Registration Dossier

Administrative data

Key value for chemical safety assessment

Effects on fertility

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
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).


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)
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
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.