Tin dioxide

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Link to relevant study records

Reference

Reference 1

Endpoint:

screening for reproductive / developmental toxicity

Data waiving:

study scientifically not necessary / other information available

Justification for data waiving:

the study does not need to be conducted because a two- (or multi-) generation reproductive toxicity study is available

Reason / purpose for cross-reference:

data waiving: supporting information

Reproductive effects observed:

not specified

Reference 2

Endpoint:

multi-generation reproductive toxicity

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

data from handbook or collection of data

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.

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

Species:

rat

Strain:

other: CPB:WU

Sex:

male/female

Details on test animals or test system and environmental conditions:

No data

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.

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

Dose / conc.:

0 mg/kg bw/day (nominal)

Remarks:

nominal in diet

Dose / conc.:

200 mg/kg bw/day (nominal)

Remarks:

nominal in diet

Dose / conc.:

400 mg/kg bw/day (nominal)

Remarks:

nominal in diet

Dose / conc.:

800 mg/kg bw/day (nominal)

Remarks:

nominal in diet

No. of animals per sex per dose:

no data

Control animals:

yes, concurrent no treatment

Details on study design:

No data

Positive control:

no data

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

Clinical signs:

no effects observed

Mortality:

no mortality 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: oestrous cycle:

not specified

Reproductive function: sperm measures:

not specified

Reproductive performance:

no effects observed

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

Dose descriptor:

NOAEC

Effect level:

800 mg/kg diet

Based on:

test mat.

Sex:

male/female

Remarks on result:

not determinable due to absence of adverse toxic effects

Dose descriptor:

dose level:

Effect level:

625 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

female

Basis for effect level:

clinical signs

mortality

body weight and weight gain

Remarks on result:

not determinable due to absence of adverse toxic effects

Critical effects observed:

no

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

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

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.

Reproductive effects observed:

not specified

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:

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 simulate the “form of the tin likely to be found in canned food,” tin(II) chloride was allowed to react in aqueous medium with the casein content of the diet. Tin did not affect growth of the parents, fertility, numbers of offspring per litter, or birth weight. Tin did not affect numbers of offspring per litter or birth weight. Increased mortality of F2 offspring 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 study 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.

Reference 3

Endpoint:

multi-generation reproductive toxicity

Type of information:

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

Adequacy of study:

key study

Justification for type of information:

1. HYPOTHESIS FOR THE ANALOGUE APPROACH
The main assumption for this read across approach is that the source substance ionic Tin and the target substance Tin (IV) dioxide NP have a common moiety (Tin ion).
Differences in the valence of atom Sn are expected to exert little effect on the physicalchemical properties of Tin (II) oxide and Tin (IV) dioxide NP, which indicates their toxicokinetic profile should 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). In addition, soluble inorganic tin like Tin (IV) chloride, Tin (II) fluoride, and Tin (II) chloride with higher water solubility and content of halogen is more toxic than insoluble tin oxides, regardless the dimension. It has to be noted that Tin dioxide bulk form and the Tin Dioxide NP are both highly insoluble in water. This support a read-across argument.

2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
Please refer to test item sections for details.
3. ANALOGUE APPROACH JUSTIFICATION
A reliable teratogenicity study is available for the source substance ionic Tin (II), showing that Tin (as 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. Since the target and the source substance dissociate to the same ion, both target and read-across substance, do share the same toxicological mechanisms and the effects of the target substance is predicted to be equal to the effects of the source substance.
Since Tin (II) salts are more readily absorbed than Tin (IV) NP and Tin (II) may be a bit more toxic than Tin (IV) NP, it is concluded that Tin (II) can be used as surrogate for Tin (IV) NP in assessing reproduction and developmental toxicity.
(see also document attached).

Reason / purpose for cross-reference:

read-across source

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

Limit test:

no

Specific details on test material used for the study:

SOURCE OF TEST MATERIAL
- Source and lot/batch number of test material:
2012-000203
- Expiration date of the lot/batch:
07/02/2013, W0167
- Purity test date:
> 99.9%, 23/01/2011

INFORMATION ON NANOMATERIALS
- Chemical Composition:
Tin Dioxide
- Density:
6.936 g/cm³
- Particle size & distribution:
10-100 nm; 78
- Specific surface area: 7.4293 ± 0.0132 m²/g

Clinical signs:

no effects observed

Mortality:

no mortality 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: neoplastic:

not specified

Other effects:

not specified

Reproductive function: oestrous cycle:

not specified

Reproductive function: sperm measures:

not specified

Reproductive performance:

no effects observed

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

Dose descriptor:

NOAEC

Effect level:

800 mg/kg diet

Based on:

test mat.

