(3R,3AS,6AR)-HEXAHYDROFURO[2,3-B]FURAN-3-OL

Endpoint summary

Description of key information

No toxicokinetic data (animal or human studies) are available on this substance.

 

Based on the moderate molecular weight (130.14 g/mol), High water solubility (>10000 mg/L), and moderate partition coefficient (log Kow 1.055 at pH 5), it can be expected that oral, dermal and respiratory absorption rates are moderate to high. The adverse effects of the 28-day oral repeated dose gavage toxicity study confirm oral absorption since oral administration resulted in adverse changes of different test parameters (clinical signs and biochemistry, mortality, food consumption and body weight) in all dose groups. However, the reproduction/developmental toxicity screening test showed no adverse effects up to 15 mg eq/kg. Furthermore, a dermal acute toxicity test showed no clinical signs, no mortality, nor gross pathology and T002675 was found to be not irritating to skin (OECD 404, Esposito, 2007).

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Absorption rate - oral (%):

50

Absorption rate - dermal (%):

50

Absorption rate - inhalation (%):

100

Additional information

T002675 (CAS 156928-09-5) is light yellow to yellow liquid with a moderate molecular weight of 130.14 g/mol. A K2 GLP study was performed according to OECD guideline 105 and EU Method A.6 (flask method). T002675 was found completely miscible (>10 g/L) in water in all proportions tested (Paulus, 2007). The partition coefficient was determined to be log Kow 1.055 at pH 5 and the vapour pressure was assessed to be 0.19 Pa at 25°C.

The backbone of the substance is a hexahydrofurofuran group with a hydroxyl substituent on position 3.

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 the substance.

Absorption

Oral/GI absorption:

The moderate partition coefficient (–1 < log Kow < 4) indicates that the substance is favourable for absorption. T002675 was also determined to be very miscible. Water soluble substances most likely dissolve into the gastrointestinal fluids. Passive diffusion through aqueous pore or through epithelial barrier by bulk passage of water is also possible given that the molecular weight is below 200 g/mol. It is generally assumed that the absorption along the gastrointestinal tract predominantly takes place in the small intestine since it has a very large surface area and the longest transit time.

In an acute oral toxicity study (OECD 423), 3 female rats were treated with a single oral gavage of either 300 or 2000 mg/kg and observed for 14 days. All animals treated with 2000 mg/kg died spontaneously 2 or 3 days after treatment, whereas no deaths occurred in the animals treated with 300 mg/kg. Consequently, the LD50 of T002675 determined was greater than 300 mg/kg bw and less than 2000 mg/kg bw.

A 28-days repeated dose toxicity test (OECD 407, Brunke et al., 2007) has been performed by oral gavage with T002675 on Wistar (Han) rats (50 animals in total) applying following doses: 50, 150 and 450 mg/kg/day (and a control group). The oral administration resulted in adverse changes of different test parameters (clinical signs and biochemistry, mortality, food consumption and body weight) in all dose groups. Test item-related adverse changes were observed at the lowest test dose of 15 mg/kg bw/day, such as elevated bilirubin, changes in the red blood cell count and elevated absolute and relative liver weights in males. Mortality before scheduled necropsy, liquid contents of the gastrointestinal tract and a reduced size of spleen were observed in animals treated with 150 mg/kg bw/day.

In a reproduction/developmental toxicity screening test, T002675 was administered daily to Wistar rats at dose levels of 5, 15 and 50 mg/kg/day and a control group (10 rats/sex/dose level) (OECD 421, Beekhuijzen, 2018) for a minimum of 14 days of treatment for the males and females, until detection of mating was confirmed. The following observations and examinations were evaluated: mortality / viability, clinical signs, body weight and food consumption, estrous cycle determination, measurement of thyroid hormone T4, macroscopy at termination, organ weights, reproductive function and histopathology on a selection of tissues.

