Calcium tin trioxide

Repeated dose toxicity: oral

Administrative data

Endpoint:

sub-chronic toxicity: oral

Type of information:

migrated information: read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: see 'Remark'

Remarks:

Published literature fulfilled basic scientific principles. From existing studies of toxicokinetic profiles of Tin (IV) dioxide and Tin (II) oxide, it can be concluded that the toxicokinetic profiles of these two substances appear to be similar. Minor differences between Tin (II) and Tin (IV) in their absorption and distribution indicate that Tin (II) may be a bit more toxic than Tin (IV). Therefore Tin (II) oxide can be used as a structural surrogate for Tin (IV) dioxide in the 90 days repeated toxicity test.

Data source

Reference

Reference Type:

publication

Title:

Unnamed

Year:

1973

Materials and methods

Test guideline

Qualifier:

no guideline followed

Principles of method if other than guideline:

In order to investigate repeated toxicity in 90 days of series of tin compounds, Two tin compounds, stannous oxide (SnO) and stannous chloride (SnCI2•2H20)examined were fed to groups of ten male and ten female rats at dietary levels of 0 (control), 0.03, 0.10, 0.30 and 1.00 % for 90 days.

GLP compliance:

no

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

stannous oxide

IUPAC Name:

stannous oxide

Constituent 2

Reference substance name:

SnO

IUPAC Name:

SnO

Constituent 3

Reference substance name:

stannous chloride

IUPAC Name:

stannous chloride

Constituent 4

Reference substance name:

SnCl2•2H2O

IUPAC Name:

SnCl2•2H2O

Details on test material:

stannous oxide (J. T. Baker Chemical Co., Phillipsburg, N.Y.), stannous chloride 2 aq. (Analar, BDH Chemicals Ltd., Poole, Dorset)

Test animals

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

Male and female weanling rats from the Institute's Wistar-derived colony were housed in groups of five in stainless steel cages with screen bottoms. The diet used for both control and treated groups was the Institute's stock diet, with the following percentage composition: soyabean-oil meal, 10; fish meal, 8; meat scraps, 4; dried whey, 2; yellow maize, 29.05; wheat, 36; grass meal, 3; brewer's yeast, 3, complete B-vitamin mixture, 0.1; vitamin-ADEK preparation, 0.6; bone meal, 0.75; trace mineral salt, 0.5; soyabean oil, 3. This diet was found to contain calcium (0.98 %), phosphorus (0.80 %), iron (205 ppm), copper (23 ppm), manganese (85 ppm) and zinc (38 ppm). Test diets were prepared by blending the stock diet and the tin compouds in a Stephan cutter. Diets and tap water were provided ad lib.

Administration / exposure

Route of administration:

oral: feed

Vehicle:

unchanged (no vehicle)

Details on oral exposure:

Two tin compounds, stannous oxide (SnO) and stannous chloride (SnCI2•2H2O) were examined in 13-wk feeding studies. Each of these compounds was fed to groups of ten male and ten female rats at dietary levels of 0.0 (control), 0.03, 0.10, 0.30 and 1.00 % for 90 days.

Analytical verification of doses or concentrations:

no

Details on analytical verification of doses or concentrations:

Due to stability of tin compounds, the analytical verification for these substances is unnecessary.

Duration of treatment / exposure:

13 weeks

Frequency of treatment:

Animals were dosed once each day at approximately the same time each day, seven days per week.

Doses / concentrations

Doses / concentrations 1

Remarks:

Doses / Concentrations:
0%
Basis:
nominal in diet

Doses / concentrations 2

Remarks:

Doses / Concentrations:
0.03%
Basis:
nominal in diet

Doses / concentrations 3

Remarks:

Doses / Concentrations:
0.1%
Basis:
nominal in diet

Doses / concentrations 4

Remarks:

Doses / Concentrations:
0.3%
Basis:
nominal in diet

Doses / concentrations 5

Remarks:

Doses / Concentrations:
1.0%
Basis:
nominal in diet

No. of animals per sex per dose:

10 males and 10 femels

Control animals:

yes, concurrent no treatment

Details on study design:

