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Link to relevant study record(s)

Reference
Endpoint:
basic toxicokinetics, other
Remarks:
Expert statement
Type of information:
other: Expert statement
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: No GLP-conform guideline study, but scientifically valid expert statement based i.a. on studies assessed with Klimisch 1 or 2
Objective of study:
absorption
distribution
excretion
metabolism
toxicokinetics
Qualifier:
no guideline required
Principles of method if other than guideline:
An extensive assessment of the toxicokinetic behaviour of 2,3-Epoxypropyl isopropyl ether (IPGE) was performed, taking into account the chemical structure, the available physico-chemical and toxicological data.
GLP compliance:
no
Radiolabelling:
other: not applicable
Species:
other: not applicable
Strain:
other: not applicable
Details on test animals or test system and environmental conditions:
not applicable
Route of administration:
other: All relevant routes of administration are discussed in the expert statement.
Vehicle:
other: not applicable
Details on exposure:
not applicable
Duration and frequency of treatment / exposure:
not applicable
Remarks:
not applicable
Control animals:
other: not applicable
Positive control reference chemical:
not applicable
Details on study design:
not applicable
Details on dosing and sampling:
not applicable
Statistics:
not applicable
Type:
absorption
Results:
The relevant absorption rates were estimated to: Oral absorption: approx. 100%, Dermal absorption: approx. 100%, Inhalative absorption: approx. 100%
Type:
distribution
Results:
Systemic bioavailability of the substance is very high. A high peak exposure can be expected, a very relevant AUC is not to be expected.
Type:
metabolism
Results:
O-dealkylation and Aliphatic hydroxylation were identified as the mode of action during Phase-I-metabolism, and subsequent conjugation is expected.
Type:
excretion
Results:
IPGE and its estimated metabolites are small and soluble in water. A very fast excretion of the compounds via the kidneys, urine and potentially lungs can be expected. IPGE has a minor potential for bioaccumulation, and will be excreted rapidly.
Details on absorption:
Absorption
In this chapter, the physico-chemical properties of the substance are used to draw general conclusions for its behaviour and how these properties will influence its oral, inhalatory and dermal absorption. Furthermore, these conclusions will be supported by the available literature data and studies.
In general, absorption of a chemical is possible, if the substance crosses biological membranes. In case where no transport mechanisms are involved, this process requires a substance to be soluble, both in lipid and in water, and is also dependent on its molecular weight (substances with molecular weights below 500 g/mol are favourable for absorption). Generally, the absorption of chemicals which are surfactants or irritants may be enhanced, because of damage to cell membranes.
IPGE was found to be moderately irritating to both skin and eyes, but no corrosive. Hence, the possibility of an enhanced absorption due to damaged cell membranes cannot be completely excluded, but may be less significant.
Due to the lack of experimental absorption data, the following physico-chemical parameters of IPGE will be taken into account when discussing its absorption into the body:
- Molecular weight = 116.1583 g/mol
- Physical state: liquid
- Water solubility = 19 g/L at 25°C
- Partition Coefficient log Pow = 0.8 at 25°C
- Vapour pressure = 13 mbar at 25°C
- Melting point = -54.70°C (MPBPWIN v1.43 estimation)
- Boiling point = 137°C

