A mixture of: 2,2,6,6-tetramethylpiperidin-4-yl-hexadecanoate; 2,2,6,6-tetramethylpiperidin-4-yl-octadecanoate

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics

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:

2014

Report date:

2014

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 mass of 2,2,6,6-tetramethylpiperidin-4-yl-hexadecanoate and 2,2,6,6-tetramethylpiperidin-4-yl-octadecanoate 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:

A mixture of: 2,2,6,6-tetramethylpiperidin-4-yl-hexadecanoate; 2,2,6,6-tetramethylpiperidin-4-yl-octadecanoate

EC Number:

415-430-8

EC Name:

A mixture of: 2,2,6,6-tetramethylpiperidin-4-yl-hexadecanoate; 2,2,6,6-tetramethylpiperidin-4-yl-octadecanoate

Cas Number:

86403-32-9

Molecular formula:

C25H49NO2 C27H53NO2

IUPAC Name:

Reaction mass of 2,2,6,6-tetramethylpiperidin-4-yl hexadecanoate and 2,2,6,6-tetramethylpiperidin-4-yl octadecanoate

Test material form:

other: not applicable

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 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

Results and discussion

Main ADME results

Main ADME results 1

Type:

absorption

Results:

The relevant absorption rates were, also with regard to the hydrolysis products of SABOSTAB UV-91, estimated to: Oral absorption: approx. 80% Dermal absorption: approx. 30% Inhalative absorption: approx. 30%, provided that aerosols are formed

Main ADME results 2

Type:

distribution

Results:

The absolute systemic bioavailability of the unchanged SABOSTAB UV-91 is rather low . A rapid distribution of both the hydrolysis products and their metabolites in the aqueous compartments of the body is expected as well as a rapid excretion.

Main ADME results 3

Type:

metabolism

Results:

The substance is expected to hydrolyze into 2,2,6,6-Tetramethylpiperidin-4-ol and Palmitic Acid resp. Stearic Acid, the former will be degraded by Amine hydroxylation, Alcohol oxidation and Aliphatic hydroxylation.

Main ADME results 4

Type:

excretion

Results:

The substance has a minor potential for bioaccumulation in its non-metabolized form, and will be excreted rapidly after hydrolysis and accompanying / subsequent metabolism.

Toxicokinetic / pharmacokinetic studies

Details on absorption:

Absorption

Here, 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.
SABOSTAB UV-91 is slightly to moderately irritating to the skin of rabbits, but not sufficient for classification, and is severely irritating to the eyes of rabbits [Information from migrated NONS file]. Hence, the possibility of an enhanced absorption due to damaged cell membranes can be considered as less likely, but cannot be excluded.
Due to the lack of experimental absorption data, the following physico-chemical parameters of SABOSTAB UV-91 will be taken into account when discussing its absorption into the body:
- Molecular weight = 395.67 g/mol resp. 423.73 g/mol
- Water solubility = approx. 0.5 mg/L (at 20°C and pH=7.5); due to hydrolysis and adsorption onto glass, the water solubility is assumed to be lower than the measured value, probably even < 0.1 mg/L; slightly soluble (0.1-100 mg/L) [Information from migrated NONS file]
- Partition Coefficient Log Pow > 6.5 (at 40°C and pH7) [Sabo S.r.l., 2009]
- Vapour pressure = 0.037 Pa at 20°C, 0.049 Pa at 23.67°C, 0.051 Pa at 25°C (estimated), 0.07 Pa at 29.75°C, 0.26 Pa at 50°C [Information from migrated NONS file]
- Melting point = 29.6 °C [Information from migrated NONS file]
- Boiling point = 246°C at 39 kPa [Information from migrated NONS file]
- Physical state: waxy solid

