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Administrative data

Description of key information

Acute oral toxicity: Key study. Test method according to OECD 423, GLP study. The LD50 of the test item is higher than 2000 mg/kg body weight by oral route in the rat. The LD50 cut-off may be considered to be 2500 mg/kg body weight by oral route in the rat.

Acute inhalation toxicity: Data waiving (study scientifically not necessary): According to REACH Annex VIII, column 2: In addition to the oral route, for substances other than gases, the information mentioned under 8.5.2 to 8.5.3 shall be provided for at least one other route. The information is provided for dermal route.

Acute dermal toxicity: Key study. Test method according to OECD 402, GLP study. The LD50 of the test item is higher than 2000 mg/kg body weight by dermal route in rats.

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 May 2018 - 29 May 2018
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)
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Test type:
acute toxic class method
Limit test:
yes
Species:
rat
Strain:
Sprague-Dawley
Remarks:
(SPF Caw)
Sex:
female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Elevage JANVIER LABS (53940 Le Genest St Isle – France)
- Females nulliparous and non-pregnant: yes
- Age at study initiation: 8 or 9 weeks
- Weight at study initiation: 214.0 g (SD = 18.9 g)
- Fasting period before study: Food was removed on D-1 and then redistributed 4 hours after the test item administration.
- Housing: Rats were housed by group of three in solid-bottomed clear polycarbonate cages with a stainless steel mesh lid. Each cage contained sawdust bedding which was changed at least 2 times a week. Each cage was installed in conventional air conditioned animal husbandry.
- Diet (e.g. ad libitum): Ad libitum. Teklad Global 16% Protein Rodent Diet (ENVIGO 2016).
- Water (e.g. ad libitum): Ad libitum. Drinking water (tap-water from public distribution system). Microbiological and chemical analyses of the water were carried out once every six months by Bureau Veritas – Eurofins (FRANCE).
- Acclimation period: the animals were acclimatized for at least 5 days before treatment.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19ºC to 25ºC
- Humidity (%): 30 to 70%
- Air changes (per hr): >10 air changes/hour
- Photoperiod (hrs dark / hrs light): 12 hours light (07.00 to 19.00) and 12 hours dark cycle.
Route of administration:
oral: gavage
Vehicle:
unchanged (no vehicle)
Details on oral exposure:
MAXIMUM DOSE VOLUME APPLIED: 2.26 mL/kg body weight (corresponding to 2 g/kg, according to the calculated density)

CLASS METHOD (if applicable)
- Rationale for the selection of the starting dose: Available information suggests that mortality is unlikely at the highest starting dose level (2000 mg/kg body weight). Hence, the study is initiated with the starting dose of 2000 mg/kg body weight.
Doses:
2000 mg/kg bw
No. of animals per sex per dose:
6 (3 female rats per step)
Control animals:
yes
Remarks:
(study performed on three animals receiving distilled water under requirements of OECD Guideline 423)
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: At each step, the animals were observed four times on test day 0 (day of administration), i.e. at T0+30 min, T0+1h, T0+3h and T0+4h, and once daily during days 1 to 14 post administration. The body weights were recorded on test day 0 (just before administration) then on D2, D7, and D14.
- Necropsy of survivors performed: yes. At termination, gross pathological findings were recorded and reported.
- Other examinations performed:
Clinical observations included: spontaneous activity, Preyer’s reflex (noise), respiratory rate, convulsions, tremors, body temperature, muscle tone, palpebral opening, pupil appearance, salivation, lachrymation, righting reflex, back hair appearance.
Key result
Sex:
female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Key result
Sex:
female
Dose descriptor:
LD50 cut-off
Effect level:
2 500 mg/kg bw
Based on:
test mat.
Mortality:
Two mortalities were noted in animals treated at the dose of 2000 mg/kg body weight at 24 hours post dose (one in each step).
Clinical signs:
other: The mortalities were preceded by a decrease or an absence of spontaneous activity (2/2), Preyer’s reflex (2/2), muscle tones (2/2), righting reflex (2/2), associated with eyes partly closed (1/2). Rigor mortis (2/2) was noted before the necropsy. In survi
Gross pathology:
The macroscopic examination of the animals found dead revealed a thinning of corpus (1/2) and forestomach (1/2) with red spots (1/2).
The macroscopic examination of the surviving animals at the end of the study did not reveal treatment related changes.

