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Toxicological information

Acute Toxicity: inhalation

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Administrative data

acute toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2009-11-25 to 2010-04-02
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference Type:
study report
Report date:

Materials and methods

Test guideline
according to guideline
OECD Guideline 403 (Acute Inhalation Toxicity)
GLP compliance:
Test type:
other: Defined LC50
Limit test:

Test material

Constituent 1
Chemical structure
Reference substance name:
Trinickel disulphide
EC Number:
EC Name:
Trinickel disulphide
Cas Number:
Molecular formula:
trinickel disulfide
Details on test material:
- Name of test material (as cited in study report): Nickel subsulfide
- Physical state: grey-bronze powder
- Analytical purity: 100%
- Stability under test conditions: was expected to be stable for the duration of testing
- Storage condition of test material: stored at room temperature with a nitrogen pad inserted into the container after initial testing
- Other: insoluble in water

Test animals

Details on test animals or test system and environmental conditions:
- Source: Ace Animals, Inc., Boyertown, PA on Novenmber 17 and December 22, 2009
- Age at study initiation: 9 - 11 weeks
- Weight at study initiation: males: 288-385 grams, and females: 190-259 grams
- Fasting period before study: not reported
- 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 except during exposure
- Acclimation period: 14 or 23 days

- Temperature (°C): 18-22C
- Humidity (%): 42-66%
- Air changes (per hr): 284
- Photoperiod (hrs dark / hrs light): 12-hour light/dark cycle

Administration / exposure

Route of administration:
inhalation: aerosol
Type of inhalation exposure:
nose only
other: unchanged (no vehicle)
Mass median aerodynamic diameter (MMAD):
>= 3.1 - <= 3.25 µm
Details on inhalation exposure:
- Exposure apparatus: Nose Only Inhalation Chamber, ADG Developments, LTD
- Exposure chamber volume: 6.7 L
- Method of holding animals in test chamber: polycarbonate holding tubes
- Source and rate of air: air compressor (JUN-AIR, Model #6-15)
- Method of conditioning air: The test substance was aerosolized as received, without additional grinding, using a modified Wright Dust Generator driven by a variable speed motor (Dayton, Model #4Z538A) D.C. speed control with 0-100 potentiometer. The test substance was packed into the dust container (Wright, Model DF 183 or 183A) and compressed to 1000 lbs/in^2 using a lab press (Carver, Model C). The container was then fitted with a stainless steel cutting head (Model DF 194SS or 193SS) and cutting blade (Model DF 191SS or 190SS). Compressed air was supplied to the dust generator at 30 psi. The aerosolized dust was then fed directly into the chamber through the dust outlet assembly.
- System of generating particulates/aerosols: Wright Dust Generator driven by variable speed motor (Dayton, Model #4Z538A or a D.C. speed control with 0-100 potentiometer.
- Method of particle size determination: An eight-stage Andersen cascade impactor was used to assess the particle size distribution of the test atmosphere. Samples were withdrawn from the breathing zone of the animals at two intervals during each exposure. The fIlter paper collection stages were weighed before and after sampling to determine the mass collected upon each stage. The aerodynamic mass median diameter and geometric standard deviation were determined graphically using two-cycle logarithmic probit axes.
- Temperature, humidity, pressure in air chamber: temperature and relative humidity values were recorded every 15 minutes for the fIrst hour of exposure and every 30 minutes thereafter.

- Brief description of analytical method used: Gravimetric samples were withdrawn at five or six intervals from the breathing zone ofthe animals during each exposure. Samples were collected using 37 mm glass fiber filters (GF/B Whatman) in a filter holder attached by 1/4-inch tygon tubing to a vacuum pump (Reliance Electric, Model #G557X). Filter papers were weighed before and after collection to determine the mass collected. This value was
divided by the total volume of air sampled to determine the chamber concentration. Sample airflows were measured using a Mass Flowmeter (Omega, Model #FMA-5610).
- Samples taken from breathing zone: yes

not applicable

TEST ATMOSPHERE (if not tabulated)
- Particle size distribution: 3.3-3.5 µm
- MMAD (Mass median aerodynamic diameter) / GSD (Geometric st. dev.): 3.1, 3.2, 3.35 µm for doses 0.205, 1.02, and 5.15 mg/L, respectively

Analytical verification of test atmosphere concentrations:
gravimetric sampling
Duration of exposure:
4 h
0.206, 1.02, and 5.15 mg nickel subsulfide/L
No. of animals per sex per dose:
5 males and 5 females per dose group
Control animals:
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: examined upon removal from chamber and at least once daily thereafter; bodyweight measured prior to exposure, and 7 and 14 days post exposure
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs (included gross evaluation of skin and fur, eyes and mucous membranes, respiratory, circulatory, autonomic and central nervous systems, somatomotor activity and behavior pattern, including tremors, convulsions, salivation, diarrhea, and coma), body weight, and gross pathology (focus on thoracic and abdominal caveties).
Probit Analysis; Finney, D.J., Probit Analysis, 3rd ed., Cambridge University Press, Cambridge, Great Britain, 1971, pp.1-333 was used for data analysis of LC50 and confidence limit calculations.