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 395.67 g/mol resp. 423.73 g/mol, absorption in general can be considered as possible.
However, taking into account the Log Pow of > 6.5 (at 40°C and pH7), the absorption e.g. by diffusion might be hindered. Despite the fact that the partition coefficient should be determined at a temperature in the range 20 to 25°C, the available value at 40°C is considered as the more relevant one as it is closer to the average body temperature. In addition, the moderate temperature dependence of the Log Pow is in the present magnitude of the value, i.e. >6.5, not considered relevant enough to potentially modify the absorption parameters in a biological system.
Only water-soluble substances will readily dissolve into the gastrointestinal fluids and hence be available for absorption. The water solubility was determined to be approx. 0.5 mg/L (at 20°C and pH=7.5), but is assumed to be lower due to hydrolysis and adsorption onto glass, probably even < 0.1 mg/L [Information from migrated NONS file]. Hence, only taking into account the slight solubility of the substance, absorption can be considered diminished. Furthermore, as absorption onto the glass and hence very likely also on the intestinal surfaces were taken into account, and additionally a rapid hydrolysis needs to be considered, it can be concluded that the parent compound has a limited potential for absorption via the GI tract, based on its physic-chemical properties.
Taking into account the results of two GLP acute oral toxicity studies according to OECD guideline 401, no additional conclusions regarding absorption can be made. The oral LD50 in both rats and mice was determined to be >10.000 mg/kg bw, no deaths or other adverse effects on organs or general toxicity were observed [Information from migrated NONS file]. This could be either due to the intrinsic non-toxicity of the test item or due to a poor absorption. The results of the oral 28 day subacute study however are indicative for absorption via the GI tract, as clearly effects could be observed beginning from the median dose of 200 mg/kg bw/day, e.g. skin turgor. The conclusions which can be drawn from these effects regarding the toxicokinetic behaviour of the substance will be discussed in detail later on.
Considering the chemical structure of the substance, both compounds bear as a functional group a carboxylic acid ester. Aliphatic and aromatic carboxylic acid esters are in general potentially susceptible to hydrolysis. As indications were present i.a. during water solubility testing that hydrolysis occurs, one must also consider the uptake of the hydrolysis products. Most likely those are 2,2,6,6-Tetramethylpiperidin-4-ol (C9H19NO, CAS 2403-88-5, MW = 157.25326) and Palmitic Acid (C16H32O2, CAS 57-10-3, MW = 256.42408) resp. Stearic Acid (C18H36O2, CAS 57-11-4, MW = 284.47724). Due to the partly lack of experimental data, some of the relevant properties were estimated using EpiSuite v4.10 (US EPA, 2000-2008).

Tab. 1: Selected properties of hydrolysis products
Property 2,2,6,6-Tetramethylpiperidin-4-ol Palmitic Acid Stearic Acid
Molecular weight 157.25 256.42 284.48
Water solubility > 100 g/L (at 25°C) 0.04 mg/L (25°C) 0.597 mg/L (25°C)
Partition Coefficient Log Pow 0.24 (at 25°C) 7.17 8.23
Vapour pressure 2.6×10-1 Pa (25°C) 5.07E-005 Pa (25°C) 9.63E-005 Pa (25°C)
Melting point 130.6°C 4 61.8°C 68.8°C
Boiling point 212 - 215 °C (1,013 hPa) 351.5°C 383°C
pH value 0.01 % solution = 10.22 n/a n/a
0.1 % solution = 10.93
1.0 % solution = 11.47
LD50oral 1482 mg/kg (male rats) > 10 gm/kg (rat) ³ 4.64 gm/kg (rat)
1564 mg/kg (female rats) 4 > 5 gm/kg (rabbit) ³

Similar to the parent compound, the low molecular weight of all three hydrolysis products make them favourable for absorption. The uptake of the fatty acids seems to be limited due to their low water solubility and high Log Pow at first glance. However, since triglycerides and hence their cleavage products (via the enzyme lipase), i.e. the free fatty acids, are part of the daily diet and required for nutrition, transport systems have been developed. Fatty acids associate with bile salts and phospholipids to form micelles which are necessary because they transport the poorly soluble fatty acids to the surface of the enterocyte where they can be absorbed via diffusion or specific transporters. However, since these fatty acids are not toxicologically relevant, as they are non-toxic (see table 1) and required for nutrition, their toxicokinetic and –dynamic fate can be neglected. The other hydrolysis product, 2,2,6,6-Tetramethylpiperidin-4-ol, is considered toxicologically more relevant. Taking into account the rather high water solubility and Log Pow of 0.94, its oral uptake must be considered as well. This is considered to occur mainly via diffusion, less via micellular uptake, and hence it will be transported directly via the portal vein to the liver, where its Cytochrome P450 metabolism should be regarded (see chapter 3.4 Metabolism).
The exact hydrolysis rate, however, is unknown, and it cannot be stated in detail, to which extent the absorption of the hydrolysis products needs to be regarded. Taking into account only the absorption of the parent compound without hydrolysis, the oral absorption can be considered as limited, allowing an estimation of approx. 25%. Since hydrolysis is nevertheless a very likely scenario, the degradation products and their uptake should be considered, too. This leads to the estimation of a precautionary absorption rate of approx. 80%, probably overestimating the actual oral absorption.
In the 28 day repeated dose toxicity study in rats, a hyperplasia of the mucosa in the duodenum was detected as well as a swelling of the duodenum septum in all animals of the high dose groups [Information from migrated NONS file]. This may be seen indicative for a good and early absorption in the GI tract, as no effects were noted neither in the subsequent sections of the small intestine nor the large intestine, supporting the above made estimation.

