Indium trichloride

Repeated dose toxicity: inhalation

Administrative data

Endpoint:

short-term repeated dose toxicity: inhalation

Type of information:

read-across based on grouping of substances (category approach)

Adequacy of study:

key study

Study period:

No information

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

comparable to guideline study

Justification for type of information:

see section 13 in IUCLID for read-across justification report

Cross-reference

Reason / purpose for cross-reference:

reference to other study

Data source

Reference

Reference Type:

publication

Title:

Pulmonary Toxicity in Mice by 2- and 13-week Inhalation Exposures to Indium-Tin Oxide and Indium Oxide Aerosols.

Author:

Nagano K, Nishizawa T, Eitaki Y, Ohnishi M, Noguchi T, Arito H and Fukushima S.

Year:

2011

Bibliographic source:

J Occup Health 53 (3)

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

OECD Guideline 412 (Subacute Inhalation Toxicity: 28-Day Study)

GLP compliance:

not specified

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Diindium trioxide

EC Number:

215-193-9

EC Name:

Diindium trioxide

Cas Number:

1312-43-2

Molecular formula:

In2O3

IUPAC Name:

diindium trioxide

Details on test material:

- Name of test material (as cited in study report): indium oxide (IO)
- Physical state: powder
- Analytical purity: 99.9%
- Impurities (identity and concentrations): trace amounts of tin, silica and lead

Test animals

Species:

mouse

Strain:

B6C3F1

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Japan, Inc (Kanagawa, Japan)
- Age at study initiation: 4 wk old
- Weight at study initiation: M: 101-104 g (mean body weight per group); F: 92-94 g (mean body weight per group)
- Housing: individually in stainless-steel wire hanging cages, which were placed in a stainless steel inhalation exposure chamber
- Diet : sterilized commercial pellet diet (CRF-1, Oriental Yeast Co., Ltd, Tokyo, Japan)
- Water : sterilized water, ad libitum
- Acclimation period: 2 wk

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-24
- Humidity (%): 30-70
- Air changes (per hr): 12
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:

inhalation: aerosol

Type of inhalation exposure:

whole body

Vehicle:

other: no data

Mass median aerodynamic diameter (MMAD):

>= 1.9 - <= 2.3 µm

Geometric standard deviation (GSD):

2.1

Remarks on MMAD:

MMAD range: 1.9-2.3 µm
GSD: 1.5-2.1 µm

Details on inhalation exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus:
for 100mg/m3 a system was used consisting of a dust feeder equiped with an ejector, an exposure chamber and a digital dust indicator (Type AP-632T, Sibata Scientific Technology, Ltd, Tokyo, Japan)
for 10, 1 and 0.1mg/m3 a system was used consisting of the first-stage system for aerosol generation of a high concentration at 100mg/m3 and a further dilution system
- System of generating particulates/aerosols:
for 100mg/m3: drawing the powder with compressed clean air at the first ejector and introduced into the top of the exposure chamber where the filtered air had been kept flowing downward at 12 air changes/h
for 10, 1 and 0.1mg/m3: aerosol generation of the high concentration and its regulation were performed in the same manner as described above, and airflow containing the aerosol was delivered to a reservoir chamber for stabilization of the aerosol concentration. The airflow containing the aerosol was delivered to the second ejector and then introduced into the top of the exposure chambers where the filtered air had been kept flowing downward at 12 air changes/h
- Method of particle size determination: particles were collected on a filter and dissolved in a mixture solution of distilled water, hydrochloric acid and nitric acid (2:2:1 by volume ratio) at 160 °C. The resulting solution was diluted with nitric acid, and then subjected to atomic absorption spectrometry analysis (Polarized Zeeman Atomic Absorption Spectrophotometer, Z-5010)
- Particle size distribution: the material aerosol was collected with an 8-stage Andersen sampler. Using the mass of the particles on the filter collected at each stage of the Andersen sampler, mass median aerodynamic diameter (MMAD) and geometric standard deviation (GSD) were determined
- Temperature, humidity, pressure in air chamber: negative pressure (-100 Pa)


TEST ATMOSPHERE
- Analytical method used: the mass-equivalent concentration of the material aerosol was monitored with the digital dust indicator; aerosol concentration in the exposure chamber was monitored with the second digital dust indicator and regulated at a target concentration of 10, 1 or 0.1 mg/m3

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

none

Duration of treatment / exposure:

2 wk

Frequency of treatment:

6h/day, 5day/wk for 2 wk

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

0.1 mg/m³ air

Doses / concentrations 2

Dose / conc.:

1 mg/m³ air

Doses / concentrations 3

Dose / conc.:

10 mg/m³ air

Doses / concentrations 4

Dose / conc.:

100 mg/m³ air

No. of animals per sex per dose:

5 mice of each sex per dose

Control animals:

yes, concurrent no treatment

Details on study design:

none

Positive control:

None

Examinations

Observations and examinations performed and frequency:

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: animals were observed daily for their clinical signs and mortality

BODY WEIGHT: Yes
- Time schedule for examinations: weekly throughout the study periods

FOOD CONSUMPTION:
- Food consumption for each animal determined : weekly throughout the study periods

HAEMATOLOGY: Yes


OTHER: sections of lung tissue were examined.

