(3AS,4S,6AR)-4-METHOXYTETRAHYDROFURO[3,4- B]FURAN-2(3H)-ONE

Endpoint summary

Description of key information

T002907 (CAS 501921-30-8) is a white, slight beige powder with a low molecular weight (158.15 g/mol), a high water solubility (28.1 g/L), a moderate partition coefficient (log Pow of -0.4 at 21°C) and a low volatility (vapour pressure of 0.047 Pa at 25°C). In a sieving test, only about 12 % of the test item passed the 125 µm sieve.

T002907 is considered favourable for absorption since its log Pow value between -1 and 4 and its high water solubility leads to dissolution of the substance into the gastrointestinal fluids and absorption through passive diffusion. Due to its low molecular weight, T002907 may pass through aqueous pores or be carried through the epithelial barrier by the bulk passage of water.

In a 28-day oral toxicity (gavage) study according to OECD guideline 407, no treatment-related adverse toxicological effects were observed up to the highest dose tested. Furthermore, in an acute oral toxicity study performed according to the OECD guideline 423, the LD50 (female rat) was established as greater than 2000 mg/kg. No acute oral toxicity is expected. In a reproduction/developmental toxicity screening test according to OECD guideline 421, no parental, reproduction nor developmental toxicity was observed up to 1000 mg/kg/day. Therefore, the oral absorption factor is considered 50%.

Because T002907 has a low volatility, the availability of the substance for inhalation as a vapour is limited. Since the substance is hydrophilic with a very high water solubility (28.1 g/L) T002907 might be absorbed through aqueous pores or be retained in the mucus and transported out of the respiratory tract when inhaled. Furthermore, since T002907 has a moderate partition coefficient, it is expected to be favourable for absorption directly across the respiratory tract epithelium by passive diffusion. Therefore, the respiratory absorption factor is considered 100%.

From its logPow value (<0), it can be derived that the substance is rather hydrophilic and therefore penetration into the lipid rich environment of the stratum corneum will be limited leading to reduced dermal uptake. In addition, T002907 is considered to be too hydrophilic (water solubility > 10 g/L and log Kow < 0) to cross the lipid rich environment of the stratum corneum. Therefore, dermal uptake of T002907 is expected to be low. Furthermore, an acute dermal toxicity study according to OECD guideline 402 demonstrated no indications of dermal toxicity. Based on two in vivo skin irritation studies according to OECD guideline 404, the substance is demonstrated to not irritate the skin and therefore not enhancing dermal absorption. Therefore, the dermal absorption factor is considered 10%.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Absorption rate - oral (%):

50

Absorption rate - dermal (%):

10

Absorption rate - inhalation (%):

100

Additional information

Toxicokinetic assessment of T002907

T002907 (CAS 501921-30-8) is a white, slight beige powder with a low molecular weight (158.15 g/mol), a high water solubility (28.1 g/L), a moderate partition coefficient (log Pow of -0.4 at 21°C) and a low volatility (vapour pressure of 0.047 Pa at 25°C). In a sieving test, only about 12 % of the test item passed the 125 µm sieve.

The backbone of T002907 is a tetrahydrofurofuranone group with a methoxy group attached at position 4. It is expected that T002907 contains acidic groups based on the water solubility study (RCC, 2006) where the pH value of T002907 in water was determined to be between 3.81 and 4.01 at 20°C which may be caused by dissociation in water. However, the hydrolysis study showed that T002907 is hydrolytically stable at pH 4, 7 and 9.

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 T002907.

Absorption

Oral/GI absorption:

T002907 is considered favourable for absorption since its log Pow value between -1 and 4 and its high water solubility leads to dissolution of the substance into the gastrointestinal fluids and absorption through passive diffusion. Due to its low molecular weight, T002907 may pass through aqueous pores or be carried through the epithelial barrier by the bulk passage of water.

In a 28-day oral toxicity (gavage) study according to OECD guideline 407 (RCC, 2006), T002907 was administered by daily oral gavage to male and female SPF-bred Wistar rats (5 animals/sex/dose) at dose levels of 0, 50, 200 and 1000 mg/kg body weight/day for 28 days. No treatment-related adverse toxicological effects were observed up to the highest dose tested. Based on the results of this study (no effects on mortality, clinical signs, mean absolute or relative food consumption, mean absolute body weights or body weight gain, parameters of hematology or clinical biochemistry, and mean organ weights, organ-to-body weight or organ-to-brain weight ratios), 1000 mg/kg bw/day of T002907 was established as the no-observed-adverse-effect-level (NOAEL). The no-observed-effect level (NOEL) could not be established.

