Registration Dossier

Administrative data

Description of key information

Since the target substance DOTTG is only manufactured in situ with DOTE and marketed typically as 2 -3 % solutions (max 10 %) The evaluation of the repeated dose toxicity was based on three studies on the source substance DOTE supported by data on the structural analgue DOTI

DOTE has been classified and harmonized as toxic for reproduction of category 1B (H360d) and the RAC (RAC 47, November 2018) has recently come to the opinion Aquatic Acute 1 (H400), Aquatic Chronic 1 (H410) and STOT RE 1 (H372) should be added to the Annex VI CLP.

The manufactures self-classify DOTE as Skin Sens. 1A (H317).

Furthermore DOTE has been prioritized for inclusion into Annex XIV

Since DOTTG is only manufactured in low concentrations in DOTE the exposure of humans and environment towards DOTTG will only be possible in conjunction with a significantly higher exposure towards DOTE.

 

Since DOTE is already classified in the highest hazard categories it appears to be inappropriate to conduct additional animal studies on DOTTG. These studies would be incompatible with ethical standards since results of the requested studies would not be able to change the classification of stabilizers containing DOTTG as minor constituent. 

 

Any further regulatory fate of DOTTG, such as possible authorization / restriction, is closely linked to DOTE.

Since DOTTG is only manufactured and marketed as a minor constituent of DOTE further use of DOTTG is linked to the authorization of DOTE in authorized applications


- Two subchronic oral toxicity tests (rat) with mixtures containing a high concentration of DOT(2 -EHMA) (70 and 97% purity)- no guideline studies;
- One subchronic toxicity test (dog) with Dioctylin bis (IOMA) and dioctyltin bis (2-EHMA) which are isomers of the same compound and are structural analogues of each other.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
0.5 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Quality of whole database:
The key study is a 90 day study in rats dosed via the diet; the study was conducted with a mixture containing the test material however it pre-dates GLP and standardised guidelines, however study is well documented and complies to a large extent to the later implemented guideline OECD 408 and GLP requirements. The key study was therefore assigned a reliability score of 2 in line with the criteria of Klimisch (1997). Two supporting studies are included; one is a 13 week study in rats which was conducted with a mixture containing the test material, the other is a 14 week study in dogs, conducted with the read-across substance Dioctylin bis (IOMA) and dioctyltin bis (2-EHMA). Both studies were conducted via the dietary route and both studies pre-date GLP and standardised guidelines. Both studies were assigned a reliability score of 2.
The overall quality of the database is good.

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

An evaluation of the repeated dose toxicity of the substance was based on the findings of three studies, as follows.

In the key study (anonymous, 1970) repeated dose oral toxicity of a mixture of Dioctyltin bis(2-EHMA) [CAS No. 15571-58-1]:Octyltin tris(2-EHMA) [CAS No. 27107-89-7]: Trioctyltin (2-EHMA) [CAS No. 61912-55-8] (97.0:0.3:2.17% mixture) was evaluated in rats dosed continuously via the diet at concentrations of 10, 25, 50, 250, 100, 500 and 1000 ppm. Fifteen rats per sex received each dose for a period of 90 days. Body weights, food and water consumption were recorded and blood samples were collected in weeks 6 and 12 for haematological and clinical chemistry evaluation. At the end of the experimental period, animals were sacrificed and subject to pathological and histopathological examination.

Under the conditions of the study the no-observable-adverse-effect-level (NOAEL) was determined to be 10 ppm in the diet (equivalent to 0.5 mg/kg/bw/day) of rats exposed for 90 days, on the basis of reduced thymus weight at 25 ppm.

In the supporting study (anonymous, 1974) repeated dose oral toxicity of Dioctyltin bis(2-EHMA) [CAS No. 15571-58-1]:Octyltin tris(2-EHMA) [CAS No. 27107-89-7] (70:30% mixture) was evaluated in rats dosed continuously via the diet at concentrations of 25, 50 and 100 ppm. Twenty rats per sex received each test diet for a period of 90 days. Blood and urine samples for haematology and biochemistry were collected during weeks 5, 9, and 13. Clinical symptoms of toxicity were recorded daily, and body weights and food consumption were recorded weekly. An ophthalmic examination was conducted pre-exposure and in rats from the 25 and 100 ppm dose groups, during weeks 5, 9, and 13.The following organs were weighed at necropsy: adrenals, kidneys, brain, liver, heart, gonads, and thymus.  

The following organs and tissues were collected for histopathological examination: adrenals, brain, gonads, kidneys, lymph nodes, muscle,  pituitary, spleen, thymus, aorta, colon, gross lesions, liver, pancreas, prostate, uterus, spinal cord, thyroids, bone marrow,  eye, heart, lungs, mammary gland, sciatic nerve, small intestine, stomach, and urinary bladder.

No deaths occurred and no clinical symptoms of toxicity were recorded. Body weight gains, food consumption, clinical chemistry, and urine analysis for treated rats were comparable to the control group. Ophthalmic examination did not reveal any abnormalities in treated rats. There was a significant dose-related reduction in absolute and relative thymus gland weights in the 50 ppm (3.3 mg/kg) and 100 ppm (6.6 mg/kg) dose groups.

The no effect level for DOT(2-EHMA) was determined to be 25 ppm (calculated as 1.25 mg/kg/day, based on a food factor of 0.05) based on reduced absolute and relative thymus gland weights.

In the supporting study reported by Johnson (1970) repeated dose toxicity the structural analogue Di(n-octyl) tin S, S'-bis (isooctylmercaptoacetate), was evaluated in dogs dosed continuously via the diet at concentrations of 0, 20, 50, and 150 ppm. Three dogs per sex received each test diet for a period of 14 weeks. The animals were observed for mortality, body weight, general physical condition and weekly physical examinations, blood pressure, electrocardiograms and eye examinations. Haematology and clinical chemistry determinations were performed at weeks 0, 4, and 13. The dogs were sacrificed after 14 weeks and subjected to gross pathological and histopathological assessment.

All animals survived the duration of the experiment and maintained good physical condition throughout. There were no treatment related effects on body weights, food consumption, urinalysis, haematology, clinical chemistry and ophthalmic examinations were negative except for one animal. No gross pathological or histopathological changes were noted.

Therefore, under the conditions of the study the NOAEL was determined to be 150 ppm, the highest dose level tested.

 

Findings from the study reported by Appel (2004) are included in the dataset since the test material was previously regarded as being an adequate substance for read-across to the registered substance since DOT(2-EHMA) had previously been demonstrated to be 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.

However, read-across to the substance DOTC is no longer considered as wholly appropriate based on the results of the recent Hydrolysis studies, as reported by Naßhan H 2014 and Naßhan, H, 2015 (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. Findings from the study reported by Appel (2004) have therefore been disregarded and are not included in the overall assessment of repeated dose toxicity of the registered substance.


Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
The key study was selected as such as it is the study in which the test material most closely relates to the registered substance. Findings from this study are therefore deemed to be of most relevance and reliability for assessment of the registered substance.
The key study also reports the lowest NOAEL and can therefore be regarded as the most precautionary result to use for risk assessment.

Repeated dose toxicity: via oral route - systemic effects (target organ) immune system

Justification for classification or non-classification

Based on the available data on DOTE and DOITI and following the RAC 47 opinion on DOTE, DOTTG is classified according to CLP : STOT RE category 1 for specific target organ toxicity, specifically for effects on the immune system (H372).

Justification: A LOAEL is 0.7 mg/kg bw/d. This value is smaller than 10, therefore a classification 'STOT RE 1' is required according to the regulation EC no.1272/2008 (CLP).