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Description of key information

In order to assess the toxicological behaviour of 1,2,3-propanetriol, glycidyl ethers, the available physico-chemical and toxicological data have been evaluated. The substance is expected to be well absorbed after oral exposure, based on its water solubility, its logPow of -1.78 / -1.94 and acute toxicity data via oral administration. Concerning the absorption after exposure via inhalation, as the chemical has low vapour pressure and is highly hydrophilic, it is clear, that the substance is poorly available for inhalation and will not be absorbed significantly. 1,2,3-propanetriol, glycidyl ethers is also not expected to be absorbed following dermal exposure into the stratum corneum and into the epidermis, due to its molecular weight and its logPow. Concerning its distribution in the body 1,2,3-propanetriol, glycidyl ethers is expected to be distributed mainly in the intravasal compartment, due to its logPow. The substance does not indicate a significant potential for accumulation. 1,2,3-propanetriol, glycidyl ethers is expected to be metabolised mainly via epoxide hydrolases (esterases), Cytochrome P450s and alcohol dehydrogenase and subsequently eliminated unchanged or as metabolites via the urine.

Key value for chemical safety assessment

Bioaccumulation potential:
no bioaccumulation potential
Absorption rate - oral (%):
50
Absorption rate - dermal (%):
10
Absorption rate - inhalation (%):
10

Additional information

Prediction using TOXTREE

The chemical structure of 1,2,3 -Propanetriol, polymer with (chloromethyl)-oxirane was assessed by TOXTREE (v.2.5.0) modelling tool for possible metabolism. SMART Cyp is a prediction model, included in the tool, which identifies sites in a molecule that are labile for the metabolism by Cytochromes P450.

1,2,3 -Propanetriol, glycidyl ethers, containing the structural alerts: secondary alcohol, dialkylether and alkyl chloride, is expected to be well metabolized by the Cytochrome P450 group of metabolizing enzymes. The primary sites of metabolism (carbonatoms of the chain and the single oxygen at the chlorinated chain) are predicted to be subject to alcohol oxidation or O-dealkylation. The tertiary sites of metabolism (carbon atoms of the chain) are predicted to be subject to O-alkylation.

Assessment of toxicological behaviour

Background

1,2,3 -Propanetriol, glycidyl ethers is also referred to as 1,2,3-Propanetriol, polymer with (chloromethyl)-oxirane and is a UVCB substance (Unknown, of Variable Composition, or of Biological Origin).

There is data available on the physico-chemical properties of 1,2,3-propanetriol, glycidyl ethers. The substance is an odourless, colourless to slight yellowish, viscous liquid (MW ca. 260.28 g/mol, Raschig, 2011), its boiling point is > 180°C (Raschig, 2008). The substance is predicted to be very soluble in water (1000 g/L at 25°C, Chemservice S.A., 2012) and a logPow of -1.78 (main component with chlorine) and -1.94 (main component without chlorine), respectively, was calculated (Chemservice S.A., 2012). Hydrolysis (as a function of pH) has been predicted and was found to be negligible (Chemservice S.A, 2012a). Including chlorine, hydrolysis will occur on atom number 13 and 19. The total, acid-catalysed rate constant at 25 °C is predicted as 5.02E-3 L/mol-sec. Without chlorine, the hydrolysis may occur on atom number 9, 15 and 18 with identical rate constants of 2.51E-3 L/mol-sec. In this case, the total acid-catalysed rate constant at 25 °C is predicted as 7.52E-3 L/mol-sec. This, however, corresponds in both cases to a time span in years (44 and 29 years, respectively) for the half-life of 1,2,3-propanetriol, glycidyl ethers and will therefore be negligible. The vapour pressure was predicted as 2.21E-5 Pa (main component with chlorine) and 0.0392 Pa (main component without chlorine) (Chemservice S.A., 2012) which is considered to be very low for both components.

