Registration Dossier

Administrative data

Link to relevant study record(s)

Reference
Endpoint:
basic toxicokinetics, other
Remarks:
assessment of toxicokinetic behavior
Type of information:
other: In accordance with REACH Annex VIII (8.8) an assessment of toxicokinetic behavior has been conducted to the extent that can be derived from the relevant available information.
Adequacy of study:
key study
Study period:
The assessment was conducted in October 2018
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Relevant studies were reviewed by a qualified toxicologist with a view to fulfilling the requirements of Annex VIII (8.8).
Objective of study:
toxicokinetics
Qualifier:
no guideline required
Principles of method if other than guideline:
In accordance with REACH Annex VIII (8.8) an assessment of toxicokinetic behaviour has been conducted to the extent that can be derived from the relevant available information. The assessment is based on the Guidance on information requirements and chemical safety assessment R.7c: Endpoint specific guidance (ECHA, June 2017)
GLP compliance:
no
Remarks:
Not relevant for assessment
Specific details on test material used for the study:
Sponsor’s identification: ESA
Description: White powder

Absorption

Oral / GI absorption:

The relatively low molecular weight (124.1 g/mol), water solubility (714 g/L) and partition coefficient (log Pow -0.45) of the substance (ESA) support the substance having potential to cross biological membranes, via diffusion, such as those of the gastro-intestinal tract following oral ingestion. Molecular weights below 500 are favourable for absorption. Water soluble substance will readily dissolve into the gastrointestinal fluids. Moderate log Pow values (between -1 and 4) are favourable for absorption by passive diffusion.

The available acute oral toxicity study supports that absorption occurred. Mortality occurred in all animals tested at 2000 mg/kg, in additional to clinical signs and gross necropsy findings. No mortality or unusual clinical signs were observed in animals tested at 300 mg/kg. It is therefore considered likely that the effects at 2000 mg/kg are evidence of systemic absorption and not solely due to local effects at the site of contact.

The available data suggests ESA has the potential for absorption following oral administration.

Based on the rapid hydrolysis of ESA there may be an indication that it may only be present in the GI tract for a limited period of time. The proposed hydrolysis product, hydroxyethyl sulphate, would also be favourable for absorption based on low molecular weight (142.1 g/mol), estimated (using EPISUITE models) water solubility (1000 g/L) and estimated log Pow (-3.95).

Respiratory absorption - Inhalation:

Inhalation is not considered to be a significant route of exposure based on vapour pressure, low volatility and particle size. However, in the case of inhalation ESA is a hydrophilic substance and therefore may be retained in the mucus or be absorbed through aqueous pores. For absorption of deposited material similar criteria as for the GI absorption apply.

No inhalation toxicity data is available on ESA to assess if systemic toxicity, indicating absorption occurred. However, based on the systemic toxicity observed in acute oral toxicity study, it can be considered likely the substance will also be absorbed if it is inhaled.

Based on the rapid hydrolysis of ESA there may be an indication that it may only be present in the respiratory tract for a limited period of time. The proposed hydrolysis product, hydroxyethyl sulphate, would also be favourable for absorption if it is inhaled.

Dermal absorption:

The neat substance is a solid so dry particulates will have to dissolve into the surface moisture of the skin before uptake can begin.

The molecular weight (124.12 g/mol) of the substance does not highly favour dermal uptake but is not too large to discount any uptake (above 500 the molecule may be too large).

The substance has high water solubility (714 g/L) and a log Pow value below 0 (-0.45), therefore the substance may be too hydrophilic to cross the lipid rich environment of the stratum corneum, suggesting low uptake. However, the substance is corrosive to skin which may enhance penetration. The substance is also a skin sensitizer, implying that some dermal uptake of the substance must occur. These results would suggest that there is some limited potential absorption of ESA following dermal administration.

The proposed hydrolysis product, hydroxyethyl sulphate, can be assumed to have either similar or less potential for absorption following dermal administration than ESA based on its slightly higher molecular weight, estimated water solubility (1000 g/L) and estimated log Pow (-3.95). This data suggests the hydrolysis product may be to hydrophilic to cross the lipid rich environment of the stratum corneum.

Distribution:

As the substance is of low molecular weight and is water soluble, it can be assumed that any absorbed substance can be readily distributed in the water fraction of circulatory fluids. This may be supported by effects observed in the acute oral toxicity study.

 

The available carcinogenicity literature data (on the substance itself and similar structurally related compounds) shows some limited evidence of distribution of the substance.

 

As the substance evoked a skin sensitization response, this would suggest the substance may bind to circulatory proteins.

 

The octanol/water partition coefficient (log Pow -0-45) suggests limited fat solubility and that the substance is unlikely to accumulate in body fat.

 

The proposed hydrolysis product, hydroxyethyl sulphate, can also be assumed to be readily distributed based on its low molecular weight and estimated high water solubility.

 

Metabolism:

The substance is freely water soluble, suggesting that metabolism may not be required to enhance excretion.

The available in vitro genotoxicity studies do not show significant evidence that the genotoxic potential of the substance is either enhanced or diminished in the presence of a metabolising system. However, one test strain (S.typhimurium TA1537) in the ames test showed a positive response only in the presence of the metabolic activation system.

No repeat dose toxicity studies are available to assess whether the substance influenced hepatic metabolism.

 

The proposed hydrolysis product, hydroxyethyl sulphate, is freely water soluble so may also not require metabolism to enhance excretion.

Excretion:

Low molecular weight test items that are water soluble are most likely to be excreted via the kidney (urinary excretion) but there is no available evidence from available study data to indicate the route of excretion . Following oral ingestion, any test item that is not absorbed is likely to be excreted in the faeces.

The proposed hydrolysis product, hydroxyethyl sulphate, would also most likely be excreted via the kidney.

Conclusions:
The substance is a low molecular weight solid that is water soluble. Any oral ingestion of the test item may lead to absorption and systemic distribution. There may also be some limited adsorption via the dermal route and inhalation routes. There is limited evidence available regarding metabolism of the substance but excretion is most likely to be via the kidney.

Description of key information

The substance is a low molecular weight solid that is water soluble. Any oral ingestion of the test item may lead to absorption and systemic distribution. There may also be some limited adsorption via the dermal route and inhalation routes. There is limited evidence available regarding metabolism of the substance but excretion is most likely to be via the kidney.

Key value for chemical safety assessment

Bioaccumulation potential:
low bioaccumulation potential

Additional information