conclusions:
Under the conditions of this study, the acute oral LD50 value of the test item Sopromine 1686 was found to be above 2000 mg/kg bw in female Crl:WI Wistar rats.
According the GHS criteria and considering the absence of mortality and clinical signs at the dose of 2000 mg/kg bw, classification of Sopromine 1686 can be ranked as "Unclassified" for acute oral exposure.
Executive summary:

The single-dose oral toxicity study with Sopromine 1686 was performed according to the acute toxic class method (OECD 423 and Commission Regulation (EC) No 440/2008 of 30 May 2008, B.1.tris) in Crl:WI Wistar female rats. Two groups of three female Crl:WI rats were treated by gavage (single administration) with the test item at a dose level of 2000 mg active ingredient/kg body weight (bw) (Group 1 and Group 2). Initially, three females (Group 1) were treated at a dose level of 2000 mg/kg bw. As no mortality was observed, a confirmatory group (Group 2) was treated at the same dose level. No mortality was observed in the confirmatory group; therefore, no further testing was required according to OECD 423 and Commission Regulation (EC) No 440/2008 of 30 May 2008, B.1.tris.

Clinical observations were performed at 30 minutes, 1, 2, 3, 4 and 6 hours after dosing and daily for 14 days thereafter. Body weight was measured on Days -1, 0, 7 and before necropsy (Day 14). All animals were subjected to a necropsy and a macroscopic examination.

Sopromine 1686 did not cause mortality at a dose level of 2000 mg/kg bw. All animals were symptom-free during the observation period at a dose level of 2000 mg/kg bw. There were no treatment related body weight changes. Body weights were within the range commonly recorded for this strain and age. There was no evidence of macroscopic changes at a dose level of 2000 mg/kg bw.

Under the conditions of this study, the acute oral LD50 value of the test item Sopromine 1686 was found to be above 2000 mg/kg bw in female Crl:WI Wistar rats.

According the GHS criteria and considering the absence of mortality and clinical signs at the dose of 2000 mg/kg bw, classification of Sopromine 1686 can be ranked as "Unclassified" for acute oral exposure.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
discriminating dose
Value:
2 000 mg/kg bw
Quality of whole database:
GLP study conducted according to OECD guideline no. 423 (Klimish 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

Acute oral toxicity:

One klimisch score 1 study was available and was used as a key study:

The single-dose oral toxicity study with Sopromine 1686 was performed according to the acute toxic class method (OECD 423 and Commission Regulation (EC) No 440/2008 of 30 May 2008, B.1.tris) in Crl:WI Wistar female rats (CITOXlab, 2018). Two groups of three female Crl:WI rats were treated by gavage (single administration) with the test item at a dose level of 2000 mg active ingredient/kg body weight (bw) (Group 1 and Group 2). Initially, three females (Group 1) were treated at a dose level of 2000 mg/kg bw. As no mortality was observed, a confirmatory group (Group 2) was treated at the same dose level. No mortality was observed in the confirmatory group; therefore, no further testing was required according to OECD 423 and Commission Regulation (EC) No 440/2008 of 30 May 2008, B.1.tris.

Clinical observations were performed at 30 minutes, 1, 2, 3, 4 and 6 hours after dosing and daily for 14 days thereafter. Body weight was measured on Days -1, 0, 7 and before necropsy (Day 14). All animals were subjected to a necropsy and a macroscopic examination.

Sopromine 1686 did not cause mortality at a dose level of 2000 mg/kg bw. All animals were symptom-free during the observation period at a dose level of 2000 mg/kg bw. There were no treatment related body weight changes. Body weights were within the range commonly recorded for this strain and age. There was no evidence of macroscopic changes at a dose level of 2000 mg/kg bw.

Under the conditions of this study, the acute oral LD50 value of the test item Sopromine 1686 was found to be above 2000 mg/kg bw in female Crl:WI Wistar rats.

According the GHS criteria and considering the absence of mortality and clinical signs at the dose of 2000 mg/kg bw, classification of Sopromine 1686 can be ranked as "Unclassified" for acute oral exposure.

Justification for classification or non-classification

Harmonized classification:

No harmonized classification is available according to the Regulation (EC) No 1272/2008.

Self-classification:

According the GHS criteria and considering the absence of mortality and clinical signs at the dose of 2000 mg/kg bw, classification of Sopromine 1686 can be ranked as "Unclassified" for acute oral exposure.