Registration Dossier

Administrative data

Endpoint:
chronic toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
supporting study
Study period:
1961
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment

Data source

Reference
Reference Type:
publication
Title:
Zirconium lactate and barium zirconate: Acute toxicity and inhalation effects in experimental animals.
Author:
Brown, JR; Mastromatteo, E; Horwood, J.
Year:
1963
Bibliographic source:
Am Ind Hyg Assoc J 24(2):131−136.

Materials and methods

Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
Groups of guinea pigs, rats and hamsters were exposed to zirconium lactate in an inhalation chamber for 7 hours/day, 5 days per week. At the end of each day they were removed from the chambers for feeding every night. Regular observations were made on the general appearance and body weight of the exposed and control animals. Any mortality was recorded. Those animals which died during exposure were autopsied immediately. After
225 days in the chamber, five animals of each species (less any that died) were sacrificed and were autopsied immediately. Inhalation exposure was terminated after 13 1/2 months. All animals surviving at this time were sacrificed and studies and autopsied. In all, there were 285 exposure days.
GLP compliance:
no
Remarks:
Study pre-dates the introduction of GLP

Test material

Specific details on test material used for the study:
Zirconium lactate was vacuum dried at a temperature of 100°C for 12 hours before use to eliminate any moisture which may have been picked up in
shipment and in storage. The zirconium lactate was found to be very deliquescent. After drying, the material was passed through a 100-mesh screen to break up any coarse aggregates.

Test animals

Species:
guinea pig
Sex:
not specified
Details on test animals and environmental conditions:
The inhalation studies were carried out with 40 guinea pigs, 40 rats, and 40 hamsters.

Administration / exposure

Route of administration:
inhalation: dust
Type of inhalation exposure:
whole body
Vehicle:
air
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: Internal volume of chamber is 1 cubic yard
- Method of holding animals in test chamber: Four wire cages were placed mid-way in each chamber. Two of the cages continued five guinea pigs each, and the other two each contained 10 rats and 10 hamsters in separate compartments.
- System of generating particulates/aerosols: Owing to the deliquescent properties of zirconium lactate, dispersion of this material
was unsatisfactory using available equipment, therefore a special dust feed mechanism was therefore developed for the purpose
- Temperature, humidity, pressure in air chamber: Temperature and humidity within the chambers were not controlled, however, the thermal environment was not noted to cause the animals any discomfort
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
The concentration and the particle size distribution of the dust within the chambers was determined at regular intervals. The mean dust concentration in chamber 2 was 145.1 mg/m’ of zirconium lactate (36.3 mg/m3 of zirconium); in chamber 3, 18.8 mg/m3 zirconium lactate (4.7 mg/m3 of zirconium)
Duration of treatment / exposure:
7 hrs/day.5 days per week
Doses / concentrationsopen allclose all
Dose / conc.:
150 mg/m³ air
Remarks:
Chamber 2
Dose / conc.:
15 mg/m³ air
Remarks:
Chamber 3
No. of animals per sex per dose:
Not specified
Control animals:
yes, concurrent no treatment
Details on study design:
Because of the pulmonary changes noted in the animals sacrificed at 225 days, it was decided to remove some of the animals from exposure to
determine whether regression of effect would occur. Accordingly, two animals of each species were removed and maintained under ordinary laboratory conditions while the exposure was continued for the remaining animals for a further period of 60 days.

Examinations

Sacrifice and pathology:
Organ weights were determined for lungs, liver, and kidneys from each animal.
Histopathological examination was carried out on the liver, spleen, lungs, heart and muscle tissue of all the animals, with particular attention paid to the lungs.
Other examinations:
Zirconium assays on lung tissues were carried out

