Phosphonic acid, monoethyl ester, sodium salt (1:1)

Endpoint summary

Description of key information

Absorption of the test substance and its dissociation products is considered after oral ingestion whereas dermal or respiratory absorption is considered rather unlikely. Following absorption, the test substance and its dissociation products might be distributed to different body tissues. Elimination occurs either directly in the urine or following extensive metabolism via the urine and the expired air.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

 Assessment of the toxicokinetic behaviour of the test substance

 

In accordance with Regulation (EC) 1907/2006, Annex VIII, Column 1, Item 8.8 and with Guidance on information requirements and chemical safety assessment Chapter R.7c: Endpoint specific guidance (ECHA, 2017), assessment of the toxicokinetic behaviour of the test substance was conducted to the extent that can be derived from the relevant available information. This comprises a qualitative assessment of the available substance specific data on physicochemical properties. 

The test substance is a solid white powder with high water solubility (770 g/L at 20 °C), a molecular weight of 132.0 g/mol and a vapour pressure < 0.00001hPa at 20 °C. The octanol/water partition coefficient (log Pow) was determined as – 2.5 (20 °C).

 

Absorption

In general, absorption of a substance depends on the potential to cross biological membranes, which is determined by the molecular weight, the log Pow and water solubility. Mostly, substances cross the membranes by passive diffusion, which requires sufficient solubility in water and lipids, a capability which is described by the log Pow. In general, log Pow values between -1 and 4 are favourable for absorption whereas ionic substances are thought not to readily diffuse across biological membranes. Chemicals that do not offer these properties may be absorbed via active processes including facilitated diffusion, active transport or pinocytosis (ECHA, 2017).

 

Oral:

After oral ingestion, dissociation of the test substance in ethyl phosphonate (C2H6O3P-) and sodium (Na+) is expected to occur in the gastrointestinal (GI) tract (estimated with the OECD toolbox, vs. 2.3).

In general, molecular weights below 500 and log Pow values between -1 and 4 are favourable for absorption via the gastrointestinal (GI) tract, provided that the substance is sufficiently water soluble (> 1 mg/L). Lipophilic compounds may be taken up by micellar solubilisation by bile salts, but this mechanism may be of particular importance for highly lipophilic compounds (log Pow > 4), in particular for those that are poorly soluble in water (≤ 1 mg/L) as these would otherwise be poorly absorbed (ECHA, 2017).

Therefore, if oral exposure to parent did occur, molecular weight is in the favourable range and would favour absorption, so systemic exposure by this route is likely. Signs of systemic toxicity were evident in the repeated dose toxicity oral studies, which indicates systemic exposure.

Overall, in accordance to the physico-chemical properties of the test substance and the available data on Fosetyl-Sodium, the test substance and its dissociation products are considered to be orally absorbed.

 

Dermal:

To enable dermal absorption, the substance first has to penetrate into the stratum corneum and may subsequently reach the epidermis, the dermis and the vascular network (ECHA, 2017). The stratum corneum provides the first barrier against hydrophilic compounds and dermal uptake of substances with poor lipophilicity (log Pow < 0) will be impeded. Log Pow values <–1 suggest that a substance is not likely to be sufficiently lipophilic to cross the stratum corneum, and hence dermal absorption is likely to be low. In general, if water solubility is above 10000 mg/L and the log P value is below 0 the substance may be too hydrophilic to cross the lipid rich environment of the stratum corneum. Dermal uptake for such a substance will be low (ECHA, 2017).

Therefore, in regard to the low lipophilicity indicated by a log Pow of -2.5, the test substance will most probably not be able to penetrate the stratum corneum and hence will not reach the epidermis. Furthermore, the test substance does not exhibit irritating properties to the skin, and hence, facilitated penetration due to local skin damage can be excluded. However, if the stratum corneum once will be passed, the high water solubility of the test substance will afford moderate to high absorption via the skin.

 

Overall, the high water solubility, poor lipophilicity and the non-irritating properties to the skin indicate that dermal absorption of the test substance is rather unlikely.

 

Inhalation:

Substances including gases, vapours, liquid aerosols (both liquid substances and solid substances in solution) and finely divided powders/dusts may be absorbed directly from the respiratory tract or, through the action of clearance mechanisms, may be transported out of the respiratory tract and subsequently be swallowed which might lead to absorption in the GI tract (ECHA, 2017).

