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Effects on fertility

Description of key information
Data from the repeated dose studies on the dimethyltin dichloride.
Link to relevant study records
Reference
Endpoint:
toxicity to reproduction
Adequacy of study:
supporting study
Data waiving:
other justification
Justification for data waiving:
other:
Reproductive effects observed:
not specified
Effect on fertility: via oral route
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
10 mg/kg bw/day
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

Data from reproductive studies indicated that the behavioral and physiological aspects of mating, fertilization and implantation of fertilized ova were unaffected by dimethyltin chloride when compared to control rats in these studies. These data support the conclusion that the DMTC does not adversely affect fertility in rats.


Short description of key information:
Dimethyltin dichloride was fetotoxic. Dimethyltin dichloride did not adversely affect fertility nor was it teratogenic.

Effects on developmental toxicity

Description of key information
Dimethyltin chloride was tested in two teratology studies under full or partial gestational exposures. Two Developmental Neurotoxicity (DNT) studies on the chloride are also available
Effect on developmental toxicity: via oral route
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
1.16 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Quality of whole database:
Two reliable key studies were available for this endpoint. The Noda (2001) was a more typical developmental study, similar to the OECD 414 guideline, whereas the Ehman (2007) paper focussed specifically on neurotoxicity. One supporting study was available, but without sufficient detail to be a reliable study. The overall quality of the database is therefore considered to be high.
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

Two developmental neurotoxicity studies (Ehman, 2007) were conducted with dimethyltin dichloride administered in drinking water at 3, 15 and 75 ppm. In the first study, female Sprague–Dawley rats were exposed 2 weeks prior to mating and throughout mating, gestation and lactation. Male offspring were compared to controls for differences in: 1) pre-weaning learning in an associative runway task, 2) motor activity ontogeny, 3) spatial learning and retention in the Morris water maze as adults, 4) brain weight, 5) biochemical evidence of apoptosis, and 6) neuropathology. Maternal toxicity was expressed as decreased maternal weight gain and decreased fluid intake. Only in the first of the two studies was developmental toxicity expressed as minimal to slight brain histopathology vacuolization of F1 adults at all doses, decreased brain weights, and one of several neurobehavioral end points was altered.

In the second study, exposure to timed pregnant Sprague–Dawley rats occurred via drinking water from gestational day 6 to weaning and a similar battery of behavioral tests was administered to the F1 animals. The high concentration again depressed maternal weight gain and fluid intake. The F1 animals at the high dose had lower weight only during lactation, not thereafter. There was decreased brain weight but no correlating adverse histopathological findings in high-dose offspring. No significant differences in motor activity or in the spontaneous alteration activity test occurred as the result of treatment. Statistically significant learning deficits were not observed in the runway test, but a difference from controls was observed in mid-dose animals only in the water maze test.

The results of both studies demonstrate a lack of dose-response in spatial learning after perinatal DMT exposure. Changes in brain weight, and the occurrence of neuropathological lesions in offspring at the high dose indicate a potential for neurotoxicity of DMT at a maternally toxic dose. Histopathological alterations of minimal to slight severity in the brain of offspring of dams exposed to DMT in Experiment 1 were noted in the cerebral cortex of rats sacrificed at PND22 and as adults. These lesions were not observed in Experiment 2 in any brain region. The NOAEL was determined to be 15 ppm (equivalent to 1.16-2.67 mg/kg/day).

In the first teratology study (Noda, 2001), animals were treated on gestational days 7 -17. Vaginal bleeding, tremor and convulsions were observed in animals treated at 20 mg/kg/day after day 15 of gestation. Of ten dams treated with 20 mg/kg/day, two died and one exhibited total resorption. While an increase in the incidence of cleft palate was observed in fetuses of animals treated with 20 mg/kg/day DMTC, the dams so treated exhibited severe clinical signs of toxicity. Animals treated in the second study with doses of 20 or 40 mg/kg/day at one of four periods of gestation had a reduction in the adjusted body weight gain but not in gravid uterus weight and did not have an increase in the incidence of cleft palate or show any other evidence of a teratogenic effect at either dose or for any gestational period tested. These studies suggest that DMTC did not produce teratogenic effects at dose levels where no maternal toxicity was observed. It was suggested that under the conditions of the first study, since no signs of maternal or fetal toxicity could be detected up 10 mg/kg/day DMTC, this dose was chosen to represent the NOAEL.


Justification for selection of Effect on developmental toxicity: via oral route:
The NOAEL value from the Ehman (2007) paper was selected as the key value on a worst case basis.

Toxicity to reproduction: other studies

Additional information

Data from the repeated dose studies on the dimethyltin dichloride indicate no gross or histopathological effects on the reproductive tract of either sex.

Justification for classification or non-classification

These data support the conclusion that dimethyltin dichloride (DMTC) is fetotoxic. In this study severe maternal toxicity occurred at the high dose of 20 mg/kg/day. These maternal effects included two deaths [20%]; vaginal bleeding, tremors and convulsions [30%], ataxia and other clinical signs of toxicity [100%]. Fetotoxic responses observed at the high dose included total litter resorptions, cleft palate, and significantly decreased fetal body weight. The cleft palate observed at the 20 mg/kg/day dose was classified as a fetotoxic response, not a teratogenic response, because it occurred in the presence of severe maternal and fetal toxicity only after exposure for the full organogenesis period of gestation and was not observed when dosing was limited to 3-day segments of the organogenesis period, even when the 3-day segment of organogenesis included the ”sensitive” period for palate development. This outcome supports the conclusion that DMTC is not teratogenic, and that the cleft palates observed are fetotoxic responses.