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Toxicological information

Repeated dose toxicity: inhalation

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Administrative data

Endpoint:
short-term repeated dose toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
test procedure in accordance with generally accepted scientific standards and described in sufficient detail

Data source

Reference
Reference Type:
publication
Title:
Effect of inhaled yttrium oxide on blood lactic acid, erythrocyte volume, and histologic features of lungs in exercised dogs
Author:
Reece W.O., Talbot R.B., Swenson M.J.
Year:
1967
Bibliographic source:
Am. J. vet. Res., Vol. 28, N° 125

Materials and methods

Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
18 beagles dogs were subjected to treadmill exercise and exposure to a chamber atmosphere of yttrium oxide. The exposure lasted 30 days (180 exposure hours; 5 days per week for 6 weeks) and treadmill exercise was given for 10 minutes a day throughout the experiment. Postexercise value of blood lactate concentration was determined 2 times a week and erythrocyte volume, plasma volume, hemoglobin concentration and leukocyte count were determined before the start and at the end of the exposure period. Thoracic radiographs were done before the exposure to determine freedom from lung lesions and subsequent fitness for treadmill exercise.
Histologic examination was done on dogs after exposure period. Aerosol concentration, distribution and particle size were determined.
GLP compliance:
not specified
Limit test:
yes

Test material

Constituent 1
Chemical structure
Reference substance name:
Yttrium oxide
EC Number:
215-233-5
EC Name:
Yttrium oxide
Cas Number:
1314-36-9
Molecular formula:
O3Y2
IUPAC Name:
Yttrium (III) oxide
Details on test material:
The substance was guaranteed 99.9 % pure. generation of the aerosol was accomplished with a Wright dust feed mechanism.
The mean particules size diameter were: 0.393 +/- 0.345 µm.
The final concentration for the experiment was between 12.65 +/- 5.04 and 20.63 +/- 3.03 µm/m3.
73.86% w/w of yttrium oxide particles was < 1 micrometer

Test animals

Species:
dog
Strain:
Beagle
Sex:
male/female
Details on test animals or test system and environmental conditions:
Three separate experiments with 8 dogs (4 males and 4 females), 6 to 9 months, were used. The dogs were vaccined against canine distemper, infectious hepatitis ans lesptospirosis, given a physical examination and treated for internal parasitic infestation. A negative result was obtain on the examination for Dirofilaria. A commercial dry dog fees was reasonably fed according to the recommendation of the manufacturer and water was available ad libitum.

The dogs were trained (4 to 5 weeks) to run on a treadmill before the 10-week experiment. Each dog was exercised on the treadmill for 10 minutes daily, each 5 days a week in a room maintained at 22 - 23 °C. The dogs were placed in individual cages, placed in a chamber environment each afternoon for 6 hours, 5 days a week for the 10-week experiment (4 weeks air followed by 6 weeks yttrium oxide).

Administration / exposure

Route of administration:
inhalation: aerosol
Type of inhalation exposure:
whole body
Vehicle:
air
Remarks on MMAD:
MMAD / GSD: No data; see details on test material for particle size.
Details on inhalation exposure:
Preparation of aerosol:
The original pulverized powder of yttrium oxide (99.9 %) was reduced to a uniform particule size in a blender. Generation of the aerosol was accomplished with a Wright dust feed mechanism. Its operation was dependant on the removal, by a stream of air, of dust as it was scraped from a revolving cylinder tightly packed with yttrium oxide.

Exposure method:
While in the chambers the dogs were confined to individual stainless steel cages. The top, bottom, sides and ends were constructed of expanded stainless steel fabric which permitted free passage of air.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
During the experiment three kind of measurements were performed: particles size determination, aerosol distribution and mass distribution of the aerosol.
Particle Size determination: the chamber atmosphere was sampled with a point-to-plane electrostatic precipitator. The maximal diameter was analyzed by an electron photomicrograph with a particle size analyzer.

Aerosol concentration: the concentration of yttrium oxide during the exposure period was arbitrarily set at 15 mg/cu.m. to maintain this concentration, daily sampling was required and adjustments were made accordingly. A color-forming reagent was used for the quantitative determination of yttrium and rare earths concentration (according to Fritz et al.).

