Nickel(III) oxy hydroxide

Acute Toxicity: oral

Administrative data

Endpoint:

acute toxicity: oral

Type of information:

migrated information: read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Study period:

2009-06-19 through 2009-07-14

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: GLP guideline study

Cross-reference

Cross-reference 1

Reason / purpose for cross-reference:

reference to same study

Cross-reference 2

Reason / purpose for cross-reference:

reference to other study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2009

Report date:

2009

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

OECD Guideline 425 (Acute Oral Toxicity: Up-and-Down Procedure)

Deviations:

no

Principles of method if other than guideline:

AMENDMENT TO THE PROTOCOL: At the request of the Sponsor, the Main Test section of the protocol was clarified to indicate that the single dose limit dose will be 11,000 mg/kg. The sigma between dose levels remained 0.1. The proceeding dose progression was 6,300, 7,930, 9,900 and 11,000 mg/kg (calculated from the last dose level administered prior to this amendment, at 5,000 mg/kg). The above was generated to calculate an LD50 that was greater than the limit dose of 5,000 mg/kg selected in the protocol.

GLP compliance:

yes (incl. QA statement)

Test type:

up-and-down procedure

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Nickel dihydroxide

EC Number:

235-008-5

EC Name:

Nickel dihydroxide

Cas Number:

12054-48-7

IUPAC Name:

nickel(2+) dihydroxide

Details on test material:

- Name of test material (as cited in study report): nickel dihydroxide
- Physical state: solid powder, green
- Analytical purity: nickel dihydroxide, >99%
- Stability under test conditions: expected to be stable for the duration of testing
- Solubility: slightly soluble in cold water
- Storage condition of test material: closed container under nitrogen
- Expiration date: Not Applicable
- Other: Documentation of the methods, synthesis, fabrication or derivation of the test substance is retained by Umicore, Rue du Mariais 31, 1000 Bruxelles, BE Belgium

Test animals

Species:

rat

Strain:

other: Sprague-Dawley derived, albino

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Ace Animals, Inc. Boyertown PA on June 2 and 16, 2009
- Age at study initiation: 9-11 weeks
- Weight at study initiation: 171-213 grams
- Fasting period before study: overnight prior to study
- Housing: singly in suspended stainless steel caging with mesh floors; litter paper was placed beneath the cage and was changed at least three times per week
- Diet (e.g. ad libitum): Purina Roden Chow #5012
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 7-24 days
- Other: nulliparous, non-pregnant

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19-22 °C
- Humidity (%): 56-70%
- Photoperiod (hrs dark / hrs light): 12 hours light/dark cycle

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

other: distilled water

Details on oral exposure:

VEHICLE
- Concentration in vehicle: Test substance was administered as a 55% w/w mixture in distilled water

CLASS METHOD (if applicable)
- Rationale for the selection of the starting dose: estimated LD50 supplied by the sponsor

OTHER:
Test substance was administered as a 55% w/w mixture in distilled water; preliminary solubility testing conducted by EPSL indicated that mixtures in excess of 55% (i.e., 60% or 70%) were too viscous to be administered properly.

Doses:

3200, 4000, 5000, and 6300 mg/kg

Decisions to proceed with the next animal was based on the survival of the previous animal following dosing, according to specific dose progression and stopping criteria determined statistically. Dosing sequence for the 7 animals: 3200, 4000, 5000, 6300, 5000, 6300, 5000 mg/kg.

No. of animals per sex per dose:

3200 mg/kg: 1
4000 mg/kg: 1
5000 mg/kg: 3
6300 mg/kg: 2

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: observed during the first several hours post-dosing and at least once daily thereafter. Body weights were recorded prior to test substance administration (initial) and again on Days 7 and 14 (termination) following dosing or after death
- Necropsy of survivors performed: yes; gross necropsies performed on all decedents and euthanized animals. Tissues and organs of the thoracic and abdominal cavity were examined.
- Other examinations performed: clinical signs, body weight, organ weights, histopathology, other: animals were observed for mortality, signs of gross toxicity, and behavioral changes. Observations included gross evaluation of skin and fur, eyes and mucous membranes, respiratory, circulatory, autonomic and central nervous systems, somatomotor activity and behavior pattern. Particular attention was directed to observation of tremors, convulsions, salivation, diarrhea, and coma.