Two tin compounds, stannous oxide and stannous chloride were examined in 13-wk feeding studies. Each of these compounds was fed to groups of ten male and ten female rats at dietary levels of 0.0 (control), 0.03, 0.10, 0.30 and 1.00 % for 90 days. Individual body weights were recorded weekly. The food intake of each group was measured at weekly intervals up to wk 4 and in wk 11-12. Haematological studies were carried out at wk 12 and provided measurements of haemoglobin concentration and haematocrit value, counts of red blood cells and total and differential counts of white blood cells. Additional haematological observations were made in the study on tin chloride. These consisted of haemoglobin readings at wk 2, 4, 6 and 9, and terminal determinations of haptoglobin concentration, numbers of reticulocytes and the osmotic resistance of the erythrocytes. Serum activities of glutamic-oxalacetic and glutamic--pyruvic transaminases and of alkaline phosphatase were determined terminally in both experiments. Bilirubin concentrations were measured terminally only in the study with tin chloride.
Urine examinations, including appearance, pH, glucose, protein, occult blood, ketones and microscopy of the sediment were conducted upon pooled samples from each group in wk 13.

The rats fed the highest level of tin chloride were sacrificed after 8 wk because of poor condition and high mortality. Organs and tissues were fixed in buffered formalin. In wk 14, the remaining rats were killed by decapitation and examined for gross changes. The heart, kidneys, liver, spleen, brain, gonads, thymus, thyroid and adrenals were weighed and paraffin-wax sections of these and a wide range of other organs were stained with haematoxylin and eosin. Detailed microscopic examinations were performed on all rats fed 1% tin oxide, on those fed the two highest levels of tin chloride and on the controls. In the rats fed the intermediate levels of tin chloride, only the liver, kidneys and stomach were examined.

Positive control:

no

Examinations

Observations and examinations performed and frequency:

Individual body weights were recorded weekly. The food intake of each group was measured at weekly intervals up to wk 4 and in wk 11-12. Haematological studies were carried out at wk 12 and provided measurements of haemoglobin concentration and haematocrit value, counts of red blood cells and total and differential counts of white blood cells. Additional haematological observations were made in the study on tin chloride. These consisted of haemoglobin readings at wk 2, 4, 6 and 9, and terminal determinations of haptoglobin concentration, numbers of reticulocytes and the osmotic resistance of the erythrocytes. Serum activities of glutamic-oxalacetic and glutamic--pyruvic transaminases and of alkaline phosphatase were determined terminally in both experiments. Bilirubin concentrations were measured terminally only in the study with tin chloride.
Urine examinations, including appearance, pH, glucose, protein, occult blood, ketones and microscopy of the sediment were conducted upon pooled samples from each group in wk 13.

Sacrifice and pathology:

The rats fed the highest level of tin chloride were sacrificed after 8 wk because of poor condition and high mortality. Organs and tissues were fixed in buffered formalin. In wk 14, the remaining rats were killed by decapitation and examined for gross changes. The heart, kidneys, liver, spleen, brain, gonads, thymus, thyroid and adrenals were weighed and paraffin-wax sections of these and a wide range of other organs were stained with haematoxylin and eosin. Detailed microscopic examinations were performed on all rats fed 1 % tin oxide, on those fed the two highest levels of tin chloride and on the controls. In the rats fed the intermediate levels of tin chloride, only the liver, kidneys and stomach were examined.

Other examinations:

no data

Statistics:

no data

Results and discussion

Results of examinations

Clinical signs:

no effects observed

Description (incidence and severity):

For Stannous oxide

Mortality:

no mortality observed

Description (incidence):

For Stannous oxide

Body weight and weight changes:

no effects observed

Description (incidence and severity):

For Stannous oxide

Food consumption and compound intake (if feeding study):

no effects observed

Description (incidence and severity):

For Stannous oxide

Food efficiency:

no effects observed

Description (incidence and severity):

For Stannous oxide

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

not examined

Ophthalmological findings:

not examined

Haematological findings:

no effects observed

Description (incidence and severity):

