Registration Dossier

Administrative data

Key value for chemical safety assessment

Effects on fertility

Description of key information

Since DOTE is only manufactured in situ with DOTE or DOTI and marketed typically as 2.5 -10 % solution

The evaluation of the toxicity to reproduction was based on three studies on the surrogate DOTE resp DOTI

The substances are structural annalogue (dioctyltin compounds) and show similar metabolites under simulated gastric conditions.

DOTE has been harmonized classified as Repro 1B. So this claiification is adopted for the the registered substance.

Additional Testing on a substance which is only manufactured and marketed with > 90 % of a CMR substance does not make sense

Whatever would be the result of an OECD TG 421/422 study, on pure DOTTG, it would not change the classification of the manufactured and marketed form of DOTTG.

Exposure considerations:

Since DOTTG is only manufactured, formulated and industrial used in a 2.5 - 10 % DOTE/DOTI solution the exposure during manufacturing and Formulation is neglgible due to closed process equipment and low volatility of the substance

During manufacturing of PVC articles DOTTG is complety transformed into its degradation product DOTEC

Thus an exposure of consumers and the environment can be excluded.

Effect on fertility: via oral route
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
1.5 mg/kg bw/day
Study duration:
chronic
Species:
rat
Quality of whole database:
The available study was conducted under GLP conditions and in accordance with a standardised guideline. Since the study was conducted with a mixture of the registered substance, Dioctyltin bis(IOMA) [CAS No. 26401-97-8] and Octyltin tris(IOMA) [CAS No. 26401-86-5] (78.8:16.9% ), rather than with the substance, as such, the study is regarded as a read-across data and was subsequently assigned a reliability score of 2 in line with the criteria of Klimisch (1997). Read-across is justified on the basis that Dioctyltin bis(IOMA) and dioctyltin bis(2-EHMA) are isomers of the same compound and are structural analogues of each other. Based on the recently conducted developmental toxicity studies in two species it is considered that DOTI is likely to be more toxicoligically active and therefore use of data on this substance would be considered to be a worst case assessment of the registered substance. The overall quality of the database is regarded as high.
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

In the two generation study performed under GLP and according to OECD 416 (1997), the mixture Dioctyltin bis(IOMA)[Cas No. 26401 -97 -8] :Octyltin tris(IOMA)[Cas No. 26401 -86 -5] (78.8:16.9%) were administered to the F0 generation 10 weeks prior to mating, during mating (3weeks) and post-mating. The F1 generation were treated 14 weeks during premating, 3 weeks during mating. Females continued to receive the test material during gestation and lactation. The following treatment-related effects were observed : F0 generation: 

- Mortality: 1 male died at 200 ppm diet

- Absolute food consumption reduced in females at 200 ppm diet (-6% on lactation days 7-14, -9% on lactation days 14-21)

- Viability index slightly reduced at 200 ppm (96.2% vs. 98.6% in the controls).

- Lactation index significantly decreased at 200 ppm diet (88.6% vs. 94.4% in controls) after 21 days lactation.

- Slight increase in pup mortality at 200 ppm diet.

- Pup body weights significantly decreased at 200 ppm diet in both sexes after 14 and 21 days lactation.

- Slight delay in vaginal opening at 200 ppm diet.

- Slight decrease in relative thymus weight in males at 60 ppm diet; significant decrease in relative thymus weight in both sexes at 200 ppm diet.

- Increased incidence of thymic involution at 200 ppm diet (significant for males only).

- Microscopic examination of the organs found no substance-related changes.

F1 generation:

- No mortality.

- Body weight: significant reduction in males at 200 ppm diet.

-Food consumption: reduced in females at 200 ppm diet; significant on lactation days 14-21.

-Increased number of stillbirths at 200 ppm diet (26 vs. 5 in controls).

- Viability index: decreased at 200 ppm (82.0% vs. 95.7% in controls).

- Pup mortality: increased at 200 ppm diet from day 4-21 of lactation.

- Lactation index: decreased at 200 ppm diet (82.3% vs. 94.4%).

- Pup body weight: significantly reduced at 200 ppm for males and females on days 4, 7, 14, and 21 of lactation.

- Morphological changes: pinna unfolding, eye and ear opening were slightly delayed at 200 ppm diet.

- Relative thymus weight: significantly decreased in males and females at 200 ppm diet and at 60 ppm for females only

- Relative spleen weight: significantly decreased in females at 200 ppm diet.

- Increased incidence of thymic involution at 200 ppm (significant for males).

