Registration Dossier

Administrative data

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

Data source

Referenceopen allclose all

Reference Type:
publication
Title:
Zirconium, niobium, antimony, vanadium and lead in rats: life term studies.
Author:
Schroeder, HA; Mitchener, M; Nason, AP.
Year:
1970
Bibliographic source:
J Nutr 100:59−68.
Reference Type:
publication
Title:
Life term studies on the effect of trace elements on spontaneous tumors in mice and rats.
Author:
Kanisawa, M; Schroeder, HA.
Year:
1969
Bibliographic source:
Cancer Research 29(4):892−895.

Materials and methods

Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
Groups of rats had zirconium added to the diet and drinking water in a lifetime study to evaluate the effects of 5 trace metals.
GLP compliance:
no
Remarks:
Study predates introduction of GLP

Test material

Reference
Name:
Unnamed
Type:
Constituent

Test animals

Species:
rat
Strain:
Long-Evans
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Pregnant females were purchased from BLU: (LE) strain, Blue Spruce Farms, Inc., Altamont, New York, and the offspring were born and weaned in the study laboratory.
- Housing: 4 per cage
- Diet: ad libitum
- Water: ad libitum

Administration / exposure

Route of administration:
oral: unspecified
Details on route of administration:
Combination of drinking water and diet
Vehicle:
other: drinking water and diet
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
From weaning to natural death (a maximum of 1347 days).
Doses / concentrationsopen allclose all
Dose / conc.:
0.79 mg/kg bw/day (nominal)
Remarks:
males
Dose / conc.:
0.89 mg/kg bw/day (nominal)
Remarks:
females
No. of animals per sex per dose:
56 male and 58 female
Control animals:
yes, plain diet
Details on study design:
The test drinking water contained 5 ppm zirconium sulfate and the experimental rats also were fed a diet containing 2.66 μg/g zirconium. Using time-weighted average body weight and default water consumption in Long-Evans rats, the dose of 5 ppm zirconium sulfate in drinking water was converted to 0.60 mg/kg-day for males and 0.67 mg/kg-day for females. The dose of 2.66 mg/kg zirconium in feed was converted (also using time-weighted average body weights and food consumption) to 0.19 mg/kg-day for males and 0.22 mg/kg-day for females. Because the rats ingested both drinking water and feed, the doses were summed for a total equivalent dose (TED) of 0.79 mg/kg-day in males and 0.89 mg/kg-day in females.

Examinations

Observations and examinations performed and frequency:
The rats were weighed weekly from weaning until 6 weeks of age, and then monthly. As the rats died, they were weighed and dissected to identify grossly visible tumors and other lesions in the heart, lung, kidney, liver, and spleen.
Other examinations:
Blood pressure and blood samples were also taken regularly.
Portions of heart, lung, kidney, liver and spleen were frozen and later ashed and analysed for the elements given.

Results and discussion

Results of examinations

Clinical signs:
no effects observed
Mortality:
no mortality observed
Description (incidence):
There was no significant difference in survival of the zirconium-administered rats compared to controls. Mortality was not linked to treatment.
Body weight and weight changes:
effects observed, non-treatment-related
Description (incidence and severity):
Zirconium did not consistently affect the growth rates of the rats . Males administered zirconium were significantly heavier than controls at 30, 150, and 180 days and lighter than controls at 360 and 540 days, while females were significantly heavier than controls at 30, 150, and 540 days.
No differences were observed in the mean body weights of the rats administered zirconium compared to controls, while the hearts of males administered zirconium weighed 14.6% less than controls, the hearts of females weighed 7.4% more.
Description (incidence and severity):
Females administered zirconium showed significantly higher fasting serum glucose levels than controls and males administered zirconium had significantly higher cholesterol levels. Glycosuria (glucose in the urine) was noted in 23% of the controls and in 52% of 56 rats (study does not say whether in males or females) administered zirconium (significantly different by chi-square analysis at p < 0.01)
Gross pathological findings:
no effects observed
Description (incidence and severity):
No significant increase was reported in the number of tumors in rats administered zirconium compared to the controls

Effect levels

open allclose all
Dose descriptor:
LOAEL
Effect level:
0.79 mg/kg bw/day (nominal)
Based on:
element
Sex:
male
Basis for effect level:
clinical biochemistry
Dose descriptor:
LOAEL
Effect level:
0.89 mg/kg bw/day (nominal)
Based on:
element
Sex:
female
Basis for effect level:
clinical biochemistry

Target system / organ toxicity

Critical effects observed:
no

Any other information on results incl. tables

TABLE 1

Weights of rats given zirconium,

 

Age (days)

Control (g)

Zirconium (g)

Males

30

60

90

120

150

180

360

540

 