For Stannous oxide

Clinical biochemistry findings:

not examined

Urinalysis findings:

no effects observed

Description (incidence and severity):

For Stannous oxide

Behaviour (functional findings):

not examined

Organ weight findings including organ / body weight ratios:

no effects observed

Description (incidence and severity):

For Stannous oxide

Gross pathological findings:

no effects observed

Description (incidence and severity):

For Stannous oxide

Histopathological findings: non-neoplastic:

no effects observed

Description (incidence and severity):

For Stannous oxide

Histopathological findings: neoplastic:

no effects observed

Description (incidence and severity):

For Stannous oxide

Details on results:

Stannous oxide:
The feeding of stannous oxide at various dietary levels up to 1.0 % did not cause any noticeable changes in appearance or behaviour, nor in body-weight gain and food intake. The haematological values and serum-enzyme activities were not altered and there were no significant changes in the composition of the urine. No treatment-related differences were observed in the weights of the organs or in the gross and microscopic appearance of the organs examined. Since none of the criteria examined was affected, no details of this study are presented.

Stannous chloride:
The rats fed the diet containing 1 % stannous chloride ate little food and already showed abdominal distension during wk 1. Growth was slow in the first few weeks and stopped completely in males after 4 wk and in females after 6 wk. At wk 8, loss of body weight occurred in seven males and four females and one male died. At wk 9, another three males died. Since several other males were moribund it was decided to discontinue this group and autopsy was performed.
Poor appetite and abdominal distension were observed also at the 0.3 % feeding level during the first 2 wk. However, all rats kept growing, except for one female which lost weight in wk 10 and died in wk 11. It summarizes some of the data on mean body weights, consumption of food and water and food efficiency. The growth retardation that occurred at 1.0 and at 0.3 % during the first 2 wk was associated with a decrease in food consumption. Thereafter body-weight gain and food-intake figures at the 0.3 % level returned to normal. Food intake was relatively low also at the 0.1% level, but only during wk 1. Water intake per unit of food consumed was slightly increased in the 0.3 and 1.0% groups during wk 1.
The haemoglobin values determined at various stages showed decreased levels in the 1.0 and 0.3 % groups in both sexes from wk 4 onwards. At 1.0 % there was a gradual decrease in haemoglobin content, and at 0.3 %, although a gradual rise did occur, it was distinctly slower in the initial stages than that in the controls.
The terminal haematological findings are presented in Table 4 of the pubblication. The mean values of haemoglobin content and cell volume were decreased in both sexes in the group given the 0.3 % diet but the differences from the controls were statistically significant only in males.

Effect levels

Dose descriptor:

NOAEL

Effect level:

>= 10 000 mg/kg diet

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: 1% in diet can be converted to 10000 mg/kg diet.

Target system / organ toxicity

Critical effects observed:

not specified

Any other information on results incl. tables

Tin (II) oxide did not induce any effect in rats in repeated dose toxicity studies.

Applicant's summary and conclusion

Conclusions:

It suggested that insoluble tin compounds (stannic oxide and stannous oxide) are relatively harmless at dietary levels of 1%, whereas cationic tin compounds soluble in water or dilute acid may be toxic at dietary levels above 0.1%.

Executive summary:

In the test, groups of rats (Wistar; n=10/sex/group) were fed diets containing Tin (II) oxide and stannous chloride at dose of 0, 0.03, 0.10, 0.30, or 1.00% for periods of 13 weeks. Effects on behaviour, mortality, body weights, food consumption, blood, urine, biochemical parameters, and organ weights were examined; and gross microscopic examinations were performed. No adverse effects were noted at any dose of tin oxide. However, severe growth retardation, decreased food efficiency, slight anaemia, and slight histological changes in the liver were observed with 0.3% or more of stannous chloride.

 

The authors concluded that the differences in response to different tin compounds suggested that insoluble tin compounds are relatively harmless whereas cationic tin compounds soluble in water or dilute acid may be toxic at dietary levels above 0.1%. From these studies, it is concluded that dietary exposure to levels of Tin (II) oxide up to 1% for 13 weeks, did not induce any effect in rats.