Tetrahydrofurfuryl alcohol

Endpoint summary

Additional information

There are no in vivo data on the toxicokinetics of tetrahydrofurfuryl alcohol.

The following summary has therefore been prepared based on validated predictions of the physicochemical properties of the substance itself and using these data in algorithms that are the basis of many computer-based physiologically based pharmacokinetic or toxicokinetic (PBTK) prediction models. The main input variable for the majority of these algorithms is log K_ow so by using this, where appropriate, and other known or predicted physicochemical properties of tetrahydrofurfuryl alcohol, reasonable predictions or statements may be made about its potential absorption, distribution, metabolism and excretion (ADME) properties.

Human exposure can occur via the inhalation or dermal routes.

In an assessment of the metabolic fate of furanone and hydroxyl-substituted tetrahydrofuran derivatives, JECFA (2005) stated that the metabolism of the tetrahydrofurfuryl alcohol derivatives would likely be the same as that of the corresponding furfuryl alcohols, the chemical structure of the former preventing the formation of epoxides. Where available, relevant data for 2,5-dimethyl-4-hydroxy-3(2H)-furanone (DMHF) are discussed in the appropriate sections below.

Absorption

Oral

Significant oral exposure is not expected for tetrahydrofurfuryl alcohol.

However, if it did occur, it is necessary to assume that except for the most extreme of insoluble substances, that uptake through intestinal walls into the blood takes place. Uptake from intestines can be assumed to be possible for all substances that have appreciable solubility in water or lipid. Other mechanisms by which substances can be absorbed in the gastrointestinal tract include the passage of small water-soluble molecules (molecular weight up to around 200) through aqueous pores or carriage of such molecules across membranes with the bulk passage of water (Renwick, 1993).

As tetrahydrofurfuryl alcohol is very water soluble and has a molecular weight of approximately 102 it meets both of these criteria, so should oral exposure occur it is reasonable to assume systemic exposure will occur also. 

The absorption of 2,5-dimethyl-4-hydroxy-3(2H)-furanone (DMHF) was established in mice administered orally single doses in the range 0.5-1 g/kg bw; the compound appeared in the plasma 5 minutes after treatment, reached a maximum after 15-45 minutes and gradually disappeared after 2 hours, indicating a rapid absorption and metabolism (Hiramoto, 1998).

Dermal

The fat solubility and therefore potential dermal penetration of a substance can be estimated by using the water solubility and log K_owvalues. Substances with log K_owvalues between 1 and 4 favour dermal absorption (values between 2 and 3 are optimal) particularly if water solubility is high.

Although the water solubility of tetrahydrofurfuryl alcohol is favourable for absorption, the log K_owof -0.14 is not, meaning that it is likely to be too hydrophilic to cross the lipid-rich environment of the stratum corneum. After or during deposition of a liquid on the skin, evaporation of the substance and dermal absorption occur simultaneously so the vapour pressure of a substance is also relevant and becausetetrahydrofurfuryl alcoholis volatile this would further limit the potential for absorption.

However, in a repeat dose dermal study in rats (WIL, 1998) there was evidence of systemic toxicity meaning that some absorption oftetrahydrofurfuryl alcohol had occurred.

Inhalation

There is a Quantitative Structure-Property Relationship (QSPR) to estimate the blood:air partition coefficient for human subjects as published by Meulenberg and Vijverberg (2000). The resulting algorithm uses the dimensionless Henry coefficient and the octanol:air partition coefficient (K_oct:air) as independent variables.

Using these values for tetrahydrofurfuryl alcohol, results in a high blood:air partition coefficient (approximately 15000:1) so uptake would be expected into the systemic circulation. However, the high water solubility of tetrahydrofurfuryl alcohol may lead to some of it being retained in the mucus of the lungs so this may limit the potential for absorption.

In acute (WIL, 1994) and repeat dose (WIL, 1998a) inhalation studies signs of systemic toxicity were observed, and provide evidence that absorption following inhalation does occur.

Distribution

For blood:tissue partitioning a QSPR algorithm has been developed by De Jongh et al. (1997) in which the distribution of compounds between blood and human body tissues as a function of water and lipid content of tissues and the n-octanol:water partition coefficient (K_ow) is described. Using this value for tetrahydrofurfuryl alcohol predicts that distribution into the major body compartments would be minimal.

Table 5.1.1: tissue:blood partition coefficients

	Log Kow	Kow	Liver	Muscle	Fat	Brain	Kidney
tetrahydrofurfuryl alcohol	-0.14	0.72	0.6	0.8	0.4	0.8	0.8

 

Metabolism

There are no data regarding the mammalian metabolism of tetrahydrofurfuryl alcohol. Genetic toxicity tests in vitro showed no observable differences in effects with and without metabolic activation. The rapid ready biodegradation (Section 4 of the CSR) suggests that the molecule possesses metabolisable functions.

