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Key value for chemical safety assessment

Effects on fertility

Link to relevant study records
Reference
Endpoint:
three-generation reproductive toxicity
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Remarks:
no GLP
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 416 (Two-Generation Reproduction Toxicity Study)
Deviations:
not specified
GLP compliance:
not specified
Limit test:
no
Species:
rat
Strain:
other: CPB: WU randomly bred
Details on species / strain selection:
n.a.
Sex:
male/female
Details on test animals or test system and environmental conditions:
n.a.
Route of administration:
oral: feed
Vehicle:
not specified
Details on exposure:
-
Details on mating procedure:
-
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
-
Duration of treatment / exposure:
no data
Frequency of treatment:
no data
Dose / conc.:
0 other: ppm Sn in diet
Dose / conc.:
200 other: ppm Sn in diet
Dose / conc.:
400 other: ppm Sn in diet
Dose / conc.:
800 other: ppm Sn in diet
No. of animals per sex per dose:
no data
Control animals:
yes
Details on study design:
-
Positive control:
-
Parental animals: Observations and examinations:
-
Oestrous cyclicity (parental animals):
-
Sperm parameters (parental animals):
-
Litter observations:
-
Postmortem examinations (parental animals):
-
Postmortem examinations (offspring):
-
Statistics:
-
Reproductive indices:
-
Offspring viability indices:
-
Clinical signs:
no effects observed
Description (incidence and severity):
-
Description (incidence and severity):
-
Mortality:
no mortality observed
Description (incidence):
-
Body weight and weight changes:
no effects observed
Description (incidence and severity):
-
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
-
Food efficiency:
no effects observed
Description (incidence and severity):
-
Water consumption and compound intake (if drinking water study):
no effects observed
Description (incidence and severity):
-
Ophthalmological findings:
no effects observed
Description (incidence and severity):
-
Haematological findings:
no effects observed
Description (incidence and severity):
-
Clinical biochemistry findings:
no effects observed
Description (incidence and severity):
-
Urinalysis findings:
no effects observed
Description (incidence and severity):
-
Behaviour (functional findings):
no effects observed
Description (incidence and severity):
-
Immunological findings:
no effects observed
Organ weight findings including organ / body weight ratios:
no effects observed
Description (incidence and severity):
-
Histopathological findings: non-neoplastic:
no effects observed
Description (incidence and severity):
-
Histopathological findings: neoplastic:
not examined
Description (incidence and severity):
-
Other effects:
no effects observed
Description (incidence and severity):
-
Reproductive function: oestrous cycle:
no effects observed
Description (incidence and severity):
-
Reproductive function: sperm measures:
no effects observed
Description (incidence and severity):
-
Reproductive performance:
no effects observed
Description (incidence and severity):
-
-
Key result
Dose descriptor:
NOAEL
Effect level:
ca. 800 other: ppm Sn diet
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: no effect reported
Remarks on result:
not determinable due to absence of adverse toxic effects
Key result
Critical effects observed:
no
Clinical signs:
no effects observed
Description (incidence and severity):
-
Description (incidence and severity):
-
Mortality:
no mortality observed
Description (incidence):
-
Body weight and weight changes:
no effects observed
Description (incidence and severity):
-
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
-
Food efficiency:
no effects observed
Description (incidence and severity):
-
Water consumption and compound intake (if drinking water study):
no effects observed
Description (incidence and severity):
-
Ophthalmological findings:
no effects observed
Description (incidence and severity):
-
Haematological findings:
no effects observed
Description (incidence and severity):
-
Clinical biochemistry findings:
no effects observed
Description (incidence and severity):
-
Urinalysis findings:
no effects observed
Description (incidence and severity):
-
Behaviour (functional findings):
no effects observed
Description (incidence and severity):
-
Immunological findings:
no effects observed
Description (incidence and severity):
-
Organ weight findings including organ / body weight ratios:
no effects observed
Description (incidence and severity):
-
Gross pathological findings:
