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Repeated dose toxicity: inhalation

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Administrative data

Endpoint:
short-term repeated dose toxicity: inhalation
Type of information:
migrated information: read-across based on grouping of substances (category approach)
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: non-GLP, no guideline provided

Data source

Referenceopen allclose all

Reference Type:
publication
Title:
Macrophage Reaction in Rabbit Lung following Inhalation of Iron Chloride.
Author:
Johansson A, Curstedt T, Rasool O, Jarstrand C, Camner P
Year:
1992
Bibliographic source:
DOI 10.1016/S0013-9351(05)80205-1 PMID 1597169 Environmental Research 58(1-2):66-79.
Reference Type:
other: Authority assessment
Title:
Unnamed
Year:
2004
Report Date:
2004

Materials and methods

Test guideline
Qualifier:
no guideline available
Principles of method if other than guideline:
Inhalation study of 60 days, MMAD: 1 µm, exposure frequency 5 days/week, 6 hours/day, 2 dose groups + control, 8 male rabbits/group.
GLP compliance:
no
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): Iron chloride
- Molecular formula: FeCl3

Test animals

Species:
rabbit
Strain:
not specified
Sex:
male
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: no data
- Age at study initiation: no data
- Weight at study initiation: 2.8±0.5 kg
- Fasting period before study: no data
- Housing: no data
- Diet (e.g. ad libitum): no data
- Water (e.g. ad libitum): no data
- Acclimation period: no data

ENVIRONMENTAL CONDITIONS
- Temperature (°C): no data
- Humidity (%): no data
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): no data

Administration / exposure

Route of administration:
inhalation: aerosol
Type of inhalation exposure:
not specified
Vehicle:
air
Remarks on MMAD:
MMAD / GSD: 1 µm
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- System of generating particulates/aerosols: ultrasonic nebulizer (De Vilbiss 35B)
- Method of particle size determination: impactor (Mitchell and Pilcher, 1959)

TEST ATMOSPHERE
- Brief description of analytical method used: Metal concentration was estimated by sucking air through a filter (Satorius, 100 N, pore size 0.8 µm) and by analyzing the metal deposited on the filter with atomic absorption spectrophotometry (Varian AA6)
- Samples taken from breathing zone: yes
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Metal concentration was estimated by sucking air through a filter (Satorius, 100 N, pore size 0.8 µm) and by analyzing the metal deposited on the filter with atomic absorption spectrophotometry (Varian AA6)
Duration of treatment / exposure:
2 months
Frequency of treatment:
5 days/week, 6 hours/day
Doses / concentrations
Remarks:
Doses / Concentrations:
1.4±0.7, 3.1±1.8 mg/m3
Basis:
no data
No. of animals per sex per dose:
8
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: no data
- Rationale for animal assignment (if not random): no data
- Section schedule rationale (if not random): no data

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: No data

DETAILED CLINICAL OBSERVATIONS: No data

BODY WEIGHT: No data

FOOD CONSUMPTION:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: No data

FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: No data

WATER CONSUMPTION: No data

OPHTHALMOSCOPIC EXAMINATION: No data

HAEMATOLOGY: No data

CLINICAL CHEMISTRY: No data

URINALYSIS: No data

NEUROBEHAVIOURAL EXAMINATION: No data

OTHER:
Lung tissue analysis: gross data, histological data, ultrastructural data
Alveolar macrophages: light microscopic data, ultrastructural data, scanning electron microscopic data, functional data, phospholipid data
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes
Statistics:
Morphological data were evaluated with the Mann-Whitney U test and data on phospholipids and lung weights were evaluated with the t test. Level of significance was 0.05, two-tailed test.

Results and discussion

Results of examinations

Clinical signs:
not specified
Mortality:
not specified
Body weight and weight changes:
not specified
Food consumption and compound intake (if feeding study):
not specified
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Haematological findings:
not specified
Clinical biochemistry findings:
not specified
Urinalysis findings:
not specified
Behaviour (functional findings):
not specified
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
The lung weight, expressed as the weight (mean±SD) of the left lower lobe, was 1.9±0.4 in the control group, 2.0±0.7 in the low-Fe group, 2.3±0.3 in the high-Fe group.
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
7 of the 8 rabbits in the high-Fe group, 2 in the low-Fe group, and none of the controls had black-spotted lungs.
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
Foci of interstitial inflamatory reaction, involving mostly lymphocytes in the high-Fe group. Accumulation of normal as well as granular macrophages in alveoli of rabbits: both exposed groups.
Histopathological findings: neoplastic:
not specified
Details on results:
CLINICAL SIGNS AND MORTALITY
no data