Absorption from the gastrointestinal tract
In the small intestine absorption occurs mainly via passive diffusion or lipophilic compounds may form micelles and be taken into the lymphatic system. Additionally, metabolism can occur by gut microflora or by enzymes in the gastrointestinal mucosa. However, the absorption of highly lipophilic substances (LogPow of 4 or above) may be limited by the inability of such substances to dissolve into gastrointestinal fluids and hence make contact with the mucosal surface. The absorption of such substances will be enhanced if they undergo micellular solubilisation by bile salts. Substances absorbed as micelles enter the circulation via the lymphatic system, bypassing the liver. Consequently, immediate Cytochrome P450 metabolism is less important here as for substances which directly enter the hepatic system via the portal vein.
According to ECHA’s guidance R.7c [ECHA 2008] [ECHA 2014], it is stated that the smaller the molecule the more easily it may be taken up. Molecular weights below 500 g/mol are favourable for absorption. With a molecular weight of 116.1583 g/mol, absorption in general can be considered as possible, and it is indeed very low, absorption is in general favourable. Also, substances with moderate log P values (between -1 and 4) are favourable for absorption by passive diffusion. With a LogPow of 0.8 at 25°C, a passive diffusion in the gastrointestinal fluids is indicated; as it is directly in between those boundary values, absorption is also highly likely based on the LogPow. Water-soluble substances will readily dissolve into the gastrointestinal fluids [ECHA 2014], and the determined solubility of 19 g/L at 25°C is magnitudes above the guidance value of 1 mg/l, so water solubility does also not indicated a hindered absorption.
The substance is not readily biodegradable, but a certain hydrolysis was detected. With half-lives at 25°C of 15.6 days (pH 4), 22.7 days (pH 7), and 24.8 days (pH 9), the formation of the hydrolysis product 3-(1-methylethoxy)-1,2-propanediol (CAS 17226-43-6) is rather negligible. Although a very slight pH-dependence of the half-lives was noted, and it can be expected that the hydrolysis product may be formed slightly faster in the very acidic environment (pH = 1-2) of the stomach, it would take too long for CAS 17226-43-6 to be formed. Half of the product will be transformed after two weeks or more, and the substance, as will be outlined below, is expected to remain way less in the body. Skin irritation tests e.g. have exposure durations of 4 hours, and taking into account the physico-chemical properties of the substance, no bioaccumulation can be expected and (assuming no transformation) it will be removed from the body within few days. So taking into account this discrepancy, the hydrolysis product 3-(1-methylethoxy)-1,2-propanediol does not need to be regarded when estimating the absorption of IPGE. Only IPGE as such is relevant for absorption. Also, a possible metabolism as described in chapter 3.4 Metabolism does only have to be regarded after absorption already has occurred.
Taking into account the acute and short term oral toxicity data, at least some information can be taken to prove the conclusions that absorption occurs. Via all three exposure routes, LD50 values could have been determined, indicating that absorption occurred. However, they are all rather high, the lowest values are LD50 = 1300 mg/kg (oral, mouse), LC50 = 1100 ppm corresponding to 5.226 mg/L (inhalation, rat), and LD50 = 9650 mg/kg (dermal, rabbit). So it cannot be clearly deducted from these results whether the substance is poorly absorbed or not very toxic as such. Further, the LOAEL of 100 mg/kg (female, reproductive toxicity) as found in an OECD 422 study on rats, indicates in general that absorption occurs. And, due to the fast that an effect on reproductive toxicity occurred, a wide distribution of the test items throughout the body is strongly indicated.
Hence, a preliminary occurrence of oral absorption of the test item after gavage can reasonably deducted.
So in summary, taking into account the available physico-chemical data of IPGE, especially its small molecular weight and high water solubility, its absorption via the GI tract can be considered to be very high. This conclusion is supported by effects after oral application in an OECD 422 study indicating a distribution of the compounds throughout the body. Due to the lack of further data, an absorption of 100% should be taken into account when performing the subsequent risk assessment.

