Phosphinylidynetrimethanol

Endpoint summary

Link to relevant study record(s)

Reference

Endpoint:

basic toxicokinetics, other

Remarks:

Expert statement

Type of information:

other: Expert statement

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: No GLP-conform guideline study, but scientifically valid expert statement based i.a. on studies assessed with Klimisch 1 or 2

Objective of study:

absorption

distribution

excretion

metabolism

toxicokinetics

Qualifier:

no guideline required

Principles of method if other than guideline:

An extensive assessment of the toxicokinetic behaviour of Tris(hydroxymethyl)phosphine oxide (THPO) was performed, taking into account the chemical structure, the available physico-chemical and toxicological data.

GLP compliance:

no

Radiolabelling:

other: not applicable

Species:

other: not applicable

Strain:

other: not applicable

Details on test animals or test system and environmental conditions:

not applicable

Route of administration:

other: All relevant routes of administration are discussed in the expert statement.

Vehicle:

other: not applicable

Details on exposure:

not applicable

Remarks:

not applicable

No. of animals per sex per dose / concentration:

not applicable

Control animals:

other: not applicable

Positive control reference chemical:

not applicable

Details on study design:

not applicable

Details on dosing and sampling:

not applicable

Statistics:

not applicable

Type:

absorption

Results:

The relevant absorption rates were estimated to: Oral absorption: approx. 100%; Dermal absorption: approx. 10%; Inhalative absorption: approx. 100%

Type:

distribution

Results:

Systemic bioavailability of the substance is very high. A high peak exposure can be expected, a very relevant AUC is not to be expected.

Type:

metabolism

Results:

Alkohol oxidation was identified as the mode of action during Phase-I-metabolism, and subsequent conjugation is possible.

Type:

excretion

Results:

THPO and its estimated metabolite are small, charged, hydrophilic and very soluble in water. A very fast excretion of the compounds via the kidneys and urine can be expected. THPO has a minor potential for bioaccumulation, and will be excreted rapidly.

Details on absorption:

Absorption
In general, absorption of a chemical is possible, if the substance crosses biological membranes. In case where no transport mechanisms are involved, this process requires a substance to be soluble, both in lipid and in water, and is also dependent on its molecular weight (substances with molecular weights below 500 are favourable for absorption). Generally, the absorption of chemicals which are surfactants or irritants may be enhanced, because of damage to cell membranes. However, since Tris(hydroxymethyl)phosphine oxide was found to be non-irritating to the skin, the possibility of an enhanced absorption due to damaged cell membranes can be excluded.
Due to the lack of experimental absorption data, the following physico-chemical parameters of Tris(hydroxymethyl)phosphine oxide will be taken into account when discussing its absorption into the body:
- Molecular weight = 140.07 g/mol
- Water solubility = 1000 g/L at 25 °C
- Partition Coefficient Log Pow = -4.77
- Vapour pressure = 0.000721 Pa at 25°C
- Boiling point: Evaporation of gas under decomposition, starting at 146 °C
- Particle size: not relevant, ropy liquid
- Hydrolysis: no hydrolysable groups
- Biodegradation: not readily biodegradable

Absorption from the gastrointestinal tract
In the small intestine absorption occurs mainly via passive diffusion or lipophilic compounds may form micelles and be taken into the lymphatic system. Additionally, metabolism can occur by gut microflora or by enzymes in the gastrointestinal mucosa. Substances absorbed as micelles enter the circulation via the lymphatic system, bypassing the liver. Consequently, immediate Cytochrome P450 metabolism is less important here as for substances which directly enter the hepatic system via the portal vein.
According to ECHA’s guidance R.7c [ECHA 2008], it is stated that the smaller the molecule the more easily it may be taken up. Molecular weights below 500 are favourable for absorption. With a molecular weight of 140.07 g/mol, absorption in general can be considered as favoured for adsorption. Further, according to Guidance R.7C table R.7.12-1, Absorption of very hydrophilic substances by passive diffusion may be limited by the rate at which the substance partitions out of the gastrointestinal fluid. However, if the molecular weight is low (less than 200) the substance may pass through aqueous pores or be carried through the epithelial barrier by the bulk passage of water. So in consequence a rather high absorption can be assumed, which is supported by the negative logPow. As the substance does not need to be classified as acutely toxic and has an NOAEL of 1000 mg/kg in an OECD 422 study, it can be concluded that the substance is intrinsically relatively non-toxic.
Tris(hydroxymethyl)phosphine oxide is not biodegradable, so a preliminary metabolism by gut bacteria is less likely, so additional metabolites prior to absorption do also not have to be regarded.
Based on the available data, an absorption rate of nearly 100% as worst case can be estimated, predominantly due to the high solubility of the substance in water and the negative logPow.