Mass distribution of aerosol: a Casella cascade impactor was used to determine the mass distribution of aerosol and the percentage of particles less than 1 µm. When distribution samples were collected, glass coverslips coated with stopcock grease were affixed to the stages. A filter retained particles not impinged at the stages. Samples were collected for 30 seconds. The size of the particles collected on the various stages was determined by electron microscopy. Electron microscopy girds were mounted in the line of deposition at each stage and particles were impinged directly on these girds and measured.
Duration of treatment / exposure:
6 weeks
Frequency of treatment:
6 hours/day, 5 days/week
Doses / concentrations
Dose / conc.:
12.65 mg/m³ air
Remarks:
analytical conc.
No. of animals per sex per dose:
Three groups of six dogs (male and female) were treated with the same mean dose (15 mg Y2O3/m3)
Control animals:
yes, concurrent no treatment
Details on study design:
The dogs were trained (4 to 5 weeks) to run on a treadmill, then, the 10-week experiment was started. Each dog was exercised on the treadmill (between 10:00 and 12:00 a.m.) for 10 minutes daily for 5 days a week. The exercising was accomplished in a room where the temperature was maintained at 22 to 23°C. The dogs were placed in individual cages and the cages were placed in a chamber environment each afternoon for 6 hours, 5 days a week for the 10-week experiment.

The dogs were in a paired experiment in which the first 4 weeks comprised the control period and the next 6 weeks, the treatment period. During the control period, increases in receptivity and running ability were noticed. Also a treadmill speed was set for each dog in two groups of six dogs that appeared to obtain satisfactory work output and that correlated with a plateau of blood lactate concentration. In the third group of dogs, they were exercised at the same treadmill speed and it became apparent that the running abilities were not equal. Establishing a lactic acid plateau seemed logical in that any blood lactate increase which might be observed later would be relative to previous level.
With this design it was possible to establish normal values before yttrium oxide was introduced and to obtain a series of observations during the inhalation or treatment period.
The various responses could then be expressed as « change » over the treatment period. To provide for histologic comparisons, 1 male and 1 female dog from each group of 8 were placed in chambers in which yttrium oxide was not introduced during the 6 weeks treatment. The 2 dogs never became good runners and tended to hang back in the harness. Because of their poor performance, the corresponding blood lactate concentration and other values relative to exercise were not meaningful.
Positive control:
No data

Examinations

Observations and examinations performed and frequency:
Several analysis have been realised after the exposure period:

1. Postexercise blood lactate concentration, obtained 2 times a week during the experiment
2. Erythrocyte volume measurement was performed on each dog before and after the end of the experiment.
3. Plasma Volume for each dog was determined before and at the end of the exposure period.
4. Other hematologic values: Leukocyte counts, packed cell volume and total hemoglobin concentration were determined before and at the end of the experiment.
5. Radiographic examination of thorax on each dogs were made before and at the end of the exposure period.
6. Necropsy was realised after the end of each experiment.
Sacrifice and pathology:
6. Necropsy
After the end of each experiment the dogs were euthanatized and necropsied. Portion of sternum, lungs, heart, liver, spleen, adrenal gland, kidneys, bronchial lymph nodes, gonad and mesenteric lymph nodes were obtained for histologic examination. These tissues were fixed in 10 M formalin and paraffin sections were cut at a thickness of 6 µm and stained with hematoxin-eosin stain
Other examinations:
1. Postexercise blood lactate concentration, obtained 2 times a week during the experiment
5 ml of blood was withdrawn from the right and left jugular vein approximately 30 sec after the treadmill exercice. The blood was withdrawn in a seringue containing crystalline ammonium fluoride to avoid coagulation.
The same day, the lactate concentration was determined buy the method of Barker and Summerson.

2. Erytrocyte volume measurement
The erythrocyte volume of each dog was determine before and after the end of the experiment, using Na2CrO4 which is a modification of Sterling and Grey. Radioactivity was determined in a well-type, thallium actived NaI crystal scintillation counter.

3. Plasma Volume measurement
Plasma volume for each dog was determined before and at the end of the exposure period by a modification of the T-1824 dye dilution method of Gregerson as already described in the literature.

