Registration Dossier

Expert Statement

2018

2017

Bioavailability via oral route is strongly linked to physico-chemical properties of the substance. Generally, oral absorption is favoured for molecular weights below 500 g/mol. Furthermore, a relatively high water solubility of more than 100 mg/L enables the substance to readily dissolve in the gastrointestinal fluids, allowing direct uptake into the systemic circulation through aqueous pores or via carriage of the molecules across membranes with the bulk passage of water. The test item molecular weight ranges between 254 - 344 g/mol and is well soluble in water up to 1.045 g/L. Above this concentration the substance forms micelles under aqueous conditions. The substance is therefore expected to be well absorbed in gastro intestinal tract (GIT). Further, the substance being the sodium salt of phosphate ester derivates is expected to readily dissociate into its ionic moieties in aqueous environments such as the intestinal fluids. The small ionised molecules are expected to be well absorbed by bulk passage of water. Taken together, the physiochemical properties indicate that the test item becomes well bioavailable via the oral route. This assumption is supported by the results of acute and repeated oral toxicity studies with aqueous solutions of the test item. Systemic signs of toxicity were observed related to substance treatment at actue high doses of 5000 mg/kg bw and above as well as at repeated doses of 450 mg/kg bw/d. This indicates that the substance becomes bioavailable via the oral route.

The volatility of a substance indicates whether it may be available for inhalation as a vapour or not. Highly volatile substances are those with a vapour pressure greater than 25 KPa and substances with low volatility have a vapour pressure of less than 0.5 kPa. Vapor pressure of the test item was determined to be very low (1.1E-4 Pa at 20 °C). Therefore, the substance is considered as non-volatile. Taking into account the boiling point of 173.8 °C it cannot completely excluded that the substance may become available via the inhalation route when working with high temperature processes. If this were the case, absorption via inhalation route would be expected to occur due to the relatively low molecular weight and good water solubility.

Dermal uptake is favoured for substances with a molecular weight < 100 g/mol. The molecular weight of the test item is above this threshold (245-344 g/mol). Further, the substance must be sufficiently soluble in water to partition from the stratum corneum into the epidermis. Absorption is anticipated to be moderate to high if water solubility is between 100 10000 mg/L. Water solubility of the test item falls in this range. Further, based on its amphiphilic character and surface tension it is considered to be surface active and thus well pass cell membranes. Therefore, dermal absorption is probably supported. Furthermore, the test item is classified as skin corrosive. Therefore, it will highly likely become bioavailable as it would destroy upper layers of the skin and thus ease absorption.

In general, the smaller molecules are the wider their distribution in the organism is expected. The test item has a relatively low molecular weight. In addition, it is well soluble in water. Therefore, it is expected to be rapidly and widely distributed. Due to its amphipathic character it can be expected to be distributed intra- as well as inter-cellular. Based on its low logPow the test item is not expected to bioaccumulate in the organism.

The test item and/or its metabolites are most likely excreted via the urine due to its relatively low molecular weight and its good water solubility.

Based on the chemical structure of the test item the aliphatic part may be metabolized by Phase I enzymes while undergoing functionalization reactions, i. e. oxidation, increasing its hydrophilicity. Esterases will probably accomplish cleavage of the ester function. Furthermore, Phase II conjugation reactions may covalently link an endogenous substrate to the parent compound, especially the phosphate part, or the Phase I metabolite in order to ultimately facilitate excretion.

Metabolism to more toxic metabolites is not expected. This consideration could be supported by QSAR predictions (QSAR toolbox). The main constituent was evaluated and possible metabolites (rat liver metabolism) were predicted.
The aliphatic chain of the test item is predicted to become oxidized and or hydroxylised, probably by Phase I CYP 450 enzymes increasing the hydrophilicity of the molecule. QSAR Toolbox only provides prediction for Phase I metabolism. Thus, these anticipated metabolites likely undergo further conjugation reactions faciliated by Phase II enzymes.

Based on physicochemical characteristics (low molecular weight, good water solubility, amphipathic character and surface activity) well absorption by the oral, inhalative and dermal route is anticipated for the test item. Further, rapid and wide distribution of the test substance in the organism is expected. The test item is expected to undergo metabolic transformation in the organism. Renal excretion of the test item or its metabolites is expected and was confirmed by experimental results of a structural analogue substance. The test item is not considered to bioaccumulate in the organism.

Toxicological profile of the test item

The test item is concluded to be corrosive to skin and severely damaging to the eye based on test results of respective in vitro testing battery.

Therefore, acute oral toxicity was not tested with the test item. However, studies are available with aqueous solutions of the test item. Based on the results of these studies, corrected LD50 values would be greater than 2000 mg/kg bw in the rat. Nevertheless signs of systemic toxicity were observed at high doses of 5000 mg/kg and above, indicating that the substance became bioavailable via the oral route.

Acute dermal toxicity as well as skin sensitising potential was not investigated with the test item because it is classified as skin and eye corrosive.

