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Description of key information

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 300 - 2000 mg/kg body weight (CLP - Category 4, H302: Harmful if swallowed.).

The acute dermal median lethal dose (LD50) of the test item in the Wistar strain rat was found to be greater than 2000 mg/kg body weight. The test item does not meet the criteria for classification according to CLP Regulation.

The characterisation phase of the acute toxicity inhalation study according to OECD 436 resulted that a formal exposure is not required as it proved impossible to generate a suitable vapour atmosphere of the test item which would be in compliance with the test guideline.

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:
08-03-2017 to 29-03-2017
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:
17 Dec 2001
Qualifier:
according to
Guideline:
EU Method B.1 (Acute Toxicity (Oral))
GLP compliance:
yes (incl. certificate)
Test type:
fixed dose procedure
Limit test:
no
Species:
rat
Strain:
Wistar
Remarks:
RccHan:WIST
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Envigo RMS Limited, UK
- Females nulliparous and non-pregnant: yes
- Age at study initiation: 8 - 12 weeks
- Weight at study initiation: 163 - 185g (main study)
- Fasting period before study: overnight fast immediately before and approx. 3 -4 hours after dosing
- Housing: in groups of up to four in suspended solid-floor polypropylene cages with woodflakes
- Diet: free access to food (2014C Teklad Global Rodent diet)
- Water: free access to main drinking water
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19 - 25°C
- Humidity (%): 30 - 70%
- Air changes (per hr): at least 15
- Photoperiod (hrs dark / hrs light): 12 / 12
Route of administration:
oral: gavage
Vehicle:
DMSO
Doses:
300 mg/kg
2000 mg/kg
No. of animals per sex per dose:
2000 mg/kg: 1 animal (sighting study)
300 mg/kg: 1 animal (sighting study)
300 mg/kg: 5 animals
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Morbidity and mortality checks twice daily, once daily at weekend and public holidays; weighing on days 0, 7 and 14 d or at death
- Necropsy of survivors performed: yes
- Clinical observations: 30 min, 1, 2, 4 h afer dosing, then daily up to 14 d
Preliminary study:
Sighting study: In the absence of toxicity at a dose level of 300 mg/kg tested in one animal, an additional animal was treated with 2000 mg/kg. At this dose level, the signs of systemic toxicity noted were hunched posture, lethargy, noisy and labored respiration, pilo-erection and dehydration. The tested animal was killed for humane reasons, 1 day after dosing.
Due to mortality and signs of systemic toxicity in the "main test" a group of five animals was tested with 300 mg/kg.

Sex:
female
Dose descriptor:
LD50
Effect level:
> 300 - < 2 000 mg/kg bw
Based on:
test mat.
Mortality:
Dose level - 2000 mg/kg (sighting study): the animal was killed 1 day after dosing, due to the occurrence of clinical signs of toxicity that were considered likely to exceed the severity limit.
Dose level - 300 mg/kg: no death
Clinical signs:
Dose level - 2000 mg/kg (sighting study): Signs of systemic toxicity noted were hunched posture, lethargy, noisy and labored restiration, pilo-erection and dehydration
Dose level - 300 mg/kg: No signs of systemic toxicity noted during the observation period.
Body weight:
Dose level - 2000 mg/kg (sighting study): at 0d: 185g; at Death: 164g
Dose level - 300 mg/kg: at 0d (mean): 170g; at 14d (mean): 187g; Animals showed expected gains in body weight over the observation period except for one animal, which showed expected gain in body weight during the first week but body weight loss during the second week.
Gross pathology:
Necropsy:
Dose level - 2000 mg/kg (sighting study): Gaseous stomach and test item present in the stomach
Dose level - 300 mg/kg: No abnormalities
Interpretation of results:
Category 4 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 300 - 2000 mg/kg body weight (CLP - Category 4).
Executive summary:

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 300 - 2000 mg/kg body weight (CLP - Category 4).