Results and discussion

Results of examinations

Mortality:
mortality observed, non-treatment-related
Description (incidence):
Throughout the whole period of the study only three animals died. These were guinea pigs which were exposed in chamber 3 to zirconium lactate 15 mg/m3. These deaths occurred on the 200th, 209th and 235th exposure day.
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
Lung weights were generally greater for the exposed animals than for the controls
Description (incidence and severity):
Animals exposed to zirconium lactate at concentrations of 150 mg/m3 showed marked pathological changes in the lungs, including pleural thickening, thickening and round cell infiltration of the alveolar walls, localized deposits of round cells in subpleural areas, perivascular
and peribronchiolar cuffing with round cells, and hypertrophy of the media and intima of the arterioles. Scattered throughout the lungs were numerous dust containing phagocytes. Changes in the bronchi and bronchioles were minimal.
Animals exposed to zirconium lactate at concentrations of 15 mg/m3 showed marked pathological changes, similar to those seen in the higher dose group, but to a greater degree. In addition to the findings noted above, a number of giant cells, but no granulomata were seen. In some animals, particularly those guinea pigs which died during exposure, there were marked degenerative changes in the epithelium of the bronchi and the bronchioles.
The heart was examined in all animals, but none showed any evidence of rightsided hypertrophy. There was no evidence of arteriolar change in any other organ.
Description (incidence and severity):
Cultures were taken from the cut surfaces of the lungs in both exposed and control animals and these did not show the presence of any pathogenic organisms.

Effect levels

Dose descriptor:
LOAEL
Effect level:
15 mg/m³ air
Based on:
test mat.
Basis for effect level:
histopathology: non-neoplastic

Target system / organ toxicity

Key result
Critical effects observed:
yes
Lowest effective dose / conc.:
15 mg/m³ air
System:
respiratory system: lower respiratory tract
Organ:
lungs
Treatment related:
yes
Dose response relationship:
no
Relevant for humans:
not specified

Any other information on results incl. tables

TABLE I

Mean Particle Size Distribution of Dust in Exposure Chambers

 

Particle Size (microns)

Per Cent Distribution

Zirconium Lactate

Less than 0.3

82.27

0.3-0.6

9.97

0.6-1.2

4.53

1.2-1.8

2.13

1.8-2.4

0.88

2.4-3.0

0.19

3.0-3.8

0.03

3.8-4.5

--

4.5-6.0

--

6.0-7.5

--

 

TABLE II

Average Body Weight and Average Weight of Lungs, Liver and Kidneys

in Animals in Inhalation Chambers After 225 Exposure Days

 

Animal

Organ

Average wet organ weight (grams)

Chamber 1 (control)

Chamber 2

(150 mg/m3)

Chamber 3 *

(15 mg/m3)

Guinea pig

 

 

 

 

Rat

 

 

 

 

Hamster

 

Lungs

Liver

Kidneys

Body weight

 

Lungs

Liver

Kidneys

Body weight

 

Lungs

Liver

Kidneys

Body weight

5.7

26.9

7.8

781

 

3.4

20.8

3.5

485

 

0.8

5.7

1.0

162

5.8

29.6

8.4

918

 

2.8

15.8

2.9

389

 

0.9

6.1

1.1

112

6.2

27.6

9.8

739

 

4.0

16.6

3.5

422

 

1.0

6.7

1.6

145

*Includes organ weights of two guinea pigs which died prior to 225 days in exposure.

TABLE III

Zirconium Content of Lune After 225 Exposure Days-

(% Zirconium by Weight)

 

 

 

Zirconium Content

 

Animal

Chamber

Lung Ash

Wet Lung

Guinea pig

 

 

 

Rat

 

 

 

Hamster

 

1 (Control)

2 (150 mg/m3)

3 (15 mg/m3)

 

1 (Control)

2 (150 mg/m3)

3 (15 mg/m3)

 

1 (Control)

2 (150 mg/m3)

3 (15 mg/m3)

0.01

0.22

0.05

 

0.04

Insuff. Ash

Insuff. Ash

 

<0.05

0.4

0.10

 

 

 

 

0.0017

0.032

0.04

 

0.007

0.017

0.021

 

Applicant's summary and conclusion

Conclusions:
Guinea pigs, rats and hamsters were exposed to 15 mg/m3 or 150 mg/m3 zirconium lactate, 7 hrs/day, 5 days/week for up to 285 days. The exposed animals showed reduced weight gain, pathological changes consistent with chronic interstitial pneumonitis, very little deposition of fibrous tissue, no granuloma, and an increase in the zirconium content of the lung tissue.
Executive summary:

Guinea pigs, rats and hamsters were exposed to 15 mg/m3 or 150 mg/m3 zirconium lactate, 7 hrs/day, 5 days/week for up to 285 days. The exposed animals showed reduced weight gain, pathological changes consistent with chronic interstitial pneumonitis, very little deposition of fibrous tissue, no granuloma, and an increase in the zirconium content of the lung tissue.