The results of the first parental anmimals show no clinical signs of toxicity were noted during the observation period at dose levels up to 15 mg eq/kg. It was decided to terminate the high dose group of 50 mg eq/kg on day 15, based on the severe body weight loss of the animals (up to 12% vs initial weight on pre-mating Day 1), at this point not considered sufficiently healthy for mating. At 15 and 5 mg eq/kg, body weight gain was similar to controls for the males and females during premating and the females during the lactation phase. The statistically significantly increased serum T4 levels in males at 5 mg eq/kg were considered not to represent a sign of toxicological relevance. There were no test item-related alterations in organ weights up and microscopic observations to 15 mg eq/kg and no gross observations at the dose up to 50 mg eq/kg.Length and regularity of the estrous cycle were considered not affected by treatment up to 50 mg eq/kg and stage aware evaluation of the testes did not show any indication for abnormal spermatogenesis. As all animals at 50 mg eq/kg were sacrificed in the premating period, reproduction data is available for females up to 15 mg eq/kg only. The total number of offspring born compared to the total number of uterine implantations was considered not to be affected by treatment up to 15 mg eq/kg. The results of the first generation showed no clinical signs, no mortality up to 15 mg eq/kg, no change in body weight, no macroscopic findings, no change in thyroid hormone T4, and no influence on sex ratio.

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

Respiratory absorption:

Given its low volatility (vapour pressure < 0.5 kPa), the availability of T002675 for inhalation as a vapour is limited.

Generally, liquids readily diffuse/dissolve into the mucus lining of the respiratory tract. In the case of T002675, the high water solubility will favor the rate at which the particles dissolve into the mucus. Very hydrophilic substances such as T002675 might be absorbed through aqueous pores especially with its molecular weight is <200 g/mol. T002675 can also be retained in the mucus and transported out of the respiratory tract. The moderate log Kow (between -1 and 4) would indicate favourable absorption directly across the respiratory tract epithelium by passive diffusion but to a limited extend since the log Kow is only 1.055.

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

 

Dermal absorption:

T002675 is a liquid substance and therefore it is more easily taken up by the skin in comparison to solid products. In order to cross the skin, a compound must first penetrate into the stratum corneum (non-viable layer of corneocytes forming a complex lipid membrane) and may subsequently reach the viable epidermis, the dermis and the vascular network. It is expected that the penetration of T002675 into the lipid rich environment of the stratum corneum will be favoured to a small extent due to the limited lipophilic character (log Kow of 1.055) of the substance resulting in a low to moderate dermal absorption. Considering, its high water solubility, dermal uptake of T002675 is expected to be moderate to high. It is soluble enough in water to partition from the stratum corneum into the epidermis (water solubility >10000 mg/l). A dermal acute toxicity test (OECD 402, Esposito 2007), performed on both female and male rats (10 animals in total), treated with a single dose of 2000 mg/kg bw, showed no clinical signs, no mortality, nor gross pathology. The LD50 was determined to be greater than 2000 mg/kg bw. Furthermore, T002675 was found to be not irritating to skin (OECD 404, Esposito, 2007).

 

As a result, the dermal absorption factor is set to 50%.

 

Distribution

The high water solubility of T002675 can favour its distribution in the body through aqueous channels and pores. the substance will distribute into the cells to a limited extent. Based on the toxicological studies, the target organs may be the liver, the gastrointestinal tract and the spleen. The liver being the most sensitive organ since it is affected at the lowest dose in the 28-day study (OECD 407).

Based on these observations it can be concluded that T002675 will distribute within the body to a limited extent. 

 

Accumulation

Based on the liquid form of T002675 no accumulation is expected within the lungs. T002675 is only moderately lipophilic it is not expected to accumulate within the adipose tissue or the stratum corneum.

 

Metabolism

Based on the structure, T002675 was found completely miscible in water, the hydroxyl group already part of the molecule can undergo a conjugation reactions (phase II) such as glucuronidation (by the enzyme glucuronosyltransferase) and sulfation (by the enzyme sulfotransferase). The Phase II conjugation reactions will further increase the water solubility and hydrophilic character of the substance. 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

The water soluble conjugated metabolites of T002675 from Phase II biotransformation will be excreted from the systemic circulation through 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 conjugated derivatives (such as glucuronides) is the bile. 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 faeces and can thus undergo enterohepatic recycling which will prolong their half-life.