[carbonato(2-)]tetrahydroxytrinickel

Acute Toxicity: oral

Administrative data

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: GLP guideline study

Data source

Reference

Reference 1

Reference Type:

study report

Title:

Unnamed

Year:

2009

Report date:

2009

Reference 2

Reference Type:

publication

Title:

Acute Oral Toxicity of Nickel Compounds

Author:

Henderson RG, Durando J, Oller A, Merkel DJ, Marone PA, and Bates HK.

Year:

2012

Bibliographic source:

Regul Toxicol and Pharmacol (doi.org/10.1016/j.yrtph.2012.02.002)

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

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

Deviations:

no

GLP compliance:

yes

Test type:

up-and-down procedure

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

[carbonato(2-)]tetrahydroxytrinickel

EC Number:

235-715-9

EC Name:

[carbonato(2-)]tetrahydroxytrinickel

Cas Number:

12607-70-4

Molecular formula:

Ni3(OH)4CO3

IUPAC Name:

trinickel monocarbonate tetrahydroxide

Details on test material:

- Name of test material (as cited in study report): Nickel hydroxycarbonate
- Physical state: green powder
- Analytical purity: 100%
- Stability under test conditions: was expected to be stable for the duration of testing
- Storage condition of test material: room temperature under nitrogen
- Other: soluble in water: 34.5 mg/L (pH 6); 7.1 mg/L (pH 8)

Test animals

Species:

rat

Strain:

Sprague-Dawley

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Ace Animals, Inc., Boyertown, PA on July 21, August 4, 11, and 26, 2009
- Age at study initiation: 9 - 11 weeks
- Weight at study initiation: females: 180-210 grams
- Fasting period before study: fasted overnight prior to dosing by removing feed from cage.
- Housing: singly housed in suspended stainless steel caging with mesh floors which conform to the size recommendations in the most recent Guide for the Care and Use of Laboratory Animals (Natl. Res. Council, 1996). Litter paper was placed beneath the cage and was changed at least three times per week.
- Diet (e.g. ad libitum): Purina Rodent Chow #5012
- Water (e.g. ad libitum): Tap water was supplied ad libitum by an automatic water dispensing system
- Acclimation period: 6-12 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19-24%
- Humidity (%): 58-78%; the humidity was above the targeted upper limit for 7 days during the study. A portable dehumidifier was used to decrease the humidity levels during this time.
- Photoperiod (hrs dark / hrs light): 12-hour light/dark cycle


IN-LIFE DATE (Day 12 for animal #3102): August 12, 2009

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

CMC (carboxymethyl cellulose)

Details on oral exposure:

VEHICLE
- Concentration in vehicle: 30% w/w mixture, 0.5% w/w solution of carboxymethylcellulose (CMC) in distilled water


MAXIMUM DOSE VOLUME APPLIED: 0.3, 0.38, 0.5, 0.62, 0.77, 0.92, and 1.2 ml for all but the highest dose; 1.5 and 1.7 ml for the two animals receiving the highest dose.


CLASS METHOD (if applicable)
- Rationale for the selection of the starting dose: Based on an estimate of the LD50 supplied by the Sponsor (790 mg/kg), an initial dose of 630 mg/kg
was administered to one healthy female rat by oral gavage.

Doses:

630, 790, 990, 1250, 1580, 1980, 2500, and 3100 mg/kg

No. of animals per sex per dose:

1 animal for each of the first 6 dose groups, 3 animals for the 2500 mg/kg dose group, and 2 animals for the 3100 mg/kg dose group.

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: prior to exposure, then days 7 and 14 post exposure
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs (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) and body weight.

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 applicable

Effect levels

Sex:

female

Dose descriptor:

LD50

Effect level:

2 000 mg/kg bw

Remarks on result:

other: 95% confidence interval cannot be calculated with any precision

Mortality:

630 and 790 mg/kg doses: both animals survived to necropsy.
990 and 1250 mg/kg doses: both animals died within 4 days of dose administration.
1580 and 1980 mg/kg doses: both animals survived to necropsy.
2500 mg dose: 1 of the 3 animals died within 4 days of dose administration; the other 2 survived to necropsy.
3100 mg/dose: both animals died within 3 days of dose administration.