The substance is acutely toxic, when administered to rats orally (LD50 is near 2000 mg/kg bw, Manciaux, 1999). At the 2000 mg/kg dose-level 3/5 males and 2/5 females died between days 1 and 4. In a dermal acute toxicity study in rats, LD50 was greater than 2000 mg/kg bw (Manciaux, 1998). No deaths or clinical signs were noted in treated animals. Regarding the irritation potential, no cutaneous reactions were observed in animals treated dermally for 24 hours (Manciaux, 1998). The substance was shown not to bear a potential to cause allergic reactions (not sensitising, LLNA, Wang-Fan, 2006). Repeated oral exposures to the structurally similar read-across substance polyglycidyl ether of substituted glycerine (0.04, 0.2 and 1 % in diet) did not cause mortalities and no significant pathology (Hine etal., 1981). This substance is reported to be highly irritating after repeated dermal exposures (Hine et al., 1981). However, repeated inhalation exposure did not cause any signs of toxicity or irritation attributable to the exposure aside from a slight encrustation of the eyelids in some animals (Hine et al., 1981). Additionally, the target substance was reported to bear genotoxic potential (Ames-test mutagenic, Banduhn, 1986). Concerning the carcinogenic potential, polyglycidyl ether of substituted glycerine was reported to cause carcinomas of the skin, when painted onto the skin of mice and sarcomas, when administered subcutaneously to rats (Hine etal., 1981). However, no tumours were produced in rabbits treated dermally and in rats fed with 0.2 % of the substance of interest by diet (Hine etal., 1981). Similarly, no clear carcinogenic activity was identified in mortality studies with workers who were exposed over a lot of years to finishing agent containing glycerol polyglycidyl ether (Lanes et al., 1994; Watkins et al., 2001).

Assessment of toxicological behaviour

The available physico-chemical and toxicological information of the substance has been evaluated and used to assess the toxicological behaviour. The results of this analysis will address the question on how the chemical will react in the body.

The EU Technical Guidance Document on Risk Assessment (TGD, Part I, Appendix VI, 2003) provides guidance, which physico-chemical properties commonly determine oral, inhalatory and dermal absorption, distribution, metabolism and elimination of substances (Access to Guidance Document: http://ecb.jrc.ec.europa.eu/tgd/).

Absorption

In general, absorption of a chemical is possible, if the substance crosses biological membranes. 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 are favourable for absorption). Generally, the absorption of chemicals which are surfactants or irritants may be enhanced, because of damage to cell membranes.

Despite the molecular weight of ca. 260.28 g/mol, 1,2,3-propanetriol, glycidyl ethers is not favourable for absorption, due to its very high water solubility (1000 g/L). Moreover, the value of the logPow of -1.78 /-1.94 demonstrates that the absorption into the body is expected to be low. LogPow between 0 and 4 are favourable for absorption while logPow values below -1 suggest that a substance is not likely to be sufficiently lipophilic to cross the stratum corneum. The substance may be to hydrophilic to cross the lipid rich cell membrane. The substance does not bear significant surface activity, therefore further enhancement of absorption is not expected. The above mentioned properties determine the absorption of 1,2,3-propanetriol, glycidyl ethers to be, despite the low molecular-weight, rather limited, based on the absorption-hindering properties (high water solubility and negative logPow) and the observed effects in toxicological experiments.

Absorption from the gastrointestinal tract

Regarding oral absorption, in the stomach, a substance will most likely be hydrolysed, because this is a favoured reaction in the acidic environment of the stomach. For 1,2,3-propanetriol, glycidyl ethers, its potential to hydrolyse was predicted using EPIWIN. The substance does not contain hydrolysable functional groups.

In the small intestine, absorption occurs mainly via passive diffusion or lipophilic compounds may form micelles and be taken into the lymphatic system. Hydrophilic substances can pass cell membranes through aqueous pores or with the bulk passage of water. as a result, GE-100 is the substance with physico-chemical characteristics that are not favourable for absorption (negative logPow, high water solubility). Nevertheless, it could still reach systemic circulation because specific mechanisms exist to enable the absorption. Based on the results of the oral acute toxicity study, 1,2,3-propanetriol, glycidyl ethers is considered to be well absorbed orally (deaths occurred at 2000 mg/kg bw and clinical signs were observed in treated animals). In conclusion, 50% oral absorption is considered for 1,2,3 -propanetriol, glycidyl ethers for the purpose of DNEL calculation.

Absorption from the respiratory tract

Concerning absorption in the respiratory tract, any gas or vapour has to be sufficiently lipophilic to cross the alveolar and capillary membranes (moderate logPow values between 0-4 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. Very hydrophilic substances can be absorbed through aqueous pores (for substances with molecular weights below and around 200) or be retained in the mucus.

1,2,3 -Propanetriol, glycidyl ethers has a very low vapour pressure, which indicates only marginal availability for inhalation. Due to its low logPow, the amount available might be absorbed through aqueous pores. This however, is unlikely as the molecular weight is above 200. Based on this data, it can be expected that 1,2,3-propanetriol, glycidyl ethers is marginally available in the air for inhalation and inhaled substance is expected not to be absorbed, due to its low vapour pressure and its molecular weight. Conclusively, 10% absorption by inhalation is considered for 1,2,3 -propanetriol, glycidyl ethers for the purpose of DNEL calculation.

