Dialuminium nickel tetraoxide

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics in vivo

Type of information:

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

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Meets generally accepted scientific standards with acceptable restrictions

Data source

Reference

Reference Type:

publication

Title:

Toxicology of Inhaled NiO and CoO in Syrian Golden Hamsters

Author:

Wehner AP, Craig DK

Year:

1972

Bibliographic source:

Am. Industrial Hygiene Assn Jour. March: 146-155

Materials and methods

Objective of study:

distribution

other: lung clearance

Principles of method if other than guideline:

NiO distribution and lung clearance were evaluated based on three inhalation studies: (1) 3-week subacute study, (2) 3-month subacute study, and (3) 2-day pulmonary deposition and clearance study. In the first two studies, hamsters were exposed to NiO dusts for a specified portion of the day, 5 days per week; following exposure, tissues were collected and evaluated for Ni content using atomic absorption.

The gastrointestinal absorption of NiO was also assessed in a single-dose gavage study. 24-hours following exposure, animals were sacrificed and tissues analyzed for NiO.

GLP compliance:

not specified

Test material

Test material information

Constituent 1

Reference substance name:

Nickel monoxide

EC Number:

215-215-7

EC Name:

Nickel monoxide

Cas Number:

1313-99-1

IUPAC Name:

oxonickel

Details on test material:

- Name of test material (as cited in study report): NiO dusts, NiO aerosols

Test animals

Species:

hamster, Syrian

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Age at study initiation: 3-week Study – 3-month old hamsters; 3-Month Study – 4 to 5 week old hamsters; 2-day deposition study – 2-month old hamsters; Absorption study = e week old
- Fasting period before study: Not Reported except for Absorption study, in which the animals were not starved either before or after administration
- Housing: single cages

Administration / exposure

Route of administration:

other: gavage and inhalation (dust and aerosol used interchangeably)

Vehicle:

other: unchanged for inhalation; 0.9% NaCl solution for gavage

Details on exposure:

3-Week Study:
TYPE OF INHALATION EXPOSURE: no data

GENERATION OF TEST ATMOSPHERE / CHAMPER DESCRIPTION
- Exposure apparatus: 37.5 liter cylindrical chamber; diameter of about 28 cm

TEST ATMOSPHERE (if not tabulated)
- Particle size distribution: measured using cascade impactors calibrated in terms of unit density spheres
- MMAD (Mass median aerodynamic diameter) / GSD (Geometric st. dev.): MMAD between 1.0 and 2.5 µm, GSD in the range of 1.6 to 2.6


3-Month and 2-Day Studies:

TYPE OF INHALATION EXPOSURE: whole body

GENERATION OF TEST ATMOSPHERE / CHAMPER DESCRIPTION
- Exposure apparatus: Wright dust feed mechanism
- Method of holding animals in test chamber: individual cages
- Source and rate of air; Method and System: 1 cfm (at STP) of dust-laden air passed through an elutriator to the exposure chamber (figured provided in original manuscript). The aerosol supply system was diluted to an appropriate degree with filtered room air after large nonrespirable particles were removed in the elutriator.
- Method of particle size determination: electron micrographs of samples taken directly onto EM grids with a point-to-plane electrostatic precipitator


TEST ATMOSPHERE (if not tabulated)
- Particle size distribution: measured using cascade impactors calibrated in terms of unit density spheres
- MMAD (Mass median aerodynamic diameter) / GSD (Geometric st. dev.): MMAD between 1.0 and 2.5 µm, GSD in the range of 1.6 to 2.6


Single Dose Absorption Study:
VEHICLE
- Justification for use and choice of vehicle (if other than water): 0.9% NaCl solution
- Concentration in vehicle: 5 mg of NiO suspended in0.5ml of 0.9% NaCL solution

Duration and frequency of treatment / exposure:

Inhalation Studies:
3-Week study: 6 hrs daily, 5 days per week, for 3 weeks
3-Month Study: 4 hours daily, 5 days per week, for up to 3 months
2-Day Study: two 7-hour exposures over 2 days

Absorption Study: single gavage administration

Doses / concentrations

Remarks:

Doses / Concentrations:
Inhalation Studies:
3-Week study: mean NiO concentration was 39 µg/liter with a maximum value of 170 µg/liter. Integrated Exposure (µg min/liter): total for experiment = 2.11 x 10^5, max/day = 61,200.
3-Month study: mean NiO concentration was 61.6 +/- 30.3 µg/liter with a maximum value of 184 µg/liter over a 4-hour period. The authors note that although the daily fluctuations were quite large, the fact that the samples were continuous and of the same duration as the exposures enables the total amount of dust to which the animals were exposed to be determined. Over a 4-hr period, animals were exposed to 14,400 µg-min/liter assuming a concentration of 60 µg/liter, and assuming a minute volume of 60 ml/min, each animal would have inhaled 864 µg on that day. Integrated Exposure (µg min/liter): total for experiment = 8.48 x 10^5, max/day = 44,160.
2-Day Study: total integrated exposure reported as 61,740 µg-min/liter. Integrated Exposure (µg min/liter): total for experiment = 6.17 x 10^4, max/day = 32,802.


