Tetrahydro-4-methyl-2H-pyran

Endpoint summary

Link to relevant study record(s)

Reference

Endpoint:

basic toxicokinetics, other

Type of information:

other: A qualitative assessment based on physicochemical properties and available information on MTHP and two structurally related compounds according to the guidance provided in the ECHA Guidelines (ECHA, 2014).

Adequacy of study:

weight of evidence

Study period:

2018-05-03

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

data from handbook or collection of data

Justification for type of information:

The toxicokinetics of absorption, distribution metabolism and excretion (ADME) of MTHP have not been evaluated in vivo. As a result, this analysis of the toxicokinetics is a qualitative assessment based on physicochemical properties and available information on MTHP and two structurally related compounds according to the guidance provided in the ECHA Guidelines (ECHA, 2014).

Details on absorption:

Oral
According to the ECHA Guidelines (2014), molecules with molecular weights of less than 500 g/mol are small enough to be candidates for absorption by passive diffusion from the gastrointestinal tract tract. The molecular weight of MTHP is 100 g/mol, it is water soluble (19 g/L) and has an octanol-water partition coefficient (log Pow) of 2.1. This combination of aqueous and lipid solubility favours absorption by the oral route. Therefore MTHP is likely to be well absorbed. This conclusion is supported by data from a study in rats and mice in which the excretion of an oral dose of 14C-THF was investigated. The study was summarized in an EPA review of THF (EPA, 2012) and the EPA concluded that THF was nearly completely absorbed.

In a 28-day oral toxicity study in rats MTHP was administered to males and females by oral gavage at doses up to 500 mg/kg bw/d (Kuraray, 2010). There was a decrease in motor activity noted in animals in the highest dose group. In a combined reproduction/developmental toxicity screening study MTHP was administered to male and female rats at doses up to 500 mg/kg bw/day (Kuraray, 2018). Reduced spontaneous activity and apathy in the top dose group was observed. These findings indicate that systemic exposure occurred after oral dosing.

Based on the available information, it is reasonable to assume that 100% of MTHP, will gain systemic circulation by the oral route of administration. Although the test item can be expected to be well absorbed by the oral route, in the absence of experimental absorption data, default values are used in the derivation of DNELs according to REACH guidance R.8 page 19. For oral absorption this is 50%.

Dermal
Based on the physicochemical properties, MTHP is likely to be absorbed after dermal application. According to the ECHA Guidelines (ECHA, 2014) molecules with molecular weights of less than 500 g/mole are capable of migration through the skin into systemic circulation. In addition, both water and lipid solubility influences the potential for dermal penetration.

In an in vitro skin corrosion test MTHP was concluded to be classifiable as ”Corrosive” (Kuraray, 2017). This may have the effect of enhancing dermal permeability though a damaged skin barrier.

Although the test item can be expected to be absorbed by the dermal route, in the absence of experimental absorption data, default values are used in the derivation of DNELs according to REACH guidance R.8 page 19. For dermal absorption this is 50%.

Inhalation
MTHP is a liquid at room temperature with limited volatility. The vapor pressure of MTHP is 30 hPa at 20°C which limits the likelihood of significant systemic exposure by inhalation of vapors. However, if MTHP were aerosolized, absorption across the respiratory epithelium would likely be rapid based on its partition coefficient and low molecular weight.

Although the test item can be expected to be absorbed by the inhalation route, in the absence of experimental absorption data, default values are used in the derivation of DNELs according to REACH guidance R.8 page 19. For inhalation absorption this is 100%.

Details on distribution in tissues:

The distribution of MTHP has not been characterized. Following oral administration, MTHP would enter hepatic portal circulation resulting in distribution primary to the liver. Given its size and water solubility, MTHP is expected to freely distribute systemically via the blood. Widespread tissue distribution of radioactivity was seen in the 14C-THF study in rats and mice (EPA, 2012). Dermal absorption would result in general systemic exposure. By inhalation the distribution would also be expected to be more general as absorption by the lungs would result in distribution systemically via cardiac output, and this is supported by studies of distribution of 14C-THF following inhalation exposure (EPA, 2012).

Details on excretion:

The polarity and water solubility of MTHP would facilitate its rapid excretion in urine. Any of the metabolic steps described below would further increase its polarity and thus enhance urinary excretion, or enable complete metabolism to CO2 which would be eliminated via expired air.