Absorption from the respiratory tract
Concerning absorption in the respiratory tract, any gas, vapour or other substances inhaled as respirable dust (i.e. particle size ≤ 15 µm) has to be sufficiently lipophilic to cross the alveolar and capillary membranes (moderate LogPow values between 0-4 are favourable for absorption). The rate of systemic uptake of very hydrophilic gases or vapours may be limited by the rate at which they partition out of the aqueous fluids (mucus) lining the respiratory tract and into the blood. Such substances may be transported out of the lungs with the mucus and swallowed or pass across the respiratory epithelium via aqueous membrane pores. Lipophilic substances (LogPow >0) have the potential to be absorbed directly across the respiratory tract epithelium. Any lipophilic compound may be taken up by micellular solubilisation but this mechanism may be of particular importance for highly lipophilic compounds (log P >4), particularly those that are poorly soluble in water (1 mg/l or less) that would otherwise be poorly absorbed [ECHA, 2008].
As IPGE is a liquid at room temperature, dust inhalation does not need to be regarded. However, IPGE has a vapour pressure of 13 mbar at 25°C, i.e. 13 hPa or 1.3 kPa. According to the BG Bau [BG Bau 2017], a vapour pressure of p < 0.01 hPa is very low, p = 1-10 hPa low and p > 10 hPa is high. The 31. BImSchV describes a organic substance as volatile if it has a vapour pressure of 0.01 kPa or more at 293.15 K. Also, according to ECHA’s guidance, substances are not available for inhalation as a gas in a relevant manner with a vapour pressure less than 0.5 kPa (or a boiling point above 150°C) [ECHA, 2008]. This does not apply to IPGE having a boiling point of 137°C and a vapour pressure of 1.3 kPa. Hence, IPGE has to be considered as volatile and absorption via inhalation is considered possible, in case the taken safety measures fail. Similar applies if accidentally aerosols are formed. As a consequence, there could be a certain fraction potentially reaching the alveolar region of the respiratory tract beyond the bronchi. Although handling of the substance does not lead to a significant exposure due to implemented Risk Management Measures, the potential absorption will be regarded theoretically.
In general, either a prolonged exposure due to deposition and subsequent absorption or immediate absorption by micellular solubilisation has to be assumed. The latter mechanism may be of particular importance for highly lipophilic compounds (LogPow >4), particularly those that are poorly soluble in water (1 mg/l or less) and is hence not relevant here. To be readily soluble in blood, a gas, vapour or dust must be soluble in water and increasing water solubility would increase the amount absorbed per breath. However, the gas, vapour or dust must also be sufficiently lipophilic to cross the alveolar and capillary membranes. Therefore, a moderate log P value (between -1 and 4) would be favourable for absorption. Generally, liquids, solids in solution and water-soluble dusts would readily diffuse/dissolve into the mucus lining the respiratory tract. Hence, with a LogPow of 0.8 at 25°C and a water solubility of 19 g/L at 25°C, IPGE must be considered to be readily absorbed once reaching the lung, at least as vapour, and the absorption of the fraction which may not be subjected to ciliary clearance can be considered as rather high. Without having concrete droplet sizes of potential aerosols, no statements regarding the deposition place and hence place-specific clearance mechanisms, e.g. ciliary movements, can be made.
In summary, once that IPGE reached the lower respiratory tract, taking into account its potential to be absorbed and a certain precaution due to the lack of toxicokinetic test data, the inhalative absorption can be estimated to be 100% as a worst case assumption.