The NOAEL for F0 males and females was 20 ppm diet (approx. 1.5 mg/kg bw/day) based on a slightly reduced relative thymus weight for males at 60 ppm (approx. 4.4 mg/kg bw/day). 

The NOAEL for the F1 generation was 20 ppm diet (approx. 1.6 mg/kg bw/day), based on a reduction in relative thymus weights for males and females at 60 ppm diet (approx. 4.7 mg/kg bw/day).

No teratogenic effects were observed in this study.


Short description of key information:
A two-generation study (1997) was performed using mixture of DOT(isooctythioglycolate, (CAS No. 26401-97-8)/Octyltin tris (IOMA) (CAS No. 26401-86-5)) (78.8:16.9% mixture). Dioctyltin bis (IOMA) and dioctyltin bis (2-EHMA) are isomers of the same compound and are structural analogues of each other. Based on the recently conducted developmental toxicity studies in two species it is considered that DOTI is likely to be more toxicoligically active and therefore use of data on this substance would be considered to be a worst case assessment of the registered substance.

Under the experimental conditions of this two generation study, the NOAEL for the F0 parental generation was 20 ppm (~1.5 mg/kg/bw), based on a reduction in the relative thymus weight of males at 60 ppm. The NOAEL for the F1 generation until weaning was 20 ppm (~1.6 mg/kg/bw/d), based on a decrease in relative thymus weight in male and female pups at 60 ppm. The NOAEL for the F1 generation post-lactation was 20 ppm, based on a slight decrease in the relative thymus weight of males and an increase in stillbirth at 60 ppm.

Justification for selection of Effect on fertility via oral route:
Only one study is avaiable.

Effects on developmental toxicity

Description of key information
> Key Studies
- Mouse
The NOAEL for maternal toxicity was determined to be 15 mg/kg based on a biologically relevant depression in thymus size at the 30 mg/kg dose. However, no treatment-related effects were noted in any of the developmental toxicity parameters investigated; therefore the NOAEL for developmental toxicity was concluded to be 60 mg/kg, the highest dose tested.
- Rabbit
The NOAEL for maternal toxicity was determined to be 20 mg/kg based on a biologically relevant depression in thymus weight at the 80 mg/kg dose. However, no treatment-related effects were noted in any of the developmental toxicity parameters investigated; therefore the NOAEL for developmental toxicity was concluded to be 80 mg/kg, the highest dose tested.
> Supporting Study
The NOAEL for maternal toxicity and embryofetal development in the rat study were set at 5 mg/kg/day (based on decrease in maternal body weight gain and increase in the percentage of dead fetuses at 25 mg/kg/day).
Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
15 mg/kg bw/day
Study duration:
subacute
Species:
mouse
Quality of whole database:
Two developmental toxicity studies were conducted with the substance itself, the studies are regarded as key studies; they were performed under GLP conditions and in accordance with strandardised guideline OECD 414. The key studies were assigned a reliability score of 1 in line with the criteria of Klimisch (1997). A single study is included as supporting information; the study was conducted with a mixture of Dioctyltin bis(IOMA) [CAS No. 26401-97-8]:Octyltin tris(IOMA) [CAS No. 26401-86-5] (80:20%). Information on the mixture is considered to be suitable for read across since DOT(2-EHMA) and DOT(IOMA) are isomers of the same compound and are structural analogues of each other. Based on the recently conducted developmental toxicity studies in two species it is considered that DOTI is likely to be more toxicoligically active and therefore use of data on this substance would be considered to be a worst case assessment of the registered substance.


The supporting study was performed under GLP conditions and followed a method similar to that which is outlined in the standardised guidelines and was subsequently assigned a reliability score of 2. The overall quality of the database is 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 key studies, investigating the developmental toxicity of the registered substance itself, are available; one study was conducted in mice and the other in rabbits. Both studies were performed under GLP conditions and in accordance with the standardised guideline OECD 414.

 

The purpose of the mouse study was to assess the effects of prenatal exposure of pregnant female Swiss mice and their developing foetuses to the test material when administered by oral gavage in a peanut oil vehicle at 5 mL/kg to the mated females from gestation day [GD] 5 to 17. In life examinations included checks for mortality and clinical signs of toxicity, body weight measurements and an evaluation of food consumption. All the animals were sacrificed on gestation day 18 by carbon dioxide exposure and subjected to detailed gross pathology; the gross pathology included a determination of thymus and liver size. The gravid uterus was collected by hysterectomy and foetuses were removed by caesarean section. Foetuses were subjected to external, soft tissue and skeletal examination.