4. Other hematologic values
Leukocyte counts, packed cell volume and total hemoglobin concentration were determined before and at the end of the yttrium oxide exposure.

5. Radiographic examination of thorax
Thoracic radiographs of each dogs were made before and at the end of the exposure period to determine freedom of lung lesions and subsequent fitness for treadmill exercise. The occurrence of any increase in radiographic density due to the exposure was also observed.
Statistics:
The Student's test was used to determine the relevance of observed difference after exposure and/or exercice. A variance test was also conducted to determine any difference due to the sex of dogs.

Results and discussion

Results of examinations

Clinical signs:
no effects observed
Description (incidence and severity):
no mortality
Mortality:
no mortality observed
Description (incidence):
no mortality
Body weight and weight changes:
not specified
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
Description (incidence and severity):
No effect on plasma volume & hemoglobin concentration. Significant increase of white blood cells & decrease of the erythrocyte volume which should indicate Y2O3 was being transported from the lungs to other tissues, having negative erythropoiesis effect.
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
no effects observed
Description (incidence and severity):
Lungs exposed dogs were reddish gray and were firmer than the lungs of the controls. Bronchial lymph nodes in exposed dogs were enlarged 8 - 10 times; other body lymph nodes were normal in size. With regards to gross appearance, other organs were normal.
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
not specified
Details on results:
Histologic examination showed no effect on: heart, liver, spleen, mesenteric lymph nodes, testis or ovaries, kidneys, adrenal gland, and bone marrow.
Thoraxic radiography showed subtle changes which are consistent with the slightly increased density at the hilus of the lung. Possibly the enlarged bronchial lymph nodes which contained numerous dustladen macrophages contributed to the slight increase in density.

Blood lactate concentration:
This parameter was obtained by subtracting a normal value before the exposure and after 30 days of exposure for the same dog.
Normal value was determined as the average of results for 4 determinations (2 made during the week before exposure and 2 during the weeks after exposure began).
The mean of the difference was + 5.00 mg/100 mL of blood. This difference was tested as relevant according to the Student’s test (p = 0.05). It was assumed that, with repeated treadmill exercise under conditions of no exposure, post exercise blood lactate concentration would decrease. This decrease was demonstrated by Yoder and al.
A variance analysis showed no significant difference due to replication of test or sex of dog.

A highly positive increase occurred in 3 dogs, 1 from each experiment which indicated that some alteration had occurred in their ability to transfer, transport or utilize oxygen. Toward the end of the experiment, it became difficult to these dogs to complete their 10-minute exercise period. It was observed that certain dogs respond to treadmill exercising quite favorably, whereas others are more reluctant to increase work output. In an ideal situation only dogs responding favorably should be selected and subjected to a greater work task.

Erythrocyte volume:The overall mean of the difference was 3.9 mL/kg of body weight and was only significant at the 0.10 level. No difference was observed regarding replication or sex. The mean of this difference was negative. One might assume that with increased tissue demands for oxygen an increase in erythrocyte volume might occur. It is possible that enough yttrium oxide was being transported from the lungs to other tissues to have an inhibiting effect upon erythropoiesis. One might have observed a more significant decrease in erythrocyte volume if the period of exposure and exercise had been extended.

Plasma volume and hemoglobin concentration: the mean of the differences were not significant.

Leukocyte count: The overall mean of the difference is 2.333 lecuocytes/cm3 of blood. This was significant increase (p = 0.01) indicating an active response of the body to remove foreign material. Regarding the absence of difference observed in white blood cell counts by Davison if mice and guinea pigs were exposed to dust aerosols of neodymium, this result could be a peculiarity of species response or effect of yttrium oxide (combined with treadmill exercise).
A slightly significant decrease in circulating monocytes was seen at the end of the exposure period. This was significant at the 0.10 level.
No significant change in distribution of other white blood cell types was detected.

Necropsy results:
Lungs of exposed dogs were reddish grey instead of pink. Bronchial lymph nodes in exposed dogs were enlarges 8 to 10 times but other body lymph nodes were normal in size. With regards to gross appearance, all other organs were normal.

