Indium trihydroxide

Repeated dose toxicity: inhalation

Administrative data

Endpoint:

sub-chronic 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:

guideline study

Justification for type of information:

see section 13 in IUCLID for read-across justification report

Data source

Reference

Reference Type:

publication

Title:

Two- and 13-week Inhalation Toxicities of Indium-Tin Oxide and Indium Oxide in Rats.

Author:

Nagano K, Gotoh K, Kasai T, Aiso S, Nishizawa T, Ohnishi M, Ikawa N, Eitaki Y, Yamada K, Arito H and Fukushima S

Year:

2011

Bibliographic source:

J Occup Health 53 (2)

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

OECD Guideline 413 (Subchronic Inhalation Toxicity: 90-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:

rat

Strain:

Fischer 344/DuCrj

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):

>= 2.1 - <= 2.3 µm

Geometric standard deviation (GSD):

1.7

Remarks on MMAD:

dose 0.1 mg/m3 : MMAD: 2.1 µm, GSD: 1.7µm
dose 1mg/m3: MMAD: 2.3 µm, GSD: 1.7µm

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:

13 wk

Frequency of treatment:

6h/day, 5day/wk for 13 wk

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

0.1 mg/m³ air

Doses / concentrations 2

Dose / conc.:

1 mg/m³ air

No. of animals per sex per dose:

10 rats 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 13wk 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. Histopathological findings in the 13 weeks study were analyzed by chi-square. 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 nor abnormal clinical sign, such as irregular sounds of respiration, was observed in any group exposed to the test material for 13 weeks. There was no growth retardation in any group exposed to the test material for 13 weeks as compared with the growth rate in the respective control.

HAEMATOLOGY: potassium was significantly decreased in both 0.1 and 1 mg/m3 indium oxide exposed rats. Significant decreases in sodium and chlorine in the 0.1 and 1 mg/3 indium oxide exposed rats and significantly decreased triglyceride in the 0.1 and 1 mg/m3 indium oxide exposed female rats were also observed.

ORGAN WEIGHTS: significantly increased relative lung weights in the rats of both sexes exposed to indium oxide at 0.1 and 1 mg/m3

HISTOPATHOLOGY: NON-NEOPLASTIC:
-test material particles were deposited in the lung of all the exposed rats , primarly within the alveolar macrophages and partly as a free form in the alveolar space. The test material particles were also observed to a lesser extent in the bronchus-associated lymhoid tissue (BALT) of the lung of 1mg/m3 indium oxide exposed rats, in the mediastinal lymph nodes (MLN) of both 0.1 and 1mg/m3 indium oxide exposed rats and in the nasal-associated lymphoid tissue (NALT) of the nasopharyngeal duct of the 1mg/m3 indium oxide exposed rats
- significant increase of alveolar proteinosis in the 1 mg/m3 indium oxide exposed rats
- incidences of alveolar macrophage infiltration were significantly increased in the 0.1 and 1mg/m3 indium oxide exposed rats
- significant infiltration of inflammatory cells was observed in the 1 mg/m3 indium oxide exposed rats
- significant increase hyperplasia of alveolar epithelium occured in the 1mg/m3 indium oxide exposed rats

Effect levels

1

Dose descriptor:

LOAEL

Effect level:

1 mg/m³ air

Based on:

test mat.

Sex:

male/female

Basis for effect level:

organ weights and organ / body weight ratios

other: lung effects

2

Dose descriptor:

NOAEL

Effect level:

0.1 mg/m³ air

Based on:

test mat.

Sex:

male/female

Remarks on result:

other: The only effects are: infiltration of alveolar macrophage and neutrophils, increased lung weight. The 0.1 mg/m3 dose level shows an adaptive response to the clearance of a relatively insoluble metallic salt and could therefore be defined as a NOAEL

Target system / organ toxicity

Critical effects observed:

yes

Lowest effective dose / conc.:

1 mg/m³ air

System:

respiratory system: lower respiratory tract

Organ:

alveoli

bronchi

bronchioles

lungs

Treatment related:

yes

Dose response relationship:

yes

Relevant for humans:

yes

Any other information on results incl. tables

Lung and blood contents of indium: -) lung contents of indium were increased with an increase in the concentration of exposure to indium oxide or indium tin oxide: -the exposure concentration related increase in the whole lung content of indium was disproportionally lowered to greater extent in the indium tin oxide exposed rats than in the indium oxide exposed rats. -the whole lung contents of indium in the 0.1 mg/m3 indium tin oxide exposed rats of both sexes were higher than those of the 0.1mg/m3 indium oxide exposed rats of both sexes. -the whole lung contents of indium in the indium tin oxide exposed rats of both sexes measured at the end of the 26 wk post exposure period were lowered to 40% as compared with those measured at the end of the 13 wk exposure -) the blood contents of indium in the 1mg/m3 indium tin oxide exposed groups of both sexes were 4 -fold higher than those in 1mg/m3 indium oxide group of both sexes. The blood contents of indium in the 0.1 mg/m3 indium tin oxide exposed rats of both sexes measured at the end of the 26 week post exposure period were 1.3 fold higher than those measured at the end of the 13 week exposure period.

Applicant's summary and conclusion

Conclusions:

Persistent pulmonary lesions including alveolar proteinosis and macrophage infiltration occured after 13 wk inhalation exposure of F344 rats to indium oxide.
In this study the rats were also administered by inhalation indium tin oxide and the results indicate that the pulmonary toxicity of inhaled indium tin oxide particles is more severe than that of indium oxide particles and that alveolar macrophages play a critically important role in the induction of indium toxicity as evidenced by alveolar proteinosis, alveolar macrophage infiltration and swollen alveolar macrophages engulfing the particles, all of which occur at the lowest exposure concentration of 0.1 mg/m3 indium tin oxide.

Executive summary:

A study was conducted to determine the effects of sub-chronic exposure of the test material on the respiratory system in F344 rats.

The test material was administered by inhalation 6 h /d and 5 d/wk for 13 wk at 0, 0.1 or mg/m3 to groups of 10 rats/sex/dose. Blood and lung contents of indium were elevated in a dose-related manner in the indium oxide exposed rats. The indium oxide particles were deposited in the lung, mediastianl 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.

In conclusion, persistent pulmonary lesions including alveolar proteinosis and macrophage infiltration occured after 13 wk inhalation exposure of rats to indium oxide.