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Description of key information

Mortality: No mortality occurred in the study during the 14-day observation period at the dose levels of 300 or 2000 mg/kg bw.

Clinical Observations: All animals were symptom-free during the 14-day observation period.

Body Weight and Body Weight Gain: There were no test item related body weight changes. Body weights were within the range commonly recorded for this strain and age.

Necropsy: There was no evidence of macroscopic changes at dose levels of 300 or 2000 mg/kg bw at necropsy.

Under the study testing conditions, the acute oral LD50 of pNMC hydroxide (8:1:1) was found to be greater than 2000 mg/kg bv in female Crl:WI rats.

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records
Reference
Endpoint:
acute toxicity: oral
Remarks:
OECD TG 423
Type of information:
experimental study
Adequacy of study:
key study
Study period:
6 July 2020 - 1 October 2020
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:
17 December 2001
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Test type:
acute toxic class method
Limit test:
no
Specific details on test material used for the study:
Batch/Lot number: PVX-144A PVX14
Description: Grey Powder
Purity: 100% (7.44% Co ; 6.99% Mn ; 59.67% Ni)
Manufacturer: Umicore
Expiry date: 30 April 2021
Storage conditions: Controlled room temperature (15-25 °C, ≤70% relative humidity). Protected from light and humidity (store in a tightly closed container).
The Certificate of Analysis is attached in Appendix 1 of the study report.
Species:
rat
Strain:
Wistar
Sex:
female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories, Research Models and Services, Germany GmbH (Address: Sandhofer Weg 7, D-97633 Sulzfeld, Germany)
- Females (if applicable) nulliparous and non-pregnant: yes
- Age at study initiation: Young adult rats, 8-9 weeks old
- Weight at study initiation: 188-222 g. The maximum difference of individual animal weights from the mean of the treatment group was not exceed 20%.
- Fasting period before study: night before treatment
- Housing: group caging (3 animals/cage)
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: at least 5 days
- SPF
- Method of randomisation in assigning animals to test and control groups : animals were selected by hand at time if devilevry. It was checked that all animals were within 20% of the overall mean at the start of the study

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20.1-25.0°C
- Humidity (%): 31-69%
- Air changes (per hr): 15-20 air changes/hour
- Photoperiod (hrs dark / hrs light): 12 hours daily, from 6.00 am to 6.00pm

Route of administration:
oral: gavage
Vehicle:
methylcellulose
Remarks:
1%
Details on oral exposure:
VEHICLE: Methylcellulose 1%
- Concentration in vehicle: 300 mg/kg bw and 2000 mg/kg bw
- Justification for choice of vehicle: The selection of the vehicle was made during trial formulations with the test item. In order of preference, recommended vehicles were: distilled water, 0.5 or 1% methyl cellulose or carboxymethylcellulose, PEG 400, oil (corn or sunflower) and DMSO (Dimethyl sulfoxide). On the basis of the trial formulations with the test item, the vehicle chosen was 1% Methyl cellulose.
- Lot/batch no. (if required): S11184/S11186/S11187

MAXIMUM DOSE VOLUME APPLIED: 10 mL/kg bw

CLASS METHOD (if applicable)
- Rationale for the selection of the starting dose: the main test a starting dose of 300 mg/kg bw was selected based on the information provided by the Sponsor
Doses:
300 mg/kg bw
2000 mg/kg bw
No. of animals per sex per dose:
300 mg/kg bw: 3/group, 2 groups
2000 mg/kg bw: 3/group, 2 groups
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Detailed clinical observations were made individually after dosing at least once during the first 30 minutes, then 1, 2, 3, 4 and 6 hours after the treatment and once each day for 14 consecutive days thereafter. The body weights were recorded at least on Days -1 (prior to removal of food), 0 (prior to administration), 7 and 14 with a precision of 1 g.
- Necropsy of survivors performed: yes
- Clinical signs including body weight :Individual observations were performed on the skin and fur, eyes and mucous membranes and also respiratory, circulatory, autonomic and central nervous system, somatomotor activity and behaviour pattern. Particular attention was directed to observation of tremors, convulsions, salivation, diarrhoea, lethargy, sleep and coma. The time of death was recorded as precisely as possible.
- Other examinations performed: histopathology = After examination of the external appearance, the cranial, thoracic and abdominal cavities were opened and the appearance of the tissues and organs were observed. All gross macroscopic changes were recorded for each animal.
Statistics:
no statistics
Key result
Sex:
female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
No mortality occurred in the study during the 14-day observation period at the dose levels of 300 or 2000 mg/kg bw.
Clinical signs:
other: All animals were symptom-free during the 14-day observation period.
Gross pathology:
There was no evidence of the macroscopic changes at dose levels of 300 or 2000 mg/kg bw at necropsy.

