Registration Dossier

Administrative data

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

Data source

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

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to
Guideline:
OECD Guideline 420 (Acute Oral Toxicity - Fixed Dose Method)
Version / remarks:
2001
Deviations:
no
Qualifier:
according to
Guideline:
EU Method B.1 bis (Acute Oral Toxicity - Fixed Dose Procedure)
Version / remarks:
2008
Deviations:
no
GLP compliance:
yes (incl. certificate)
Test type:
fixed dose procedure
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Type:
Constituent
Type:
impurity
Type:
impurity
Type:
impurity
Type:
impurity
Test material form:
liquid

Test animals

Species:
rat
Strain:
Wistar
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: by Envigo RMS (UK) Limited, Oxon, UK
- Females nulliparous and non-pregnant: yes
- Age at study initiation: 8 to 12 weeks
- Fasting period before study: overnight fast immediately before dosing and for approximately 3 to 4 hours after dosing
- Housing: in groups of up to four in suspended solid floor polypropylene cages furnished with woodflakes
- Diet (e.g. ad libitum): 2014C Teklad Global Rodent diet ad libitum
- Water (e.g. ad libitum): mains drinking water , ad libitum
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19 to 25 °C
- Humidity (%): 30 to 70%
- Air changes (per hr): at least 15
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
DMSO
Details on oral exposure:
VEHICLE
- Concentration in vehicle: 5 and 30 mg/mL
- Justification for choice of vehicle: Dimethyl sulfoxide was used because the test item did not dissolve/suspend in distilled water or arachis oil BP

MAXIMUM DOSE VOLUME APPLIED: 10 mL/kg bw

DOSAGE PREPARATION:
The test item was formulated within 2 hours of being applied to the test system. It is assumed that the formulation was stable for this duration.
Doses:
50, 300 mg/kg bw
No. of animals per sex per dose:
1 female at 300 mg/kg bw, 5 females at 50 mg/kg bw
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing:
Clinical observations were made 30 minutes, 1, 2, and 4 hours after dosing and then daily for up to 14 days. Morbidity and mortality checks were made twice daily, early and late during normal working days, and once daily at weekends and public holidays.
Individual body weights were recorded on Day 0 (the day of dosing) and on Days 7 and 14 or at death.
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight

Results and discussion

Effect levels
Sex:
female
Dose descriptor:
LD50
Effect level:
>= 50 - <= 300 mg/kg bw
Based on:
act. ingr.
Mortality:
The animal dose at 300 mg/kg bw was killed for humane reasons, due to the occurrence of clinical signs of toxicity that approached the severity limit set forth in the UK Home Office Project License.
There were no deaths at 50 mg/kg bw.
Clinical signs:
300 mg/kg bw: Signs of systemic toxicity noted were hunched posture, lethargy, pilo-erection, ataxia, decreased respiratory rate, hypothermia, ptosis and dehydration.

50 mg/kg bw: Hunched posture was noted in one animal 1 hour after dosing. No other signs of systemic toxicity were noted during the observation period.
Body weight:
300 mg/kg bw: weightloss

50 mg/kg bw: All animals showed expected gains in body weight over the observation period.
Gross pathology:
300 mg/kg bw: Abnormalities were noted at necropsy of the animal that was killed during the study were dark liver, thickened non-glandular region of the stomach and gaseous small intestine.

50 mg/kg bw: No abnormalities were noted at necropsy.

Applicant's summary and conclusion

Interpretation of results:
Category 3 based on GHS criteria
Conclusions:
The acute oral median lethal dose (LD50) of the test item in the female Wistar strain rat was estimated to be in the range of 50 - 300 mg/kg body weight (Globally Harmonized Classification System - Category 3).
Executive summary:

The study was performed to assess the acute oral toxicity of the test item in the Wistar strain rat according to OECD Guideline 420 and EU method B1 bis (fixed dose procedure).

 

Following a sighting test at dose levels of 300 mg/kg bw and 50 mg/kg bw, a further group of four fasted females was given a single oral dose of test item, as a solution in dimethyl sulfoxide, at a dose level of 50 mg/kg body weight. Clinical signs and body weight development were monitored during the study. All animals were subjected to gross necropsy.

 

Mortality. The animal treated at a dose level of 300 mg/kg was killed for humane reasons, due to the occurrence of clinical signs of toxicity that approached the severity limit set forth in the UK Home Office Project License.

Clinical Observations. Signs of systemic toxicity noted in the animal that was humanely killed were hunched posture, lethargy, pilo-erection, ataxia, decreased respiratory rate, hypothermia, ptosis and dehydration. Hunched posture was noted in one animal treated at a dose level of 50 mg/kg. No other signs of toxicity were noted.

Body Weight. Surviving animals showed expected gains in body weight.

Necropsy  Abnormalities noted at necropsy of the animal that was killed during the study were dark liver, thickened non-glandular region of the stomach and a gaseous small intestine.

 

The acute oral median lethal dose (LD50) of the test item in the female Wistar strain rat was estimated to be in the range of 50 - 300 mg/kg body weight (Globally Harmonized Classification System-Category 3).

 

The test item was also classified as Category 3 according to Regulation (EC) No. 1272/2008, relating to the Classification, Labelling and Packaging of Substances and Mixtures.