Table 1: Body weight and weight gain in grams

Females

D0

D2

D2-D0

D7

D7-D0

D14

D14-D0

Rf 2491

195

225

30

239

44

269

74

Rf 2492

197

218

21

247

50

269

72

Rf 2493

202

 

 

 

 

 

Rf 2535

229

229

0

252

23

271

42

Rf 2536

241

246

5

290

49

316

75

Rf 2537

220

 

 

 

 

 

MEAN

214.0

229.5

14.0

257.0

41.5

281.3

65.8

SD

18.9

11.9

13.9

22.6

12.6

23.2

15.9

Note: †: Rf2493 and Rf2537 found dead on D1

Interpretation of results:
other: Not classified (CLP Regulation EC no. 1272/2008)
Conclusions:
The LD50 of the test item is higher than 2000 mg/kg body weight by oral route in the rat. The LD50 cut-off may be considered to be 2500 mg/kg body weight by oral route in the rat.
Executive summary:

The acute oral toxicity of the test item was tested in accordance with OECD Test Guideline 423, following GLP. 6 female Sprague-Dawley rats divided in 2 groups were administered sequentially with test item by oral gavage. The first set of 3 female rats was given a single dose of 2000 mg/kg body weight. One mortality was observed after 24 h of treatment, so the second set of 3 female rats was treated at the same dose level. One mortality was also observed at this dose level and at 24 hours post dose. In surviving animals (4/6), a decrease of spontaneous activity (4/4), Preyer’s reflex (2/4), muscle tones (4/4), righting reflex (4/4), associated with eyes partly closed (2/4) were noted in the first hours of the test. The animals recovered a normal activity at 24 hours post-dose. The body weight evolution of the animals remained normal during the study. The macroscopic examination of the animals found dead revealed a thinning of corpus (1/2) and forestomach (1/2) with red spots (1/2), while the animals which survived until the end of the study did not reveal treatment related changes. Based on these results, the LD50 of the test item was determined to be higher than 2000 mg/kg bw and, as per OECD Test Guideline 423, the LD50 cut-off of the test item may be considered to be 2500 mg/kg bw.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
2 500 mg/kg bw
Quality of whole database:
Key study with Klimisch score = 1

Acute toxicity: via inhalation route

Link to relevant study records
Reference
Endpoint:
acute toxicity: inhalation
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
other:
Justification for type of information:
JUSTIFICATION FOR DATA WAIVING
According to REACH Annex VIII, column 2: In addition to the oral route (Annex VII, 8.5.1.), for substances other than gases, the information mentioned under 8.5.2 to 8.5.3 shall be provided for at least one other route. The information is provided for dermal route.

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:
09 May 2018 - 29 May 2018
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Test type:
fixed dose procedure
Limit test:
yes
Species:
rat
Strain:
Sprague-Dawley
Remarks:
(SPF Caw)
Sex:
female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Elevage JANVIER LABS (53940 Le Genest St Isle – France)
- Females nulliparous and non-pregnant: yes
- Age at study initiation: 8 or 9 weeks
- Weight at study initiation: 226.7 g (SD = 26.1 g)
- Fasting period before study: not specified.
- 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 stainless steel mesh lid. Each cage contains dust free wood shavings which were changed at least 2 times a week. Each cage was installed in conventional air conditioned animal husbandry.
- Diet (e.g. ad libitum): Ad libitum. Teklad Global 16% Protein Rodent Diet (ENVIGO 2016).
- Water (e.g. ad libitum): Ad libitum. Drinking water (tap-water from public distribution system). Microbiological and chemical analyses of the water were carried out once every six months by Bureau Veritas – Eurofins (FRANCE).
- Acclimation period: the animals were acclimatized for at least 5 days before treatment.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19ºC to 25ºC
- Humidity (%): 30 to 70%
- Air changes (per hr): >10 air changes/hour
- Photoperiod (hrs dark / hrs light): 12 hours light (07.00 to 19.00) and 12 hours dark cycle.
Type of coverage:
semiocclusive
Vehicle:
unchanged (no vehicle)
Details on dermal exposure:
TEST SITE
- Area of exposure: dorsal area of the trunk
- % coverage: at least 10% of the body surface area.
- Type of wrap if used: porous gauze dressing (50 mm x 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 microporeTM adhesive tape from 3M).

REMOVAL OF TEST SUBSTANCE
- Washing (if done): no
- Time after start of exposure: 24h