Absorption after dermal exposure
In order to cross the skin, a compound must first penetrate into the stratum corneum and may subsequently reach the epidermis, the dermis and the vascular network. The stratum corneum provides its greatest barrier function against hydrophilic compounds, whereas the epidermis is most resistant to penetration by highly lipophilic compounds. Substances with a molecular weight below 100 are favourable for penetration through the skin and substances above 500 g/mol are normally not able to penetrate. The substance must be sufficiently soluble in water to partition from the stratum corneum into the epidermis. Therefore, if the water solubility is below 1 mg/L, dermal uptake is likely to be low. Additionally, logPow values between 1 and 4 favour dermal absorption.
Above 4, the rate of penetration may be limited by the rate of transfer between the stratum corneum and the epidermis, but uptake into the stratum corneum will be high. Above 6, the rate of transfer between the stratum corneum and the epidermis will be slow and will limit absorption across the skin. Uptake into the stratum corneum itself may be slow. Moreover vapours of substances with vapour pressures below 100 Pa are likely to be well absorbed and the amount absorbed dermally is most likely more than 10% and less than 100% of the amount that would be absorbed by inhalation. If the substance is a skin irritant or corrosive, damage to the skin surface may enhance penetration. During the whole absorption process into the skin, the compound can be subject to biotransformation.
In case of IPGE, an evaporation after skin contact is considered possible. Although the boiling point of 137°C is 100°C higher than body temperature, the vapour pressure of 13 mbar at 25°C indicates at least a certain potential for evaporation. However, the evaporation is not considered to be fast enough to exclude a certain exposure duration and hence absorption. As stated above, IPGE was found to be moderately irritating to both skin and eyes, but no corrosive. Hence, the possibility of an enhanced absorption due to damaged cell membranes cannot be completely excluded, but may be less significant, and additional, relevant absorption-enhancing effects can be disregarded. So for the majority of the substance spilled onto skin, absorption through the intact skin after a certain exposure period must be considered.
The molecular weight of IPGE is with 116.1583 g/mol rather low, which in general indicates a certain potential to penetrate the skin. Further, with a water solubility of 19 g/L at 25°C, IPGE is considered sufficiently soluble to pass the epidermis. Also, it is most likely not too high to penetrate the stratum corneum and to be absorbed via the skin. This is supported by its partition coefficient. It is with 0.8 at 25°C only slightly below the indicative guidance value of 1 – 4, which is considered not to affect its potential to be absorbed significantly.
Therefore, a nearly non-hindered dermal absorption can be assumed, most reasonably a resulting maximum dermal penetration rate of IPGE of 100% as a worst case, which is compliant with i.a. the European ECHAs Guidance documents [ECHA, 2008] and scientifically reasonable when e.g. performing route-to-route extrapolations during risk assessment.
Details on distribution in tissues:
Distribution
In general, it can be stated that the smaller the molecule, the wider is its distribution. A lipophilic molecule (LogPow >0) is likely to distribute into cells and the intracellular concentration may be higher than extracellular concentration particularly in fatty tissues. It is not possible to absolutely foresee protein binding, which can limit the amount of a substance available for distribution. In the case of IPGE, ToxTree modelling [Ideaconsult Ltd, 2004-2013] gave a protein binding alert. The epoxy group of the molecule was identified to potentially undergo a SN2-nucleophilic aliphatic substitution. Hence, the substance may be partially retained in the tissue of first impact due to covalent binding, and hence the distribution of IPGE through the body may be reduced by that amount. Furthermore, if a substance undergoes extensive first-pass metabolism, predictions made on the basis of the physico-chemical characteristics of the parent substance may not be applicable.
In case of IPGE, no quantitative data is available for distribution patterns. Taking into account its rather low molecular weight of 116.1583 g/mol, its hydrophilicity and high water solubility, the absolute systemic bioavailability is very high, both being able to distribute via the in the aqueous compartment and to pass biological membranes.
After oral exposure, the first target will be the gastrointestinal tract, where the substance and possibly bacterial metabolites will be absorbed in high quantities, most likely close to 100% of the ingested amount, and transferred via the blood stream to the liver.
After reaching the liver via the portal vein, the substance will be further distributed via the bloodstream. Here, especially the kidneys due to their filter function and the heart due to its enormous need for nutrients and consequently large blood flow through coronary arteries will be exposed.
