D-Glucitol, 1,5-anhydro-1-C-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methylphenyl]-, 2,3,4,6-tetraacetate, (1S)-

Endpoint summary

Description of key information

No toxicokinetic data (animal or human studies) are available on this substance. The data present in this dossier are based on physicochemical and toxicological parameters and will allow a qualitative assessment of the toxicokinetic behaviour of T003066.

Oral absorption of T003066 is expected to be limited based on its high partition coefficient (log Pow 5.5), low water solubility (<2.00 µg/L at 20°C and pH 6.7) and high molecular weight (MW > 500). The assumption of limted absorption is supported by the absence of systemic toxicity after oral absorption in the experiments carried out with T003066.

Based on the physicochemical properties and the absence of systemic toxicity after oral administration, the oral absorption factor is considered to be 50%.

Based on its low MMAD (7.638 µm), T003066 can be considered as a dust and thus has the potential to be inhaled and reach the thoracic region. Due to its low water solubility, the rate at which the particles will dissolve into the mucus will limite the amount that can be absorbed directly. A small amount can be taken up by phagocytosis in the tracheo-bronchal region and engulfed by alveolar macrophages in the alveolar region (which translocate the particles to the ciliated airways or pulmonary interstitium and lymphoid tissues). Its high lipophilic character implies that the product has the potential to be taken up by micellular solubilisation.

Based on the physicochemical properties, the respiratory absorption factor is considered to be 100%. 

Due to its low water solubility (<2.00µg/L) partitioning from the stratum corneum into the epidermis of the skin and therefore dermal absorption is likely to be low. In addition, the rather high molecular weight hampers dermal uptake. However, as T003066 is considered to be a skin sensitizer (category 1B) some uptake must have occurred although it may only have been a small fraction of the applied dose.

Based on the above, low to moderate dermal uptake is expected and thus the dermal absorption factor for T003066 is considered to be 50%.

Information on distribution, accumulation, metabolism and excretion is given below.

Key value for chemical safety assessment

Absorption rate - oral (%):

50

Absorption rate - dermal (%):

50

Absorption rate - inhalation (%):

100

Additional information

T003066 (CAS 866607-35-4) is a white, light yellow powder with a rather high molecular weight (612.68 g/mol), a particle size of 7.638 µm (Mass Median Aerodynamic Diameter or MMAD), a low water solubility (<2.00 µg/L at 20°C and pH 6.7), a high partition coefficient (Pow 3.4 x 10⁵; log Pow 5.5 at pH 7 and 20°C) and a low volatility (vapour pressure < 1.3 x 10^-8 Pa at 20°C).

The backbone of T003066 is tetraacetate-D-glucitol with a 3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methylphenyl attached to the first carbon. No dissociation of T003066 is expected as the substance does not contain ionizable groups.

No toxicokinetic data (animal or human studies) are available on this substance. The data present in this dossier are based on physicochemical and toxicological parameters and will allow a qualitative assessment of the toxicokinetic behaviour of T003066.

Absorption

Oral/GI absorption:

Oral absorption of T003066 is not favoured based on its high partition coefficient (log Pow 5.5) and low water solubility (<2.00 µg/L at 20°C and pH 6.7) causing limited dissolution of the substance into the gastrointestinal fluids and subsequent absorption through passive diffusion. In addition, its molecular weight is rather high (MW > 500) which is not favourable for absorption. 

However, the substance is considered to be a highly lipophilic (log Pow > 4) compound which may be taken up by micellular solubilization by bile salts. Substances absorbed as micelles enter the circulation via the lymphatic system, bypassing the liver. Therefore, limited absorption could be expected.

The assumption of limited oral absorption is supported by the absence of systemic toxicity in the experiments carried out with T003066:

- Following a single administration by oral route at the limit dose of 2000 mg/kg bw T003066 in an acute oral toxicity study with Wistar rats (OECD 423; Giannini, 2008), the LD50 was determined to be >2000 mg/kg body weight as no clinical signs of systemic toxicity or changes in body weight and no gross abnormalities upon necropsy following administration of the test item were observed.

