Phosphorous trichloride, reaction products with 1,1'-biphenyl and 2,4-bis(1,1-dimethylethyl)phenol

Basic toxicokinetics

Administrative data

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

Data source

Reference

Reference Type:

other: expert statement

Title:

Unnamed

Year:

2016

Report date:

2016

Materials and methods

Objective of study:

absorption

distribution

excretion

metabolism

toxicokinetics

Test guideline

Qualifier:

no guideline required

Principles of method if other than guideline:

An extensive assessment of the toxicokinetic behaviour of Reaction products of phosphorous trichloride, with 1,1-biphenyl and 2,4-bis(1,1-dimethylethyl)phenol was performed, taking into account the chemical structure, the available physico-chemical and toxicological data.

GLP compliance:

no

Test material

Test material information

Constituent 1

Reference substance name:

-

EC Number:

432-130-2

EC Name:

-

Cas Number:

119345-01-6

Molecular formula:

Not applicable ( a generic molecular formula cannot be provided for this UVCB substance)

IUPAC Name:

Reaction products of phosphorous trichloride, with 1,1′-biphenyl and 2,4-bis(1,1- dimethylethyl)phenol

Test material form:

solid: particulate/powder

Remarks:

migrated information: powder

Details on test material:

not applicable

Radiolabelling:

other: not applicable

Test animals

Species:

other: not applicable

Strain:

other: not applicable

Details on test animals or test system and environmental conditions:

not applicable

Administration / exposure

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

Doses / concentrations

Remarks:

Doses / Concentrations:
not applicablenot 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

Results and discussion

Main ADME results

Main ADME results 1

Type:

absorption

Results:

The relevant absorption rates were estimated to: Oral absorption: approx. 20% Dermal absorption: approx. 10% Inhalative absorption: approx. 25%

Main ADME results 2

Type:

distribution

Results:

the absolute systemic bioavailability is rather low and expected to be more extensive in fat tissues than in other tissues. A rather minor absorption is indicated, , no relevant peak exposure, AUC and prolonged bioavailability will occur.

Main ADME results 3

Type:

metabolism

Results:

The sites of metabolism of the all parent compounds were identified as the aromatic rings, aromatic hydroxylation is the most likely scenario for Phase-I-metabolism.

Main ADME results 4

Type:

excretion

Results:

After metabolism, the excretion of the metabolites, either as such or after Phase 2 metabolism, will occur faster than the parent compounds. The substance will be subject to metabolism by cytochrome P450 enzymes and subsequent conjugation.

Toxicokinetic / pharmacokinetic studies

Details on absorption:

Absorption
In this chapter, the physico-chemical properties of the substance are used to draw general conclusions for its behaviour and how these properties will influence its oral, inhalatory and dermal absorption. Furthermore, these conclusions will be supported by the available literature data and studies.
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.
Available data on the substance of interest indicate that CAS 119345-01-6 is not irritating to the skin and eyes of rabbits [Information from migrated NONS file]. This information is supported by Toxtree estimation on the single components, which were either found to be not irritating or corrosive to skin or not resulting in lesions leading to classification as R34, R35, R36 or R41. Hence, the possibility of an enhanced absorption due to damaged cell membranes can be considered as non-existing.
Due to the lack of experimental absorption data, the following physico-chemical parameters of CAS 119345-01-6 and its constituents will be taken into account when discussing its absorption into the body:
- Molecular weight: average > 500 g/mol, based on values of 646.94 g/mol (CAS 31570-04-4), 1035.44 g/mol (CAS 38613-77-3), 594.82 g/mol (CAS 91362-37-7), 1035.44 g/mol (CAS 118421-00-4), 1035.44 g/mol (CAS 118421-01-5)
- Water solubility: insoluble, based on values of < 1 mg/L at 20 °C [Information from migrated NONS file] (CAS 119345-01-6), 2.854 * 10-14 mg/L at 25°C / 6.47 * 10-7 mg/L at 25°C (CAS 31570-04-4), 1.05 * 10-24 mg/L at 25°C / 1.04 * 10-6 mg/L at 25°C (CAS 38613-77-3), 1.023 * 10-11 mg/L at 25°C / 5.95 * 10-11 mg/L at 25°C (CAS 91362-37-7), 1.05 * 10-24 mg/L at 25°C / 1.04 * 10-6 mg/L at 25°C (CAS 118421-00-4), 1.05 * 10-24 mg/L at 25°C / 1.04 * 10-6 mg/L at 25°C (CAS 118421-01-5)
- Partition Coefficient: Log Pow >6, based on values of > 6 at 20°C (CAS 119345-01-6), 18.08 (CAS 31570-04-4), 27.23 (CAS 38613-77-3), 15.49 (CAS 91362-37-7), 18.08 (CAS 118421-00-4), 18.08 (CAS 118421-01-5)
- Vapour pressure = < 0.000001 Pa
- Melting point = Melting range 85 - 103 °C [Information from migrated NONS file] (CAS 119345-01-6)
- Boiling point = Decomposition at 260 - 280 °C [Information from migrated NONS file] (CAS 119345-01-6)
- Physical state: solid at 20°C and 1013 hPa (CAS 119345-01-6)