Absorption from the respiratory tract
Concerning absorption in the respiratory tract, any gas, vapour or other substances inhaled as respirable dust (i.e. particle size ≤ 15µm) has to be sufficiently lipophilic to cross the alveolar and capillary membranes (moderate Log Pow values between 0-4 are favourable for absorption). The rate of systemic uptake of very hydrophilic gases or vapours may be limited by the rate at which they partition out of the aqueous fluids (mucus) lining the respiratory tract and into the blood. Such substances may be transported out of the lungs with the mucus and swallowed or pass across the respiratory epithelium via aqueous membrane pores. Lipophilic substances (Log Pow >0) have the potential to be absorbed directly across the respiratory tract epithelium. Any lipophilic compound may be taken up by micellular solubilisation but this mechanism may be of particular importance for highly lipophilic compounds (Log Pow >4), particularly those that are poorly soluble in water (1 mg/L or less) that would otherwise be poorly absorbed [ECHA, 2008].
Tris(hydroxymethyl)phosphine oxide has a very low vapour pressure (0.000721 Pa at 25°C) and decomposes above 146°C, clearly showing that the inhalative absorption as a gas does not have to be regarded.
Particle size is irrelevant, as the substance is a ropy liquid.
According to the BG Bau [BG Bau, 2017], a vapour pressure of p < 0.01 hPa is very low, p = 1-10 hPa low and p > 10 hPa is high. The 31. BImSchV describes an organic substance as volatile if it has a vapour pressure of 0.01 kPa (i.e. 10 Pa) or more at 293.15 K. Also, according to ECHA’s guidance, substances are not available for inhalation as a gas in a relevant manner with a vapour pressure less than 0.5 kPa (i.e. 500 Pa) (or a boiling point above 150°C) [ECHA, 2008].
The boiling point could not have been determined as at 146 °C the sample starts to decompose slowly. Vapour pressure was determined to be 0.000721 Pa at 25°C (25 °C), i.e. very low, and the substance does not need to be regarded a volatile. Hence, the potential inhalation of the substance as a gas is not given and does not need to be regarded. Further, sufficient precautionary measures exclude the formation of droplets of inhalable size or aerosols. In consequence, exposure of humans via inhalation is not likely, so the potential absorption can only be regarded theoretically.
For absorption of deposited material similar criteria as for GI absorption can be applied. In general, either a prolonged exposure due to deposition and subsequent absorption or immediate absorption by micellular solubilisation has to be assumed. The latter mechanism may be of particular importance for highly lipophilic compounds (LogPow >4), particularly those that are poorly soluble in water (1 mg/l or less) and is hence not relevant here.
According to Guidance R.7C table R.7.12-2, if the potential for absorption following ingestion is given, it is likely the substance will also be absorbed if it is inhaled. So no deposition or ciliary clearances need to be regarded, and a precautionary absorption rate of nearly 100% can be estimated here, too.