In the absence of experimental data we must infer the likely pathways for the metabolic degradation of THFA using data available in the open literature for similar chemical structures and model compounds having some of the structural attributes of THFA. Additionally, there is a vast amount of literature available on catabolic degradation biochemistry from which one may infer general rules as to what metabolites may be formed. This information has been assessed and used to construct a postulated metabolic scheme (see below), in which the metabolites are numbered (2) to (12) and oxidative events catalysed by cytochromes P450 as [O].

Since THFA possesses a free primary alcohol group it would be expected that the initial and major metabolic event would be the formation of a conjugate (a glucuronide in the case of human metabolism): metabolite (2). THFA is highly hydrophilic; with a negative log K_ow value and no further phase I oxidative metabolism would be expected prior to conjugate formation. Consequently, metabolite (2) would be expected to be the major primary urinary metabolite in humans and other mammals. This deduction is supported by the fate of the model compound of 2,5-dimethyl-4-hydroxy-3(2H)-furanone (DMHF), a furfuryl alcohol, administered to four male and two female volunteers was studied. Identification and quantification of DMHF glucuronide in human urine were achieved; male and female excreted in the 24 hour urine 59–69 % and 81–94 % of the DMHF dose as DMHF-glucuronide, respectively, the amount of DMHF excretion being independent of the dose (Roscher et al., 1997).

Probable minor metabolites may be formed from THFA by further oxidative events, such as cytochrome P450-catalysed oxidation of the primary alcohol to give carboxylic acid derivatives (3, 5, 7, 9 and 10), which would probably be sufficiently polar to be excreted in the urine without phase II conjugation. However, the significant difference between THFA and other non-cyclic glycol ethers is that ring-strain in the tetrahydrofuran ring facilitates its ring-opening. 

In studies on the metabolic pathways of tetrahydrofuran (THF) catabolism, THF was shown to undergo oxidative metabolism by liver microsomal CYP450 enzymes followed by further hydrolysis catalysed by lactonase (also known as paraoxonase1 or PON1) and additional oxidation by cytosolic dehydrogenases. Based on the available in vivo and in vitro data, the ultimate metabolite of THF is CO₂ (Couper and Marinetti, 2002; DuPont Haskell Laboratory, 2000).

According to this pathway, THF undergoes oxidative metabolism to form the intermediates 5-hydroxy-THF and 4-hydroxybutanal, which may undergo further oxidation to γ-butyrolactone (GBL), γ-hydroxybutyric acid (GHB), and succinaldehyde via hydrolysis and ring opening.

In vivo studies on THF metabolism indicated that CO₂is the major terminal metabolite (DuPont Haskell Laboratory, 1998). In mice administered a single gavage dose of 50 mg/kg¹⁴C-THF, the percent of the radioactivity recovered as CO₂was 58.2% in males and 74.6% in females. Volatile organics (probably un-metabolised THF) accounted for 17.8% of the administered dose in males and 24.5% of the administered dose in females. In mice administered a single dose of 500 mg/kg¹⁴C-THF, the percent of the administered dose recovered as CO₂was 51.1 and 36.2% for males and females, respectively. Rat metabolism studies also demonstrated that oxidative metabolism of THF to CO₂is an important pathway. In rats given a single gavage dose of 50 mg/kg of¹⁴C-THF, 47.8 and 47.5% of ¹⁴C-THF in males and females, respectively, was recovered in the form of CO₂. In rats given 500 mg/kg of radiolabelled THF, these percentages were 21.9% in males and 18.8% in females.

These experiments provide a mechanism whereby the tetrahydrofuran ring moiety of THFA can be metabolised via an oxidative and hydrolytic mechanism, which leads to opening of the ring. It also shows that the tetrahydrofuran moiety can be totally oxidatively metabolised to CO₂. Applying this to THFA, we may suggest that THFA could the hydoxylated in the 5-position (metabolite 4), which is further oxidised to the lactone (6). Hydrolysis and oxidation then gives alpha-hydroxyglutaric acid (9) and finally alpha-ketoglutaric acid (10) which is metabolised from (9) by specific alpha-hydroxyglutarate dehydrogenases, which in humans are two enzymes called D2HGDH and L2HGDH. alpha-Ketoglutaric acid may also be formed via a similar set of reaction of the oxidised metabolites (3, 5, 7, 9) and is a substrate for the Krebs’ (tricarboxylic acid) cycle, consequently it is oxidised to CO₂via normal cell oxidative metabolism. Additional reactions of (10) are transamination, usually with alanine as the amino donor to give the amino acid L-glutamic acid (11), which would be incorporated in proteins or decarboxylation to the neurotransmitter gamma-aminobutyric acid (12). 