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

Acute toxicity: via inhalation route

Link to relevant study records
Reference
Endpoint:
acute toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
supporting study
Study period:
2018-06-25 to 2018-07-20
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
OECD Guideline 436 (Acute Inhalation Toxicity: Acute Toxic Class Method)
Version / remarks:
2009
Deviations:
yes
Remarks:
It proved impossible to generate a suitable vapour atmosphere of the test item which would be in compliance with the test guideline. This was considered not to have affected the validity of the study.
Qualifier:
according to
Guideline:
EU Method B.52 (Acute Inhalation Toxicity - Acute Toxic Class Method)
Version / remarks:
2014
Deviations:
yes
Remarks:
It proved impossible to generate a suitable vapour atmosphere of the test item which would be in compliance with the test guideline. This was considered not to have affected the validity of the study.
GLP compliance:
yes (incl. certificate)
Test type:
acute toxic class method

The mean non-volatile component of the test item was found to be 70.88% (n=10).

The test item vapor was generated and the following results were achieved in terms of atmosphere concentrations: 

Duration of Exposure (minutes)

Flow (L/min)

Volume of Air Sampled (L)

Atmosphere Concentration (mg/L)

Air

Exhaust

13

5

50

10

0.0059

30

10

50

2

0.1199

42

15

50

1

0.2219

53

20

50

1

0.2827

 

Although it was possible to generate a vapor atmosphere of the test item, the concentrations achieved were much lower than those required by the test guidelines (0.5 to 20 mg/L).  It was considered, that generation of the test item as an aerosol would not be appropriate due to the nature of the test item.

Interpretation of results:
study cannot be used for classification
Conclusions:
In view of the physical nature of the test item it is considered unlikely to represent a significant hazard by the 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:
14-03-2017 to 05-04-2017
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Version / remarks:
adopted 24 Februrary 1987
Qualifier:
according to
Guideline:
EU Method B.3 (Acute Toxicity (Dermal))
GLP compliance:
yes (incl. certificate)
Limit test:
yes
Species:
rat
Strain:
Wistar
Remarks:
RccHan:WIST
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Envigo RMS (UK) Limited
- Females (if applicable) nulliparous and non-pregnant: yes
- Age at study initiation: 8 to 12 weeks
- Weight at study initiation: at least 200 g
- Fasting period before study: no
- Housing: individually in the initial test, and individually in the "main test" during the exposure time and in groups of four, by sex, for the remainder of the study; suspended solid floor polypropylene cages furnished with woodflakes
- Water and Diet: free access to mains drinking water and food (2014C Teklad Global Rodent diet)
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19 to 25
- Humidity (%): 30 to 70
- Air changes (per hr): at least 15 changes per hour
- 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: approx. 10% of 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
- Washing (if done): the bandage was carefully removed and the treated skin and surrounding hair wiped with cotton wool moistened with dimethyl sulphoxide to remove any residual test item.
- Time after start of exposure: 24h

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 2000 mg/kg bw

Duration of exposure:
24 hours
Doses:
2000 mg/kg bw
No. of animals per sex per dose:
1 (initial test)
4 ("main test")
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: 30 min, 1, 2 and 4 hours, subsequently once daily for 14 days.
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight, dermal reactions
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
No deaths
Clinical signs:
No signs of systemic toxicity were noted during the observation period.
Body weight:
one female showed body weight loss during the first and second week. One other female showed no gain in body weight during the first week with expected gain in body weight during the second week. The remaining animals showed expected gains in body weight over the study period.
Gross pathology:
No abnormalities were noted at necropsy
Other findings:
Dermal reactions:
Yellow colored staining, not preventing evaluation of dermal responses, was noted at the test sites of five animals 1 day after dosing.
Very slight erythema was noted at the test sites of the initial two treated animals 1 and 2 days after dosing and persisted in the initial treated male 3 and 4 days after dosing.
There were no signs of dermal irritation noted at the test sites of the additional group of eight animals.
Interpretation of results:
GHS criteria not met
Conclusions:
The acute dermal median lethal dose (LD50) of the test item in the Wistar strain rat was found to be greater than 2000 mg/kg body weight.
The test item does not meet the criteria for classification according to CLP Regulation.
Executive summary:

The acute dermal median lethal dose (LD50) of the test item in the Wistar strain rat was found to be greater than 2000 mg/kg body weight.

The test item does not meet the criteria for classification according to CLP Regulation.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
2 000 mg/kg bw

Additional information

Justification for classification or non-classification

The acute oral LD50 was estimated to be in the range of 300 - 2000 mg/kg bw, therefore the substance is classified as acute toxicity oral Category 4, H302 (harmful if swallowed).

In the available acute dermal test, no adverse effects were observed. Thus, the substance is not classified for dermal toxicity.