Registration Dossier

Administrative data

Description of key information

LD50 in the range of 50 - 300 mg/kg bw (rat, OECD TG 420)

 

Acute inhalation toxicity: no study available; exposure considerations

Acute dermal toxicity: LD50 could not accurately evaluated due to the corrosive nature of the test item

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:
09 January 2018 - 01 March 2018
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
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
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

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
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.
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.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LD50
Value:
300 mg/kg bw

Acute toxicity: via inhalation route

Endpoint conclusion
Endpoint conclusion:
no study available

Acute toxicity: via dermal route

Link to relevant study records
Reference
Endpoint:
acute toxicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Study period:
23 May 2018 - 24 May 2018
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Version / remarks:
2017
Deviations:
no
GLP compliance:
yes (incl. certificate)
Test type:
fixed dose procedure
Limit test:
no
Species:
rat
Strain:
Wistar
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Envigo RMS (UK) Limited, Oxon, UK
- Females nulliparous and non-pregnant: yes
- Weight at study initiation: 209 g
- Fasting period before study:
- Housing: individually throughout the study in suspended solid floor polypropylene cages furnished with wood flakes
- Diet (e.g. ad libitum): 2014C Teklad Global Rodent diet , ad libitum
- Water (e.g. ad libitum): tap water, ad libitum
- Acclimation period: 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

Type of coverage:
semiocclusive
Vehicle:
unchanged (no vehicle)
Details on dermal exposure:
TEST SITE
- Area of exposure: back and flanks
- % coverage: approximately 10% of the total body surface area
- Type of wrap if used: A piece of surgical gauze was placed over the treatment area and semi occluded with a piece of self adhesive bandage.

REMOVAL OF TEST SUBSTANCE
- After the 24 Hour contact period the bandage was carefully removed and the treated skin and surrounding hair wiped with cotton wool moistened with dimethyl sulfoxide followed by distilled water to remove any residual test item.

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 1000 mg/kg bw, corresponding to 0.96 mL/kg bw
- Concentration (if solution): neat substance

Duration of exposure:
24 h
Doses:
1000 mg/kg bw
No. of animals per sex per dose:
1 female
Control animals:
no
Details on study design:
The animal was observed for deaths or overt signs of toxicity 30 minutes, 1, 2, 4 and 6 hours after dosing and on Day 1. After removal of the dressings the test sites were examined for evidence of primary irritation.
The animal was humanely killed by cervical dislocation on Day 1. The animal was subjected to gross necropsy. This consisted of an external examination and opening of the abdominal and thoracic cavities and examination of the sub-cutaneous layer below the treatment site. The appearance of any macroscopic abnormalities was recorded. No tissues were retained.
Remarks on result:
not determinable
Remarks:
The dermal LD50 of the test item could not be accurately evaluated due to the corrosive nature of the test item.
Mortality:
The animal was killed for humane reasons due to due to the corrosive nature of the test item in accordance with the severity limit set forth in the UK Home Office Project License.
Clinical signs:
Clinical signs noted one day after dosing were hunched posture, lethargy and tiptoe gait. It was considered that these signs may have been due to the dermal reactions causing uncomfortable movement as opposed to systemic toxicity.
Body weight:
The animal lost weight over the study period.
Gross pathology:
Full thickness necrosis and hemorrhage of the underlining tissues were noted at the visual inspection of the sub-cutaneous layer at the treatment site.
Other findings:
Dark green dermal necrosis over the majority of the treatment site was surrounded by a margin of blanching and moderate erythema.
Interpretation of results:
study cannot be used for classification
Conclusions:
The acute dermal median lethal dose (LD50) of CGE-PMDA adduct could not be accurately evaluated due to the corrosive nature of the test item.
Executive summary:

This study was performed to assess the acute dermal toxicity of CGE-PMDA adduct in the Wistar strain rat in accordance with OECD Guideline 402 (2017).

One female animal was given a single, 24-hour, semi‑occluded dermal application of the undiluted test item to intact skin at a dose level of 1000 mg/kg body weight. Based on the results of the initial animal, no further animals were treated. Clinical signs and body weight development were monitored during the study. The animal was subjected to gross necropsy.

The animal was killed for humane reasons due to due to the corrosive nature of the test item in accordance with the severity limit set forth in the UK Home Office Project License.

Clinical signs noted one day after dosing were hunched posture, lethargy and tiptoe gait.

Dark green dermal necrosis over the majority of the treatment site surrounded by a margin of blanching and moderate erythema was noted one day after dosing.

The animal lost weight over the study period.

Full thickness necrosis and hemorrhage of the underlining tissues were noted at the visual inspection of the sub-cutaneous layer at the treatment site. 

The acute dermal median lethal dose (LD50) of the test item in the female Wistar strain rat could not be accurately evaluated due to the corrosive nature of the test item.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed

Additional information

Acute oral Toxicity

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.

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.

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 bw. No other signs of toxicity were noted.

Surviving animals showed expected gains in body weight.

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).

Acute dermal toxicity

This study was performed to assess the acute dermal toxicity of CGE-PMDA adduct in the Wistar strain rat in accordance with OECD Guideline 402 (2017).

One female animal was given a single, 24-hour, semi‑occluded dermal application of the undiluted test item to intact skin at a dose level of 1000 mg/kg body weight. Based on the results of the initial animal, no further animals were treated. Clinical signs and body weight development were monitored during the study. The animal was subjected to gross necropsy.

The animal was killed for humane reasons due to due to the corrosive nature of the test item in accordance with the severity limit set forth in the UK Home Office Project License.

Clinical signs noted one day after dosing were hunched posture, lethargy and tiptoe gait.

Dark green dermal necrosis over the majority of the treatment site surrounded by a margin of blanching and moderate erythema was noted one day after dosing.

The animal lost weight over the study period.

Full thickness necrosis and hemorrhage of the underlining tissues were noted at the visual inspection of the sub-cutaneous layer at the treatment site. 

In this study, the test item CGE-PMDA adduct was found to be corrosive.

The acute dermal median lethal dose (LD50) of the test item could not be accurately evaluated.

 

Justification for classification or non-classification

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

The acute dermal median lethal dose (LD50) of the test item could not be accurately evaluated in an acute dermal toxicity study due to the corrosive nature of the test item.

Labelling with H301: Toxic if swallowed and the signal word Danger is required

No studies are available for acute inhalation toxicity.