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].
SABOSTAB UV-91 has a rather low vapour pressure (0.037 Pa at 20°C, 0.049 Pa at 23.67°C, 0.051 Pa at 25°C (estimated), 0.07 Pa at 29.75°C, 0.26 Pa at 50°C [Information from migrated NONS file]) and a boiling point of 246°C at 39 kPa [Information from migrated NONS file], showing that the inhalative absorption as a gas does not have to be regarded.
In addition, it is a waxy solid, i.e. not particles of an inhalable size are expected to be present. In humans, particles with aerodynamic diameters below 100 μm have the potential to be inhaled [ECHA, 2008], which is not relevant here. In addition, there is only a very limited potential for inhalation during use, e.g. the aerosol formation of solutions of SABOSTAB UV-91 is very low. Nevertheless, 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.
With a Log Pow of > 6.5 (at 40°C and pH7) [Information from migrated NONS file], even solved molecules of SABOSTAB UV-91 have a minimal potential for absorption via respiratory tract epithelium by micellular solubilisation. The same applies for the possible hydrolysis products palmitic and stearic acid. Also, without having concrete droplet sizes of potential aerosols, no statements regarding the deposition place and hence place-specific clearance mechanisms, e.g. ciliary movements, can be made. 2,2,6,6-Tetramethylpiperidin-4-ol with a Log Pow of 0.24 however, has a certain potential for absorption, and may be formed in the aqueous environment of the lung epithel.
As a consequence, although the absorption of the parent compound can be neglected and the concrete hydrolysis rate is not available, a precautionary absorption rate of up to 30% can be estimated.

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 SABOSTAB UV-91, an evaporation after skin contact does not need to be regarded due to the high boiling point and 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 slightly to moderately irritating to the skin of rabbits, but the effects are not sufficient to be classified as skin irritant [Information from migrated NONS file]. It is severely irritating to the eyes of rabbits, triggering classification as corrosive to the eye [Information from migrated NONS file]. Hence, although not classified as skin irritant, a slightly enhanced uptake upon irritation after skin contact compared to a non-irritating substance with similar physico-chemical properties should be taken into account.
With a molecular weight of 395.67 g/mol resp. 423.73 g/mol, a high absorption via the skin and hence a default dermal absorption rate of 100% [ECHA, 2008] could be assumed.
Taking into account a Log Pow of > 6.5 (at 40°C and pH7) and a water solubility ≤ 0.5 mg/L (20°C, pH 7), it can be concluded that the uptake into the stratum corneum will be high, but a further passage into the epidermis and subsequent blood vessels will be hindered due to the high Log Pow and slight solubility in water. Also, the results from the water solubility testing hint to an absorption onto the surface as well as hydrolysis. In addition, dry particulates will have to dissolve into the surface moisture of the skin before uptake can begin [ECHA, 2008].
Upon contact with the moisturized skin, solubilisation and subsequent hydrolysis need to be taken into account, and hence the physico-chemical properties of the proposed hydrolysis products 2,2,6,6-Tetramethylpiperidin-4-ol, Palmitic Acid resp. Stearic Acid. Regarding the fatty acids, similar considerations apply as for the parent compound, and hence an uptake of the toxicologically less relevant degradation products can be considered as minor.
2,2,6,6-Tetramethylpiperidin-4-ol, on the other hand, has a molecular weight of 157.25, a high water solubility (> 100 g/L at 25°C), a Log Pow of 0.24 (at 25°C), and a 1.0% solution has a pH value of 11.47, which probably triggers slightly irritating effects. Although the Log Pow is slightly below 1 and hence its uptake into the stratum corneum might be slightly hindered, this hydrolysis product can considered to be absorbable via the skin.
Regarding solely the absorption of the parent compound without hydrolysis, the dermal absorption can be considered as hindered, probably only triggering an absorption rate of 10% max. Since hydrolysis is nevertheless a likely scenario, the degradation products and their uptake should be considered, too. Since the concrete hydrolysis rate is not available, the absorption rate of SABOSTAB UV-91 including its toxicologically more relevant hydrolysis product 2,2,6,6-Tetramethylpiperidin-4-ol is most likely in the range of 30%.