- A combined 28-day repeated dose toxicity test with reproduction/developmental toxicity screening (according to OECD guideline 422; Mounier, 2017) has been performed with T003066 administration by oral gavage in Wistar rats at dose levels of 0, 110, 330 and 1000 mg/kg bw/day. No adverse toxicity at any dose level was observed (NOAEL≥1000 mg/kg).

Based on the physicochemical properties and the absence of systemic toxicity after oral administration, the oral absorption factor is considered to be 50%.

Respiratory absorption:

Given its low volatility, the availability of T003066 for inhalation as a vapour is limited. However, because its MMAD is smaller than 50 µm (7.638 µm), the solid particles can be considered as a dust and thus have the potential to be inhaled and reach the thoracic region.

Due to its low water solubility (<2.00 µg/L), the rate at which the particles dissolve into the mucus will limit the amount that can be absorbed directly. Poorly water-soluble dusts, such as T003066, depositing in the nasopharyngeal region could be coughed or sneezed out of the body or swallowed. When depositing in the tracheo-bronchial region the dusts would mainly be cleared from the lungs by the mucocilliary mechanism and swallowed. However, a small amount may be taken up by phagocytosis and transported to the blood via the lymphatic system. Poorly water-soluble dusts depositing in the alveolar region would mainly be engulfed by alveolar macrophages. The macrophages will then either translocate particles to the ciliated airways or carry particles into the pulmonary interstitium and lymphoid tissues.

In addition, its high lipophilic character (log Pow 5.5) implies that the product has the potential to be taken up by micellular solubilisation.

Based on the physicochemical properties, the respiratory absorption factor is considered 100%.

Dermal absorption:

T003066 is a solid substance and therefore not readily taken up by the skin in comparison to liquid products. The product will have to dissolve into the surface moisture of the skin before uptake can take place.

In order to cross the skin, a compound must first penetrate into the stratum corneum and may subsequently reach the viable epidermis, dermis and vascular network. Dermal absorption represents the amount of topically applied test substance that is found in the epidermis and dermis.

It is expected that the penetration of T003066 into the lipid rich environment of the stratum corneum will be enhanced by the highly lipophilic character of the substance. However, due to its low water solubility (<2.00µg/L) partitioning from the stratum corneum into the epidermis and therefore dermal absorption is likely to be low. In addition, the rather high molecular weight hampers dermal uptake.

T003066 was not assessed to be skin irritant or corrosive. However, as T003066 is considered to be a skin sensitizer (category 1B) some uptake must have occurred although it may only have been a small fraction of the applied dose.

Based on the above, low to moderate dermal uptake is expected and thus the dermal absorption factor for T003066 is considered to be 50%.

Distribution

The low water solubility and rather high molecular weight predict that T003066 won’t readily distribute through the body. Since the substance is highly lipophilic (log Pow 5.5), the substance is likely to distribute into cells leading to a higher intracellular concentration in comparison to the extracellular concentration particularly in fatty tissues.

Accumulation

Based on the physicochemical properties of T003066 (low water solubility, high partition coefficient, low particle size), no or only limited accumulation is expected within the body. However, as T003066 is a lipophilic substance, it tends to concentrate in adipose tissue and may accumulate depending on the conditions of exposure. In addition, T003066 can persist in the stratum corneum after penetrating this lipid rich skin layer. Eventually, they will be cleared as the stratum corneum is sloughed off.

Metabolism

Once absorbed, T003066 might undergo phase I biotransformation (including reduction, oxidation or hydroxylation) followed by conjugation reactions (phase II) such as glucuronidation and sulfation, increasing the hydrophilicity.

Excretion

Given the rather high molecular weight (612.68 g/mol), low water solubility and hydrophobic character, T003066 and its metabolites (such as conjugated glucuronides) will most likely actively be excreted through the bile. Substances in the bile pass through the intestines before they are excreted in the faeces and thus may undergo enterohepatic recycling which will prolong their biological half-life. Non-ionized and lipid soluble molecules may be excreted in the saliva, where they may be swallowed again, or in the sweat.