Individual clinical observations

Dose level: 300 mg/kg bw, treatment on day 0

*Observation days: 0 (30', 1h, 2h, 3h, 4h, 5h, 6h), 1, 2, 3, 4, 5, 6, 7 -14)

 Cage No.  Animal No.  Obervations*  Frequency
 1  5293   Symptom Free   20/20
   5294   Symptom Free   20/20
   5295   Symptom Free   20/20
 2  5296   Symptom Free   20/20
   5297   Symptom Free   20/20
   5298   Symptom Free   20/20

Individual clinical observations

Dose level: 2000 mg/kg bw, treatment on day 0

*Observation days: 0 (30', 1h, 2h, 3h, 4h, 5h, 6h), 1, 2, 3, 4, 5, 6, 7 -14)

 Cage No.  Animal No.  Observations*  Frequency
 3  5579   Symptom Free   20/20
   5580   Symptom Free   20/20
   5581   Symptom Free   20/20
 4  5582   Symptom Free   20/20
   5583   Symptom Free   20/20
   5584   Symptom Free   20/20

Body Weight and Body Weight Gain

 300

mg/kg

 bw

(g)

  

bw

(g)

 

bw

(g)

 
  

bw

(g)

 absolute

bw

(g)

 

absolute

bw

(g)

 
  

absolute

bw

(g)

   -1  0  7  14  0-7  7 -14  0 -14

5293

5294

5295

5296

5297

5298

212

224

227

230

229

215 

199

206

219

222

220

206 

235

242

245

246

249

231 

267

263

257

252

259

248 

36

36

26

24

29

25 

32

21

12

6

10

17 

68

57

38

30

39

42 

Mean

SD

Max

Min

N

222.8

7.6

230

212

212.0

9.5

222

199

241.1

6.9

249

231

257.7

7.0

267

248

29.3

5.4

36

24

16.3

9.3

32

6

45.7

14.1

68

30

 2000

mg/kg bw

  

bw

(g)

 

bw

(g)

 
  

bw

(g)

  

bw

(g)

  

absolute

bw

(g)

 

absolute

bw

(g)

 
 

absolute

bw

(g)

 
   -1  0  7  14  0 -7  7 -14  0 -14

5579

5580

5581

5582

5583

5584

208

211

212

201

205

205 

196

198

199

188

193

188 

214

217

214

215

219

222 

367

353

353

234

244

237 

18

19

15

27

26

34 

153

136

139

19

25

15 

171

155

154

46

51

49 

Mean

SD

Max

Min

N

207.0

4.1

212

201

193.7

4.8

199

188

216.8

3.2

222

214

298.0

65.6

367

234

23.2

7.1

34

15

81.2

67.7

153

15

104.3

61.3

171

46

Interpretation of results:
other: GHS: unclassified; CLP: No category
Conclusions:
Mortality: No mortality occurred in the study during the 14-day observation period at the dose levels of 300 or 2000 mg/kg bw.
Clinical Observations: All animals were symptom-free during the 14-day observation period.
Body Weight and Body Weight Gain: There were no test item related body weight changes. Body weights were within the range commonly recorded for this strain and age.
Necropsy: There was no evidence of macroscopic changes at dose levels of 300 or 2000 mg/kg bw at necropsy.

CONCLUSION
Under the conditions of this study, the acute oral LD50 value of the test item nickel cobalt manganese oxide (8:1:1) was found to be above 2000 mg/kg bw in female Crl:WI rats.
According to the GHS criteria, nickel cobalt manganese oxide (8:1:1) can be ranked as "Unclassified" for acute oral exposure.
According to the CLP criteria, nickel cobalt manganese oxide (8:1:1) can be ranked as "No category" for acute oral exposure.
Executive summary:

The single-dose oral toxicity study of pNMC oxide (8:1:1) in rats was performed according to the acute toxic class method (OECD 423 and Commission Regulation (EC) No 440/2008 of 30 May 2008, B.1.Tris) in Crl:WI Wistar rats.

Four groups of three female Crl:WI rats were treated with the test item at dose levels of 300 mg/kg body weight (bw) (Group 1 and Group 2) and 2000 mg/kg bw (Group 3 and Group 4).

A single oral treatment was carried out by gavage for each animal after an overnight food withdrawal. Food was made available again 3 hours after the treatment. The test item was administered at the dose levels of 300 and 2000 mg/kg bw.

Initially, three females (Group 1) were treated at a dose level of 300 mg/kg bw. As no mortality was observed, a confirmatory group (Group 2) was treated at the same dose level. No mortality was observed in the confirmatory group; therefore, one further group (Group 3) was treated at the dose level of 2000 mg/kg bw. As no mortality was observed, a confirmatory group (Group 4) was treated at the same dose level. No mortality was observed in this group; therefore, no further testing was required according to OECD 423 and Commission Regulation (EC) No 440/2008 of 30 May 2008, B.1.tris.

Clinical observations were performed at 30 minutes, 1, 2, 3, 4 and 6 hours after dosing and daily for 14 days thereafter. Body weight was measured on Days -1, 0, 7 and before necropsy (Day 14). All animals were subjected to a necropsy and a macroscopic examination.

The results of the study were summarized as follows:

Mortality - No mortality occurred in the study during the 14 -day observation period at the dose levels of 300 or 2000 mg/kg bw.

Clinical observations - All animals were symptom-free during the 14 -day observation period

Body weight and body weight gain - There were no test item related body weight changes. Body weight were within the range commonly recorded for this strain and age.

Necropsy - There was no evidence of the macroscopicchanges at dose levels of 300 or 2000 mg/kg bw at necropsy.

Conclusion: Under the conditions of this study, the acute oral LD50 value of the test item pNMC oxide (8:1:1) was found to be above 2000 mg/kg bw in female Crl:WI rats.

According to the GHS criteria, pNMC oxide (8:1:1) can be rankes as "Unclassified' for acute oral exposure.

According to the CLP criteria, pNMC oxide (8:1:1) can be ranked as "No category" for acute oral exposure.

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

According to CLP-criteria, pNMC oxide (8:1:1) does not meet the crireria to be classified for acute oral exposure.