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. With a molecular weight of > 500 g/mol (594.82 - 1035.44 g/mol of the single constituents) of CAS 119345-01-6, absorption in general can be considered as hindered, the uptake via micellular solubilisation could occur also in a relevant proportion compared to the uptake via gastrointestinal fluids.
This is supported by the rather high log Pow of > 6, which is above the boundary value of 4, further indicating a hindered absorption e.g. by diffusion. Further, only water-soluble substances will readily dissolve into the gastrointestinal fluids and hence be available for absorption. The substance can be considered as rather insoluble. In summary, this allows the conclusion that the uptake of CAS 119345-01-6 from the gastrointestinal tract is diminished.
The results of the available animal studies with oral application are not suitable to provide clarity on that issue. No indication of toxicity was seen in the EU method B.1 study. In the 28 day repeated dose study, no signs of toxicity were observed either up top the highest dose tested, 1000 mg/kg bw/d. The same applies to the available OECD 421 study. Here, no effects were seen up to the highest dose tested, 10000 ppm in feed, which corresponds to 607.85 mg/kg bw/d in males and 793.98 mg/kg bw/d in females. In consequence, it cannot be concluded whether the lack of effects is due to the inherent low toxicity of the substance or the lack of absorption.
In general, the phosphite and phosphonite groups could be susceptible for hydrolysis, but due to the lack of solubility in water, this possibility may be neglected and only the parent compounds should be regarded, so, another possibility for GI uptake was excluded.
So in summary, as there is only indication given that CAS 119345-01-6 is poorly absorbed and only micellular solubilisation by bile salts needs to be regarded, the absorption rate via oral application can be in a precautionary approach estimated to 20%, probably overestimating the actual oral absorption.

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].
CAS 119345-01-6 has a very low vapour pressure of < 0.000001 Pa (estimation) and decomposes at 260 - 280 °C before boiling [Information from migrated NONS file], showing clearly that the inhalative absorption as a gas does not have to be regarded. 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 (or a boiling point above 150°C) [ECHA, 2008].
The substance, however, is commonly distributed in powder form, and although precautions are taken to avoid dusting, exposure may occur accidently. So in order to estimate the potential of the substance to be absorbed via the inhalatory route for this rare cases, its physico-chemical properties will be taken into account. According to particle size distribution measurement by laser diffraction (dry method), the average particle size of the test substance is 39.609 µm (D10 = 2.119 µm, D50 = 15.735 µm, D90 = 107.745 µm). So, the inhalation of particles has to be regarded:

- ~ 89% are <100 µm (inhalable fraction)
- ~ 40% are <10 µm (thoracic fraction)
- ~19% are < 4µm (respirable fraction)

In humans, particles with aerodynamic diameters below 100 μm have the potential to be inhaled. Particles with aerodynamic diameters below 50 (40) μm may reach the thoracic region and those below 15 (4) μm the alveolar region of the respiratory tract [ECHA, 2008] ([ECHA, 2015]). As a consequence, there is a certain fraction reaching the alveolar region of the respiratory tract beyond the bronchi, where no mechanical excretion mechanism as the ciliary movements is available. 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 relevant here. 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 favorable for absorption. Generally, liquids, solids in solution and water-soluble dusts would readily diffuse/dissolve into the mucus lining the respiratory tract.
Hence, with a logPow of > 6, and by being practically insoluble in water, CAS 119345-01-6 does not fulfil the criteria of being perfectly absorbed via the lungs. However, an immediate absorption by micellular solubilisation still needs to be regarded.
As a consequence, the potential absorption of the single compounds can be estimated with a certain precaution due to the lack of toxicokinetic test data to an absorption rate of up to 25%.

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 CAS 119345-01-6, evaporation after skin contact does not need to be regarded due to the high decomposition temperature and very low vapour pressure, and hence it can be assumed that the substance will remain on the skin until mechanical removal. The substance was tested to be not irritating to the skin and eyes of rabbits [Information from migrated NONS file]. Hence, an enhanced dermal absorption due to irritating / corrosive properties does not need to be regarded.
With a molecular weight of > 500 g/mol (594.82 - 1035.44 g/mol of the single constituents), only a minor absorption via the skin and hence a dermal absorption rate of ca. 10% could be assumed. Taking further into account the very high logPow of > 6, a slow uptake into the stratum corneum and a negligible transfer between the stratum corneum and the epidermis and hence very hindered dermal absorption can be assumed. Last but not least, the insolubility in water attributes furthermore to the very hindered dermal absorption as it limits the uptake and partition from the stratum corneum into the epidermis and subsequent blood vessels.
In consequence, a very low dermal absorption rate of 10% can 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. 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 CAS 119345-01-6, no quantitative data is available for distribution patterns. Taking into account its molecular weight of > 500 g/mol (594.82 - 1035.44 g/mol of the single constituents), its very lipophilic character and water insolubility, the absolute systemic bioavailability is rather low 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 single compounds and possibly bacterial metabolites will be absorbed in rather small quantities and transferred via the blood stream to the liver. After first pass metabolism, the substances 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.
Since the solubility and hence absorption via the GI tract of the parent compounds is rather limited, an excessive formation of their metabolites is unlikely and so is a peak exposure to the metabolites. Due to their tendency to be excreted rather fast compared to the parent compounds as they are expected to bear additional hydroxyl groups, also a relevant AUC is not to be expected. After absorption of the parent compounds via other routes, only a subsequent metabolism has to be taken into account, also leading to no relevant peak exposure.
Based on the available repeated dose toxicity data, no additional information can be gathered, as no effects were seen which may allow any conclusions on predominantly affected organs or tissues.