no effects observed
Description (incidence and severity):
-
Neuropathological findings:
not examined
Description (incidence and severity):
-
Histopathological findings: non-neoplastic:
not examined
Description (incidence and severity):
-
Histopathological findings: neoplastic:
no effects observed
Description (incidence and severity):
-
Other effects:
no effects observed
Description (incidence and severity):
-
Details on results:
-
Reproductive function: oestrous cycle:
no effects observed
Description (incidence and severity):
-
Reproductive function: sperm measures:
no effects observed
Description (incidence and severity):
-
Reproductive performance:
no effects observed
Description (incidence and severity):
-
-
Key result
Dose descriptor:
NOAEL
Effect level:
ca. 800 other: ppm Sn diet
Based on:
test mat.
Basis for effect level:
other: no effect
Remarks on result:
not determinable due to absence of adverse toxic effects
Key result
Critical effects observed:
no
Clinical signs:
no effects observed
Description (incidence and severity):
-
Description (incidence and severity):
-
Mortality / viability:
no mortality observed
Description (incidence and severity):
-
Body weight and weight changes:
no effects observed
Description (incidence and severity):
-
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
-
Food efficiency:
no effects observed
Description (incidence and severity):
-
Water consumption and compound intake (if drinking water study):
no effects observed
Description (incidence and severity):
--
Ophthalmological findings:
not examined
Description (incidence and severity):
-
Haematological findings:
no effects observed
Description (incidence and severity):
-
Clinical biochemistry findings:
no effects observed
Description (incidence and severity):
-
Urinalysis findings:
no effects observed
Description (incidence and severity):
-
Sexual maturation:
no effects observed
Description (incidence and severity):
-
Organ weight findings including organ / body weight ratios:
no effects observed
Description (incidence and severity):
-
Gross pathological findings:
no effects observed
Description (incidence and severity):
-
Histopathological findings:
no effects observed
Description (incidence and severity):
-
Other effects:
no effects observed
Description (incidence and severity):
-
Behaviour (functional findings):
not examined
Description (incidence and severity):
--
Developmental immunotoxicity:
not examined
Description (incidence and severity):
-
-
Key result
Dose descriptor:
NOAEL
Generation:
F1
Effect level:
ca. 800 other: ppm Sn in diet
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: no effects observed
Remarks on result:
not determinable due to absence of adverse toxic effects
Key result
Critical effects observed:
no
Clinical signs:
no effects observed
Description (incidence and severity):
-
Mortality / viability:
no mortality observed
Description (incidence and severity):
-
Body weight and weight changes:
no effects observed
Description (incidence and severity):
-
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
-
Food efficiency:
no effects observed
Description (incidence and severity):
-
Water consumption and compound intake (if drinking water study):
no effects observed
Description (incidence and severity):
-
Ophthalmological findings:
not examined
Description (incidence and severity):
-
Haematological findings:
no effects observed
Description (incidence and severity):
-
Clinical biochemistry findings:
no effects observed
Description (incidence and severity):
-
Urinalysis findings:
no effects observed
Description (incidence and severity):
-
Sexual maturation:
no effects observed
Description (incidence and severity):
-
Organ weight findings including organ / body weight ratios:
no effects observed
Description (incidence and severity):
-
Gross pathological findings:
no effects observed
Description (incidence and severity):
-
Histopathological findings:
no effects observed
Description (incidence and severity):
-
Other effects:
no effects observed
Description (incidence and severity):
-
Behaviour (functional findings):
not examined
Description (incidence and severity):
-
Developmental immunotoxicity:
not examined
Description (incidence and severity):
-
-
Key result
Dose descriptor:
NOAEL
Generation:
F2
Effect level:
ca. 800 other: ppm Sn in diet
Based on:
test mat.
Sex:
not specified
Basis for effect level:
other: no effect
Remarks on result:
not determinable due to absence of adverse toxic effects
Key result
Critical effects observed:
no
Key result
Reproductive effects observed:
no