Statistics:

The Acute Oral Toxicity (Guideline 425) Statistical Program (Weststat, version 1.0, May 2001) was used for all data analyses including: dose progression selections, stopping criteria determinations and/or LD50 and confidence limit calculations.

Results and discussion

Preliminary study:

Not Reported

Effect levels

Sex:

female

Dose descriptor:

LD50

Effect level:

5 000 mg/kg bw

95% CL:

3 390 - 5 800

Mortality:

3200 and 4000 mg/kg (n=1 per dose group): no mortality
5000 mg/kg (n=3): 2 animals died within four days of test substance administration
6300 mg/kg (n=2): both animals died within four days of test substance administration

See table below for individual animal data

Clinical signs:

other: 3200 and 4000 mg/kg (n=1 per dose group): no signs of gross toxicity, adverse pharmacologic effects, or abnormal behavior 5000 mg/kg (n=3): Toxic signs in the two decedents prior to death included hypoactivity, soft feces, ano-genital staining and/or redu

Gross pathology:

3200 and 4000 mg/kg (n=1 per dose group): no gross abnormalities
5000 mg/kg (n=3): discoloration of the intestines and/or liver in the two decedents; no gross abnormalities in the surviving female euthanized at the conclusion of the observation period
6300 mg/kg (n=2): discoloration intestines

Individual animal data provided in the attached study report

Other findings:

Not Applicable

Any other information on results incl. tables

Results of Main Test

Dosing Sequence	Animal No	Dose Level (mg/kg)	Short-Term Outcome	Long-Term Outcome
1	3101	3200	S	S
2	3102	4000	S	S
3	3103	5000	S	D
4	3104	6300	D	D
5	3105	5000	S	S
6	3106	6300	D	D
7	3107	5000	D	D

Applicant's summary and conclusion

Interpretation of results:

not classified

Remarks:

Migrated information Criteria used for interpretation of results: not specified

Conclusions:

Under the conditions of this study, the acute oral LD50 of Nickel dihydroxide is estimated to be 5,000 mg/kg (the one dose with partial response) of body weight in female rats with a 95% PL confidence interval of 3,390 mg/kg (lower) to 5,800 mg/kg (upper).

Executive summary:

Eurofins Product Safety Laboratory (EPSL) conducted an acute toxicity up and down procedure in female rats according to OECD Test # 425 guidelines and using GLP standards. This test allows for the estimation of an LD50 with a confidence interval and the results allow a substance to be classified for acute toxicity according to the Globally Harmonized System of classification and labeling of chemicals. The initial dose used in this study (3,200 mg/kg) was higher than the OECD limit (2,000 mg/kg) and was based on an estimated LD50 provided by the Sponsor. For the main test, a young female rat was exposed to a single oral dose of 3,200 mg/kg Nickel dihydroxide (>99%, described as a solid green powder) in distilled water (55% w/w mixture). In accordance with the Up and Down procedure, two additional animals were dosed at levels of 4,000 or 5,000 mg/kg. At the request of the Sponsor, the protocol was then amended to indicate the single limit dose to be 11,000 mg/kg; the proceeding dose progression was then calculated from the last dose level of 5,000 mg/kg and four additional females received doses of 5,000 or 6,300 mg/kg. Seven rats were tested using the following sequence: 3,200, 4,000, 5,000, 6,300, 5,000, 6,300, 5,000 mg/kg. All animals were observed for mortality, signs of gross toxicity, and behavioral changes at least once daily; body weight was monitored prior to dosing and again on Days 7 and 14, and all animals were necropsied following death or at study termination (Day 14). Animals exposed to 3,200 and 4,000 mg/kg (n=1 per dose group) did not exhibit mortality, adverse clinical signs, or gross abnormalities. Of the three animals exposed to 5,000 mg/kg, 2 animals died within four days of test substance administration. These two animals exhibited hypoactivity, soft feces, ano-genital staining and/or reduced fecal volume prior to death, as well as discoloration of the intestines and/or liver upon necropsy. The third animal survived, gained body weight, and did not exhibit signs of any adverse response. The two animals exposed to 6,300 mg/kg both died within four days of test substance administration, exhibited reduced fecal volume prior to death, and were reported to have discolored intestines upon necropsy. Based on these findings, the acute oral LD50 of nickel dihydroxide was estimated to be 5,000 mg/kg (the one dose with partial response) of body weight in female rats with a 95% PL confidence interval of 3,390 mg/kg (lower) to 5,800 mg/kg (upper) under the conditions of this study.