Sex:

male/female

Remarks on result:

not determinable due to absence of adverse toxic effects

Dose descriptor:

dose level:

Effect level:

625 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

female

Basis for effect level:

clinical signs

mortality

body weight and weight gain

Remarks on result:

not determinable due to absence of adverse toxic effects

Critical effects observed:

no

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

In the study, tin did not affect numbers of offspring per litter or birth weight. Increased mortality of F2 of-spring 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 in-crease in the incidence of fetal malformations

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.

Reproductive effects observed:

not specified

Effect on fertility: via oral route

Dose descriptor:

NOAEL

40 mg/kg bw/day

Additional information

From existing studies of toxicokinetic behaviour of Tin (IV) dioxide and Tin (II) chloride, it can be concluded that the toxicokinetic profiles of the 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) chloride can be used as a structural surrogate for Tin (IV) dioxide in the reproductive toxicity study.

In a multigeneration study, CPB:WU rats were given tin in the diet at 0, 200, 400, or 800 mg/kg (as Tin (II) chloride) for three generations. From the test, Tin did not affect growth of the parents, fertility, numbers of offspring per litter, or birth weight (WHO, 2005). Therefore the NOAEL of Tin (IV) dioxide was considered to be 800 mg/kg in diet for rat (NOEC_{mammal, food_repro.}). According to REACH guidance “Guidance on information requirements and chemical safety assessment Chapter R.10: Characterisation of dose [concentration]-response for environment” the NOAEL_{mammal, food_chr}= NOEC_{mammal, food_chr}/ CONV_mammal(CONVmammal for Rattus norvegicus (> 6 weeks) was default as 20). The NOAEL_repro of Tin (IV) dioxide to rat, 40 mg/kg bw per day can be estimated by above method.

Short description of key information:
Tin did not affect growth of the parents, fertility, numbers of offspring per litter, or birth weight at level of 800 mg/kg (as Tin II) in diet.

Effects on developmental toxicity

Description of key information

Groups of 9–10 female Sprague-Dawley rats were given diets containing tin at 0, 125, 156, 250, 312, 500, or 625 mg/kg (as tin salts (SnF2, NaSn2F5, NaSn2Cl5) throughout pregnancy (to day 20).  At these doses, the stannous (Tin II) has no teratogenic effect to rats. 

Link to relevant study records

Reference

Reference 1

Endpoint:

developmental toxicity

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: see 'Remark'

Remarks:

Published literature fulfilled basically scientific principles. 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 did not 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 pre natal toxicity study is feasible.

Qualifier:

no guideline followed

Principles of method if other than guideline:

Sprague-Dawley rats were given diets containing tin at 125 - 625 mg/kg (SnF2, NaSn2F5, NaSn2Cl5) throughout pregnancy (to day 20) to figure out the prenatal toxicity of tin and fluorion.

GLP compliance:

no

Remarks:

Publication

Limit test:

no

Species:

rat

Strain:

Sprague-Dawley

Details on test animals or test system and environmental conditions:

Weanling female rats of Sprague-Dawley derivation 2 were housed individually in screened-bottom galvanized cages and fed a low fluoride basal dietat libitum.

Route of administration:

oral: feed

Vehicle:

unchanged (no vehicle)

Details on exposure:

Each salt was blended with about 50 times its weight of this starch, and micropulverized. Sodium fluoride and stannous fluoride in the proper molar ratio (1:2) and sodium pentachlorostannite, were control salts for sodium pentafluorostannite. In addition, one diet was made with added sodium chloride to control for the sodium contributed by the highest level of sodium fluoride (242 ppm sodium)

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

All fluoride- and tin-containing test salts and sodium chloride were ground in a mortar and pestle and triturated in partially hydrolyzed cornstarch to ensure adequate distribution in the diets. After formulation, the diets were analyzed for fluoride and tin. The added amounts and analytical data for tin and fluoride are compared in table 1 -refer to section "Any other information on materials and methods inl.tables". Agreement between the added and analyzed fluoride levels improved as the levels of fluoride in the diets increased.
Tin levels in diets, placentas, and fetuses were determined by emission spectroscopy. Samples of diets or individual fetuses were placed in Vycor dishes, concentrated nitric acid was added, and the samples were charred. Following complete combustion of the organic material, the sample was mixed with ultra-pure graphite and lithium carbonate buffer, placed in a graphite electrode, and excited using the standard Stallwood Jet method of excitation. The lower limit of detection of the method was 0.5 ppm tin in the diets and 0.05 ppm tin in the fetuses and placentas.

Details on mating procedure:

no detailed information is available.
Mating was indicated by the detection of sperm in the daily vaginal smear.

