2-ethylhexyl 10-ethyl-4,4-dimethyl-7-oxo-8-oxa-3,5-dithia-4-stannatetradecanoate

Developmental toxicity / teratogenicity

Administrative data

Endpoint:

developmental toxicity

Type of information:

migrated information: read-across based on grouping of substances (category approach)

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Preferred study for this SIDS endpoint. Methodology was similar to OECD Guideline 414; however, study was conducted using less than the recommended number of animals per dose group.

Data source

Reference

Reference Type:

publication

Title:

Maternal and fetal toxicity of dimethyltin in rats.

Author:

Noda, T.

Year:

2001

Bibliographic source:

Journal of Health Science. 47(6):544-551.

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 414 (Prenatal Developmental Toxicity Study)

Deviations:

not specified

GLP compliance:

not specified

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Dimethyltin dichloride

EC Number:

212-039-2

EC Name:

Dimethyltin dichloride

Cas Number:

753-73-1

Molecular formula:

C2H6Cl2Sn

IUPAC Name:

dimethyltin dichloride

Constituent 2

Reference substance name:

Stannane, dichlorodimethyl-

IUPAC Name:

Stannane, dichlorodimethyl-

Details on test material:

- Name of test material (as cited in study report): Dimethyltin chloride
- Molecular formula (if other than submission substance): C2H6Cl2Sn
- Molecular weight (if other than submission substance): 219.67 g/mol
- Smiles notation (if other than submission substance): C[Sn](C)(CL)CL
- Analytical purity: >99.0%
- Stability under test conditions: stable

Test animals

Species:

rat

Strain:

Wistar

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: CLEA Japan, Inc.
- Age at study initiation: 3 months
- Weight at study initiation:
- Housing: individually housed
- Diet (e.g. ad libitum): NMF; ad libitum
- Water (e.g. ad libitum): ad libitum


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 23 +/- 2 deg C
- Humidity (%): 60 +/-20%
- Photoperiod (hrs dark / hrs light): 12 hour light / 12 hour dark

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

other: Saline

Details on exposure:

PREPARATION OF DOSING SOLUTIONS: test substance dissolved in saline



VEHICLE
- Justification for use and choice of vehicle (if other than water): solubility
- Amount of vehicle (if gavage): 2 mL/kg

Analytical verification of doses or concentrations:

not specified

Details on analytical verification of doses or concentrations:

no data

Details on mating procedure:

- Impregnation procedure: cohoused
- If cohoused:
- M/F ratio per cage: 1:1
- Length of cohabitation: overnight
- Verification of same strain and source of both sexes: yes
- Proof of pregnancy: sperm in vaginal smear referred to as day 0 of pregnancy
- Any other deviations from standard protocol: less than the recommended number of animals per dose.

Duration of treatment / exposure:

days 7 - 17 of gestation- first study
days 7-9, 10-12, 13-15, or 16-17; on two or three consecutive days- second study

Frequency of treatment:

daily

Duration of test:

20 days

Doses / concentrations

Doses / concentrations 1

Remarks:

Doses / Concentrations:
5, 10, 15, and 20 mg/kg/day
Basis:
nominal conc.

Doses / concentrations 2

Remarks:

Doses / Concentrations:
20 and 40 mg/kg/day
Basis:
nominal conc.

No. of animals per sex per dose:

mated females were assigned to five groups of 10 rats each- first study
mated females were assigned to eight groups of 8-11 rats each- second study

Control animals:

yes, concurrent vehicle

Details on study design:

- Dose selection rationale: In the second study, higher doses were selected, at shorter periods of gestation, in order to reduce maternal toxicity
- Rationale for animal assignment (if not random): random

Examinations

Maternal examinations:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily


DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: daily


BODY WEIGHT: Yes
- Time schedule for examinations: daily


FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: No data
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: No data


WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No data


POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day # 20
- Organs examined: Maternal thymus  and brain weights

Ovaries and uterine content:

The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: Yes - in the second teratology study only
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes - total resorptins
- Number of late resorptions: Yes - total resorptions

Fetal examinations:

- External examinations: Yes: all per litter
- Visceral examinations: Yes: half per litter
- Skeletal examinations: Yes: half per litter
- Head examinations: No data

Statistics:

Fisher's exact test was used to analyze data on the number of dams with  living fetuses, number of dams with total resorptions, and the number of  malformed fetuses.  Other data were analyzed using Dunnett's (1964)  multiple comparison method in a parametric or non-parametric manner.  The  litter was used as the statistical unit for calculation of fetal values.

Indices:

no data

Historical control data:

no data

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:

Maternal toxic effects:yes

Details on maternal toxic effects:
First teratology study: There was a dose-dependent reduction of maternal  body weight gain of pregnant rats treated orally with the test substance during days  7-17 of gestation.  Maternal body weight gain was significantly reduced  in pregnant rats treated with 15 or 20 mg/kg/day of the test substance.  Maternal food  intake was also significantly reduced in animals treated with 20  mg/kg/day.  Changes in food intake were not significantly different in  pregnant rats in the remaining dose groups. Two animals receiving the test substance at 20 mg/kg/day died, one on day 18 of  gestation and the other on day 19 of gestation.  These animals exhibited clinical signs of toxicity, including piloerection, ataxia, perinasal and  periocular staining, vaginal bleeding, tremor, and convulsion for about  four days prior to death.  No gross pathological changes in the organs of the dead dams were noted at necropsy.  No other mortalities were observed  in either the control or test substance-treated groups. During the late treatment period, all animals at 20 mg/kg/day  showed clinical signs of toxicity, including perinasal and periocular  staining, piloerection, and ataxia.  Vaginal bleeding, tremor, and  convulsion were also observed in three pregnant animals from this group.   No clinical signs of toxicity were observed in the other treated  groups. There was a dose-dependent reduction in maternal thymus weights, with a  significant reduction at 15 and 20 mg/kg/day on day 20 of gestation.   Maternal brain weight was not affected in any treated group. Total resorption was observed in one of the eight living pregnant rats at 20 mg/kg/day on day 20 of gestation.  There was no significant  difference in the number of corpora lutea, number of implants, number of  living fetuses, or the incidence of post-implantation loss and sex ratio.

