Sodium zirconium lactate

Repeated dose toxicity: oral

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

Reference

Reference 1

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 2

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

Test material information

Constituent 1

Reference substance name:

Zirconium sulphate

EC Number:

238-694-4

EC Name:

Zirconium sulphate

Cas Number:

14644-61-2

Molecular formula:

H2O4S.1/2Zr

Test animals

Species:

rat

Strain:

Long-Evans

Sex:

male/female

Details on test animals or test system 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 / concentrations

Doses / concentrations 1

Dose / conc.:

0.79 mg/kg bw/day (nominal)

Remarks:

males

Doses / concentrations 2

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

1

Dose descriptor:

LOAEL

Effect level:

0.79 mg/kg bw/day (nominal)

Based on:

element

Sex:

male

Basis for effect level:

clinical biochemistry

2

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± 4.2^1 189.5± 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± 2.3^2 204.0± 4.7 285.7± 6.2 313.7± 8.7 377.5± 6.3^3 392.0 ± 6.5^4 405.2± 8.4^5 469.0 ± 8.1^3
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± 2.1^2 159.3± 1.9 204.4±1.9 232.0± 2.7 250.0 ± 2.5^4 263.7± 4.3 267.0± 4.2 299.2± 5.3^3

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	Longevity^1
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±3.6^2 106.1± 9.9	134.4± 5.1 133.3± 4.7	77.5± 2.1 89.7± 5.6^3
Females Control Zirconium	698 921	79.6± 8.2 111.4± 5.6^4	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	Controls^2			Fed Zirconium^3		Difference (µg/g)
	No rats	Mean (µg/g)	No N.D.	No rats	Mean (µg/g)
Males Kidney Liver Heart Lung Spleen Tumours Mean^7	42 35 39 35 33 3 -	10.5 10.5 7.8 6.4 3.1 2.7 7.8	4 3 26^4 3 3 1 -	10 9 10 3 10 - -	9.7 11.2 17.2 7.4 35.1^5 - 17.7	-0.8 +0.7 +9.4 +1.0 +32.0 - +9.9
Males Kidney Liver Heart Lung Spleen Tumours Mean^7	38 38 31 38 31 3 -	5.4 3.4 7.7 9.6 22.3 4.5 9.3	9^5 0 5^6 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.