72.1± 4.21

189.5± 6.0

270.0± 8.9

312± 9.3

341.5± 8.9

364.7±8.7

443.8± 14.9

507.4±16.6

 

88.5± 2.32

204.0± 4.7

285.7± 6.2

313.7± 8.7

377.5± 6.33

392.0 ± 6.54

405.2± 8.45

469.0 ± 8.13

Females

30

60

90

120

150

180

360

540

 

64.7± 2.1

154.2±6.0

197.1± 5.4

225.2± 5.3

238.8± 4.0

250.5± 4.9

262.6± 5.9

262.4± 9.8

 

82.1± 2.12

159.3± 1.9

204.4±1.9

232.0± 2.7

250.0 ± 2.54

263.7± 4.3

267.0± 4.2

299.2± 5.33

Mean3SEM. Differences from controls have been analysed by Student’s t-test, giving the P values of footnote 2,3,4 and 5.

2P <0.005

3P < 0.025

4P < 0.01

5P < 0.05

TABLE 2

Survival and longevity of rats, days

 

No rats

Mean age

50% dead

75% dead

90% dead

Last

Longevity1

Control

Male

Female

 

52

54

 

819

910

 

872

912

 

975

1050

 

1057

1157

 

1232

1347

 

1160 ± 27.8

1304 ± 36.0

Zirconium

Male

Female

 

56

58

 

870

935

 

881

947

 

1077

1187

 

1077

1187

 

1189

1291

 

1127 ± 23.0

1247 ± 17.4

1Mean ± SEMof last 10% of animals surviving.

TABLE 3

Serum glucose and cholesterol levels in rats fed zirconium

 

 

Age (days

Glucose (Fasting)

Glucose (non-fasting)

Cholesterol (mg/100ml)

Males

Control

Zirconium

 

718

921

 

106.5±3.62

106.1± 9.9

 

134.4± 5.1

133.3± 4.7

 

77.5± 2.1

89.7± 5.63

Females

Control

Zirconium

 

698

921

 

79.6± 8.2

111.4± 5.64

 

114.2± 5.4

120.5 ± 3.3

 

116.0± 6.0

100.7± 9.0

 

2 Mean±SEM Differences from comparable controls have been analysed by Student’s t test, giving the P values of footnotes 3, 4 and 5.

3 P < 0.01.

4 P < 0.005.

5 P < 0.025.

TABLE 4

Mean heart and body weights of rats and gross tumors

 

 

No rats autopsied

Weight at death (g)

Heart weight (mg)

Ration x 1000 HW/BW

Tumours

 

No

%

Control

Male

Female

 

50

39

 

334

234

 

1498

949

 

4.49

4.06

 

10

14

 

20.0

35.9

Zirconium

Male

Female

 

46

53

 

324

244

 

1280

1019

 

3.95

4.18

 

7

20

 

15.2

37.7

TABLE 5

Zirconium in rat tissues, wet weight1

 

Organ/sex

Controls2

Fed Zirconium3

Difference

(µg/g)

No rats

Mean

(µg/g)

No N.D.

No rats

Mean

(µg/g)

Males

Kidney

Liver

Heart

Lung

Spleen

Tumours

Mean7

 

42

35

39

35

33

3

-

 

10.5

10.5

7.8

6.4

3.1

2.7

7.8

 

4

3

264

3

3

1

-

 

10

9

10

3

10

-

-

 

9.7

11.2

17.2

7.4

35.15

-

17.7

 

-0.8

+0.7

+9.4

+1.0

+32.0

-

+9.9

Males

Kidney

Liver

Heart

Lung

Spleen

Tumours

Mean7

 

38

38

31

38

31

3

-

 

5.4

3.4

7.7

9.6

22.3

4.5

9.3

 

95

0

56

0

4

1

-

 

37

35

37

37

35

-

-

 

12.5

6.7

9.9

10.5

19.9

-

11.9

 

+7.1

+6.3

+2.2

+0.9

-2.4

-

+2.6

 

1 Tissues were pooled in groups of 2 to 16, usually 4 to 7.

2 Control rats were 144 to 900 days old.

3 Zirconium-fed rats were 427 to 1172 days old. All zirconium-fed rats had zirconium in their tissues. Limit of detection of the method was 0.01 to 0.017µg/gram wet weight. N.D., not detected.

Differences between controls and zirconium-fed rats have been treated by chi-square analysis,

resulting in the P values of footnotes 4, 5 and 6.

4 P < 0.001

5 P < 0.005

6 P < 0.05

7 Excluding tumors.

Applicant's summary and conclusion

Conclusions:
A LOAEL of 0.79 mg/kg-day (males) and 0.89 mg/kg-day (females) is identified based on significantly increased incidence of glycosuria, higher fasting glucose levels in females and higher cholesterol levels in males. A NOAEL is not determined because only one dose (in addition to controls) was tested.