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 SABOSTAB UV-91, no quantitative data is available for distribution patterns. Taking into account its medium molecular weight of 395.67 g/mol resp. 423.73 g/mol, its lipophilicity and poor water solubility, 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. Taking into account most likely occurring hydrolysis, however, the systemic bioavailability of the hydrolysis products, especially 2,2,6,6-Tetramethylpiperidin-4-ol, is rather high.
After oral exposure, the first target will be the gastrointestinal tract, where the parent compound, its hydrolysis products and possibly bacterial metabolites will be absorbed in small (SABOSTAB UV-91) or high (2,2,6,6-Tetramethylpiperidin-4-ol) 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.
However, the estimated hydrolysis products and metabolites are much smaller and hydrophilic due to the hydroxyl groups, so that a possible accumulation can be neglected. The resulting fatty acids however will be taken up via chylomicrons and either stored in adipocytes or broken down, which is a normal biological process occurring. Since the solubility and hence absorption via the GI tract of the parent compound is rather limited, an excessive formation of its metabolites is unlikely and so is a peak exposure to the metabolites. Due to their tendency to be excreted rather fast, also a relevant AUC is not to be expected. 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. An accumulation of the parent compound in all directly and indirectly (general supply via bloodstream) involved organs does not need to be considered excessively as it is not considered hydrolytically stable.
Since the uptake of all three hydrolysis products is favoured, a certain peak exposure of both the hydrolysis products and their metabolites is expected. Nevertheless, due to the high water solubility of 2,2,6,6-Tetramethylpiperidin-4-ol and the furthermore expected high solubility of the metabolites due to their hydroxyl groups, a rapid distribution in the aqueous compartments of the body is expected as well as a rapid excretion.
Taking into account the results of the 28 day repeated dose toxicity study in rats, i.e. the fact that two females of the high dose group did not show the ear reflex, increased activities for ALAT in the males of the high dose group, an increase of the number of thrombocytes and an enlargement of the prothrombin time [Information from migrated NONS file], a body-wide distribution is indicated. Especially the increased ALAT activity is indicative for liver involvement, which supports the assumption of a substance uptake via the portal vein and afterwards, most likely after first pass metabolism, a body-wide distribution via the blood stream.

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 SABOSTAB UV-91 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. However, if unchanged excretion is assumed, based on the chemical structure of SABOSTAB UV-91, its molecular weight and its non-existent water solubility, it is unlikely to be excreted via the urine. The excretion, if any, of the parent compound will occur via the gastrointestinal tract (unabsorbed material) and the bile (small amounts of unchanged compound), and it could be subject to enterohepatic recycling.
Regarding the hydrolysis products of SABOSTAB UV-91 and their metabolites, either a fast excretion for the unconjugated metabolites containing hydroxyl groups, or a fast elimination of the Phase 2 conjugated metabolites, which applies mainly to the ketone, but also to the metabolites containing hydroxyl groups.

Metabolite characterisation studies

Metabolites identified:

yes

Details on metabolites:

Considering the chemical structure of the substance, both compounds bear as a functional group a carboxylic acid ester. Aliphatic and aromatic carboxylic acid esters are in general potentially susceptible to hydrolysis. As indications were present i.a. during water solubility testing that hydrolysis occurs, one must also consider the uptake of the hydrolysis products. Most likely those are 2,2,6,6-Tetramethylpiperidin-4-ol (C9H19NO, CAS 2403-88-5, MW = 157.25326) and Palmitic Acid (C16H32O2, CAS 57-10-3, MW = 256.42408) resp. Stearic Acid (C18H36O2, CAS 57-11-4, MW = 284.47724). Due to the partly lack of experimental data, some of the relevant properties were estimated using EpiSuite v4.10 (US EPA, 2000-2008).

Route specific toxicity results from several phenomena, such as hydrolysis within the gastrointestinal or respiratory tracts, also metabolism by gastrointestinal flora or within the gastrointestinal tract epithelia (mainly in the small intestine), respiratory tract epithelia (sites include the nasal cavity, tracheo-bronchial mucosa [Clara cells] and alveoli [type 2 cells]) and skin.
First of all, an at least partial hydrolysis of the ether bonds may occur in the acidic, aqueous environment and elevated temperature (approx. 37°C) of the stomach.
Due to the lack of experimental data, Cytochrome P450 mediated metabolism was estimated by the Toxtree modelling tool [Ideaconsult Ltd, 2004-2013]. The sites of metabolism of the parent compound were identified as the amine group and any aliphatic moiety.