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 2.26 mL/kg body weight
- Concentration (if solution): N/A
- Constant volume or concentration used: yes
- For solids, paste formed: N/A
Duration of exposure:
24 h
Doses:
Range finding study: 2000 mg/kg body weight
Main study: 2000 mg/kg body weight
No. of animals per sex per dose:
Range finding study: 1 female per dose
Main study: 2 females per dose
Control animals:
yes
Remarks:
(study performed on three females receiving distilled water by topical application under requirements of OECD Guideline 402)
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: At each step, the animals were observed three times on test day 0 (day of administration), i.e. at T0+30 min, T0+3h and T0+5h, and once daily during days 1 to 14 post administration. The body weights were recorded on test day 0 (just before administration) then on D2, D7, and D14.
- Necropsy of survivors performed: yes. At termination, gross pathological findings were recorded and reported.
- Other examinations performed:
Clinical observations: spontaneous activity, Preyer’s reflex (noise), respiratory rate, convulsions, tremors, body temperature, muscle tone, palpebral opening, pupil appearance, salivation, lachrymation, righting reflex and treatment site (erythema, dryness of the skin, scab, etc.)
Key result
Sex:
female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
No mortality occurred during the study.
Clinical signs:
other: Erythema was noted in treated animals (2/3) at 48 hours post dose and was totally reversible on day 6. Scab was noted in treated animals (2/3) between days 6 and 7. Dryness of the skin was noted in treated animals (2/3) between days 7 and 10.
Gross pathology:
The macroscopic examination of the animal at the end of the study did not reveal treatment-related changes.

Table 1: Body weight and weight gain in grams

Females

D0

D2

D2-D0

D7

D7-D0

D14

D14-D0

Rf 2516

200

221

21

240

40

271

71

Rf 2570

231

236

5

243

12

269

38

Rf 2571

229

241

12

254

25

278

49

MEAN

220.0

232.7

12.7

245.7

25.7

272.7

52.7

SD

17.3

10.4

8.0

7.4

14.0

4.7

16.8

Interpretation of results:
other: No category (CLP Regulation EC no. 1272/2008)
Conclusions:
The LD50 of the test item is higher than 2000 mg/kg body weight by dermal route in rats.

Executive summary:

The acute dermal toxicity of the test item was studied according to OECD Guideline 402 (GLP study). 3 female Sprague-Dawley rats were tested for a exposure period of 24 h. Initially, a range finding study was conducted at a single dose of 2000 mg/kg bw in one animal. Based on the results of this preliminary two additional rats were tested at a dose of 2000 mg/kg bw. No mortality was observed. The body weight evolution of the animals remained normal during the study. Erythema was noted in treated animals (2/3) at 48 hours post dose and was totally reversible on day 6. Scab was noted in treated animals (2/3) between days 6 and 7. Dryness of the skin was noted in treated animals (2/3) between days 7 and 10. No other clinical signs were observed. The macroscopic examination of the animals at the end of the study did not reveal treatment related effects. Based on these results, the test item was found to be non toxic, with an LD50 > 2000 mg/kg bw.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
2 000 mg/kg bw
Quality of whole database:
Key study with Klimisch score = 1

Additional information

Acute oral toxicity: Key study. The acute oral toxicity of the test item was tested in accordance with OECD Test Guideline 423, following GLP. 6 female Sprague-Dawley rats divided in 2 groups were administered sequentially with a single dose of 2000 mg/kg body weight of test item by oral gavage. Two mortalities were noted at 24 hours post dose (one in each step). In surviving animals (4/6), some clinical signs were noted in the first hours of the test but all recovered a normal activity at 24 hours post-dose. The body weight evolution of the animals remained normal during the study. The macroscopic examination of the animals found dead revealed a thinning of corpus (1/2) and forestomach (1/2) with red spots (1/2), while the animals which survived until the end of the study did not reveal treatment related changes. Based on these results, the LD50 of the test item was determined to be higher than 2000 mg/kg bw and, as per OECD Test Guideline 423, the LD50 cut-off of the test item may be considered to be 2500 mg/kg bw.

Acute inhalation toxicity: Data waiving (study scientifically not necessary): According to REACH Annex VIII, column 2: In addition to the oral route, for substances other than gases, the information mentioned under 8.5.2 to 8.5.3 shall be provided for at least one other route. The information is provided for dermal route.

Acute dermal toxicity: Key study. The acute dermal toxicity of the test item was studied according to OECD Guideline 402 (GLP study). 3 female Sprague-Dawley rats were tested for a exposure period of 24 h. Initially, a range finding study was conducted at a single dose of 2000 mg/kg bw in one animal. Based on the results of this preliminary two additional rats were tested at a dose of 2000 mg/kg bw. No mortality was observed. The body weight evolution of the animals remained normal during the study.Erythema was noted in treated animals (2/3) at 48 hours post dose and was totally reversible on day 6. Scab was noted in treated animals (2/3) between days 6 and 7. Dryness of the skin was noted in treated animals (2/3) between days 7 and 10. No other clinical signs were observed.The macroscopic examination of the animals at the end of the study did not reveal treatment related effects.Based on these results, the test item was found to be non toxic, with an LD50 > 2000 mg/kg bw.

Justification for classification or non-classification

Based on the available data, the substance is not classified for acute toxicity according to CLP Regulation (EC) no. 1272/2008.