In general, substances with a low vapour pressure of ‹ 500 Pa are not favourable for respiratory absorption as those substances are not available for inhalation as vapour (ECHA, 2017). The test substance has a low vapour pressure of < 0.00001 hPa at 25°C and thus being of low volatility. Therefore, resorption of the test substance following inhalation is not expected to be significant under normal use and handling. However, inhalation of aerosols cannot be excluded. As the test substance is highly soluble in water, passive transfer through cell membranes in the respiratory tract will strongly be impeded. However, absorption via active processes and/or passage through aqueous pores or carriage with the passage of water has to be considered as possible for the test substance in the respiratory tract.

 

Overall, due to the low vapour pressure, respiratory absorption following inhalation is not considered as significant. However, after inhalation of aerosols, absorption via the respiratory tract cannot be excluded due to the possibility of active transport mechanisms or passage through aqueous pores.

 

Distribution:

Distribution of a compound within the body depends on the physico-chemical properties of the substance; especially the molecular weight, the lipophilic character and the water solubility. In general, the smaller the molecule, the wider is the distribution. If the molecule is lipophilic, it is likely to distribute into cells and the intracellular concentration may be higher than extracellular concentration, particularly in fatty tissues (ECHA, 2017).

Therefore, based on the low molecular weight and the high water solubility a a diffusion through aqueous channels and pores is likely. The rate at which very hydrophilic molecules diffuse across membranes could limit their distribution. In repeated dose toxicity studies treatment-related effects e.g. in kidney, liver and spleen are observed.

 

Overall, the available information indicates that the test substance and its dissociation products might be distributed to different tissues following absorption.

 

 

Accumulation:

In general, lipophilic substances have the potential to accumulate within the body if the dosing interval is shorter than 4 times the whole body half-life. Other substances that can accumulate within the body include poorly soluble particulates that deposit in the alveolar region of the lungs, substances that bind irreversibly to endogenous proteins and certain metals and ions that interact with the matrix of the bone, e.g. lead and fluoride (ECHA, 2017). In contrast, substances with moderate to high water solubility will most probably be excreted via the urine or faeces instead.

 

Therefore, due to its physico-chemical properties, accumulation of the test substance and its dissociation products is expected to be negligible.

 

Metabolism:

In general, xenobiotics are mostly metabolised in the liver which represents the organ with the greatest metabolic capacity especially following oral uptake (ECHA, 2017). Furthermore, hydrolysis within the GI tract and metabolism by the GI flora or within the GI tract epithelia (mainly in the small intestine) may occur. In addition, hydrolysis is possible in the respiratory tract or the skin (ECHA, 2017).

After oral ingestion, dissociation of the test substance in C2H6O3P- and sodium (Na+) is expected to occur in the GI tract (OECD toolbox vs. 2.3). Using the OECD toolbox 3, 5 or 2 potential metabolites were identified for the test substance with the skin (C(C)OP(=O)O, O-.[Na]+and C(O)COP(=O)O), liver (C(C)OP(=O)O, O-.[Na]+, C(C)O, C(C)=O, C(C)(=O)O) and hydrolysis simulator (O=P(O)O-.[Na]+, C(C)O), respectively. Furthermore, the microbial metabolism simulator provided 5 potential metabolites. However, it has to be considered that the high water solubility of Fosetyl-sodium most probably enables gastrointestinal dissolution and subsequent elimination of the test substance and its dissociation products via the urine.

 

Overall, based on the physico-chemical properties of the test substance, it is likely that the test substance is either excreted directly in the urine or metabolised into phosphite and ethanol.

 

Excretion:

The major routes of excretion for substances from systemic circulation are the urine and the faeces. Characteristics favourable for urinary excretion are low molecular weight (below 300 in the rat), good water solubility, and ionization of the molecule at the pH of urine. Substances that are excreted in the bile tend to have higher molecular weights. Moreover, elimination via the feces is generally favored for non-absorbed substances (ECHA, 2017).

Therefore, based on the physico-chemical proerties, it is reasonable to conclude that the test substance is either excreted directly in the urine or extensively metabolised into products that are rapidly eliminated via the urine and the expired air.

 

References not included in IUCLID

 

ECHA. 2017. Guidance on information requirements and chemical safety assessment – Chapter 7c: Endpoint specific guidance. European Chemicals Agency, Helsinki

 

Renault, 2004. POSITION PAPER Fosetyl-sodium (AE C529354): Waiver for additional toxicokinetic, fertility and teratology studies. Bayer CropScience. Company report number M-468056-01-1.