Zirconium, acetate lactate oxo ammonium complexes

Repeated dose toxicity: oral

Administrative data

Endpoint:

sub-chronic toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: see 'Remark'

Remarks:

Non GLP study. The study was conducted according to a method equivalent to the OECD 408 guideline without major deviations. However, no data on test conditions, preparation of animals are reported. Follow-up of body weight was done weekly, however no individual animal data were reported. No histopathology observations were done. No individual reporting was done.

Cross-reference

Reason / purpose for cross-reference:

reference to same study

Data source

Reference

Reference Type:

publication

Title:

The acute, chronic and topical toxicity of zirconium carbonate.

Author:

Harrison J.W.E., Trabin B, Martin E.W

Year:

1951

Bibliographic source:

J Pharmacol Exp Ther; 102(3): 179-84

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)

Deviations:

yes

Remarks:

no histopathology was done, detailed data on study set-up and results are lacking

GLP compliance:

no

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

zirconium(4+);dicarbonate

Cas Number:

57219-64-4

Molecular formula:

ZrC2O6

IUPAC Name:

zirconium(4+);dicarbonate

Constituent 2

Reference substance name:

560-633-5

IUPAC Name:

560-633-5

Constituent 3

Reference substance name:

Zirconium basic carbonate

IUPAC Name:

Zirconium basic carbonate

Details on test material:

- Name of test material (as cited in study report): hydrated zirconium carbonate
- Composition of test material, percentage of components: containing 20.9 % ZrO2
- Molecular formula (if other than submission substance): 3ZrO2.CO2.H2O
- Physical state: water insoluble moist paste
- Analytical purity: no data
- Impurities (identity and concentrations): no data

Test animals

Species:

rat

Strain:

other: Albino

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: no data
- Age at study initiation: recently weaned
- Weight at study initiation: 50 g
- Fasting period before study: no data
- Housing: no data
- Diet (e.g. ad libitum): normal diet
- Water (e.g. ad libitum): normal diet
- Acclimation period: no data

Administration / exposure

Route of administration:

oral: feed

Vehicle:

unchanged (no vehicle)

Details on oral exposure:

Three groups of 20 rats each were distributed as litter mates and fed during 17 weeks with a mixture of standard rat diet and hydrated zirconium carbonate (HZC) at 0.2%, 2.0% and 20% (w/w).

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

17 weeks

Frequency of treatment:

continuously in the diet

Doses / concentrations

Doses / concentrations 1

Remarks:

Doses / Concentrations:
0.2% (w/w) equivalent of 300 to 130 mg/kg bw/day calculated in week 1 and week 15 respectively
Basis:
nominal in diet

Doses / concentrations 2

Remarks:

Doses / Concentrations:
2.0% (w/w) equivalent of 3300 to 1300 mg/ kg bw/day calculated week 1 and week 15 respectively
Basis:
nominal in diet

Doses / concentrations 3

Remarks:

Doses / Concentrations:
20% (w/w) equivalent of 33900 to 15100 mg/kg bw/day calculated week 1 and week 15 respectively
Basis:
nominal in diet

No. of animals per sex per dose:

10 males and 10 females

Control animals:

yes, plain diet

Details on study design:

Three groups of 20 rats each were distributed as litter mates.

Positive control:

No positive control

Examinations

Observations and examinations performed and frequency:

Animals observed daily and weighed weekly. Records were kept of the quantities of food and water consumed.

Sacrifice and pathology:

Gross pathology of the organs.

Other examinations:

- Sample of blood were obtained from 8 animals in each group ( 4 males/4 females) at the weeks 8 & 16 of the test
- Hemoglobin was determined, erythrocytes and leucocytes were counted, and differential counts were made
- Urine was also examined

Statistics:

No data

Results and discussion

Results of examinations

Clinical signs:

no effects observed

Mortality:

no mortality observed

Body weight and weight changes:

no effects observed

Food consumption and compound intake (if feeding study):

no effects observed

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

no effects observed

Ophthalmological findings:

not examined

Haematological findings:

no effects observed

Clinical biochemistry findings:

not examined

Urinalysis findings:

no effects observed

Behaviour (functional findings):

not examined

Organ weight findings including organ / body weight ratios:

not examined

Gross pathological findings:

no effects observed

Histopathological findings: non-neoplastic:

not examined

Histopathological findings: neoplastic:

not examined

Details on results:

- No mortality during the test
- Growth curves were normal and identical to control rats
- No significant differences in the hematologic findings were noted among the various groups examined
- The urine did not differ significantly among the groups in color, reaction, odor, albumin content or microscopic appearance
- for all animals, their fur was smooth, their eyes and noses were clear and their mucous membranes were healthy in appearance
- The heart, lungs, thyroid, thymus, liver, spleen, kidneys, adrenals, stomach, intestines, bladder and genital organs were grossly normal in all animals

Effect levels

Dose descriptor:

NOAEL

Effect level:

3 150 - 7 080 mg/kg bw/day (actual dose received)

Based on:

other: 20.9% ZrO2 in the test material (HZC)

Sex:

male/female

Basis for effect level:

other: The NOAEL is based on the daily consumption calculated from equivalent intake levels of ZrO2 and body weights of rats.

Target system / organ toxicity

Critical effects observed:

not specified

Any other information on results incl. tables

Level of HZC in diet: 0%, 0.2%, 2.0% and 20%

Total intake food: 2182 g, 2176 g, 2149 g and 2475 g

Total intake ZrO2: 0 g, 0.9 g, 9.0 g and 103.5 g

Total intake water: 4193 g, 4774 g, 4097 g and 4021 g

Initial weight males: 52 -54 g; females: 50 -51 g

Weight after 17 weeks males: 340 -349 g; females 210 -230 g

Weight gain (average) males: 285 -295 g; females 160 -179 g

Daily consumption of HZC: 0, 0.13 -0.30 g/kg, 1.3 -3.3 g/kg and 15.1 - 33.9 g/kg

Applicant's summary and conclusion

Conclusions:

Ingestion of equivalent cumulative doses of 0.9 g, 9 g and 103.5 g of ZrO2 in the form of hydrated zirconium carbonate for a period of 17 weeks does not cause any death on the 60 rats submitted to the test. This indicate the absence of cumulative toxic effects. After autopsy, no abnormality was observed on heart, lungs, thyroids, thymus, liver, spleen, kidneys, adrenals, stomach, intestines, bladder and genitals organs, so it can be concluded that ingestion of HZC (containing 20.9% ZrO2) does not induce harmful effects.