No deaths were observed during the experimental period and there were no clinical signs recorded which were indicative of overt toxicity. There were no statistically significant differences in maternal body weights across the dose groups on any single gestation day. However, there was a clear dose-related pattern of reduced body weights beginning after GD6, the first day of dosing, and continuing for the duration of the study. The high dose was the most severely affected and a dose-related decrement relative to the control body weights can be seen across all doses particularly from GD16 to GD18. At 30 mg/kg the maternal weight effect was marginal, but maternal body weight gain in the 60 mg/kg high dose group was 11.5 [uncorrected] and 26.6 % [corrected] less than the vehicle control, a clear adverse effect. There was a treatment-related macroscopic finding of reduced maternal thymus weight.

The mean maternal thymus weight was statistically significantly reduced in the 30 mg/kg [mid] and 60 mg/kg [high] dose groups. The mean maternal thymus weight in the low dose mice was reduced relative to controls, but was not a statistically significant difference. No other gross pathological findings were noted in any dose group.

No treatment related effects were noted in mean gravid uterus weight, no. of corpora lutea, no. of implantations in all the groups, no. of early or late resorptions and percentage of post implantation loss.

No external abnormalities were noted during gross examinations of foetuses at any dose and no treatment-related abnormalities were observed during visceral examinations of foetuses at any dose.

Therefore, under the conditions of the study the NOAEL for maternal toxicity was determined to be 15 mg/kg based on a biologically relevant depression in thymus size at the 30 mg/kg dose. However, no treatment-related effects were noted in any of the developmental toxicity parameters investigated; therefore the NOAEL for developmental toxicity was concluded to be 60 mg/kg, the highest dose tested.

 

The purpose of the rabbit study was to assess the effects of prenatal exposure of pregnant female New Zealand White rabbits and their developing foetuses to the test material when administered by oral gavage in a peanut oil vehicle at 2 mL/kg to the mated females from gestation day [GD] 6 to 28. In life examinations included checks for mortality and clinical signs of toxicity, body weight measurements and an evaluation of food consumption. All the animals were sacrificed on gestation day 29 by iv injection of sodium thiopentone and subjected to detailed gross pathology; the gross pathology included a determination of thymus weight. The gravid uterus was collected by hysterectomy and foetuses were removed by caesarean section. Foetuses were subjected to external, soft tissue and skeletal examination.

No deaths or abortions were observed during the experimental period and there were no clinical signs recorded which were indicative of overt toxicity and there were no treatment related differences in average feed consumption or body weights observed at any dose. A total number of 19 (79 %), 21 (88 %), 19 (79 %) and 20 (83 %) mated females were confirmed pregnant in groups G1, G2, G3 and G4, respectively. Gross necropsy revealed a treatment-related effect on the thymus. The mean maternal thymus weight was reduced 5.1, 9.6, and 12.8 % in the 4 mg/kg [low], 20 mg/kg [mid], and 80 mg/kg [high] dose groups, respectively. No other gross pathological findings were noted in any dose group.

Investigation of reproduction parameters revealed no treatment related effects in any of the following: mean gravid uterus weight, number of corpora lutea, number of implantation sites, number of early or late resorptions, percentage of pre and post implantation loss, sex ratio, mean litter size, foetal weight or the number of live foetuses per doe across all the groups.

The mean foetal weights [combined sexes] were 36.6, 37.3, 35.5, and 32.3 grams for groups G1, G2, G3 and G4, respectively. Mean foetal weights were not statistically significantly different across the dose groups when compared to controls. However, at the high dose the mean foetal body weight is -11.9 % relative to controls which suggests a biologically-relevant, but marginal effect on foetal maturation. This however, was found to be disproportionately affected by a single litter in this group who had low body weights. The other litters in this group did not follow the same trend.

Foetal crown-rump length was statistically significantly different from the controls in the highest dose group. This result was affected by one litter in this group who had disproportionately low crown-rump lengths when compared to the other litters of this group. In addition, there were no correlating statistically significant differences for any other developmental parameter.

No external abnormalities were noted during gross examinations of foetuses at any dose and no treatment-related abnormalities were observed during visceral examinations of foetuses at any dose.

Therefore, under the conditions of the study the NOAEL for maternal toxicity was determined to be 20 mg/kg based on a biologically relevant depression in thymus weight at the 80 mg/kg dose. However, no treatment-related effects were noted in any of the developmental toxicity parameters investigated; therefore the NOAEL for developmental toxicity was concluded to be 80 mg/kg, the highest dose tested.

