1-[([[(3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl]oxy]carbonyl)oxy]pyrrolidine-2,5-dione

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 T002632.

Based on the physico-chemical properties and the observed systemic toxicity after oral administration, the oral absorption factor is considered to be 100%. Due to its rather high MMAD (253.14 µm), the solid particles are not considered to be inhalable as in humans. Therefore, the respiratory absorption factor is considered 50%. Low to moderate dermal uptake is expected based on the physicochemical properties and the classification of the substance as skin sensitizer. Thus, the dermal absorption factor for T002632 is considered 50%. More information, see below.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Absorption rate - oral (%):

100

Absorption rate - dermal (%):

50

Absorption rate - inhalation (%):

50

Additional information

T002632 (CAS 253265-97-3) is a white powder with a low to moderate molecular weight (271.23 g/mol), a rather high particle size (Mass Median Aerodynamic Diameter or MMAD of 253.14 µm), a low partition coefficient (log Pow <0.3 at pH 7 and 20°C) and a low volatility (vapour pressure≤8.1 x 10^-8– 4.6 x 10^-6Pa at 20°C). As the substance is considered hydrolytically unstable, the water solubility could not be determined.

The backbone of T002632 is pyrrolidine-2,5-dione with a hexahydrofuro[2,3-b]furan-3-yl]oxy]carbonyl)oxy attached to the nitrogen.No dissociation of T002632 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 T002632.

Absorption

Oral/GI absorption:

Oral absorption of T002632 by passive diffusion is favoured based on its moderate partition coefficient (log Pow <0.3) and low to moderate molecular weight (<500 g/mol). The substance is considered to be hydrolytically unstable and therefore rapid breakdown in aqueous environments is suspected. The assumption of oral absorption is supported by the signs of systemic toxicity in the experiments carried out with T002632:

·        Following a single administration by oral route at 2000 mg/kg bw and 300 mg/kg bw T002632 in an acute oral toxicity study with Wistar rats (OECD 423; van Sas, 2019), the LD50 was determined to be 1000 mg/kg body weight as at 2000 mg/kg bw 2 animals were found dead on day 1 or 2, clinical signs of systemic toxicity (uncoordinated movements, piloerection, hunched posture, etc.) and changes in body weight were observed. For one animal found dead, macroscopic post mortem examination revealed abnormalities of the stomach, duodenum, jejunum and ileum. For the other animal found dead, macroscopic post mortem examination revealed abnormalities of the gastrointestinal tract, trachea and lungs. Macroscopic post mortem examination of the surviving animals did not reveal any abnormalities.

The LD50 cut-off value was considered to be 1000 mg/kg body weight and the substance was classified as harmful if swallowed (category 4) for acute toxicity by the oral route.

 

·        A combined 28-day repeated dose toxicity test with reproduction/developmental toxicity screening (according to OECD guideline 422; Hartman-Van Dycke, 2019) has been performed with T002632 administration by oral gavage in Wistar rats at dose levels of 0, 11, 33 and 90 mg/kg bw/day. Test item-related body weight and food consumption changes were observed and haematological and clinical biochemistry findings were noted. The No Observed Adverse Effect Levels (NOAEL) was determined to be 33 mg/kg.

Based on the physico-chemical properties and the observed systemic toxicity after oral administration, the oral absorption factor is considered to be 100%.

Respiratory absorption:

Given its low volatility, the availability of T002632 for inhalation as a vapour is limited. Due to its rather high MMAD (253.14 µm), the solid particles are not considered to be inhalable as in humans, particles with aerodynamic diameters below 100 μm have the potential to be inspired.

If inhalation would take place, the moderate log Pow value (between -1 and 4) is considered to be favourable for absorption directly across the respiratory tract epithelium by passive diffusion. No information on water solubility is available as the substance is considered to be hydrolytically unstable.

Based on the physicochemical properties, the respiratory absorption factor is considered 50%.

Dermal absorption:

T002632 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.

The molecular weight (> 100 g/mol) and the partition coefficient (log Pow < 0.3) are not expected to favour dermal uptake of T002632 to a large extent. In addition, no information on the water solubility is available due to the hydrolytic instability, so no conclusions can be drawn on the partitioning of the substance from the stratum corneum into the epidermis.

T002632 was not assessed to be skin irritant or corrosive. However, as T002632 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 T002632 is considered 50%.

Distribution

The low to moderate molecular weight suggests that T002632 can easily and widely distribute through the body. Based on the oral toxicity studies, the target organs can be identified as stomach, duodenum, jejunum and ileum, trachea and lungs.

Accumulation

Based on the physicochemical properties of T002632 (such as low partition coefficient), no or only limited accumulation is expected within the body.

Metabolism

Once absorbed, T002632 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 moderate molecular weight (271.23 g/mol), low partition coefficient, lack of ionizable groups and instability in water, T002632 and its metabolites (such as conjugated glucuronides) will most likely be excreted mainly through the urine. Non-ionized and lipid soluble molecules may be excreted in the saliva, where they may be swallowed again, or in the sweat.