Results of histologic examination:
Many cellular elements were within the alveoli of lungs of exposed dogs. The most apparent histologic change occurring as a result of 30 day’s exposure to yttrium oxide was the presence of many macrophages and leukocytes in the alveoli. According to Hatch & gross, these alveolar macrophages or “dust cells” are desquamated alveolar cells. The extreme hypertrophy of alveolar epithelial cells prior to desquamation is shown.
The leukocytes were mainly neutrophils. Many had elongated nuclei and were probably in the process of diapedesis. Seemingly, a leukotactic substance was attracting many leucocytes to the lungs and this was reflected by the increased leukocyte count.
Examination of the lungs indicated no connective tissue increase.

Results of examination of bronchial lymph nodes from exposed dogs indicated the presence of many dust-laden macrophages. These macrophages were seen after 30 days of exposure.
The same result of the macrophages increase was observed by Davison in mice tracheobronchial lymph nodes after 100-day’s exposure to neodymium oxide and in guinea pigs after a 50-day’s exposure to neodymium oxide.
This experiment indicated that the lymphatics of the dog seem quite efficient in removing the contaminant from the lungs to the bronchial lymph nodes.

Radiographic examination: slight increase of the lung density probably due to the increase of dust-laden macrophages.

Effect levels

open allclose all
Key result
Dose descriptor:
NOAEC
Remarks:
systemic
Effect level:
>= 12.65 mg/m³ air (analytical)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: no systemic effects observed
Key result
Dose descriptor:
LOAEC
Remarks:
local
Effect level:
12.65 mg/m³ air (analytical)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: local effect: inflammatory response to dust overload in lungs and bronchial lymph nodes

Target system / organ toxicity

Key result
Critical effects observed:
no

Applicant's summary and conclusion

Conclusions:
In a subacute repeated dose inhalation study with yttrium oxide, no relevant systemic effects were observed, exposing dogs 30 days to 12.65 mg/m3. An overall systemic NOAEL was established to be >= 12.65 mg/m3, based on the absence of change in organ weights, macroscopic observations at necropsy and histopathology at the tested concentration. A local LOAEL of 12.65 mg/m3 could be derived based on the inflammatory response to dust overload in lungs and bronchial lymph nodes.
Executive summary:

An inhalation study was was performed with dogs exposed to yttrium oxide for 6 hours/day, 5 days/week for 6 weeks. The exposure lasted 30 days (180 exposure hours in total) and treadmill exercise was given for 10 minutes a day throughout the experiment. Post-exercise value of blood lactate concentration was determined 2 times a week and erythrocyte volume, plasma volume, hemoglobin concentration and leukocyte count were determined before the start and at the end of the exposure period. Thoracic radiographs were done before the exposure to determine freedom from lung lesions and subsequent fitness for treadmill exercise. Histologic examination was done on dogs after exposure period. Aerosol concentration, distribution and particle size have been determined. At necropsy, lungs of the exposed dogs were found to be reddish grey and were firmer than the lungs of the controls. Bronchial lymph nodes in exposed dogs were enlarged 8 - 10 times compared to controls; other body lymph nodes were normal in size. With regards to gross appearance, other organs were normal. Histopathological examination did not reveal any effects on heart, liver, spleen, mesenteric lymph nodes, testis or ovaries, kidneys, adrenal gland and bone marrow. Thoracic radiographs of each dogs were made before and at the end of the exposure period to determine freedom of lung lesions and subsequent fitness for treadmill exercise. No relevant effects were found. Significant increase of white blood cells, dust-laden macrophages in the bronchial lymph nodes & decrease of the erythrocyte volume indicated Y2O3 was being transported from the lungs to other tissues, having negative effect on erythropoiesis. The observed effects were rather consistent with a species-specific phenomenon of "lung overload" inflammatory response in the rat following inhalation of poorly soluble particles of low toxicity and resulting "portal-of-entry" effects, with a limited relevance to the human occupational situation given the levels of exposure. This resulted in overall systemic NOAEL of >= 12.65 mg/m3, based on the absence of change in organ weights, macroscopic observations at necropsy and histopathology at the tested concentration. The increased leucocyte counts in exposed dogs was considered to be secondary to the local effects. A local LOAEL of 12.65 mg/m3was derived based on the inflammatory response to dust overload in lungs and bronchial lymph nodes.