Trinickel disulphide

Acute Toxicity: oral

Administrative data

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

June 11 - July 1, 2008

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 1

Reference Type:

study report

Title:

Unnamed

Year:

2008

Report date:

2008

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

Principles of method if other than guideline:

AMENDMENT TO FINAL PROTOCOL
Per the study Sponsor's request, an amendment to the protocol was implemented in an effort to reduce the number of animals and to generate more diversity in the calculations of a LD50 if needed. As stated in the study report:

The LD50 of this test substance is unknown. This study is to identify an LD50 possibly between 5,000 and 11,000 mg/kg. The sigma between dose levels will be 0.1. The single dose dilution limit is 11,000 mg/kg or 20 mL/kg. The test substance will be prepared as a 50% suspension in 0.5% CMC. The first dose will be 11,000 mg/kg. If this animal survives, the study will be treated as a Limit Test. If the animal dies, the study will be considered a Main Test and the 0.1 sigma progression will be followed starting with the next lower dose level.

GLP compliance:

yes

Test type:

up-and-down procedure

Limit test:

yes

Test material

Test material information

Constituent 1

Reference substance name:

Trinickel disulphide

EC Number:

234-829-6

EC Name:

Trinickel disulphide

Cas Number:

12035-72-2

Molecular formula:

Ni3S2

IUPAC Name:

(trinickel-1-ylidene)-1λ⁴-disulfene

Details on test material:

- Name of test material (as cited in study report): nickel subsulfide, Code #N18A-PTL
- Physical state: grey powder
- Composition of test material, percentage of components: Nickel Subsulfide, Other Ingredients
- Solubility: sparingly soluble in water
- Expiration date of the lot/batch: Not Applicable
- Stability under test conditions: test substance was expected to be stable for the duration of testing
- Storage condition of test material: tightly closed under nitrogen
- Other: Documentation of the methods, synthesis, fabrication, or derivation of the test substance retained by Sponsor.

Test animals

Species:

rat

Strain:

Sprague-Dawley

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Ace Animals, Boyertown, PA. May 20 and June 3, 2008.
- Age at study initiation: young adult (10-11 weeks).
- Weight at study initiation: 184-200 grams at experiment start
- Fasting period before study: overnight prior to dosing
- Housing: singly housed 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 Rodent Chow #5012 ad libitum
- Water (e.g. ad libitum): filtered tap water ad libitum
- Acclimation period: 14-23 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19-21 °C
- Humidity (%): Test 1: 55-69%
- Photoperiod (hrs dark / hrs light): 12-hour light/dark cycle

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

CMC (carboxymethyl cellulose)

Details on oral exposure:

VEHICLE
- Concentration in vehicle: test substance administered as a 50% w/w mixture in a 0.5 % w/w mixture of CMC in distilled water

Doses:

11,000 mg Ni3S2/kg

No. of animals per sex per dose:

3 females

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: cage-side observations during the first several hours post-dosing and at least once daily thereafter for 14 days
- Necropsy of survivors performed: yes; gross necropsies performed on all animals, tissues and organs of the thoracic and abdominal cavities were examined
- Other examinations performed: clinical signs, body weight, organ weights, histopathology, other: individual body weights were recorded prior to test substance administration (initial) and again on Days 7 and 14 (termination) following dosing. Cage-side observations included mortality, signs of gross toxicity, and behavioral changes including: 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 observations of tremors, convulsions, salivation, diarrhea, and coma.

Statistics:

Not Applicable

Results and discussion

Preliminary study:

All animals survived (short-term and long-term outcomes indicated “survival”)

Effect levels

Sex:

female

Dose descriptor:

LD50

Effect level:

> 11 000 mg/kg bw

Mortality:

All animals survived

Clinical signs:

other: No signs of abnormal behavior were observed. All animals appeared active and healthy during the study.

Gross pathology:

No signs of gross toxicity or adverse pharmacologic effects were observed. No gross abnormalities were noted for any of the animals when necropsied at the conclusion of the 14-day observation period.

Other findings:

Not Applicable

Any other information on results incl. tables

Limit Test - Weight and Survival Outcomes

Dose Sequence	Animal No.	Dose Level (mg/kg)	Short-term Outcome	Long-term Outcome	BW-I	BW-7D	BW-14D
1	3101	11,000	Survived	Survived	188	206	248
2	3102	11,000	Survived	Survived	200	221	253
3	3103	11,000	Survived	Survived	184	204	250

BW-I, Initial Body weight (grams) BW-7D, Body weight at 7 days (grams) BW-14D, Body weight at 14 days (grams) All animals healthy and active after 14 days. No gross abnormalities at necropsy for any animals.

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 Ni3S2 is estimated to be greater than 11,000 milligrams per kilogram of body weight in female rats.

Executive summary:

Eurofins Product Safety Laboratory (EPSL) reported the findings of the acute oral toxicity of Ni3S2 as determined by the acute toxicity up and down procedures in female rats (carried out according to OECD Test # 425 guidelines and using GLP standards). Per the study Sponsor's request, an amendment to the protocol was implemented in an effort to reduce the number of animals and to generate more diversity in the calculations of a LD50 if needed. As such, the approach involved administration of a first dose of 11,000 mg/kg. If this animal survived, the study would have been treated as a Limit Test. If the animal died, the study would have been considered a Main Test and the 0.1 sigma progression would have been followed starting with the next lower dose level. Young adult female rats (n=3 per compound) were administered a single gavage dose of nickel subsulphide (Code #N18A-PTL, described as a grey powder). The test substance was administered as a 50% w/w mixture in a 0.5% w/w mixture of CMC in distilled water. 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). Following a single oral exposure to 11,000 mg/kg Ni3S2 , all animals survived, gained body weight, and appeared healthy and active during the study. No signs of gross toxicity, adverse pharmacologic effects, abnormal behavior, or gross abnormalities were observed. Under the conditions of these studies, the acute oral LD50 of Ni3S2 was estimated to be greater than 11,000 milligrams per kilogram of body weight in female rats. STUDY RATED BY AN INDEPENDENT REVIEWER