An acute oral toxicity study was performed according to the OECD guideline 423 (RCC, 2006) in which T002907 was administered on a single occasion by oral gavage to 2 subsequent groups of 3 female Wistar rats at 2000 mg/kg body weight. Slightly ruffled fur was observed in 5 of the treated animals on the day of testing from 30 minutes to 3 hours after dosing or 2−3 hours or 5 hours after dosing. A hunched posture was observed in two of the animals 3 hours after the treatment and persisted in one of the animals at the 5-hour reading. For the remaining days of the study no clinical signs were observed. One of the animals was absent of clinical signs throughout the study. The body weight of the animals was within the range commonly recorded for this strain and age with the exception of animal No. 3 in which a very minor (1.3%) body weight loss was observed during the second week of observation. No macroscopic findings were recorded at necropsy.

The LD50 (female rat) was established as greater than 2000 mg/kg. No acute oral toxicity is expected.

In a reproduction/developmental toxicity screening test of T002907 in rats by oral gavage according to OECD guideline 421 (Charles River, 2017), T002907 was administered by daily oral gavage to male and female SPF-bred Wistar rats (10 animals/sex/dose) at dose levels of 0, 110, 330 and 1000 mg/kg body weight/day. No parental, reproduction nor developmental toxicity was observed up to 1000 mg/kg/day.

Based on the physicochemical properties and the results of the toxicity studies, the oral absorption factor is considered 50%.

Respiratory absorption:

Because T002907 has a low volatility, the availability of the substance for inhalation as a vapour is limited. Based on the fact that the substance is a powder with particles mainly larger than 125 µm as determined in a sieving test, the respiratory uptake is considered reduced since the potential to be inhaled is estimated to be low. Since the substance is hydrophilic with a very high water solubility (28.1 g/L) T002907 might be absorbed through aqueous pores or be retained in the mucus and transported out of the respiratory tract when inhaled. Furthermore, since T002907 has a moderate partition coefficient, it is expected to be favourable for absorption directly across the respiratory tract epithelium by passive diffusion. No toxicity study with administration via the inhalation route was performed.

Therefore, the respiratory absorption factor is considered 100%.

Dermal absorption:

Since T002907 is a solid, the product will not be readily taken up by the skin in comparison to liquid products. The dry product will have to dissolve into the surface moisture of the skin before uptake can take place. In order to cross the skin, the compound must first penetrate into the (lipid rich) stratum corneum. From its logPow value (<0), it can be derived that the substance is rather hydrophilic and therefore penetration into the lipid rich environment of the stratum corneum will be limited leading to reduced dermal uptake. In addition, T002907 is considered to be too hydrophilic (water solubility > 10 g/L and log Kow < 0) to cross the lipid rich environment of the stratum corneum. Therefore, dermal uptake of T002907 is expected to be low.

An acute dermal toxicity study according to OECD guideline 402 (RCC, 2006) where 2000 mg/kg of T002907 was applied to 5 male and 5 female Wistar rats, demonstrated no indications of dermal toxicity. Furthermore, based on two in vivo skin irritation studies with New Zealand White rabbits according to OECD guideline 404 (RCC, 2006 and SPL, 2004), the substance is demonstrated to not irritate the skin and therefore not enhancing dermal absorption.

Based on the above, a moderate dermal uptake is expected and thus the dermal absorption factor is considered 10%.

Distribution

T002907 is considered favourable for distribution since the molecular weight is low. Since its water solubility is high, diffusion of the substance through aqueous channels and pores may take place. Since the substance is slightly hydrophilic (logPow <0), the substance is not likely to distribute into cells.

Accumulation

Since T002907 is a highly water soluble and hydrophilic substance, no or only limited accumulation is expected within the body.

Metabolism

Based on the structure, T002907 might undergo phase I biotransformation such as hydroxylation, reduction and dealkylation followed by conjugation reactions (phase II) such as glucuronidation (by the enzyme glucuronosyltransferase) and sulfation (by the enzyme sulfotransferase). The Phase II conjugation reactions largely increase the hydrophilic character of the product. Metabolism mainly takes place in the liver, causing route specific presystemic (or first pass) effects, especially after oral intake. Other metabolic changes may take place in the gastrointestinal (GI) flora or within the GI tract epithelia (mainly in the small intestine), respiratory tract epithelia (in the nasal cavity, trachea-bronchial mucosa and alveoli and skin), etc.

Excretion

A possible route of excretion of T002907 from the systemic circulation is the urine. In general, conjugated metabolites such as glucuronides and sulfates from Phase II biotransformation reactions, which are more water soluble than the parent compound, are excreted in the urine. Most of them will have been filtered out from the blood by the kidneys, though a small amount can enter the urine directly by passive diffusion. There is also the potential for re-absorption into the systemic circulation across the tubular epithelium. Another route of excretion of T002907 can be the bile. Substances excreted in the bile may be conjugated (such as glucuronides). The excretion via the bile is highly influenced by hepatic function since metabolites formed in the liver may be excreted directly into the bile without entering the bloodstream. Products in the bile pass through the intestine before excretion in the feces and can thus undergo enterohepatic recycling which will prolong their half-life.