[No public or meaningful name is available]

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

Study period:

2018-05-04

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

other: accumulation

Qualifier:

no guideline required

Principles of method if other than guideline:

An extensive assessment of the toxicokinetic behaviour of Amines, C12-14-tert-alkyl, reaction products with O,O-di-C1-14-alkyl hydrogen phosphorodithioate 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

Duration and frequency of treatment / 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. 100%, Inhalative absorption: approx. 100%.

Type:

distribution

Results:

A certain systemic bioavailability is given.

Type:

metabolism

Results:

Aliphatic hydroxylation (cation) and desulphurization of phosphor, O-dealkylation, and aliphatic hydroxylation (anion) were identified as the only mode of action during Phase-I-metabolism, and subsequent conjugation is expected.

Type:

excretion

Results:

A rather fast excretion of the substance and its metabolites via the kidneys and urine can be expected. They have 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 Amines, C12-14-tert-alkyl, reaction products with O,O-di-C1-14-alkyl hydrogen phosphorodithioate 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 physico-chemical parameters of Amines, C12-14-tert-alkyl, reaction products with O,O-di-C1-14-alkyl hydrogen phosphorodithioate noted below will be taken into account when discussing its absorption into the body. However it should be taken into account that the main structures are present as two independent ions in contact with water, i.e. the Amines, C12-14-tert-alkyl and the O,O-di-C1-14-alkyl hydrogen phosphorodithioate part. Hence the substance will be assessed i.a. based on the molecular weights, logPow and water solubility values of the single molecule parts.
- Molecular weight:
O,O-Di-C1-14-alkyl hydrogen phosphorodithioate: 353.54 g/mol
Amines, C12-14-tert-alkyl: 172.33 g/mol (C12), 186.36 g/mol (C13), 200.38 g/mol (C14)
- Water solubility:
O,O-Di-C1-14-alkyl hydrogen phosphorodithioate: 10.5 mg/l
Amines, C12-14-tert-alkyl: 13 mg/l
- Partition Coefficient logPow:
O,O-Di-C1-14-alkyl hydrogen phosphorodithioate: 4.80
Amines, C12-14-tert-alkyl: 2.43
- Vapour pressure = 1.5 x 10E-5 Pa (25 °C)
- Melting point: none observed above -20 °C, substance is a liquid
- Boiling point: not determinable, 130.3 °C the sample starts to decompose slowly and at 225.0 °C the decomposition becomes more rapidly

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. However, the absorption of highly lipophilic substances (Log Pow of 4 or above) may be limited by the inability of such substances to dissolve into gastrointestinal fluids and hence make contact with the mucosal surface. The absorption of such substances will be enhanced if they undergo micellular solubilisation by bile salts. 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. Also, substances with moderate log P values (between -1 and 4) are favourable for absorption by passive diffusion. The molecular weight of the main constituents of the substance as such are with 527.90 – 555.95 g/mol actually too large for absorption. However, taking into account the fact that, after oral intake in contact with gastrointestinal fluids, the substance will be most likely present dissociated into the single anion and cations, their molecular weight must be taken into account. With 353.54 g/mol, the dithioate moiety is not too large to be absorbed, and the amines can with 172.33 g/mol (C12), 186.36 g/mol (C13), or 200.38 g/mol (C14) rather easily be absorbed.
Substances with high logPow values, are less favourable for absorption by passive diffusion, which diminishes the ability of the O,O-di-ethylhexyl hydrogen phosphorodithioate anion to be absorbed. The experimentally determined logPow of 4.80 is above the guidance value, allowing the conclusion that this part of the substance is rather is poorly absorbed. The logPow of 2.43 for the Amine, C12-14-tert-alkyl cation content however must be considered as moderate, and so this part of the substance is favourable for absorption.
Only water-soluble substances will readily dissolve into the gastrointestinal fluids and hence be available for absorption. The substance of interest though has a rather low water solubility, i.e. 13 mg/l for the Amine, C12-14-tert-alkyl cation content, and 10.5 mg/l for the O,O-di-ethylhexyl hydrogen phosphorodithioate anion content. Nevertheless a certain water solubility is given here, so a very high limitation of absorption in e.g. the upper GI tract cannot be assumed. From the acute oral toxicity data no relevant information can be drawn, but the results of the available OECD 422 study allow some conclusions: Absorption to a certain extent occurred, as in the available study a NOAEL of 130 mg/kg bw/d was determined, but this value is in general not too low, which indicates either a relative non-toxicity of the substance or a poor absorption.
Amines, C12-14-tert-alkyl, reaction products with O,O-di-C1-14-alkyl hydrogen phosphorodithioate is not biodegradable, so a preliminary metabolism by gut bacteria is less likely, and additional metabolites prior to absorption do also not have to be regarded.
Based on the available data, a precautionary absorption rate of 100% should be further taken into account, as the absorption of at least the amine part can be considered rather high, and it cannot be unambiguously determined which part of the molecule is responsible for possible effects.