 

Supporting information is available in the form of an embryotoxicity and teratogenicity study which was conducted with a read across material, which was a mixture of Dioctyltin bis(IOMA) [CAS No. 26401-97-8]:Octyltin tris(IOMA) [CAS No. 26401-86-5] (80:20% mixture). Read across is considered justified on the basis DOT(2-EHMA) and DOT(IOMA) are isomers of the same compound and are structural analogues of each other. Based on the recently conducted developmental toxicity studies in two species it is considered that DOTI is likely to be more toxicologically active and therefore use of data on this substance would be considered to be a worst case assessment of the registered substance.

 

In this study dams were treated with mixture of DOT (IOTG) and MOT(IOTG) (80:20%) at 1, 5 and 25 mg/kg/day during day 6 -15 of gestation. Alopecia was observed in single animals of all four groups and was not attributed to treatment. There was a slight (non-significant) decrease in corrected body weight and corrected body weight gain from day 6 to day 21 at 25 mg/kg/day dose.  This reduction was attributed largely to one single dam. There was a statistically significant increase in the percentage of dead foetuses at 25 mg/kg/day. However, the seven dead foetuses concerned only one litter.  Though clear-cut effects were found in only one dam in 25 mg/kg/day dose group, the test substance was considered to induce marginal maternal toxicity at 25 mg/kg/day. The dose-level without maternal and/or embryofoetotoxicity was 5 mg/kg/day (equivalent to 0.77 mg Sn/kg b.w/day).

 

Disregarded studies

Two additional studies have been included in the substance dataset for the purpose of completeness however, both studies have been disregarded and the results from those studies are not included in the overall assessment of the developmental toxicity of the registered substance.

 

The study reported by Faqi (2001) failed to fulfil the requirements of a GLP OECD 414 guideline study since detailed information on the following were not included: maternal body weight, food consumption, housing, dosing, analysis of the dosing formulations or individual animals data. Furthermore, no information was given on foetal sex ratio, foetal weight per sex or internal malformations and no comparison to historical control data was carried out. The study was therefore considered to be deficient and the results are not taken forward for hazard classification.

 

The study reported by Battenfeld (1992) was also disregarded since it was not possible to interpret the results of the study based on the information presented in the study report. During the study maternal disease was reported; the disease that is described in the report is common in rabbits of the age and strain used in the study. It was not possible to ascertain whether maternal effects which were observed resulted from the disease or from treatment with the test material since detailed examination of the immune system are not included in developmental toxicity studies and were not included as part of this study. There was one case of torticollis, a symptom of encephalitozoonosis, a parasitic disease occurring in immunodeficient animals, which was reported. Since no effects were seen in the rangefinder study, at doses up to 30 mg/kg bw/day, the maternal findings observed in the main study were considered spurious. Overall the study was considered to be deficient and the results are not taken forward for hazard classification.


Justification for selection of Effect on developmental toxicity: via oral route:
Two devlopmental toxicity studies have been conducted using the substance itself as test material. The mouse study has been selected since the mouse was found to be the more sensitive species, generating the lower NOAEL.

Toxicity to reproduction: other studies

Additional information

Together with the data outlining the toxicological, endocrine and reproductive properties of dioctyltin compounds, two additional studies with Dichlorodioctylstannane (dioctyltin dichloride) are included for completeness since the substance was initially considered to be a relevant substance to use for read-across purposes since findings from a gastric hydrolysis study showed that DOT(2-EHMA) was readily hydrolysed to Dichlorodioctyltilstanane (CAS no.3542-36-7) under physiological conditions (see section 7.1.1). Thus DOTC(Dichlorodioctylstannane) was considered to be an appropriate anchor compound and surrogate for the mammalian toxicology endpoints of repeated dose, in vivo genetic toxicity, reproduction and developmental effects, when it is dosed via the oral route of administration.

Read-across to the substance DOTC is no longer considered as wholly appropriate based on the results of the recent Hydrolysis study, as reported by Naßhan, H, 2014 (see section 7.1.1) which indicate the substance DOTECl is the only metabolite of DOTE which is formed in a simulated mammalian gastric environment; no dioctyltindichloride was formed under the conditions of the study. The studies with DOTC have therefore been disregarded in the overall assessment of the registered substance with regards to reproductive and developmental toxicity.

Justification for classification or non-classification

There are no data to suggest that classification of the substance for either reproductive or developemental toxicity is required.

In accordance with the criteria for classification as defined in Annex I, Regulation (EC) No. 1272/2008 (CLP), the substance does not require classification with respect to either reproductive or developemental toxicity.

In accordance with the criteria for classification as defined in Annex VI, Directive 67/548/EEC (DSD), the substance does not require classification with respect to either reproductive or developmental toxicity.