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Diss Factsheets

Administrative data

Description of key information

Acute oral toxicity:
300 mg/kg bw < LD50(female rats)< 2000mg/kg bw

Acute dermal toxicity:

LD50 (female rats) > 2000 mg/kg bw

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:
2016-11-04 to 2017-01-06
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)
Version / remarks:
dated December 17th, 2001
Deviations:
yes
Remarks:
Environmental parameters : relative humidity lower than 30% (minimum = 21%) and tempearature lower than 19°C (minimum = 18°C) reported - these deviations are considered without impact on the conclusion of the study.
Qualifier:
according to guideline
Guideline:
EU Method B.1 tris (Acute Oral Toxicity - Acute Toxic Class Method)
GLP compliance:
yes (incl. QA statement)
Remarks:
dated October 23rd, 2015
Test type:
acute toxic class method
Limit test:
yes
Species:
rat
Strain:
Sprague-Dawley
Sex:
female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Elevage JANVIER LABS, Le Genest St Isle, France
- Age at study initiation:8 or 9 weeks old at the beginning of the study
- Weight at study initiation: 196 - 226 g (fasted body weight)
- Fasting period before study: The rats were fasted approx. 1 day prior to dosing, with food being returned to the rats 4 hours after dosing.
- Housing: Animals were housed by group of three in solid-bottomed clear plycarbonate cages with a stainless steel mesh lid. Each cage contains sawdust and was installed in conventional air conditioned animal husbandry
- Diet (ad libitum): Envigo - 2016
- Water: ad libitum
- Acclimatization period: at least 5 days


ENVIRONMENTAL CONDITIONS
- Temperature: 19 - 25 °C
- Relative humidity: 30 - 70 %
- Photoperiod (hrs dark / hrs light): 12/12
- Rate of air exchange : at least 10 changes per hour
Route of administration:
oral: gavage
Vehicle:
other: none for the first step of the study and olive oil for second and third steps
Details on oral exposure:
In the first step of the study, the test item was administered by gavage under a volume of 1.95 mg/kg body weight (corresponding to 2g/kg, according to the calculated density) using a suitabe graduated syringue fitted with an oesophageal canula.
In the second and third steps of the study, for each step, 0.29 mL of the test item (corresponding to 300 mg) were added to 1.66 mL of olive oil. The preparations were stirred by vortex to obtain blue solutions just before the administration.
Each preparation was administered under a volume of 1.95 mL/kg body weight using a suitable syringe graduated fitted with an oesophageal metal canula.
Doses:
2000 and 300 mg/kg
No. of animals per sex per dose:
2000 mg/kg: three females
300 mg/kg: 6 females
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Daily examination: Systematic examination were carried out to identify any behavioural or toxic effects on the major physiological functions during 14 days following the administration of the test item. These observations were compared to historical control data. Observations and a mortality report were then carried out every day for 14 days.
- Periodical examinations: The animals were weighed on D0 (just before administering the test item) then on D2, D7 and D14. Weight changes were calculated and recorded.
- Examination at the end of the test: On D14, the animals were anesthetised with sodium pentoarbital and administration continued to fatal levels. Macroscopic observations were entered on individual autopsy sheets. 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.
Key result
Sex:
female
Dose descriptor:
LD50
Effect level:
> 300 - < 2 000 mg/kg bw
Based on:
test mat.
Remarks on result:
other: In accordance with the O.E.C.D. test guideline n° 423, the LD50 cut-off of the test item may be considered as 500 mg/kg body weight.
Mortality:
Three mortalities were noted in animals treated at the dose of 2000 mg/kg body weight, at 24 hours post-dose.
No mortality occured during the study at the dose of 300 mg/kg body weight.
Clinical signs:
other: other: At the dose of 2000 mg/kg body weight, the mortalities were preceeded by an absence or decrease of spontaneous activity (3/3), muscle tone (3/3), righting reflex (3/3), Peeyer's reflex (3/3), associatd with bradypnea (3/3), hypothermia (3/3), eyes
Gross pathology:
At the dose of 2000 mg/Kg body weight, the macroscopic examination of the animals revealed remains important test item in the stomach (3/3), blue coloration of a forestomach and corpus (3/3) and cellular lysis of main organs in the abdomen (1/3).
At the dose of 300 mg/Kg body weight, the macrosscopic examination of the animals at the end of the study did not reveal treatment related changes.
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 body weight by oral route in the rat.
In accordance with the O.E.C.D. test guideline n° 423, the LD50 cut-off of the test item may be considered as 500 mg/kg body weight.
According to the criteria for classification, packaging and labelling of dangerous substances and preparations in accordance with the Regulation EC n°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.
Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LD50
Value:
500 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:
2019-01-25 to 2019-04-09
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Version / remarks:
dated October 9th, 2017
GLP compliance:
yes (incl. QA statement)
Remarks:
Certificate dated 27 April 2017
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
Sprague-Dawley
Sex:
female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Elevage Janvier Labs, Le Genest St Isle, France
- Age at study initiation: 8 weeks
- Weight at study initiation: 219 to 231 g prior to dosing
- Housing: During the treatment the animals were kept in individual cages. On D1, the animals were put together into their cage. The rats were kept in solid-bottomed clear polycarbonate cages with a stainles seelt mesh lid. Each cage contains dust free wood shavings which were changed at least 2 times per week. Each cage was installed in conventional air conditioned animal husbandry.
- Diet (ad libitum): ENVIGO 2016
- Water (ad libitum): tap-water from public distribution system)
- Acclimation period: at least 5 days prior to the start of the study

