Nickel Cobalt Manganese Hydroxide

Acute Toxicity: oral

Administrative data

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

8 July 2020 - 24 September 2020

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2020

Report date:

2020

Materials and methods

Test guideline

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

Test material

Test material information

1

Reference substance name:

Nickel Cobalt Manganese Hydroxide

EC Number:

839-353-8

Cas Number:

189139-63-7

Molecular formula:

Molecular formula: Ni1-x-yMnxCoy(OH)2, Stoechiometry of (Me = Ni + Co + Mn) equals 1, ranges of the elements approx. as: Ni/Me = 0.25 – 0.95 Mn/Me = 0.02 – 0.40 Co/Me = 0.02 – 0.40 OH = 2.00

IUPAC Name:

Nickel Cobalt Manganese Hydroxide

Constituent 1

Reference substance name:

Manganese dihydroxide

Cas Number:

18933-05-6

Molecular formula:

Mn(OH)2

IUPAC Name:

Manganese dihydroxide

Constituent 2

Reference substance name:

Cobalt dihydroxide

EC Number:

244-166-4

EC Name:

Cobalt dihydroxide

Cas Number:

21041-93-0

Molecular formula:

CoH2O2

IUPAC Name:

cobalt(2+) dihydroxide

Constituent 3

Reference substance name:

Nickel dihydroxide

EC Number:

235-008-5

EC Name:

Nickel dihydroxide

Cas Number:

12054-48-7

Molecular formula:

H2NiO2

IUPAC Name:

nickel(2+) dihydroxide

Test material form:

solid: particulate/powder

Specific details on test material used for the study:

Batch/Lot number: PVX-089 PVX 14
Description: Dark Grey Powder
Purity: 100% (6.31% Co ; 5.96% Mn ; 50.87% 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.

Test animals

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, nulliparous and non-pregnant: yes
- Age at study initiation: 8-9 weeks old
- Weight at study initiation: 184-244 g. The maximum difference of individual animal weights from the mean of the treatment group was not exceed 20%
- Fasting period before study: the night before treatment the animals were fasted (food but not water)
- Housing: group caging (3 animals/cage, with enrichment
- Historical data: no
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: at least 5 days
- Microbiological status when known: SPF
- Method of randomisation in assigning animals to test and control groups: The animals were selected by hand at time of delivery. 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 exchanges/hour
- Photoperiod (hrs dark / hrs light): 12 hours/12 hours

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

methylcellulose

Remarks:

1% in distilled water

Details on oral exposure:

VEHICLE: 1% methylcellulose in distilled water
- 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) and DMSO (Dimethyl sulfoxide). 1% methyl cellulose was appropriate for treatment; therefore, it was found to be a suitable vehicle for formulations.
- Lot/batch no.: 7105702 (methyl cellulose), 202001013/202003032 (aqua purificata)

MAXIMUM DOSE VOLUME APPLIED: 10 ml/kg bw

DOSAGE PREPARATION: The test item was freshly formulated at appropriate concentrations in the vehicle in the Pharmacy of the Test Facility on the day of administration. The formulations were stirred with a magnetic stirrer until completion of treatment

CLASS METHOD
- Rationale for the selection of the starting dose: In agreement with the Sponsor, in the main test a starting dose of 300 mg/kg bw was selected based on the information provided by the Sponsor.

Doses:

300 and 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:
Animals were inspected for signs of morbidity and mortality twice daily (at the beginning and end of each working day)
Any clinical sign noted during dosing or at any other occasions was recorded at the time seen
Detailed clinical observations were made individually after dosing 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 on Days -1 (prior to removal of food), 0 (prior to administration), 7 and 14 with a precision of 1 g. Terminal body weight of animals sacrificed in extremis was also recorded.

- Clinical signs: 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.