Duration of treatment / exposure:

throughout pregnancy (From day 0 to day 20)

Frequency of treatment:

dietary every day

Duration of test:

no data

Dose / conc.:

156 mg/kg bw/day (nominal)

Dose / conc.:

125 mg/kg bw/day (nominal)

Dose / conc.:

250 mg/kg bw/day (nominal)

Dose / conc.:

312 mg/kg bw/day (nominal)

Dose / conc.:

500 mg/kg bw/day (nominal)

Dose / conc.:

625 mg/kg bw/day (nominal)

No. of animals per sex per dose:

groups of 9–10 female rats

Control animals:

yes, concurrent no treatment

Details on study design:

At day 20 of pregnancy, the females were decapitated and bled. The fetuses were removed, weighed and frozen individually on dry ice. Placentas were similarly collected. Implantation sites in each uterus were counted and reabsorptions calculated. The frozen samples were stored prior to analysis for tin and fluoride.

Maternal examinations:

Food and water intakes and body weight changes were observed during test.

Ovaries and uterine content:

The ovaries and uterine content was examined after termination: Yes / No / No data
Examinations included:
- Gravid uterus weight: yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes

Fetal examinations:

No. of live fetuses per litter, average fetal weight, and average placental weight were observed.

Statistics:

Statistically significant effects of test salts and test salt level were determined by two-way analysis of variance of the values for the animals in relevant groups. Duncan's multiple range test was used to determine statistically significant differences between individual means at the 95% confidence level.

Indices:

No data

Historical control data:

no data

Details on maternal toxic effects:

Maternal toxic effects:yes. Remark: Less food consumed and less body weight gain

Details on maternal toxic effects:
The rats fed the highest level of sodium pentafluorostannite consumed significantly (P < 0.05) less food in the first 7 days of gestation than animals fed the lowest level of this salt. The total 20-day food intake of the rats fed the highest level of each test salt was less than that of the rats fed the lowest level. The net weight gain of the rats fed the highest level of stannous fluoride was significantly (P < 0.05) lower than that of the rats in any other group.

Dose descriptor:

NOAEL

Effect level:

625 mg/kg diet

Based on:

test mat.

Basis for effect level:

other: developmental toxicity

Remarks on result:

not determinable due to absence of adverse toxic effects

Fetal body weight changes:

no effects observed

Details on embryotoxic / teratogenic effects:

Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
The greatest number of foetal resorptions was found in groups fed sodium pentafluorostannite, but the observation was not considered toxicologically significant. There were no effects on the numbers of litters, resorptions, or live fetuses per litter. Mean placental and fetal weights were also unaffected.

Key result

Dose descriptor:

NOAEL

Effect level:

625 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

female

Basis for effect level:

fetal/pup body weight changes

changes in litter size and weights

Remarks on result:

not determinable due to absence of adverse toxic effects

Abnormalities:

no effects observed

Developmental effects observed:

no

Lowest effective dose / conc.:

625 mg/kg bw/day (nominal)

Conclusions:

From the test, it can be concluded that the stannous (Tin II) has no teratogenic effect to rats. Based on existing information, tin (IV) is of lower toxic than Tin II. Therefore the substance tin dioxide has no developmental or teratogenic concern to animals or human.

Executive summary:

When groups of 9–10 female Sprague-Dawley rats were given diets containing tin at 0, 125, 156, 250, 312, 500, or 625 mg/kg (as tin salts (SnF2, NaSn2F5, NaSn2Cl5) throughout pregnancy (to day 20). Untreated rats had foetuses containing 0.64 mg Sn/kg. Foetal tin values were found to be elevated (0.8-1.3 mg Sn/kg) when the maternal diets contained tin salts. The greatest number of foetal resorptions was found in groups fed sodium pentafluorostannite, but the observation was not considered toxicologically significant. There were no effects on the numbers of litters, resorptions, or live fetuses per litter. Mean placental and fetal weights were also unaffected (Theuer et al., 1971).

Reference 2

Endpoint:

developmental toxicity

Type of information:

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

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Justification for type of information:

1. HYPOTHESIS FOR THE ANALOGUE APPROACH
The main assumption for this read across approach is that the source substance ionic Tin and the target substance Tin (IV) dioxide NP have a common moiety (Tin ion).
Differences in the valence of atom Sn are expected to exert little effect on the physicalchemical properties of Tin (II) oxide and Tin (IV) dioxide NP, which indicates their toxicokinetic profile should 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). In addition, soluble inorganic tin like Tin (IV) chloride, Tin (II) fluoride, and Tin (II) chloride with higher water solubility and content of halogen is more toxic than insoluble tin oxides, regardless the dimension. It has to be noted that Tin dioxide bulk form and the Tin Dioxide NP are both highly insoluble in water. This support a read-across argument.