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].
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 130.3 °C the sample starts to decompose slowly and at 225.0 °C the decomposition becomes more rapidly. Vapour pressure however was determined to be 1.5 x 10E-5 Pa (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). To be readily soluble in blood, a gas, vapour or dust must be soluble in water and increasing water solubility would increase the amount absorbed per breath. However, the gas, vapour or dust must also be sufficiently lipophilic to cross the alveolar and capillary membranes. Therefore, a moderate log P value (between -1 and 4) would be favourable for absorption. Generally, liquids, solids in solution and water-soluble dusts would readily diffuse/dissolve into the mucus lining the respiratory tract. With an logPow of 4.80 of the O,O-di-ethylhexyl hydrogen phosphorodithioate anion, which is is above the guidance value, absorption may be considered hindered. The logPow of 2.43 for the Amine, C12-14-tert-alkyl cation content however must be considered as moderate, and so this part of the substance is favourable for absorption, similar to oral absorption. Although having a rather low water solubility, i.e. 13 mg/l for the Amine, C12-14-tert-alkyl cation content, and 10.5 mg/l for the O,O-di-ethylhexyl hydrogen phosphorodithioate anion content, the substance cannot be considered as poorly soluble, and so water solubility is also not considered to hinder absorption in a relevant matter.
Despite of physical limitations, i.e. low vapour pressure and taken precautions, and so only a very minor portion of the substance reaching the lungs and being deposited, in theory no clear evidence is given that absorption may be hindered. So, if absorption was not limited by physicochemical parameters, a similar absorption rate a via the oral route, i.e. 100%, could be assumed. Due to the physicochemical limitations however, an inhalative absorption of approx. 10% can be assumed as a worst case. So as inhalation was stated to be regarded only in theory, the theoretical absorption will be taken into account for further assessment.
Due to ciliary movements in the upper respiratory tract, the secretion of possibly deposed material with a subsequent swallowing and hence oral exposure after inhalation has to be additionally regarded.

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.
In case of Amines, C12-14-tert-alkyl, reaction products with O,O-di-C1-14-alkyl hydrogen phosphorodithioate, an evaporation after skin contact does not need to be regarded due to the 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.
In contact with the moist skin, it can be reasonably assumed that the substance will be present in its dissociated form, and the constituents need to be regarded separately. Due to its rather high molecular weight of 527.90 g/mol to 555.95 g/mol, the non-dissociated form would not be able to penetrate the skin anyway.
With a molecular weight of 353.54 g/mol (O,O-Di-C1-14-alkyl hydrogen phosphorodithioate) resp. between 172.33 g/mol (C12) and 200.38 g/mol (C14) (Amines, C12-14-tert-alkyl) in theory absorption via the skin and hence a default dermal absorption rate of 100% [ECHA, 2008] could be assumed. With a logPow of 4.80 of the O,O-di-ethylhexyl hydrogen phosphorodithioate anion, its absorption may be hindered, but the logPow of 2.43 for the Amine, C12-14-tert-alkyl cation content indicates a non hindered absorption. So as the absorption of at least the amine part can be considered rather high, and it cannot be unambiguously determined which part of the molecule is responsible for possible effects, a precautionary dermal absorption rate of 100% will be assumed.

Details on distribution in tissues:

Distribution
In general, it can be stated that the smaller the molecule, the wider is its distribution. A lipophilic molecule (Log Pow >0) is likely to distribute into cells and the intracellular concentration may be higher than extracellular concentration particularly in fatty tissues. It is not possible to foresee protein binding, which can limit the amount of a substance available for distribution. ToxTree modelling [Ideaconsult Ltd, 2004-2013] revealed no protein or DNA binding alerts, so covalent binding to the tissues and hence remaining bond in the body is unlikely. Furthermore, if a substance undergoes extensive first-pass metabolism, predictions made on the basis of the physico-chemical characteristics of the parent substance may not be applicable.
In case of Amines, C12-14-tert-alkyl, reaction products with O,O-di-C1-14-alkyl hydrogen phosphorodithioate, no quantitative data is available for distribution patterns. Taking into account the molecular weights of the present ions after dissociation, i.e. 353.54 g/mol (O,O-Di-C1-14-alkyl hydrogen phosphorodithioate) resp. between 172.33 g/mol (C12) and 200.38 g/mol (C14) (Amines, C12-14-tert-alkyl), the moderate to high logPow values and water solubility of 10.5 or 13 mg/l, a certain systemic bioavailability is given, and expected to be more extensive in fat tissues than in other tissues, especially when absorption occurred while bypassing the liver.
After oral exposure, the first target will be the gastrointestinal tract, where the substance will be absorbed in small quantities and transferred via the blood stream to the liver. After first pass metabolism (see 3.4), 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 will be affected. In general, the estimated metabolites are slightly more hydrophilic due to the hydroxyl groups, which is however expected to be of minor importance. Since the absorption via the GI tract of the substance and is rather complete, a high peak exposure to the compound(s) and hence high systemic bioavailability can be expected. However, due to their tendency to be excreted rather fast after conjugation, a very high AUC is not to be expected. This applies to all three possible exposure routes, although the formation of metabolites will be most relevant for the oral route. The affection of the lymphatic system via micellar uptake however is only of minor importance.
After absorption of the parent compound via other routes, only a subsequent metabolism has to be taken into account, also leading to no relevant peak exposure.
These conclusions are based on the physico-chemical properties of the substance, and which are also applicable for its metabolites, are furthermore supported by the results of the repeated dose / reproductive toxicity OECD 422 study. Besides local effects on the stomach, effects on ALT, AST, ALP and bile acid levels were noted, liver, adrenal, heart and spleen weights were affected, and there were histopathological findings in liver, kidneys, stomach and thyroids. Also, slightly impaired bodyweight gain and food consumption were seen at the high dose group, which clearly shows that the substance was distributed throughout the body. As a consequence, a wide distribution of the test items throughout the body can be reasonably assumed.