BODY WEIGHT AND WEIGHT GAIN
no data

FOOD CONSUMPTION
no data

FOOD EFFICIENCY
no data

WATER CONSUMPTION
no data

OPHTHALMOSCOPIC EXAMINATION
no data

HAEMATOLOGY
no data

CLINICAL CHEMISTRY
no data

URINALYSIS
no data

NEUROBEHAVIOUR
no data

ORGAN WEIGHTS
The lung weight, expressed as the weight (mean±SD) of the left lower lobe, was 1.9±0.4 in the control group, 2.0±0.7 in the low-Fe group, 2.3±0.3 in the high-Fe group.

GROSS PATHOLOGY
7 of the 8 rabbits in the high-Fe group, 2 in the low-Fe group, and none of the controls had black-spotted lungs.

HISTOPATHOLOGY: NON-NEOPLASTIC
Foci of interstitial inflamatory reaction, involving mostly lymphocytes in the high-Fe group. Accumulation of normal as well as granular macrophages in alveoli of rabbits: both exposed groups. The control rabbits showed essentially normal lung tissue with some small accumulations of macrophages and occasional small inflamatory reactions.

OTHER FINDINGS
Ultrastructural data: Volume density of the alveolar type II cells was measured in the control group and in the high-Fe group. The value of the high-Fe group, 0.061±0.018 (mean±SD), was significantly higher than that of the control group, 0.045±0.012 (P<0.05).

Alveolar macrophages
Light microscopic data: Significantly more macrophages were obtained by lavage from both Fe groups than from the controls. The number was significantly higher in the high- than in the low-Fe group.
Ultrastructural data: The most characteristic findings were enlarged lysosomal complexes in macrophages from Fe-exposed rabbits. The percentage of cells with a surface lacking protrusions (smooth surface) in the high-Fe group was also higher than in the controls.
Phospholipid data: The concentration of total phospholipids was significantly increased in the high-Fe group compared to controls as well as to the low-dose group.

Effect levels

Dose descriptor:
LOAEL
Effect level:
1.4 mg/m³ air (analytical)
Based on:
element
Remarks:
Fe
Sex:
male
Basis for effect level:
other: overall effects basing on gross pathology; organ weights; histopathology / the Health Council of the Netherlands Committee on Updating of Occupational Exposure Limits conclude on an OEL = 0.1 mg/m³.

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
The Committee on Updating of Occupational Exposure Limits of the Health Council of the Netherlands concludes that the lowest-observed-adverse-effect level (LOAEL) from this study is 1.4 mg Fe/m3, as respirable aerosols/particles, for effects on the lungs of rabbits after subacute inhalation exposure.
Executive summary:

The purpose of the present non-GLP and not conforme to OECD guideline study was to investigate the effects of inhaled FeCl3 on rabbit lung with special reference to alveolar macrophages, alveolar epithelial cells, and surfactant in order to have a basis for designing combined inhalation studies with iron and other metals and to investigate whether potentiations occur.

Groups of eight rabbits were inhalation-exposed to iron, 1.4±0.7 mg/m³ (low Fe), or 3.1±1.8 mg/m³ (high Fe) as FeCl3 or to filtered air (controls) for 2 months, 5 days/week and 6 hours/day. The alveolar macrophages were increased in number in both exposed groups. Noduli of granular macrophages were found in lungs of all the rabbits in the high-Fe group, in one from the low-Fe group, and in one control rabbit. Especially in the high-Fe group there were prominent changes in the macrophages such as enlarged lysosomes containing fibrous-looking structures, iron-rich inclusions, and densely packed, 5 -nm electron-dense granules. The number of cells filled with surfactant-like inclusions as well as smooth surface was inceased in the high-Fe group and the macrophages had enhanced phagocytic capacity. There was an increase in the phospholipid concentration and in the volume density of type II cells in the high-Fe group but the level of phosphatidylcholines was not significantly changed. The fact that Fe(3 +) affected mainly the alveolar macrophages might be due to the relatively high concentration of iron in these cells caused by the precipitation of iron in their lysosomes.

The Committee on Updating of Occupational Exposure Limits of the Health Council of the Netherlands concludes that the lowest-observed-adverse-effect level (LOAEL) from this study is 1.4 mg Fe/m³, as respirable aerosols/particles, for effects on the lungs of rabbits after subacute inhalation exposure.