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Toxicological information

Toxicity to reproduction

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Administrative data

Endpoint:
three-generation reproductive toxicity
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Reliability:
4 (not assignable)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
This information is from the Concise International Chemical Assessment Document for Tin and Inorganic Tin Compounds which was issued by World Health Organization, but no details for the test procedure. Various animal data on inorganic compounds indicate even lower toxicity of Tin (IV) than Tin (II) and insoluble inorganic tin than soluble inorganic tin. Both Tin (II) oxide and Tin (IV) dioxide didn’t induce any effect in rats in repeated dose toxicity studies. Based on above, the use of Tin (II) oxide, Tin (IV) chloride, Tin (II) fluoride and Tin (II) chloride, as well as other stannic or stannous compounds as a structural surrogate for Tin (IV) dioxide (CAS No. 18282-26-4) for reproductive toxicity study is feasible.
Justification for type of information:
For justification of Weight-of-Evidence, please refer to attached WoE justification documentation in IUCLID Chapter 13.
Cross-reference
Reason / purpose for cross-reference:
assessment report
Remarks:
justification for weight-of-evidence approach

Data source

Referenceopen allclose all

Reference Type:
secondary source
Title:
Unnamed
Year:
2005
Reference Type:
publication
Title:
Tin and stannous chloride.
Author:
JECFA
Year:
1982
Bibliographic source:
Toxicological evaluation of certain food additives and contaminants. Prepared by the 26th meeting of the Joint FAO/WHO Expert Committee on Food Additives. Geneva, World Health Organization (WHO Food Additive Series 17)

Materials and methods

Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
In a multigeneration study, CPB:WU rats were given tin in the diet at 0, 200, 400, or 800 mg/kg for three generations to investigate the reproductive and developmental toxicity for Tin (as Tin(II) chloride).
GLP compliance:
not specified
Remarks:
Secondary source without such information
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
Tin dichloride
EC Number:
231-868-0
EC Name:
Tin dichloride
Cas Number:
7772-99-8
Molecular formula:
Cl2Sn
Details on test material:
No data

Test animals

Species:
rat
Strain:
other: CPB:WU
Details on species / strain selection:
randomly bred
Sex:
male/female
Details on test animals or test system and environmental conditions:
Iron content of the diets was maintained at 70 ppm, but for the F2 generation onwards was increased to 140 ppm.

Administration / exposure

Route of administration:
oral: feed
Vehicle:
unchanged (no vehicle)
Details on exposure:
CPB:WU rats were given tin in the diet at 0, 200, 400, or 800 mg/kg for three generations.
The stannous chloride was allowed to react in aqueous medium with the casein component of the diet, in order to simulate the form of tin likely to be found in canned food.
Details on mating procedure:
No data
Analytical verification of doses or concentrations:
not specified
Details on analytical verification of doses or concentrations:
no data
Duration of treatment / exposure:
three generations
No detailed information for accurate exposure duration
Frequency of treatment:
no data
Details on study schedule:
No data
Doses / concentrationsopen allclose all
Remarks:
Doses / Concentrations:
0
Basis:
nominal in diet
Remarks:
Doses / Concentrations:
200 mg/kg
Basis:
nominal in diet
Remarks:
Doses / Concentrations:
400 mg/kg
Basis:
nominal in diet
Remarks:
Doses / Concentrations:
800 mg/kg
Basis:
nominal in diet
No. of animals per sex per dose:
no data
Control animals:
yes, concurrent no treatment
Details on study design:
A teratogenicity study was carried out with 20 females/group of the F2b generation. Rats from F3b and F3c generationswere submitted to clinical and pathological examination.
Positive control:
no

Examinations

Parental animals: Observations and examinations:
Yes, growth of the parents and fertility were examined during the test.
Oestrous cyclicity (parental animals):
No data
Sperm parameters (parental animals):
no data
Litter observations:
numbers of offspring per litter and birth weight were observed.
Postmortem examinations (parental animals):
no data
Postmortem examinations (offspring):
Yes, F3b and F3c generations;
Statistics:
No data
Reproductive indices:
No data
Offspring viability indices:
No data

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:
no effects observed
Body weight and weight changes:
not specified
Food consumption and compound intake (if feeding study):
not specified
Organ weight findings including organ / body weight ratios:
not specified
Histopathological findings: non-neoplastic:
not specified
Other effects:
not specified

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:
not specified
Reproductive function: sperm measures:
not specified
Reproductive performance:
no effects observed

Details on results (P0)

Tin did not affect growth of the parents, fertility, numbers of offspring per litter, or birth weight.