Second teratology study: Significant reductions in maternal body weight gain on days 13, 16, and 17 of gestation and food intake on the consecutive days of gestation after day 12, were reported for pregnant  rats exposed at 40 mg/kg/day on days 10-12 of gestation.   Maternal body weight gain was not significantly reduced in the other treated groups.  General behavior among groups, including the control group, was not significantly different. Maternal thymus weights and adjusted body weight gain in pregnant rats exposed to 20 mg/kg/day on days 10-12 and in every treatment group at 40 mg/kg/day were significantly reduced.  Gravid uterus and maternal body weights were not affected in either the 20 or 40 mg/kg/day groups. Total resorption was observed in one of 10 dams exposed to 40 mg/kg/day during days 7-9 of gestation.    No  significant differences were reported in the number of corpora lutea, implants, or living fetus.  The incidence of post-implantation loss, the sex ratio were not significant in any treatment group.   At 40 mg/kg/day, maternal body weight gain and maternal thymus weights were significantly reduced.   Maternal thymus weights and adjusted body weight gain were also significantly reduced at 20 mg/kg/day on days 10-12 of gestation.

Effect levels (maternal animals)

Dose descriptor:

NOAEL

Effect level:

10 mg/kg bw/day

Basis for effect level:

other: maternal toxicity

Results (fetuses)

Details on embryotoxic / teratogenic effects:

Embryotoxic / teratogenic effects:yes

Details on embryotoxic / teratogenic effects:
First teratology study: There was a dose-dependent reduction in mean body weight of living fetuses (both sexes), with significant reduction at 15 and 20 mg/kg/day. The incidence of external malformations increased in fetuses from dams  exposed at 20 mg/kg/day during days 7-17 of gestation.  There was a statistically significant increase in the number of fetuses with dilation of the renal pelvis from dams exposed to DMTC at 20 mg/kg/day during days 7-17 of gestation. Cleft palate was observed in 21 fetuses from five of seven pregnant rats with  living fetuses on day 20 of gestation.  In addition to cleft palate, one fetus was associated with general edema and pes varus, and one with  general edema. Omphalocele was observed in two fetuses from one dam exposed to 15 mg/kg/day; however, the incidence was not statistically significant.  No other external malformations were observed in either the control or treated groups. No other visceral malformations observed were statistically significant. No statistically significant difference in the incidence of skeletal malformations and skeletal variations were observed in either the control or treated groups.

Second teratology study: Mean fetal body weight was reduced in females from dams exposed to 40 mg/kg/day during days 7-9. The incidence of male fetal body weight was not significant in any treatment group. There was no significant increase in the incidence of external, skeletal, or visceral malformations at either 20 or 40 mg/kg/day.  Cleft palate was not observed in fetuses from dams exposed at 20 or 40 mg/kg/day on days 7-9, 10-12, 13-15, or 16-17 of gestation.  The numbers of fetuses with skeletal variations, cervical ribs, and/or splitting of the first cervical vertebral arch increased significantly in the groups treated  at 40 mg/kg/day on days 7-9 and/or days 13-15 of gestation.   Fetuses with kinked ureter significantly increased in the group treated  at 40 mg/kg/day on days 16-17 of gestation.

Effect levels (fetuses)

Dose descriptor:

NOAEL

Effect level:

10 mg/kg bw/day

Basis for effect level:

other: fetotoxicity

Fetal abnormalities

Abnormalities:

not specified

Overall developmental toxicity

Developmental effects observed:

not specified

Applicant's summary and conclusion

Conclusions:

The findings of the first teratology study suggest that dimethyltin dichloride was not teratogenic, but was toxic to dams and fetuses at 15 mg/kg/day.  In the second teratology study, a  no-observed-adverse-effect-level (NOAEL) for dams could not be  established.  Adverse effects to dams were reported at both 20 and 40  mg/kg/day on days 10-12 of gestation.  
The authors reported that under the conditions of the first teratological  study, the NOAEL for maternal and fetal toxicity was considered to be 10 mg/kg/day.

Executive summary:

The maternal and fetal toxicity of dimethyltin dichloride was examined in two teratological studies in pregnant Wistar rats. In one study, the animals were treated by oral gavage with the test substance at doses of 0, 5, 10, 15 or 20 mg/kg/day on gestational days 7 -17. In the second study, animals were treated by oral gavage at doses of 0, 20 or 40 mg/kg/day on two or three consecutive days at one of four different periods of gestation (gestational days 7 -9, 10 -12, 13 -15, or 16 -17). Caesarean sections were performed in day 20 of gestation in both studies. In the first study, 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 found in fetuses of animals treated with 20 mg/kg/day, 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 show any evidence of teratogenic effects at either dose and period tested. These studies suggest that the test substance 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 to 10 mg/kg/day, this dose was chosen to represent the no-observed-adverse-effect-level (NOAEL).