Absorption after dermal exposure
In order to cross the skin, a compound must first penetrate into the stratum corneum and may subsequently reach the epidermis, the dermis and the vascular network. The stratum corneum provides its greatest barrier function against hydrophilic compounds, whereas the epidermis is most resistant to penetration by highly lipophilic compounds. Substances with a molecular weight below 100 are favourable for penetration through the skin and substances above 500 are normally not able to penetrate. The substance must be sufficiently soluble in water to partition from the stratum corneum into the epidermis. Therefore, if the water solubility is below 1 mg/L, dermal uptake is likely to be low. Additionally, Log Pow values between 1 and 4 favour dermal absorption.
Above 4, the rate of penetration may be limited by the rate of transfer between the stratum corneum and the epidermis, but uptake into the stratum corneum will be high. Above 6, the rate of transfer between the stratum corneum and the epidermis will be slow and will limit absorption across the skin. Uptake into the stratum corneum itself may be slow. Moreover vapours of substances with vapour pressures below 100 Pa are likely to be well absorbed and the amount absorbed dermally is most likely more than 10% and less than 100 % of the amount that would be absorbed by inhalation. If the substance is a skin irritant or corrosive, damage to the skin surface may enhance penetration. During the whole absorption process into the skin, the compound can be subject to biotransformation. However, if water solubility is above 10,000 mg/l and the log P value below 0 the substance may be too hydrophilic to cross the lipid rich environment of the stratum corneum. Dermal uptake for these substances will be low.
In case of Tris(hydroxymethyl)phosphine oxide, an evaporation after skin contact does not need to be regarded due to the high decomposition temperature and low vapour pressure, and hence it can be assumed that the substance will remain on the skin until mechanical removal. Furthermore, since the substance is not a skin irritant, additional absorption-enhancing effects can be disregarded, too.
With a molecular weight of 140.07 g/mol in theory a high absorption via the skin and hence a default dermal absorption rate of 100% [ECHA, 2008] could be assumed.
However, a logPow of -4.77 and a water solubility of 1000 g/L, a passage through the lipid rich environment of the stratum corneum is not favourable. Therefore, a limited dermal absorption rate can be assumed, most likely about 10%.

Details on distribution in tissues:

In general, it can be stated that the smaller the molecule, the wider is its distribution. Small water-soluble molecules and ions will diffuse through aqueous channels and pores.
Based on ToxTree [Ideaconsult Ltd, 2004-2013] modelling, no protein or DNA binding alerts were detected, so distribution via proteins does not need to be regarded. Also, no metabolism modifying the size or phys.-chem. data relevantly was identified. So predictions made on the basis of the physico-chemical characteristics of the parent substance can be considered applicable.
In case of Tris(hydroxymethyl)phosphine oxide, no quantitative data is available for distribution patterns. Taking into account its medium molecular weight of 140.07 g/mol, its hydrophilicity and high water solubility, the absolute systemic bioavailability is rather high and expected to be less extensive in fat tissues than in other tissues.
After oral exposure, the first target will be the gastrointestinal tract, where the substance (there is no need to regard bacterial metabolites due to the lacking biodegradation) will be absorbed in to a major amount and transferred via the blood stream to the liver. After first pass metabolism, which has no major effect on the distribution pattern due to the assumable physico-chemical properties of the metabolite, the substance will be further distributed via the bloodstream. Here, especially the kidneys due to their filter function and the heart due to its enormous need for nutrients and consequently large blood flow through coronary arteries could be affected.
The estimated metabolite is not expect to alter the distribution pattern in a relevant manner due to its low molecular weight and hydrophilicity due to its remaining hydroxyl groups. Consequently, a rather high peak exposure can be expected.

Details on excretion:

Excretion
In general, the major routes of excretion for substances from the systemic circulation are the urine and/or the faeces (via bile and directly from the gastrointestinal mucosa). For non-polar volatile substances and metabolites exhaled air is an important route of excretion. Substances that are excreted favourable in the urine tend to be water-soluble and of low molecular weight (below 300 in the rat) and be ionized at the pH of urine. Most will have been filtered out of the blood by the kidneys though a small amount may enter the urine directly by passive diffusion and there is the potential for reabsorption into the systemic circulation across the tubular epithelium. Substances that are excreted in the bile tend to be amphipathic (containing both polar and nonpolar regions), hydrophobic/strongly polar and have higher molecular weights and pass through the intestines before they are excreted in the faeces and as a result may undergo enterohepatic recycling which will prolong their biological half-life. This is particularly a problem for conjugated molecules that are hydrolysed by gastrointestinal bacteria to form smaller more lipid soluble molecules that can then be reabsorbed from the GI tract. Those substances less likely to recirculate are substances having strong polarity and high molecular weight of their own accord. Other substances excreted in the faeces are those that have diffused out of the systemic circulation into the GIT directly, substances which have been removed from the gastrointestinal mucosa by efflux mechanisms and non-absorbed substances that have been ingested or inhaled and subsequently swallowed. Non-ionized and lipid soluble molecules may be excreted in the saliva (where they may be swallowed again) or in the sweat. Highly lipophilic substances that have penetrated the stratum corneum but not penetrated the viable epidermis may be sloughed off with or without metabolism with skin cells.
For Tris(hydroxymethyl)phosphine oxide no data is available regarding its elimination. Concerning the above mentioned behaviour predicted for its metabolic fate, it is unclear whether the (parent) substance will be excreted unchanged. However, if unchanged excretion is assumed, based on the chemical structure of Tris(hydroxymethyl)phosphine oxide, its molecular weight and its high water solubility, it is very likely to be excreted via the urine.