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 Amines, C12-14-tert-alkyl, reaction products with O,O-di-C1-14-alkyl hydrogen phosphorodithioate no data is available regarding its elimination. Concerning the above mentioned behaviour predicted for its metabolic fate, it is unlikely that the parent substance resp. its dissociated ions will be excreted unchanged. However, if unchanged excretion is assumed, based on the chemical structure of the constituents, an excretion of the amine part via the urine is highly likely, and also only minor portions of the anion will be excreted via the bile, which could possibly be subject to enterohepatic recycling. Regarding the metabolites of Amines, C12-14-tert-alkyl, reaction products with O,O-di-C1-14-alkyl hydrogen phosphorodithioate, a elimination of the Phase 2 conjugated metabolites via the urine is expected.

Metabolites identified:

yes

Details on metabolites:

For details, see attached file. The metabolites of the substance is estimated to be formed via aliphatic hydroxylation (cation) and desulphurization of phosphor, O-dealkylation, and aliphatic hydroxylation (anion).

See attached expert statement.

Conclusions:

The present expert statement covers all relevant toxicokinetic parameters to assess the behaviour of Amines, C12-14-tert-alkyl, reaction products with O,O-di-C1-14-alkyl hydrogen phosphorodithioate in the body, the available information is sufficient to enable one to perform a proper further assessment. Hence, no further information needs to be gathered and further studies can be omitted due to animal welfare. In conclusion, the substance has a minor potential for bioaccumulation in its non-metabolized or metabolized form.

Executive summary:

In order to assess the toxicokinetic behaviour of Amines, C12-14-tert-alkyl, reaction products with O,O-di-C1-14-alkyl hydrogen phosphorodithioate, the available toxicological and physico-chemical data were evaluated.

The substance is expected to be present dissociated upon contact with water into the O,O-di-ethylhexyl hydrogen phosphorodithioate anion and the Amines, C12-14-tert-alkyl cation, which is well absorbed via the oral route. An oral absorption rate of 100% was estimated as especially the amine part of the substance is favourable for absorption due to its moderate logPow. Due to low vapour pressure of the liquid, the inhalation practically does not have to be regarded, however in theory it has a potential for absorption via respiratory tract epithelium. As a consequence, a theoretical inhalative absorption rate of 100% can be estimated. Taking into account its slight water solubility and the moderate logPow of the amine part, a dermal absorption rate of 100% can be assumed.

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

-      Absorption via oral route: 100%

-      Absorption via inhalative route: 100%

-      Absorption via dermal route: 100%

Taking into account the molecular weights of the present ions after dissociation, a certain systemic bioavailability is given, which is supported by systemic effects in various systems noted. Metabolism is not expected to alter this behaviour essentially. A wide distribution of the test items throughout the body can be reasonably assumed.

The estimated Cytochrome P450 metabolites of the main constituents of the substance are formed via aliphatic hydroxylation (cation) and desulphurization of phosphor, O-dealkylation, and aliphatic hydroxylation (anion), and need to be regarded, too, as either a first-pass metabolism or a metabolism by other tissues is expected to occur. The metabolites formed are not expected to modify essentially the molecular weights, physico-chemical properties and hence ADME behaviour of the substance. A slightly facilitated distribution may be given for the direct metabolites, which are expected to be conjugated to glucuronic acid, activated sulphate or activated methionine. A prolonged, extensive accumulation is not expected. Regarding the metabolites of Amines, C12-14-tert-alkyl, reaction products with O,O-di-C1-14-alkyl hydrogen phosphorodithioate, a elimination of the Phase 2 conjugated metabolites via the urine is expected.

In conclusion, Amines, C12-14-tert-alkyl, reaction products with O,O-di-C1-14-alkyl hydrogen phosphorodithioate has a not very high potential for bioaccumulation, and will be excreted after metabolism.

Description of key information

Expert statement: Amines, C12-14-tert-alkyl, reaction products with O,O-di-C1-14-alkyl hydrogen phosphorodithioate has a minor potential for bioaccumulation. The relevant absorption rates can be estimated by expert judgement to 100% (oral), 100% (dermal) and 100% (inhalation).

Key value for chemical safety assessment

Bioaccumulation potential:

low bioaccumulation potential

Absorption rate - oral (%):

100

Absorption rate - dermal (%):

100

Absorption rate - inhalation (%):

100