2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
Please refer to test item sections for details.
3. ANALOGUE APPROACH JUSTIFICATION
A reliable teratogenicity study is available for the source substance ionic Tin (II), showing that Tin (as Tin II) did not affect growth of the parents, fertility, numbers of offspring per litter, or birth weight at level of 800 mg/kg in diet.
Since the target and the source substance dissociate to the same ion, both target and read-across substance, do share the same toxicological mechanisms and the effects of the target substance is predicted to be equal to the effects of the source substance.
Since Tin (II) salts are more readily absorbed than Tin (IV) NP and Tin (II) may be a bit more toxic than Tin (IV) NP, it is concluded that Tin (II) can be used as surrogate for Tin (IV) NP in assessing reproduction and developmental toxicity.
(see also document attached).

Reason / purpose for cross-reference:

read-across source

Qualifier:

no guideline followed

Principles of method if other than guideline:

Sprague-Dawley rats were given diets containing tin at 125 - 625 mg/kg (SnF2, NaSn2F5, NaSn2Cl5) throughout pregnancy (to day 20) to figure out the prenatal toxicity of tin and fluorion.

GLP compliance:

no

Remarks:

pubblication

Limit test:

no

Details on maternal toxic effects:

Maternal toxic effects:yes. Remark: Less food consumed and less body weight gain

Details on maternal toxic effects:
The rats fed the highest level of sodium pentafluorostannite consumed significantly (P < 0.05) less food in the first 7 days of gestation than animals fed the lowest level of this salt. The total 20-day food intake of the rats fed the highest level of each test salt was less than that of the rats fed the lowest level. The net weight gain of the rats fed the highest level of stannous fluoride was significantly (P < 0.05) lower than that of the rats in any other group.

Dose descriptor:

NOAEL

Effect level:

625 mg/kg diet

Based on:

test mat.

Basis for effect level:

other: developmental toxicity

Remarks on result:

not determinable due to absence of adverse toxic effects

Fetal body weight changes:

no effects observed

Details on embryotoxic / teratogenic effects:

Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
The greatest number of foetal resorptions was found in groups fed sodium pentafluorostannite, but the observation was not considered toxicologically significant. There were no effects on the numbers of litters, resorptions, or live fetuses per litter. Mean placental and fetal weights were also unaffected.

Key result

Dose descriptor:

NOAEL

Effect level:

625 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

female

Basis for effect level:

fetal/pup body weight changes

changes in litter size and weights

Remarks on result:

not determinable due to absence of adverse toxic effects

Abnormalities:

no effects observed

Developmental effects observed:

no

Lowest effective dose / conc.:

625 mg/kg bw/day (nominal)

Effect on developmental toxicity: via oral route

Dose descriptor:

NOAEL

31.3 mg/kg bw/day

Additional information

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 pre natal toxicity study is feasible.

When groups of 9–10 female Sprague-Dawley rats were given diets containing tin at 0, 125, 156, 250, 312, 500, or 625 mg/kg (as tin salts (SnF2, NaSn2F5, NaSn2Cl5)) throughout pregnancy (to day 20). Untreated rats had foetuses containing 0.64 mg Sn/kg. Foetal tin values were found to be elevated (0.8-1.3 mg Sn/kg) when the maternal diets contained tin salts. The greatest number of foetal resorptions was found in groups fed sodium pentafluorostannite, but the observation was not considered toxicologically significant. There were no effects on the numbers of litters, resorptions, or live foetuses per litter. Mean placental and foetal weights were also unaffected (Theuer et al., 1971). Therefore the NOAEL of Tin (IV) dioxide was considered to be 625 mg/kg in diet for rat (NOEC_{mammal, food_develop.}). According to REACH guidance “Guidance on information requirements and chemical safety assessment Chapter R.10: Characterisation of dose [concentration]-response for environment” the NOAEL_{mammal, food_chr}= NOEC_{mammal, food_chr}/ CONV_mammal(CONVmammal for Rattus norvegicus (> 6 weeks) was default as 20). The NOAEL_develop of Tin (IV) dioxide to rat, 31.3 mg/kg bw per day can be estimated by above method.

In a multigeneration study, CPB:WU rats were given tin in the diet at 0, 200, 400, or 800 mg/kg (as Tin(II) chloride)

for three generations. Within this multigeneration study, a teratogenicity study was carried out using 20 F2b females per dose level. On visceral and skeletal examination, there was no increase in the incidence of foetal malformations (WHO, 2005). Based on above information, it can be concluded that the stannous (Tin II) has no teratogenic effect to rats. Based on existing information, the tin (IV) is lower toxic than Tin (II). Therefore the substance tin dioxide has no developmental or teratogenic concern to animals or human.

Justification for classification or non-classification

Based on existing information, the substance is not to be classified under Regulation (EC) No 1272/2008 for any category of Reproductive/developmental toxicity. For the same reason it does not satisfy with the classification criteria of Directive 67/548/EEC.