Metabolites identified:

yes

Details on metabolites:

For details, see attached file. Metabolites of the substance are estimated to be formed via alcohol oxidation.

See attached expert statement.

Conclusions:

The present expert statement covers all relevant toxicokinetic parameters to assess the behaviour of Tris(hydroxymethyl)phosphine oxide (THPO) in the body, the available information is sufficient to enable one to perform a proper risk assessment. Hence, no further information needs to be gathered and further studies can be omitted due to animal welfare. In conclusion, the substance has no potential for bioaccumulation in its non-metabolized or metabolized form.

Executive summary:

In order to assess the toxicokinetic behaviour of Tris(hydroxymethyl)phosphine oxide, the available toxicological and physico-chemical data were evaluated.

The substance is expected to be highly absorbed via the oral route. An oral absorption rate of nearly 100% was estimated due to its high water solubility and negative logPow. THPO has a very low vapour pressure and decomposes without boiling, so the inhalative absorption as a gas does not need to be regarded. In theory, the same considerations apply for oral and inhalative absorption, so it can be estimated to be also nearly 100%. The substance is neither corrosive nor a skin irritant, additional absorption-enhancing effects can be disregarded. The low molecular weight indicates a certain potential to penetrate the skin, but due to the negative logPow, the high water solubility and hence hydrophilicity, it is nearly impossible for THPO to penetrate the stratum corneum and to be absorbed via the skin. Hence a diminished dermal absorption rate can be assumed, approx. 10%.

So in summary, the absorption rates may be estimated to:

-      Absorption via oral route: 100%

-      Absorption via inhalative route:100%

-      Absorption via dermal route: 10%

The absolute systemic bioavailability of THPO is very high. Similar distribution patterns can be expected for its metabolite and a possible accumulation can be neglected. A high peak exposure can be expected, but due to the tendency to be excreted rather fast, a very relevant AUC (Area under the curve, i.e. measure for systemic bioavailability) is not to be expected. After the poorer absorption of THPO via the dermal route, a minor peak exposure has to be considered.

The negative logPow and the very high water solubility are clearly indicating that for THPO, a rather fast excretion can be expected and the potential of THPO for bioaccumulation in its classic sense is virtually not existing. Also, no protein or DNA binding alerts were detected.

Hydrolysis of the substance in the acidic, aqueous environment of the stomach can be neglected as there are no hydrolysable groups present. The primary sites of metabolism were identified to be the hydroxyl groups located at each of the three carbon atoms, no further sites were identified, and the oxidized metabolites are not expected to modify essentially the molecular weights, physico-chemical properties and hence ADME behaviour of THPO. It can be concluded that THPO will be either subject to metabolism by cytochrome P450 enzymes and subsequent conjugation, or to be excreted as such unmetabolized.

In conclusion, THPO has a minor potential for bioaccumulation, and will be excreted rapidly.

Description of key information

Expert statement: THPO has a minor potential for bioaccumulation. The relevant absorption rates can be estimated by expert judgement to 100% (oral), 10% (dermal) and 100% (inhalation).

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Absorption rate - oral (%):

100

Absorption rate - dermal (%):

10

Absorption rate - inhalation (%):

100