Effect levels (P0)

Dose descriptor:
NOAEC
Effect level:
800 mg/kg diet
Based on:
test mat.
Sex:
male/female
Basis for effect level:
reproductive performance
Remarks on result:
not determinable due to absence of adverse toxic effects

Target system / organ toxicity (P0)

Critical effects observed:
no

Results: P1 (second parental generation)

Effect levels (P1)

Dose descriptor:
NOAEC
Effect level:
800 ppm
Based on:
test mat.
Sex:
male/female
Basis for effect level:
reproductive performance
Remarks on result:
not determinable due to absence of adverse toxic effects

Target system / organ toxicity (P1)

Critical effects observed:
no

Results: F1 generation

General toxicity (F1)

Clinical signs:
no effects observed
Mortality / viability:
no mortality observed
Body weight and weight changes:
no effects observed
Sexual maturation:
not specified
Organ weight findings including organ / body weight ratios:
not specified
Gross pathological findings:
no effects observed
Histopathological findings:
not specified

Details on results (F1)

In the study, tin did not affect numbers of offspring per litter or birth weight. Increased mortality of F2 ofspring during the first half of lactation was corrected by increasing the iron content of the mothers’ diet. Tin reduced offspring growth and haemoglobin levels during lactation but not thereafter. On pathological examination
of rats from the F3b and F3c generations, the F3b pups showed microscopic changes in the liver and spleen at weaning but not at 4 weeks of age. Within this multigeneration study, a teratogenicity tudy was carried out using 20 F2b females per dose level. On visceral and skeletal examination, there was no increase in the incidence of fetal malformations

Effect levels (F1)

Dose descriptor:
NOAEC
Generation:
F1
Effect level:
800 ppm
Based on:
test mat.
Sex:
male/female
Basis for effect level:
body weight and weight gain
Remarks on result:
not determinable due to absence of adverse toxic effects

Results: F2 generation

General toxicity (F2)

Clinical signs:
not specified
Mortality / viability:
mortality observed, treatment-related
Description (incidence and severity):
The mortality of F2 generation litters during the first 10 days of lactation was higher than controls, but decreased following an increase in iron in the diet. Tin is known to decrease iron absorption in the GI tract.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
There was a decrease in body weight gain during lactation that was related to the tin content of the diet.

Effect levels (F2)

Dose descriptor:
NOAEC
Generation:
F2b
Effect level:
800 mg/kg diet
Based on:
test mat.
Sex:
female
Basis for effect level:
other: On visceral and skeletal examination, there was no increase in the incidence of foetal malformations.

Target system / organ toxicity (F2)

Critical effects observed:
no

Overall reproductive toxicity

Reproductive effects observed:
no

Applicant's summary and conclusion

Conclusions:
It can be concluded that, under test conditions, tIn II did not affect growth of the parents, fertility, numbers of offspring per litter, or birth weight of fetuses. Furthermore, there was no increase in the incidence of fetal malformations by test material.
Executive summary:

A multigeneration reproduction study over 3 generations of rats (CPB:WU randomly bred) was carried out using levels of 0 (control), 200, 400 and 800 ppm (0, 0.02, 0.04 and 0.08%) tin in the diet. The stannous chloride was allowed to react in aqueous medium with the casein component of the diet, in order to simulate the form of tin likely to be found in canned food. The iron content of the diets was maintained at 70 ppm (0.007%), but for the F2generation onwards was increased to 140 ppm (0.014%). A teratogenicity study was carried out with 20 females/group of the F2bgeneration. Rats from F3band F3cgenerations were submitted to clinical and pathological examination. There was no effect on fertility of females, number of young born per litter and body weight. There was a decrease in body weight gain during lactation that was related to the tin content of the diet. The mortality of F2generation litters during the first 10 days of lactation was higher than controls, but decreased following an increase in iron in the diet. Haematological studies showed that there was a marked decrease in haemoglobin in the pups at weaning age, that was related to the tin content of the diet. After weaning, haemoglobin content returned to normal. Microscopic changes were observed in the liver and spleen in the F3bpups at weaning but were not observed in young at 4 weeks of age. A visceral and skeletal examination of the F2bgeneration rats did not show any tin-related teratogenic effects. The growth of the parent rats was not adversely affected in any generation.