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 F2 generation 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 F3b pups at weaning but were not observed in young at 4 weeks of age. A visceral and skeletal examination of the F2b generation rats did not show any tin-related teratogenic effects.

The growth of the parent rats was not adversely affected in any generation (Sinkeldam et al., 1979).

Conclusions:
No teratogenic effects. The growth of the parent rats was not adversely affected in any generation.
Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
40 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

Sinkeldam (1979) investigated the reproductive effect of tin dichloride dihydrate in rats in a multi-generation study. The dose levels tested were 10, 20, and 40 mg tin/kg bw (nominal) administered via diet. Adverse effects were not observed in the dams. According to the authors there was no indications of any effects on the reproductive performance of rats, which could be regarded as deleterious. Therefore, the NOAEL was considered to be greater than 40 mg tin/kg bw (nominal) (reported in WHO, 1982).


Short description of key information:
NOAEL (male/female) > 40 mg tin/kg bw diet (nominal)

Justification for selection of Effect on fertility via oral route:
Conduct of study with the test item prior to establishment of current test guidelines, but the conduct of the study is otherwise equivalent or similar to OECD 416 (2001).

Effects on developmental toxicity

Description of key information
NOAEL (teratogenicity; rabbit) > 41.5 mg tin dichloride/kg diet (nominal; NOAEL for tin only: 26 mg/kg bw /day)
NOAEL (maternal toxicity; rabbit) > 41.5 mg tin dichloride/kg diet (nominal; NOAEL for tin only: 26 mg/kg bw /day)
Link to relevant study records
Reference
Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Remarks:
Reference is considered reliable with restrictions (conduct of study prior to establishment of current test guidelines, but the conduct of the study is otherwise equivalent or similar to OECD 414 (2001)) Restrictions/deviation/deficiencies in comparison to OECD TG 414: - purity of the test substance was not stated - each group should preferably contain approx. 20 female animals with implantation sites at necropsy, whereas in this study only 10 - 12 pregnant females were present in the groups. - test substance should be administered until the day prior to scheduled caesarean section. In this study the dosing was stopped eleven days before caesarean section. - body weight was neither recorded on the first day of dosing nor at least every 3 days during the dosing period. - food consumption was not recorded at three-day intervals and did not coincide with days of body weight determination. Food consumption appeared to be part of the clinical observations which were conducted daily. - gross pathological examination of the females consisted only of the examination of the urogenital tract. - uteri of non-pregnant females were not further examined (e.g. Salewski staining) to confirm the non-pregnant status - gravid uteri including the cervix were not weighed. - head examinations were not carried out - no data on clinical signs were provided. - age and individual weight of the animals were not given - no analysis of dose administered - data on number and percent of pre- and post-implantation losses were not given
Reason / purpose for cross-reference:
reference to same study
Reason / purpose for cross-reference:
reference to same study
Reason / purpose for cross-reference:
reference to same study
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Version / remarks:
Conduct of study prior to establishment of current test guidelines, but the conduct of the study is otherwise equivalent or similar to OECD 414 (2001). For details on deviations/deficiencies see technical dossier.
GLP compliance:
not specified
Remarks:
GLP was not compulsory at time of study conduct
Limit test:
no
Species:
rabbit
Strain:
other: dutch-belted
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Age: adult
- Weight (average per dose level; day 0; pregnant dams): control group: 1.99 kg; 0.42 mg/kg: 2.17 kg; 1.90 mg/kg: 2.35 kg; 8.90 mg/kg: 2.27 kg; 41.5 mg/kg: 2.42 kg: positive control: 2.39 kg
- Housing: individually housed in mesh bottom cages in temperature and humidity-controlled quarters
- Diet (ad libitum)
- Water (ad libitum): fresh tap water
Route of administration:
oral: gavage
Vehicle:
water
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:
Test substance was administered as a water solution.
Analytical verification of doses or concentrations:
not specified
Details on analytical verification of doses or concentrations:
no data
Details on mating procedure:
- Impregnation procedure: artificial insemination
On Day 0, each doe was given an injection of 0.4 mL of human chorionic gonadotropin (400 IU) via the marginal ear vein. Three hours later, each doe was inseminated artificially with 0.3 mL of diluted semen from a proven donor buck using approximately 20 x 10^6 motile sperm according to the procedure described by Vogin et al (Pharmacologist 11, 282 (1969)).
Duration of treatment / exposure:
Day 6 through Day 18
Frequency of treatment:
daily
Duration of test:
29 days
No. of animals per sex per dose:
Treatment groups: 15 - 17 mated females (11 - 12 pregnant females)
Control group: 14 mated females (10 pregnant females)
Control animals:
yes, concurrent vehicle
Details on study design:
- Positive control: 2.5 mg/kg 6-aminonicotinamide dosed on Day 9 (17 mated females received the positive control; 12 females were pregnant)
Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily
- Cage side observations checked: appearance and behaviour with particular attention to food consumption and weight

DETAILED CLINICAL OBSERVATIONS: No data

BODY WEIGHT: Yes
- Time schedule for examinations: Days 0, 6, 12, 18, and 29 of gestation

FOOD CONSUMPTION AND COMPOUND INTAKE: Yes
- Food consumption for each animal determined: Yes
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: No data