Possible metabolites and degradation products are expected to be of the same or smaller size and at least same or higher hydrophilicity as the parent compound. Hence, similar distribution patterns can be expected and no differentiation between the parent compound and metabolites has to be made regarding distribution. Due to the hydrophilicity, high water solubility and small size, a possible accumulation can be neglected. However, care should be taken in this case as, due to the epoxy group of the molecule, the substance possible binds directly to proteins and DNA. This fraction will not be distributed directly through the blood stream and must be regarded separately. Since the solubility and hence absorption via the GI tract of IPGE and its metabolites is rather complete, a high peak exposure to the compound(s) and hence high systemic bioavailability can be expected. However, due to their tendency to be excreted rather fast, a very relevant AUC is not to be expected. This applies to all three possible exposure routes, although the formation of metabolites will be most relevant for the oral route.
The affection of the lymphatic system via micellar uptake however is only of minor importance.
These conclusions are based on the physico-chemical properties of IPGE, and which are also applicable for its metabolites, are furthermore supported by the results of the repeated dose / reproductive toxicity OECD 422 study. The fact that at 600 and 300 mg/kg bw/day pregnancy was not achieved in any female, clearly shows that the substance was distributed throughout the body including the reproductive organs. Nine males and one female treated with 600 mg/kg bw/day had raised white patches on the non-glandular region of the stomach. As it did not occur at 300 mg/kg bw, secondary effects due to an localized phenomenon, i.e. inflammation of the GI tract without substance uptake, can be excluded.
As a consequence, a wide distribution of the test items throughout the body can be reasonably assumed.
Details on excretion:
Excretion
In general, the major routes of excretion for substances from the systemic circulation are the urine and/or the faeces (via bile and directly from the gastrointestinal mucosa). For non-polar volatile substances and metabolites exhaled air is an important route of excretion. Substances that are excreted favourable in the urine tend to be water-soluble and of low molecular weight (below 300 in the rat) and be ionized at the pH of urine. Most will have been filtered out of the blood by the kidneys though a small amount may enter the urine directly by passive diffusion and there is the potential for reabsorption into the systemic circulation across the tubular epithelium. Substances that are excreted in the bile tend to be amphipathic (containing both polar and nonpolar regions), hydrophobic/strongly polar and have higher molecular weights and pass through the intestines before they are excreted in the faeces and as a result may undergo enterohepatic recycling which will prolong their biological half-life. This is particularly a problem for conjugated molecules that are hydrolysed by gastrointestinal bacteria to form smaller more lipid soluble molecules that can then be reabsorbed from the GI tract. Those substances less likely to recirculate are substances having strong polarity and high molecular weight of their own accord. Other substances excreted in the faeces are those that have diffused out of the systemic circulation into the GI tract directly, substances which have been removed from the gastrointestinal mucosa by efflux mechanisms and non-absorbed substances that have been ingested or inhaled and subsequently swallowed. Non-ionized and lipid soluble molecules may be excreted in the saliva (where they may be swallowed again) or in the sweat. Highly lipophilic substances that have penetrated the stratum corneum but not penetrated the viable epidermis may be sloughed off with or without metabolism with skin cells.
For IPGE no test data is available regarding its elimination. Concerning the above mentioned behaviour predicted for its metabolic fate, it is unlikely that the parent substance will be excreted unchanged. Nevertheless a similar behaviour regarding excretion can be assumed for the parent compound and most of its degradation products. The estimated metabolites isopropanol and acetone will also be excreted both via breath and urine.
IPGE and its known and estimated degradation products are small, hydrophilic and very soluble in water. So a very fast excretion of the compounds via the kidneys and so urine can be expected. Excretion via the GI tract (unabsorbed material) and via the bile and consequent subjection to enterohepatic recycling can be neglected. Details on the fate of the fraction of IPGE bound to proteins and DNA can hardly be predicted, however, it can be expected to be removed from those larger molecules, too.
Metabolites identified:
yes
Details on metabolites:
For details, see attached file. Metabolites of the substance are estimated to be formed via O-dealkylation and Aliphatic hydroxylation.

