Cobalt Nickel Manganese Oxide

Acute Toxicity: oral

Administrative data

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

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

impurity 1

Reference substance name:

Total unspecified impurities

IUPAC Name:

Total unspecified impurities

Constituent 1

Reference substance name:

Cobalt Nickel Manganese Oxide

Cas Number:

37348-84-8

Molecular formula:

Ni1-x-yMnxCoyOz with Me=Ni+Mn+Co=1 and Ni/Me= 0.45-0.98 Mn/Me= 0.01-0.35 Co/Me= 0.01-0.35 O/Me= 1.00-1.33

IUPAC Name:

Cobalt Nickel Manganese Oxide

Test material form:

solid

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.

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 (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

Administration / exposure

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

Results and discussion

Effect levels

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.

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	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 6	212.0 9.5 222 199 6	241.1 6.9 249 231 6	257.7 7.0 267 248 6	29.3 5.4 36 24 6	16.3 9.3 32 6 6	45.7 14.1 68 30 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
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 6	193.7 4.8 199 188 6	216.8 3.2 222 214 6	298.0 65.6 367 234 6	23.2 7.1 34 15 6	81.2 67.7 153 15 6	104.3 61.3 171 46 6

Applicant's summary and conclusion

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.