WATER CONSUMPTION AND COMPOUND INTAKE: No data

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 29
- Organs examined: urogenital tract
Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: No data
- Number of corpora lutea: Yes
- Number of implantation sites: Yes
- Number of resorption sites: Yes
- Numbers of live and dead foetuses were recorded
Fetal examinations:
- External examinations: Yes, all per litter (foetal sex, body weight of live foetuses and presence of external congenital abnormalities)
The live foetuses of each litter were then placed in an incubator for 24 hours for the evaluation of neonatal survival. All surviving pups were sacrificed, and all pups were further examined as follows:
- Soft tissue examinations: Yes
- Skeletal examinations: Yes
- Head examinations: No data
Statistics:
no data
Indices:
no data
Historical control data:
no data
Details on maternal toxic effects:
Maternal toxic effects:no effects

Details on maternal toxic effects:
The administration of up to 41.5 mg/kg bw of the test material to pregnant rabbits for 13 consecutive days had no clearly discernible effect on nidation or on maternal survival.
Dose descriptor:
NOAEL
Effect level:
> 41.5 mg/kg bw/day (nominal)
Based on:
test mat.
Basis for effect level:
other: maternal toxicity
Dose descriptor:
NOAEL
Effect level:
> 26 mg/kg bw/day (nominal)
Based on:
element
Remarks:
tin, recalculated from the value of tin chloride
Basis for effect level:
other: maternal toxicity
Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
The administration of up to 41.5 mg/kg bw of the test material to pregnant rabbits for 13 consecutive days had no clearly discernible effect on foetal survival. The number of abnormalities seen in either soft or skeletal tissues of the test groups did not differ from the number occurring spontaneously in the sham-treated controls.
Dose descriptor:
NOAEL
Effect level:
> 41.5 mg/kg bw/day (nominal)
Based on:
test mat.
Basis for effect level:
other: teratogenicity
Dose descriptor:
NOAEL
Effect level:
> 26 mg/kg bw/day (nominal)
Based on:
element
Remarks:
tin, recalculated from the value of tin chloride
Basis for effect level:
other: teratogenicity
Abnormalities:
not specified
Developmental effects observed:
not specified
Conclusions:
NOAEL (maternal toxicity) > 41.5 mg/kg bw (nominal concentration)
NOAEL (teratogenicity) > 41.5 mg/kg bw (nominal concentration)
The administration of up to 41.5 mg/kg bw of the test material to pregnant rabbits for 13 consecutive days had no clearly discernible effect on nidation or on maternal or foetal survival. The number of abnormalities seen in either soft or skeletal tissues of the test groups did not differ from the number occurring spontaneously in the sham-treated controls.
Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
41.5 mg/kg bw/day
Study duration:
subacute
Species:
rabbit
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no study available
Additional information

Tin dichloride was tested in pregnant mice, rats, and hamsters for developmental toxicity (Anonymous, 1972). All three species were treated with 0.5, 2.3, 11.0, and 50.0 mg/kg (nominal) of the test material for 5 or 10 consecutive days (gestation day 6 through day 10 for hamsters; gestation day 6 through day 15 for mice and rats) by gavage. In addition to the groups treated with the test substance, a sham-exposed control group and a positive control group (aspirin) were also run. According to the author(s), the administration of up to 50 mg/kg bw of the test material (31 mg tin/kg bw/day) had no clearly discernible effect on nidation or on maternal or foetal survival. The number of abnormalities seen in either soft or skeletal tissues of the test groups did not differ from the number occurring spontaneously in the sham-treated controls. Therefore, the NOAEL for maternal toxicity and teratogenicity is greater than 50 mg/kg bw. Effects on maternal toxicity are poorly described, and there are minimal effects on maternal body weight. However, results relevant for foetal survival and visceral as well as skeletal effects are reasonably well documented, so that the studies are considered reliable with restrictions.

In another study of similar design, developmental effects of tin dichloride were investigated in pregnant rabbits (Anonymous, 1974). The rabbits were treated with 0.42, 1.90, 8.90, and 41.5 mg/kg (nominal) of the test item for 13 consecutive days (gestation days 6 through day 18) by gavage. A vehicle control group (water) and a positive control group (6-aminonicotinamide) were also run. According to the author(s), the administration of up to 41.5 mg/kg bw of the test material (26 mg tin/kg bw/day) had no clearly discernible effect on nidation or on maternal or foetal survival. The number of abnormalities seen in either soft or skeletal tissues of the test groups did not differ from the number occurring spontaneously in the sham-treated controls. Therefore, the NOAEL for maternal toxicity and teratogenicity is greater than 41.5 mg/kg bw. Effects on maternal toxicity are poorly described, and there are minimal effects on maternal body weight. However, results relevant for foetal survival and visceral as well as skeletal effects are reasonably well documented, so that the studies are considered reliable with restrictions.