Gross pathology:

630 and 790 mg/kg doses: no gross abnormalities were noted for either of the animals when necropsied at the conclusion of the 14-day observation period.
990 and 1250 mg/kg doses: discoloration of the intestines.
1580 and 1980 mg/kg doses: no gross abnormalities were noted for either of the euthanized animals when necropsied at the conclusion of the 14-day observation period.
2500 mg dose: gross necropsy of the decedent revealed discoloration of the intestines and liver and a stomach filled with a green mass; no gross abnormalities were observed for the two survivors at necropsy.
3100 mg/dose: discoloration of the intestines and liver and a stomach filled with a green mass.

Any other information on results incl. tables

NOAEL is observed at 790 mg nickel hydroxycarbonate/kg body weight.

Applicant's summary and conclusion

Interpretation of results:

Category 4 based on GHS criteria

Remarks:

Migrated information

Conclusions:

Under the conditions of this study, the acute oral LD50 of Nickel hydroxycarbonate is estimated to be 2,000 mg/kg of body weight in female rats with a 95% profile-likelihood based confidence interval of 0 mg/kg (lower) to greater than 20,000 mg/kg (upper). NOAEL is observed at 790 mg nickel hydroxycarbonate/kg body weight.

Executive summary:

Eurofins Product Safety Laboratories (EPSL, 2009) conducted an acute oral toxicity test (up and down procedure) in female Sprague Dawley rats nine to eleven weeks old to determine the potential for nickel hydroxycarbonate to produce toxicity from a single dose via the oral route. The study incorporated eight dose groups total by gavage: 630, 790, 990, 1,250, 1,580, 1,980, 2,500, and 3,100 mg nickel hydroxycarbonate/kg body weight. The lowest dose was based on an LD50 estimate of 790 mg/kg body weight provided by the study sponsor. One animal comprised the following dose groups: 630, 790, 990, 1,250, 1,580, and 1,980 mg/kg. In addition, three and two animals comprised the 2,500 and 3,100 mg/kg dose groups, respectively. All animals were observed for mortality, signs of gross toxicity, and behavioral changes at least once daily for 14 days after dosing or until death occurred. Each animal was weighed prior to exposure, and then seven and 14 days post-exposure. At Day 14 post-exposure, all surviving animals were necropsied; any animals that did not survive to Day 14 were necropsied at time of death.

The animals in the first two dose groups (630 and 790 mg/kg) showed no signs of gross toxicity, gained weight throughout the study, and survived to necropsy. No signs of gross pathologies were reported for either animal. The animals dosed with 990 and 1,250 mg/kg both died within four days of exposure. Both animals demonstrated discolored intestines. The next two higher doses (1580 and 1980 mg/kg) did not result in mortality, and though they exhibited reduced fecal volume on several test days, both animals appeared active and healthy during the remainder 14- day observation period. Of the three animals dosed with 2,500 mg nickel hydroxycarbonate/kg body weight, one animal died prior to the end of the test period (Day 4), at which time discoloration of the intestines and liver, as well as a stomach filled with a green mass, was observed. The other two animals in this dose group appeared active and healthy by the end of the study, both gained weight and neither showed gross pathologies at necropsy. Neither animal in the highest dose group survived past Day 3 of the study. The intestines and livers of these two animals were discolored, and their stomachs were filled with a green mass. Prior to death, one animal was hypoactive and both animals exhibited piloerection and reduced fecal volume.

Under the conditions of this study, the acute oral LD50 of the test substance was estimated to be 2,000 mg/kg of body weight in female rats, with a 95% profile-likelihood based confidence interval of 0 mg/kg (lower) to greater than 20,000 mg/kg (upper). STUDY RATED BY AN INDEPENDENT REVIEWER.