Bacterial Metabolism

 

THFA has been shown to be oxidised to tetrahydro-2-furanoic acid (3) in bacteria via a mitochondrial ubiquinone linked oxidase (Schräder and Andreesen, 1997). Although possibly not specifically relevant to THFA, 2-furanoic acid has also been shown to be metabolised toa-ketoglutaric acid (10) (Trudgill, 1969), which then enters the Krebs’ Cycle and is oxidised to CO₂.

Summary

 

A metabolic pathway for the breakdown of THFA is proposed in which the major metabolite is THFA-O-glucuronide, which is excreted in the urine. Minor metabolites are formed via oxidation of the –CH₂OH group to CO₂H, tetrahydrofuran ring hydroxylation and oxidation to give a cyclic lactone, which is then hydrolysed and ring opened to hydroxy acid derivatives. Further oxidation then givesa-ketoglutaric, which is, metabolised to CO₂via the normal oxidative reactions of the cell. Incorporation into proteins via L-glutamic acid may also be a possibility.

This pathway suggests that THFA would be readily metabolised, furthermore, it suggests intermediates that indicate little concern for toxicity. There is one possible exception, tetrahydro-2-furanoic acid (3) (specifically the S-(-)- optical isomer), which is a specific proline dehydrogenase inhibitor (Krishnanet al. 2008) and it is likely that the terminal metabolite of THFA in mammals is CO₂. (See the proposed metabolic pathway for THFA degradation in mammals attached).

Excretion

A determinant of the extent of urinary excretion is the soluble fraction in blood. QPSR’s as developed by De Jongh et al. (1997) using log K_owas an input parameter, calculate the solubility in blood based on lipid fractions in the blood assuming that human blood contains 0.7% lipids.

Using this algorithm, the soluble fraction of tetrahydrofurfuryl alcohol in blood is approximately 99% suggesting it is likely to be effectively eliminated via the kidneys in urine and accumulation is very unlikely.

References

 

Couper, FJ, Marinetti, LJ. (2002)g-Hydroxybutyrate (GHB)—Effects on human performance and behavior. Forensic Sci Rev14:101–121.

 

De Jongh, J., H.J. Verhaar, and J.L. Hermens, A quantitative property-property relationship (QPPR) approach to estimate in vitro tissue-blood partition coefficients of organic chemicals in rats and humans. Arch Toxicol, 1997.72 (1): p. 17-25.

DuPont Haskell Laboratory. (1998) ¹⁴C-Tetrahydrofuran: disposition and pharmacokinetics in rats and mice, with cover letter dated 10/14/1998. E.I. DuPont de Nemours and Company, Newark, DE; HLR-1998-01377. Submitted under TSCA Section 8D; EPA Document No. 86990000002; NTIS No. OTS0573852.

 

DuPont Haskell Laboratory. (2000) Tetrahydrofuran: comparative in vitro microsomal metabolism. E.I. DuPont de Nemours and Company, Newark, DE; DuPont-1103.

 

Hiramoto K, Kato T, Takahashi Y, Yugi K and Kikugawa K, 1998. Absorption and induction of micronucleated peripheral reticulocytes in mice after oral administered of fragrant hydroxyfuranones generated in the maillard reaction. Mutat Res. 415, 79-83.

JECFA, 2005: Evaluation of certain food additives. Sixty-third report of the Joint FAO/WHO Expert Committee on Food Additives. Geneva. WHO Technical Report Series, 928.

Krishnan, N., Dickman, MB., Becker, DF. (2008) Proline modulates the intracellular redox environment and protects mammalian cells against oxidative stress, Free radical biology & medicine 44: 671–681.

 

Meulenberg, C.J. and H.P. Vijverberg, Empirical relations predicting human and rat tissue:air partition coefficients of volatile organic compounds. Toxicol Appl Pharmacol, 2000. 165(3): p. 206-16.

Renwick A. G. (1993) Data-derived safety factors for the evaluation of food additives and environmental contaminants.Fd. Addit. Contam.10: 275-305.

Roscher, R., Koch, H., Herderich, M. Schreier, P., Schwab, W. (1997) Identification of 2,5-dimethyl-4-hydroxy-3[2H]-furanone β-D-glucuronide as the major metabolite of a strawberry flavour constituent in humansFood Chem. Toxicol. 35: 777-782.

 

Schräder, ZG., T Andreesen, T. JR (1997) Degradation of tetrahydrofurfuryl alcohol byRalstonia eutrophais initiated by an inducible pyrroloquinoline quinone-dependent alcohol dehydrogenaseAppl Environ Microbiol.63: 4891-4898.

 

Trudgill, PW. (1969) The Metabolism of 2-Furoic Acid byPseudomonasF2Biochem. J.113: 577-587.