See attached expert statement.

Conclusions:
The present expert statement covers all relevant toxicokinetic parameters to assess the behaviour of 2,3-Epoxypropyl isopropyl ether (IPGE) in the body, the available information is sufficient to enable one to perform a proper risk assessment. Hence, no further information needs to be gathered and further studies can be omitted due to animal welfare. In conclusion, the substance has no potential for bioaccumulation in its non-metabolized or metabolized form.
Executive summary:

In order to assess the toxicokinetic behaviour of 2,3-epoxypropyl isopropyl ether (IPGE), the available toxicological, ecotoxicological and physico-chemical data were evaluated, as toxicokinetic test data is lacking.

The molecular weight of 116.1583 g/mol, a LogPow of 0.8 at 25°C, and a water solubility of 19 g/L, a high potential for oral absorption is given. The substance is not ready biodegradable and hydrolysis occurs rather slow, so degradation products do not need to be considered. Taking into account the oral OECD 422 study, a certain absorption of the test compounds is evident, reproduction was impaired. Hence, a preliminary occurrence of oral absorption of the test item after gavage can reasonably deducted.

IPGE is considered as volatile, so the inhalative absorption as a gas is possible. As it is liquid at room temperature, no inhalable particles need to be regarded. However, with the given LogPow and a water solubility, IPGE must be considered to be readily absorbed once reaching the lung, at least as vapour.

IPGE has a certain potential for evaporation, which is not considered to be fast enough to exclude a certain exposure duration and hence absorption. The substance is only irritating, so an enhanced absorption due to damaged cell membranes may be less significant. With the above-mentioned molecular weight, logPow and water solubility, a nearly non-hindered dermal absorption can be assumed.

So in summary, the absorption rates may be estimated to:

-      Absorption via oral route: 100%

-      Absorption via inhalative route: 100%

-      Absorption via dermal route: 100%

Taking into account IPGE’s rather low molecular weight and its sufficient water solubility, the absolute systemic bioavailability is very high. Similar distribution patterns can be expected for its metabolites and a possible accumulation can be neglected, besides that fraction of IPGE which bind covalently on larger biological molecules. A high peak exposure to the compound(s) and hence high systemic bioavailability can be expected, but not a very relevant AUC, which applies to all three exposure routes. This is supported by the results of the OECD 422 study, as an impairment of reproductive function is strongly indicative for a wide distribution of the test item throughout the body.

The low logPow and the high water solubility are clearly indicating that for IPGE, a certain potential for accumulation in the body can be excluded and a rather fast excretion can be expected. Also, covalently bound molecules are likely to be excreted fast due to the bodies’ intrinsic repair mechanisms. So, the potential of IPGE for bioaccumulation in its classic sense is virtually not existing.

Regarding its metabolic fate, O-dealkylation and Aliphatic hydroxylation were identified as the mode of action during Phase-I-metabolism. The metabolites formed are not expected to modify essentially the molecular weights, physico-chemical properties and hence ADME behaviour of IPGE. These metabolites are expected to be either excreted directly or to react in Phase II of the biotransformation with different molecules, leading to the formation of conjugations. The hydroxyl groups are the most likely functional groups to be conjugated to glucuronic acid, activated sulphate or activated methionine. Further, the estimated metabolites isopropanol and acetone will also be excreted both via breath and urine. Hence, it is unlikely that IPGE will be excreted unchanged. IPGE and its estimated metabolites are small, charged and hence hydrophilic and very soluble in water. So a very fast excretion of the compounds via the kidneys and so urine can be expected.

In conclusion, IPGE has a minor potential for bioaccumulation, and will be excreted rapidly after metabolism.

Description of key information

Expert statement: IPGE has a minor potential for bioaccumulation. The relevant absorption rates can be estimated by expert judgement to 100% (oral), 100% (dermal) and 100% (inhalation).

Key value for chemical safety assessment

Bioaccumulation potential:
low bioaccumulation potential
Absorption rate - oral (%):
100
Absorption rate - dermal (%):
100
Absorption rate - inhalation (%):
100

Additional information

The present expert statement covers all relevant toxicokinetic parameters to assess the behaviour of IPGE in the body, the available information is well-investigated and sufficient to enable one to perform a proper risk assessment. The tonnage-driven data requirements under REACH are fully met and hence, no further information needs to be gathered and further studies can be omitted due to animal welfare.