Absorption Study: 5 mg NiO suspended in 0.5ml of 0.9% NaCl


Absorption Study: 5 mg NiO suspended in 0.5ml of 0.9% NaCl

No. of animals per sex per dose / concentration:

IInhalation Studies:
3-Week study: 8 males
3-Month study: 34male and females, 16 male and female controls
2-Day study: 92 males and 14 controls

Absorption Study: 6 males; 7 controls

Control animals:

yes

Details on study design:

-3-Week Study: Four days after the last dust exposure, all animals were sacrificed with an equal number of controls. One half of the lung from each animal was removed, weighed and analyzed for Ni by absorption spectrophotometry.

-3-Month Study: 8 hamsters were sacrificed 90 to 96 hours following the last exposure along with 8 controls. Lungs, liver, and kidneys were removed and weighted, and known fractions of each were analyzed for Ni by atomic absorption spectrophotometry. The remaining hamsters were held for long-term observation (still alive at time of writing).

- 2-Day Study: Immediately following the second exposure, 4 randomly selected animals were sacrificed, weighed and thoroughly washed under running water. Lungs, liver and kidneys were removed and weighted. These organs and the GI tract were analyzed by atomic absorption spectrophotometry for NiO. Subsequent sacrifices in groups of 4 animals took place at increasing intervals, the last group sacrificed after 155 days.

- Absorption Study: 24 hours after gavage, animals were sacrificed and weighed and the lungs, liver, and kidneys removed and weight. Tissues of the GI tract and skinned cadaver were analyzed for NiO.

Details on dosing and sampling:

See Details on Study Design

Statistics:

Conducted, but methods not reported

Results and discussion

Main ADME results

Main ADME results 1

Type:

other: Percent of retained sample in lungs after initial clearance

Results:

20%

Main ADME results 2

Type:

other: Percent of retained sample in lungs after 45 days

Results:

45%

Toxicokinetic / pharmacokinetic studies

Details on absorption:

Absorption Study:
-There was no increase in the Ni content of the lungs, liver, kidneys and carcass of the experimental animals as compared to the controls.
- The means of all analyzed tissues were higher in the experimental animals than in the controls; for the liver and carcass the increases were significant at the 0.05 and 0.01 levels, respectively.

Details on distribution in tissues:

Percentage of inhaled dust (NiO) found in hamster lungs at sacrifice:
-3-Week study: 19.3 %
-3-Month study: 19.7%
- 2-Day study: 16.9%
No quantitative measures of the amount of Ni in individual tissues were provided

Clearance of NiO from the lungs was described graphically in a figure in the original manuscript.

Details on excretion:

Not Reported

Metabolite characterisation studies

Metabolites identified:

not measured

Any other information on results incl. tables

-No hamsters died acutely during the course of exposures

Applicant's summary and conclusion

Conclusions:

The authors concluded that nearly 20% of the inhaled NiO was retained in the lungs after initial clearance, and 45% was present after 45 days.

Executive summary:

NiO distribution and lung clearance were evaluated by Wehner and Craig (1972) based on three inhalation studies in hamsters: (1) 3-week subacute study, (2) 3-month subacute study, and (3) 2-day pulmonary deposition and clearance study. In the first two studies, hamsters were exposed to NiO dusts (concentration of 10 to 190 µg/L, MMAD between 1.0 and 2.5 µm, GSD in the range of 1.6 to 2.6) for 6 or 4 hours daily, respectively, 5 days per week. Total integrated exposure was reported as 2.11 x 10^5 µg min/L (max/day = 61,200 µg min/L), and 8.48 x 10^5 µg min/liter (max/day = 44,160 µg min/liter), respectively. The two-day study involved two 7-hour exposures (integrated exposure of 6.17 x 10^4 µg-min/L, max/day = 32,802 µg min/liter). Following exposure, tissues were collected and evaluated for Ni content using atomic absorption. No hamsters died acutely during the course of exposures; 19.3 %, 19.7 %, and 16.9 % of the inhaled dust (NiO) were found in hamster lungs at sacrifice in the 3-Week, 3-Month, and 2-Day exposure studies, respectively (quantitative measurements of Ni in individual tissues were not provided). Clearance of NiO from the lungs was described graphically in a figure in the original manuscript; the authors concluded that nearly 20% of the inhaled NiO was retained in the lungs after initial clearance, and 45% was present after 45 days.

Though the experimental design is relatively well-documented, detailed results were not provided (rather are summarized by the authors). Furthermore, only a single dose of NiO was evaluated, and the dose appeared to vary greatly throughout exposure periods. The actual test compound was also not well characterized as no information was provided regarding source or analytical evaluation of such, and it was referred to interchangeably as dust and aerosol. Thus, use of data in this study appears to be limited to qualitative information that could be used in a weight of the evidence evaluation regarding the toxicokinetic properties of NiO following inhalation exposure. STUDY RATED BY AN INDEPENDENT REVIEWER