Sacrifice and pathology:

animals surviving to the end of the 2wk received complete necropsy

Other examinations:

Determination of indium concentrations in the lung and blood

Statistics:

Body weight, organ weight, and hematological and blood biochemical parameters were analyzed by Dunnett's test. A two tailed test was used for all statistics. a p value of 0.05 was used as the level of significance.

Results and discussion

Results of examinations

Clinical signs:

no effects observed

Mortality:

no mortality observed

Body weight and weight changes:

not examined

Food consumption and compound intake (if feeding study):

not examined

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

not examined

Ophthalmological findings:

not examined

Haematological findings:

effects observed, treatment-related

Clinical biochemistry findings:

not examined

Urinalysis findings:

not examined

Behaviour (functional findings):

not examined

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Gross pathological findings:

not specified

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Histopathological findings: neoplastic:

not examined

Details on results:

CLINICAL SIGNS AND MORTALITY: neither death, abnormal clinical sign, nor growth retardation occured in any group exposed to indium oxide for 2 weeks

HAEMATOLOGY: no induction of any hematological changes

ORGAN WEIGHTS: significantly increased relative lung weights in the mice of both sexes exposed to indium oxide at 10 and 100mg/m3

HISTOPATHOLOGY: NON-NEOPLASTIC:
-test material particles were deposited separately as single particles in the lung of almost all 1, 10 and 100mg/m3 exposed mice, primarly within the alveolar macrophages. The test material particles were also deposited in the mediastinal lymph nodes (MLN) of the 10 and 100 mg/m3 Indium oxide exposed mice, and in the nasal-associated lymphoid tissue (NALT) of the nasopharyngeal duct of a few 10 and 100mg/m3 indium oxide exposed male mice
- alveolar proteinosis in the 10 and 100 mg/m3 indium oxide exposed mice
- incidences of alveolar macrophage infiltration was found in one 100mg/m3 indium oxide exposed male mouse
- infiltration of inflammatory cells was observed primarily in the 100 mg/m3 indium oxide exposed mice
- hyperplasia of alveolar epithelium was observed primarily in the 100 mg/m3 indium oxide exposed mice

Effect levels

1

Dose descriptor:

NOAEL

Effect level:

1 mg/m³ air

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: lung effects

2

Dose descriptor:

LOAEL

Effect level:

10 mg/m³ air

Based on:

test mat.

Sex:

male/female

Basis for effect level:

organ weights and organ / body weight ratios

other: lung effects

Target system / organ toxicity

Critical effects observed:

yes

Lowest effective dose / conc.:

10 mg/m³ air

System:

respiratory system: lower respiratory tract

Organ:

lungs

Treatment related:

yes

Dose response relationship:

yes

Relevant for humans:

yes

Any other information on results incl. tables

None

Applicant's summary and conclusion

Conclusions:

Persistent pulmonary lesions including alveolar proteinosis and macrophage infiltration occured after 2 wk inhalation exposure of B6CRF1 mice to indium oxide.

Executive summary:

A study was conducted to determine the effects of sub-acute exposure of the test material on the respiratory system in B6CRF1 mice and to compare with previously reported in rats (Nagano et al 2011).

The test material was administered by inhalation 6 h /d and 5 d/wk for 2 wk at 0, 0.1, 1, 10 or 100 mg/m3 to groups of 5 mice/sex/dose. Blood and lung contents of indium were elevated in a dose-related manner in the indium oxide exposed mice. The indium oxide particles were deposited in the lung, mediastinal lymph node and nasal-associated lymphoid tissue. Exposures to the test material induced alveolar proteinosis, infiltrations of alveolar macrophages and inflammatory cells and alveolar epithelial hyperplasia in addition to increased lung weight. The indium oxide induced pulmonary lesions were milder in mice than those previously reported in rats.

In conclusion, persistent pulmonary lesions including alveolar proteinosis and macrophage infiltration occured after 2 wk inhalation exposure of mice to indium oxide.