In addition to the above mentioned studies, several supporting studies were identified:

- Sinkeldam (1979) described “a multi-generation reproduction study in rats with an incorporated developmental toxicity study with dose levels of 0, 200, 400 and 800 mg stannous chloride in the diet revealed transient adverse effects only at specific stages. These were a decrease in body weight gain during lactation, decreased haemoglobin in pups prior to weaning, and microscopic changes in the liver and spleen of pups of the F3b generation at weaning. The iron content in the diet for these pregnant rats was, respectively, 70 and 140 mg/kg feed, greater than the minimal adequate level of iron for adult non-pregnant rats (35 mg/kg feed). At the higher iron content in the feed the effects were less in the suckling pups. This led the investigators to the conclusion that the 70 mg iron/kg feed is a sub-optimal content for pregnant dams. No adverse effects were observed in the dams. Visceral and skeletal examination did not reveal any tin-related teratogenic effects (Sinkeldam et al, 1979a). As the effects in the pups seen in this study were transient and disappeared after the animals were weaned, the NOAEL can be established at 800 mg stannous chloride/kg feed which is equivalent to 40 mg/kg body weight (as also derived by the Scientific Committee on Food, Scientific Panel on Dietetic Products, Nutrition and Allergies February 2006, European Food Safety Authority, p. 470.).

- Theuer (1971) studied the developmental effects of tin fluoride in rats. Doses of 110 to 625 ppm tin were given to the animals via feed. The duration of treatment was 20 days ad libitum. A group receiving plain diet was used as control. According to the author, no effects were observed on the numbers of litters, resorptions, live foetuses per litter, mean placental and foetal weights.

- Lastly, Ridgway and Karnofsky (1952) tested the effect of tin dichloride on chicken embryos (White Leghorn chickens) by injections into the yolk or onto the chorioallantoic membrane (CAM). The embryos were eight days old. According to the authors, effects on teratogenicity were not observed. This reference is however considered not relevant for risk assessment, since the test system is considered unsuitable for the investigation of developmental effects.

Three further references relating to the developmental toxicity of tin compounds are regarded as unreliable and have been disregarded from the further assessment: Grin et al, 1988; El-Makawy, 2008; Wu et al. 1990. Please refer to the technical dossier for the rationales for disregarding these references.


Justification for selection of Effect on developmental toxicity: via oral route:
Conduct of study prior to establishment of current test guidelines, but the conduct of the study is otherwise equivalent or similar to OECD 414 (2001).

Justification for classification or non-classification

The potential for developmental toxicity of inorganic tin (II) salts was investigated with stannous chloride in four different species: mice, rats, golden hamsters and rabbits (FDRL, 1972 and 1974). The oral administration of up to 50 mg/kg bw of stannous chloride to pregnant females of all four species mice did not have any significant effect on fetal weight, number of live or dead fetuses and the incidence of skeletal or visceral malformations in the fetuses. Despite a lack of recording maternal toxicity in these studies, the upper range of doses used has been reported to elicit mild toxicity in adult rats such as reduced body weight (de Groot et al., 1973; Janssen et al., 1985) and reduced enzyme levels (Pfaff et al., 1980).

 

In a multi-generation reproduction feeding study with stannous chloride in rats incorporating a developmental toxicity study, the maximum dietary level corresponding to a dose of 40 mg tin/kg bw/d did not elicit any adverse effects in the dams, and there were no significant visceral or skeletal malformations (Sinkeldam, 1979).

In another, poorly documented study the administration of up to approximately 56 mg tin/kg/day (as tin fluoride) to rats on Gds 0–20 had no significant effect on average fetal weight or the number of live fetuses per litter (Theuer et al. 1971).

 

Despite the observed deviations in these studies from current guidelines for developmental toxicity testing, the overall absence of any adverse developmental effects in four different species is considered by weight-of-evidence to adequately justify no classification of inorganic tin(II) substances for developmental toxicity.

Additional information

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