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Description of key information

The results of the previous hydrolysis study (Anonymous 2000) which were considered to support the use of the substance DOTC as an appropriate surrogate for mammalian toxicology studies of the corresponding thioesters, DOTE and its close analogue DOTI, when dosed via the oral route are now considered by the registrant to have been recently superceded by the findings of a more modern study. Further information on teh potential for absorption of the material was available in teh form of Ward, 2003 a study on the in vitro absorption of the substnace through the skin.

Key value for chemical safety assessment

Bioaccumulation potential:
low bioaccumulation potential
Absorption rate - oral (%):
100
Absorption rate - dermal (%):
0.004
Absorption rate - inhalation (%):
100

Additional information

Absorption

The absorption of DOT(2 -EHMA) was measured in vitro (Ward 2003) through both occluded and unoccluded human and rat epidermis. The absorption through rat epidermis was much faster than through human epidermis:

 

HUMAN EPIDERMIS: A dose of 17,007 ug tin/cm2 was determined to alter the barrier function of the epidermis. From the occluded and unoccluded applications, the rates of tin absorption over the 0-24 h exposure period were below the limit of quantification (0.001 ug/cm2/h). In terms of percent applied tin, 0.0001% was absorbed from the occluded dose, and 0.0001% was absorbed from the unoccluded dose after 24 hours of exposure.

RAT EPIDERMIS: Absorption of tin through rat epidermis was much faster than through human epidermis. From the occluded application, the maximum rate of tin absorption (0.035 ug/cm2/h) occurred during 16-24 hours of exposure, and the mean rate of tin absorption over the whole 24-h exposure period was 0.021 ug/cm2/h. From the unoccluded application, the maximum rate of tin absorption occurred during 12-24 hours of exposure and was 0.033 ug/cm2/h. The mean rate of tin absorption over the whole 24-h exposure period was 0.025 ug/cm2/h. In terms of percent applied tin, 0.003% was absorbed from the occluded dose, and 0.004% was absorbed from the unoccluded dose after 24 hours of exposure. The overall recovery of tin from the test system after 24-h exposure was low and may be due to adsorption of the test substance to the glass equipment used. The recovery was 45.5% (human) and 25.2% (rat) of the applied occluded doses, and 29.6% (human) and 30.5% (rat) were recovered from the unoccluded test systems. Of the recovered tin, 2.1% (human) and 5.5% (rat) were obtained from the surface of the epidermis and donor chamber. The mean amounts of tin absorbed by 24 hours were 0.010 ug/cm2 (unoccluded) and 0.011 ug/cm2 (occluded) through human epidermis and 0.641 ug/cm2 (unoccluded) and 0.547ug/cm2 (occluded) through rat epidermis.

These results show that the absorption of tin from dioctyltin bis(2-ethylhexylmercaptoacetate) through rat epidermis significantly overestimated absorption from human epidermis. By 24 hours only a small amount of the applied tin (3% in human and 1% in the rat) is associated with the epidermis and is not regarded as systemically available.

 

Distribution

A molecule of this size would typically be considered to have a somewhat limited distribution and there is the potential for preferential partition to fatty/adipose tissues upon repeated exposure given the high log Pow and extremely low predicted water solubility of the material. 

 

Metabolism

Recent in vitro toxicokinetics studies under simulated mammalian gastric conditions, using 119-Sn-NMR to identify the reaction products, clearly show Dioctyltinchlor 2-ethylhexymercaptoacetate (DOTCE) is the only identifiable hydrolysis product. No DOTC could be detected under the conditions of the studies (Naßhan H 2014, Naßhan H 2015)

 

Elimination

A molecular weight of >300 indicates that excretion is more likely to occur via the bile.

 

Conclusion

Values of 100%, 0.004% and 100% are adopted for oral, dermal and inhalation exposure in accordance with ECHA guidance and the results of the studies performed.

 

Distribution within the body would be considered to be somewhat limited by the relatively large molecular weight of the substance with preferential partitioning to fatty tissues. 

 

A simulated gastric hydrolysis study indicates that the substance would likely form its monochloride form following substitution of one (but not both) of the thioester side chains. The molecular weight of >300 suggests elimination via the bile.