Details on metabolites:

The structure of MTHP is expected to undergo oxidative Phase I metabolism, either ring hydroxylation to give hydroxy metabolites and/or oxidation of the side chain to give a hydroxy or acid metabolite. Hydroxy and acid groups produced from Phase I metabolism could be subject to Phase II conjugation reactions to give the glucuronide conjugates. These types of reactions are predicted for tetrahydro-4-methyl-2-(2-methylprop-1-enyl) pyran and other structurally similar compounds in the Joint FAO/WHO Evaluation of certain food additives and contaminants (WHO, 2004). The Phase I metabolic reactions are likely to be catalysed by oxidases in the liver giving rise to a high first pass effect. It is also possible that oxidases in the lung and skin could also similarly metabolise MTHP following inhalation or dermal exposure. For THF, in addition to ring hydroxylation, extensive ring opening was observed via the action of lactonase and dehydrogenases. This pathway ultimately gives rise to substantial quantities of exhaled 14CO2 as the opened ring becomes a substrate for the endogenous 2-carbon pool metabolic pathway. It is not known if MTHP would be a substrate for lactonase, being a 6-membered ring unlike THF which is a 5-membered ring. However should it be metabolised via ring opening, MTHP would be expected to be similarly metabolised to CO2.

Conclusions:

1. MTHP can be assumed to be absorbed by the oral, dermal, and inhalation routes of exposure therefore systemic exposure is likely. However in the absence of experimental data default absorption values are used in the derivation of DNELs, according to REACH guidance R.8 page 19
2. MTHP is likely to be rapidly metabolized to hydroxy and acid metabolites which could then be conjugated.
3. MTHP is unlikely to bioaccumulate because of its polarity, extensive metabolism and rapid excretion.

Executive summary:

Tetrahydro-4-methyl-2H-pyran (MTHP) is a small heterocycle/alicyclic ether with a molecular weight of 100 g/mol. It is soluble in water at up to 19.2 g/L at 20°C with a partition coefficient (Log Pow) of 2.1 at 20°C and a vapour pressure of 1.2 hPa at 20°C. With these physical/chemical (phys/chem) properties, oral, dermal and inhalation absorption are all potential routes of exposure. 

 

Once absorbed, MTHP is likely to be widely distributed in tissues and rapidly metabolized by Phase I oxidation reactions and possible Phase II conjugation. Both unchanged parent and metabolites are likely to be excreted in urine.Therefore bioaccumulation is unlikely.

Description of key information

The toxicokinetics of absorption, distribution metabolism and excretion (ADME) of MTHP have not been evaluated in vivo. As a result, this analysis of the toxicokinetics is a qualitative assessment based on physicochemical properties and available information on MTHP and two structurally related compounds according to the guidance provided in the ECHA Guidelines (ECHA, 2014).

 

MTHP is a small heterocycle/alicyclic ether with a molecular weight of 100 g/mol. It is soluble in water at up to 19.2 g/L at 20oC with a partition coefficient (Log Pow) of 2.1 at 20oC and a vapour pressure of 1.2 hPa at 20oC. With these physical/chemical (phys/chem) properties, oral, dermal and inhalation absorption are all potential routes of exposure. 

 

Once absorbed, MTHP is likely to be widely distributed in tissues and rapidly metabolized by Phase I oxidation reactions and possible Phase II conjugation. Both unchanged parent and metabolites are likely to be excreted in urine. Therefore bioaccumulation is unlikely.

 

To conclude:

-  MTHP can be assumed to be absorbed by the oral, dermal, and inhalation routes of exposure therefore systemic exposure is likely. However in the absence of experimental data default absorption values are used in the derivation of DNELs, according to REACH guidance R.8 page 19

-  MTHP is likely to be rapidly metabolized to hydroxy and acid metabolites which could then be conjugated. 

-  MTHP is unlikely to bioaccumulate because of its polarity, extensive metabolism and rapid excretion. 

Key value for chemical safety assessment

Bioaccumulation potential:

low bioaccumulation potential

Absorption rate - oral (%):

50

Absorption rate - dermal (%):

50

Absorption rate - inhalation (%):

100