- Necropsy of survivors performed: yes

- Pathology:
At study termination, euthanasia was performed by sodium pentobarbital 40 % (euthanimal) terminal anaesthesia
All animals were subjected to a necropsy and a macroscopic examination. All animals were exsanguinated after verification of narcosis following an injection of sodium pentobarbital. 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

Results and discussion

Effect levels

Key result

Sex:

female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Remarks on result:

not determinable due to absence of adverse toxic effects

Mortality:

There was no mortality at dose levels of 300 and 2000 mg/kg bw

Clinical signs:

other: After treatment at 300 and 2000 mg/kg bw, all animals were symptom-free from Day 0 until the end of the 14-Day observation period

Gross pathology:

There was no evidence of any macroscopic observations in animals dosed at 300 and 2000 mg/kg bw and subjected to the necropsy on Day 14

Any other information on results incl. tables

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	5287	Symptom Free	20/20
	5288	Symptom Free	20/20
	5289	Symptom Free	20/20
2	5290	Symptom Free	20/20
	5291	Symptom Free	20/20
	5292	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	5585	Symptom Free	20/20
	5586	Symptom Free	20/20
	5587	Symptom Free	20/20
4	5588	Symptom Free	20/20
	5589	Symptom Free	20/20
	5590	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
5287 5288 5289 5290 5291 5292	234 240 243 226 230 258	214 225 233 211 220 244	253 262 260 249 243 279	268 269 282 263 261 287	39 37 27 38 23 35	15 7 22 14 18 8	54 44 49 52 41 43
Mean SD Max Min N	238.5 11.4 258 226 6	224.5 12.4 244 211 6	257.7 12.6 279 243 6	271.7 10.5 287 261 6	33.2 6.6 39 23 6	14.0 5.8 22 7 6	47.2 5.3 54 41 6

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
5585 5586 5587 5588 5589 5590	209 208 208 206 200 199	194 196 197 190 184 185	233 229 229 230 227 233	234 237 236 242 234 244	39 33 32 40 43 48	1 8 7 12 7 11	40 41 39 52 50 59
Mean SD Max Min N	205.0 4.4 209 199 6	191.0 5.6 197 184 6	230.2 2.4 233 227 6	237.8 4.2 244 234 6	39.2 6.0 48 32 6	7.7 3.9 12 1 6	46.8 8.1 59 39 6

Applicant's summary and conclusion

Interpretation of results:

Category 5 based on GHS criteria

Conclusions:

Under the conditions of this study, the acute oral LD50 value of the test item Nickel Cobalt Manganese Hydroxide (8:1:1) was found to be greater than 2000 mg/kg bw in female Crl:WI rats.

According to the CLP criteria, Nickel Cobalt Manganese Hydroxide (8:1:1) can be ranked as "No Category" for acute oral exposure.

Executive summary:

The single-dose oral toxicity study of Nickel Cobalt Manganese Hydroxide (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.

Two groups of 3 female Crl:WI rats were treated with the test item at dose level of 300 mg/kg body weight (bw) and two groups of 3 females were treated at the dose level of 2000 mg/kg bw.

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 formulated in 1% methyl cellulose at concentrations of 30 and 200 mg/mL at a dose volume of 10 mL/kg bw, respectively. Initially three females were treated at a dose level of 300 mg/kg bw. All animals survived, therefore the second group of animals were treated at a dose level of 300 mg/kg bw. No mortality was observed, therefore the third group of animals were treated at a dose level of 2000 mg/kg bw. All animals survived, the dose of 2000 mg/kg bw were repeated with 3 additional animals.

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 14 (before necropsy). All animals were subjected to a necropsy and a macroscopic examination.

The results of the study were summarized as follows:

Mortality: There was no mortality atdoselevels of 300 and 2000 mg/kg bw.

Clinical Observations: After treatment at 300 and 2000 mg/kg bw, all animals were symptom-free from Day 0 until the end of the 14-Day observation period.

Body Weight and Body Weight Gain: There were no effects on body weight or body weight gains at dose levels of 300 and 2000 mg/kg bw.

Necropsy: There was no evidence of the macroscopic observations in animals dosed at 300 and 2000 mg/kg bw and subjected to the necropsy on Day 14.

Conclusion: Under the conditions of this study, the acute oral LD₅₀value of the test item Nickel Cobalt Manganese Hydroxide (8:1:1) was found to be greater than 2000 mg/kg bw in female Crl:WI rats.

 

According to the GHS criteria, Nickel Cobalt Manganese Hydroxide (8:1:1) can be ranked as "Category 5/Unclassified" for acute oral exposure.

According to the CLP criteria, Nickel Cobalt Manganese Hydroxide (8:1:1) can be ranked as "No Category" for acute oral exposure.