A combined repeated dose toxicity study with screening on reproductive and developmental toxicity/teratogenicity according to OECD 422 with the test item indicated signs of systemic toxicity at dose levels of 450 mg/kg bw/d including decreased food consumption and body weight development.

The genotoxic potential of the test item was investigatedin vitro. The test item was not genotoxic based on the results of an Ames test, an HPRT assay and a chromosome aberration assay, all tested with and without metabolic activation, respectively.

Toxicokinetic analysis of the test item

The test item is a multi-constituent substance appearing as dark thick paste at ambient conditions with a molecular weight of ranging from ca. 254 to 344 g/mol. It is well soluble in water up to 1.045 g/L at 20 °C and above it forms micelles (1.045 g/L = critical micelle concentration). The substance has a log n-octanol/water partition coefficient of -1.1 (monoester) and 1.11 (diester). Freezing or melting point of the substance was determined to be -50 °C, boiling point 173.8 °C. Vapour pressure of the substance is 1.1E-4 Pa at 20 °C. Based on its surface tension, i. e. 38.5 mN/m, the substance is considered to be surface active.

Absorption

Bioavailability via oral route is strongly linked to physico-chemical properties of the substance. Generally, oral absorption is favoured for molecular weights below 500 g/mol. Furthermore, a relatively high water solubility of more than 100 mg/L enables the substance to readily dissolve in the gastrointestinal fluids, allowing direct uptake into the systemic circulation through aqueous pores or via carriage of the molecules across membranes with the bulk passage of water.The test item molecular weight ranges between 254 - 344 g/mol and is well soluble in water up to 1.045 g/L. Above this concentration the substance forms micelles under aqueous conditions. The substance is thereforeexpected to be well absorbed in gastro intestinal tract (GIT). Further, the substance being the sodium salt of phosphate ester derivates is expected to readily dissociate into its ionic moieties in aqueous environments such as the intestinal fluids. The small ionised molecules are expected to be well absorbed by bulk passage of water. Taken together, the physiochemical properties indicate thatthetest item becomes well bioavailable via the oral route. This assumption is supportedby the results of acute and repeated oral toxicity studies with aqueous solutions of the test item. Systemic signs of toxicity were observed related to substance treatment at acute high doses of 5000 mg/kg bw as well as repeated doses of 450 mg/kg bw/d. This indicates that the substance becomes bioavailable via the oral route.

The volatility of a substance indicates whether it may be available for inhalation as a vapour or not. Highly volatile substances are those with a vapour pressure greater than 25 KPa and substances with low volatility have a vapour pressure of less than 0.5 kPa. Vapor pressure of the test item was determined to be very low (1.1E-4 Pa at 20 °C). Therefore, the substance is considered as non-volatile. Taking into account the boiling point of 173.8 °C it cannot completely excluded that the substance may become available via the inhalation route when working with high temperature processes. If this were the case, absorption via inhalation route would be expected to occur due to the relatively low molecular weight and good water solubility.

Dermal uptake is favoured for substances with a molecular weight < 100 g/mol. The molecular weight of thetest itemis above this threshold (245-344 g/mol). Further, the substance must be sufficiently soluble in water to partition from the stratum corneum into the epidermis. Absorption is anticipated to be moderate to high if water solubility is between 100 ‑ 10000 mg/L. Water solubility of thetest item falls in this range. Further, based on its amphiphilic character and surface tension it is considered to be surface active and thus well pass cell membranes. Therefore, dermal absorption is probably supported. Furthermore, the test item is classified as skin corrosive. Therefore, it will highly likely become bioavailable as it would destroy upper layers of the skin and thus ease absorption.

Distribution

In general, the smaller molecules are the wider their distribution in the organism is expected. The test item has a relatively low molecular weight. In addition, it is well soluble in water. Therefore, it is expected to be rapidly and widely distributed. Due to its amphipathic character it can be expected to be distributed intra- as well as inter-cellular. Based on its low logPow the test item is not expected to bioaccumulate in the organism.

Metabolism

Based on the chemical structure of the test item the aliphatic part may be metabolized by Phase I enzymes while undergoing functionalization reactions, i. e. oxidation, increasingits hydrophilicity. Esterases will probably accomplish cleavage of the ester function. Furthermore, Phase II conjugation reactions maycovalently link an endogenous substrate to the parent compound, especially the phosphate part, or the Phase I metabolite in order to ultimately facilitate excretion.

Metabolism to more toxic metabolites is not expected. This consideration could be supported by QSAR predictions (QSAR toolbox). The main constituent was evaluated and possible metabolites (rat liver metabolism) were predicted.

The aliphatic chain of the test item is predicted to become oxidized and or hydroxylised, probably by Phase I CYP 450 enzymes increasing the hydrophilicity of the molecule. QSAR Toolbox only provides prediction for Phase I metabolism. Thus, these anticipated metabolites likely undergo further conjugation reactions faciliated by Phase II enzymes.

Excretion

The test item and/or its metabolites aremost likely excreted via the urine due to its relatively low molecular weight and its good water solubility.