ENVIRONMENTAL CONDITIONS
- Temperature (°C): controlled to remain within target range of 19°C to 25°C
- Humidity (%): controlled to remain within target range of 30% to 70%
- Air changes (per hr): at least 10 air changes/hour
- Photoperiod (hrs dark / hrs light): 12 h/12h
Type of coverage:
other: topical application under non occlusive porous gauze dressing, gauze dressing removed after 24-hour exposure period
Vehicle:
other: ethanol in liquid paraffin (2/8, w/w)
Details on dermal exposure:
Approximately 24 hours before the treatment, fur was removed from the dorsal area of the trunk of the tes animals by clipping. At leat 10% of the ody surface was clear for the application of the test item.
Ethanol in liquid paraffin (2/8, w/w) was chosen as it produced the most suitable formulation at the requested concentration.
6.4147 g of the test item was weighted and 25.66g of the vehicle was added to obtain a preparation weighing of 3207 g. The preparation was stirred manually and by vortex to obtai a green homogeneous emulsion just before the administration.
Animals from treated group received by topical application, under non-occlusive porous gauze dressing (50 mm * 50 mm non woven swab of 4-layer patch from MEDISTOCK) secured in position with a strip of surgical adhesive tape (50 mm wides hypoallergenic micropore adhesive tapefrom 3M), an effective dose of 2000 mg/Kg body weight administered under a volume of 10 mL/Kg body weight, during 24 hours. After 24-hour exposure period, the gauze dressings were removed.





Duration of exposure:
24-hour exposure period
Doses:
2000 mg/kg bodyweight
No. of animals per sex per dose:
1 (range-finding study) + 2 (main study) female rats
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days after dosing
* Daily examination: Systemic examinations were carried out to identify any behavioural or toxic effects on the major physiological functions during 14 days following the administration of the test item. This examination focuses particularly on a list of symptoms, recorded as present of absent on the observation sheet. These observations were compared to historical data. Observations and a mortality report were carried out every day for 14 days.
* Periodical examinations: The animal were weighed on day 0 (just before adminstering the test item) then on day 2, day 7 and day 14. Wieght changes were calculated and recorded.
* Examination at the end of the test: On day 14, the animals were anesthesised with sodium pentoarbital (Dolethal). Macroscopic observations were entered on individual autopsy sheets. Only those organs likely to be modified in cases of acute toxicity were examined. Those presenting macroscopic anomalies can be removed and preserved in view to microscopic examinations.
Statistics:
no data
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Mortality:
No mortality occured during the study.
Clinical signs:
other: other: No systemic clinical signs related to the administration of the test item were observed. Erythema was noted in treated animals (1/3) at 24 hours post dose. The reaction was totally reversible on day 3. Black coloration not preventing quotation of e
Gross pathology:
The macroscopic examination of the animals at the end of the study did not reveal treatment-related changes.
Interpretation of results:
GHS criteria not met
Conclusions:
The LD50 of the test item is higher than 2000 mg/kg body weight by dermal route in the rat.
The test item does not have to be classified in accordance with the Regulation EC n° 1272/2008 on classification, labelling and packaging of substances and mixtures. No signal word or hazard statement is required.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed

Additional information

Justification for selection of acute toxicity – oral endpoint
Key study.

Justification for selection of acute toxicity – dermal endpoint
Key study.



Justification for classification or non-classification

Acute oral toxicity

The reference Richeux (2017) is considered as the key study for acute oral toxicity and will be used for classification. According to Richeux (2017) female rats were dosed at 300 and 2000 mg/kg orally via gavage. During the conduct of the study mortalities occurred at the highest dose group. No mortality occurred at 300 mg/kg.

The LD50 of the test item is higher than 300 mg/kg body weight and lower than 2000 mg/kg body weight by oral route in the rat.

In accordance with the O.E.C.D. test guideline n° 423, the LD50 cut-off of the test item may be considered as 500 mg/kg body weight.

According to the criteria for classification, packaging and labelling of dangerous substances and preparations in accordance with the Regulation EC n°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.

 

Specific target organ toxicant (STOT) – single exposure: oral

The classification criteria according to regulation (EC) 1272/2008 as specific target organ toxicant (STOT) – single exposure, oral are not met since the toxic effects observed in the acute oral toxicity test already leads to an acute oral toxicity classification. No additional effects in animals or humans are known that would justify a specific target organ toxicant (STOT) – single exposure: oral classification.

Acute dermal toxicity

According to the key study (Richeux, 2019) conducted in accordance with the O.E.C.D. test guideline n°402, the LD50 of the test item is higher than 2000 mg/kg body weight by dermal route in the rat.

According to the criteria for classification, packaging and labelling of dangerous substances and preparations in accordance with the Regulation EC n°1272/2008, the test item does not have to be classified. No signal word or hazard statement is required.