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 ionised 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-ionised 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 CAS 119345-01-6 no data is available regarding its elimination. Concerning the above mentioned behaviour predicted for its metabolic fate, it is unlikely that the parent substance will be excreted unchanged after resorption via the GIT occurred. However, if unchanged excretion is assumed, i.e. non-absorbed molecules which have not been metabolised by gut bacteria, based on the chemical structure of CAS 119345-01-6 components, their high molecular weight and non-existent water solubility, it is unlikely to be excreted via the urine. The excretion, if any, of the parent compounds will occur via the gastrointestinal tract (unabsorbed material) and the bile (small amounts of unchanged compound), and it could be subject to enterohepatic recycling. Also, assuming a Phase I/II metabolism for CAS 119345-01-6, an excretion via the urine is less likely due to its rather high molecular weight, i.e. > 500 g/mol.

Metabolite characterisation studies

Metabolites identified:

yes

Details on metabolites:

For details, see attached file. Metabolites of the substance are estimated to be formed mainly via aromatic hydroxylation.

Any other information on results incl. tables

See attached expert statement.

Applicant's summary and conclusion

Conclusions:

Interpretation of results (migrated information): low bioaccumulation potential based on study results
The present expert statement covers all relevant toxicokinetic parameters to assess the behaviour of CAS 119345-01-6 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, CAS 119345-01-6 has no potential for bioaccumulation in its non-metabolized or metabolized form.

Executive summary:

In order to assess the toxicokinetic behaviour of CAS 119345-01-6 (Phosphorous trichloride, reaction products with 1,1'-biphenyl and 2,4-bis(1,1-methylethyl)phenol, EC No. 432-130-2), the available toxicological and physico-chemical data were evaluated and additional information gathered via QSAR estimation.

CAS 119345-01-6 is expected to be rather poorly absorbed via the oral route. With a molecular weight > 500 g/mol, absorption in general can be considered as minor. The Log Pow > 6 indicates a hindered absorption e.g. by diffusion, and the very low water solubility a low bioavailability. The presence of absorption could not be indicated by any effects observed in animal studies.

Based on the chemical structure CAS 119345-01-6, hydrolysis may to be taken into account, but due to the limited water solubility a sufficient amount would not be available to undergo relevant hydrolysis.

The solid CAS 119345-01-6 has a very low vapour pressure and decomposes at 260-280°C before boiling, showing that the inhalative absorption as a gas does not have to be regarded. Its particle size distribution however indicates, upon accidental exposure, that a relevant proportion (~19% are < 4µm) may reach the alveolar region, where no mechanical excretion mechanism as the ciliary movements is available. Due to the high logPow > 6, and its insolubility in water, immediate absorption by micellular solubilisation has to be assumed,butCAS 119345-01-6 does not fulfil the criteria of being perfectly absorbed via the lungs, hence,a precautionary absorption rate of up to 25% can be estimated.

In case of CAS 119345-01-6, neither evaporation after skin contact nor very remarkable additional absorption-enhancing effects due to corrosivity need to be regarded. Taking into account the high molecular weight, high Log Pow and very low water solubility, a passage of the compound through all layers of the skin is unlikely. So, only a minor absorption rate of 10% needs to be taken into account.

Taking into account the molecular weight of > 500 g/mol (594.82 - 1035.44g/mol of the single constituents), the very lipophilic character and poor water solubility, the absolute systemic bioavailability is rather low and expected to be more extensive in fat tissues than in other tissues. As, if any, more hydrophilic metabolites are expected to occur, and a rather minor absorption of CAS 119345-01-6 is indicated, no relevant peak exposure, AUC and prolonged bioavailability will occur.

CAS 119345-01-6 has a minor potential for bioaccumulation in its non-metabolised form as absorption is hindered, and will be excreted accompanying / subsequent metabolism. The relevant absorption rates were estimated to:

Oral absorption: approx. 20%

Dermal absorption: approx. 10%

Inhalative absorption: approx. 25%