Furthermore, the sites of metabolism were identified for the hydrolysis products, i.e. 2,2,6,6-Tetramethylpiperidin-4-ol, which will be degraded by Amine hydroxylation, Alcohol oxidation and Aliphatic 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 'Reaction mass of 2,2,6,6-tetramethylpiperidin-4-yl-hexadecanoate and 2,2,6,6-tetramethylpiperidin-4-yl-octadecanoate' 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, 'Reaction mass of 2,2,6,6-tetramethylpiperidin-4-yl-hexadecanoate and 2,2,6,6-tetramethylpiperidin-4-yl-octadecanoate' has no potential for bioaccumulation in its non-metabolized form, and the incorporation of its metabolites does not bear any potential for adverse effects but is also required to maintain the normal functionality of the body.

Executive summary:

In order to assess the toxicokinetic behaviour of SABOSTAB UV-91, the available toxicological and physico-chemical data were evaluated.

The substance, i.e. the unchanged parent compound, is expected to be rather poorly absorbed via the oral route, taking into account the Log Pow of > 6.5 (at 40°C and pH7) and the poor water solubility. However, a hydrolysis of the parent compounds needs to be taken into account, which would lead to the formation of 2,2,6,6-Tetramethylpiperidin-4-ol and the fatty acids palmitic acid resp. stearic acid. The fatty acids are also regularly fed for nutrition and will be subjected to the naturally present process of the fatty acid metabolism. Consequently, these two substances do not need to be regarded further.The low molecular weight of 2,2,6,6-Tetramethylpiperidin-4-ol, its rather high water solubility and Log Pow of 0.94, however, make it very favourable for oral absorption.Taking the hydrolysis products also into account leads to the estimation of a precautionary absorption rate of approx. 80%, probably overestimating the actual oral absorption.

The inhalative absorption of the waxy solid SABOSTAB UV-91 as a gas does not have to be regarded. Thinking of a possible inhalation of an aerosol with the solved hydrolysis product 2,2,6,6-Tetramethylpiperidin-4-ol, however, a precautionary absorption rate of up to 30% can be estimated. Regarding dermal absorption, a passage of the unchanged SABOSTAB UV-91through the stratum corneum is unlikely. 2,2,6,6-Tetramethylpiperidin-4-ol, on the other hand, has a relevant potential in general to be absorbed through the skin. Hence, the absorption rate of SABOSTAB UV-91 including its toxicologically more relevant hydrolysis product 2,2,6,6-Tetramethylpiperidin-4-ol is most likely in the range of 30%.

The absolute systemic bioavailability of the unchanged SABOSTAB UV-91 is rather low and expected to be more extensive in fat tissues than in other tissues. The systemic bioavailability of the hydrolysis products, especially 2,2,6,6-Tetramethylpiperidin-4-ol, is rather high, leading toa certain peak exposure of both the hydrolysis products and their metabolites. A rapid distribution in the aqueous compartments of the body is expected as well as a rapid excretion.

Since SABOSTAB UV-91 is not considered hydrolytically stable, a prolonged, extensive accumulation is not expected. After metabolism, the excretion of the metabolites, either as such or after Phase 2 metabolism, will occur rather fast, as well as the unchanged hydrolysis products and their metabolites would, an accumulation is not very likely, too.

Besides Amine hydroxylation and Aliphatic hydroxylation of the parent compound being subject to further hydrolysis, the most likely metabolizing processes for 2,2,6,6-Tetramethylpiperidin-4-ol areAmine hydroxylation, Alcohol oxidation (resulting in2,2,6,6-Tetramethyl-4-piperidone) and Aliphatic hydroxylation. In general, it is hence unlikely that the parent substance will be excreted unchanged, the metabolites however will be excreted rather fast either unchanged or as Phase 2 conjugated metabolites via the urine.

In summary, SABOSTAB UV-91 has a minor potential for bioaccumulation in its non-metabolized form, and will be excreted rapidly after hydrolysis and accompanying / subsequent metabolism. The relevant absorption rates were, also with regard to the hydrolysis products of SABOSTAB UV-91, estimated to:

Oral absorption: approx. 80%

Dermal absorption: approx. 30%

Inhalative absorption: approx. 30%, provided that aerosols are formed