Results and discussion

Preliminary study:
Not applicable
Effect levelsopen allclose all
Dose descriptor:
Effect level:
0.924 mg/L air
95% CL:
> 0.521 - < 1.636
Exp. duration:
4 h
Dose descriptor:
Effect level:
1.352 mg/L air
95% CL:
> 0.337 - < 5.422
Exp. duration:
4 h
Dose descriptor:
Effect level:
1.138 mg/L air
Exp. duration:
4 h
Remarks on result:
other: Average of males and females
0.206 mg/L: 0/10
1.02 mg/L: 4/10 (1/5 males; 3/5 females)
5.15 mg/L: 10/10
Clinical signs:
other: 0.206 mg/L: Immediately following exposure, all animals appeared active and healthy. Although three males showed signs of facial staining or ocular discharge on Day 1, all rats continued to appear active and healthy over the 14-day observation period. The
Body weight:
0.206 mg/L: All animals gained weight.
1.06 mg/L: Although all survivors lost body weight through Day 7, they gained weight over the entire observation period.
Gross pathology:
0.206 mg/L: No gross abnormalities were noted for any of the animals when necropsied at the conclusion of the 14-day observation period.
1.06 mg/L: Gross necropsy ofthe decedents revealed discoloration of the lung, liver and/or intestines, and/or rigor mortis. No gross abnormalities were noted for any of the euthanized animals necropsied at the conclusion of the 14-day observation period.
5.15 mg/L: Gross necropsy of the decedents revealed discoloration of the lungs and/or intestines.
Other findings:
Not applicable

Any other information on results incl. tables

Incidence of Mortality

Exposure Levels (mg/L)  Males  Females  Total 
0.206 0/5  0/5 0/10 
1.02 1/5  3/5 4/10 
5.15 5/5  5/5  10/10 

Applicant's summary and conclusion

Interpretation of results:
GHS criteria not met
Under the conditions of this study, the acute inhalation defined LC50 of Nickel subsulfide is 1.352 mg/L in male with 95% confidence intervals of 0.3371 mg/L (lower) to 5.422 mg/L (upper). The defined LC50 is 0.9237 mg/L for female rats with 95% confidence intervals of 0.5215 mg/L (lower) and 1.6359 mg/L (upper).
Executive summary:

Eurofins Product Safety Lab (EPSL) conducted an acute inhalation study in an effort to provide information on health hazards likely to arise from a short-term exposure to nickel subsulfide following inhalation. This study was done in accordance with OECD Guidelines for the Testing of Chemicals, Test No. 403. The four-hour exposures were conducted in a nose-only exposure chamber with an internal volume of approximately 6.7 liters. Prior to initiation of the study, pre-test trials were conducted in order to determine the targeted chamber concentration and desired particle size distribution (MMAD between 3.1-3.35 µm); chamber concentration and particle size distributions were determined periodically throughout the pre-test and main test. After determining the desired conditions, the main test was conducted. This GLP study involved exposure of 30 healthy rats (10 per group; 5 males and 5 females in each group) to nickel subsulfide at concentrations of 0.206, 1.02, or 5.15 mg/L. Following exposure, animals were observed for mortality, gross toxicity, and behavioral changes daily (at a minimum) for 14 days or until death. All surviving animals were necropsied at the end of the study. Body weights were recorded prior to exposure and on Days 7 and 14 (or after death); weights were also obtained on Day 5 in the 1.02 mg/L dose group. In the low dose group, nickel subsulfide was not lethal to any animals. All animals in this group appeared to be active and healthy following exposure, though three males showed signs of ocular discharge the first day following exposure. In the mid-dose group, the incidence of mortality was 1 out of 5 males and 3 of 5 females. Although animals appeared active and healthy following exposure, all rats exhibited clinical signs (e.g., facial staining, hypoactivity) by Day 3. Surviving animals recovered from clinical symptoms by Day 12. None of the animals survived in the high-dose group; these animals died within five days of exposure. Clinical signs emerged by Day 2 and included facial staining, abnormal respiration, hypoactivity, hunched posture, reduced food consumption, and/or reduced fecal volume. Upon necropsy, animals displayed discoloration of the lungs and/or intestines. Under the conditions of this study, the acute inhalation defined LC50 of nickel subsulfide was 1.352 mg/L (95% CI of 0.3371 to 5.422 mg/L) in male rats and 0.9237 mg/L (95% CI of 0.5215 to 1.6359 mg/L) in female rats. STUDY RATED BY AN INDEPENDENT REVIEWER