Absorption following 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 of the skin and substances above 500 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 (values between 2 and 3 are optimal; TGD, Part I, Appendix VI). 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 substances with vapour pressures below 100 Pa are likely to be well absorbed and the amount absorbed dermally is most likely more than 10% 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 1,2,3-propanetriol, glycidyl ethers, the molecular weight is above 100 and below 500, which indicates already a lower potential to penetrate the skin. This is accompanied by a high hydrophilicity (log Pow of -1.78/1.94) of the substance and the stratum corneum is very resistant against penetration by highly hydrophilic substances. However, the negligible amount of 1,2,3-propanetriol, glycidyl ethers, which is absorbed following dermal exposure into the stratum corneum is however likely to be also transferred into the epidermis. As the substance is irritating to skin and eyes, this might enhance dermal absorption. However, the systemic toxicity of 1,2,3-propanetriol, glycidyl ethers via the skin has been shown to be very low (acute dermal toxicity, LD50 value of greater than 2000 mg/kg bw for rats, Mansiaux, 1998).

In conclusion, the evaluation of all the available indicators and the results of toxicity studies allow the allocation of the chemical in question into the group of chemicals with a very low dermal absorption. In detail, despite it’s molecular weight, the use of a factor of 10 % for the estimation of dermal uptake for 1,2,3-propanetriol, glycidyl ethers is justified, due to water solubility, logPow and the results for acute toxicity (please refer to the section "DNEL calculation").

Distribution

In general, the following principle applies: the smaller the molecule, the wider the distribution. A hydrophilic molecule (logPow< 0) is not likely to distribute into cells and the intracellular concentration is not higher than extracellular concentration. If a substance binds to proteins, it will limit the amount of the substance available for distribution. 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 1,2,3-propanetriol, glycidyl ethers, no data is available for distribution patterns. The distribution is expected to be limited, reaching predominantly the intravasal compartment, due to its better solubility in water than in octanol (logPow-1.78/-1.94). However, an absorption into the cell inner cannot be ruled out due to the positive genotoxicity result in bacterial cells (Banduhn, 1986).

Accumulation

It is also important to consider the potential for a substance to accumulate or to be retained within the body. Lipophilic substances have the potential to accumulate within the body (mainly in the adipose tissue), if the dosing interval is shorter than 4 times the whole body half-life. Although there is no direct correlation between the lipophilicity of a substance and its biological half-life, substances with high logPow values tend to have longer half-lives. On this basis, there is the potential for highly lipophilic substances (logPow >4) to accumulate in biota which are frequently exposed. Highly lipophilic substances (logPow between 4 and 6) that come into contact with the skin can readily penetrate the lipid rich stratum corneum but are not well absorbed systemically. Although they may persist in the stratum corneum, they will eventually be cleared as the stratum corneum is sloughed off. A turnover time of 12 days has been quoted for skin epithelial cells.

Accordingly, the experimentally determined logPow, water solubility and predicted behaviour concerning absorption and metabolism of 1,2,3-propanetriol, glycidyl ethers do not indicate a potential for accumulation in the body.

Metabolism:

Route specific toxicity results from several phenomena, such as hydrolysis within the gastrointestinal or respiratory tracts, also metabolism by gastrointestinal flora or within the gastrointestinal tract epithelia (mainly in the small intestine), or respiratory tract epithelia (sites include the nasal cavity, tracheo-bronchial mucosa [Clara cells] and alveoli [type 2 cells]) and skin.

As specified above, non-enzymatical hydrolysis is expected to be negligible for 1,2,3-propanetriol, glycidyl ethers. Its metabolism is likely to occur also via the Cytochrome P450 group of metabolising enzymes, as it has been predicted by the TOXTREE modelling tool (Chemservice S.A., 2012) and the OECD QSAR Toolbox (v. 3.3., 2014). In detail, the chemical has been identified to bear primary and tertiary sites and more than 4 sites for metabolism by the Cytochrome P450 group of metabolising enzymes. The primary sites of metabolism (carbon-atoms of the chain and the single oxygen at the chlorinated chain) are predicted to be subject to alcohol oxidation or O-dealkylation. The tertiary sites of metabolism (carbon atoms of the chain) are predicted to be subject to O-alkylation. According to modelling results obtained using TOXTREE, 1,2,3-propanetriol, glycidyl ethers, contains the structural alerts: secondary alcohol and dialkylether (and alkylchlorine in case of chlorinated 1,2,3-propanetriol, glycidyl ethers). To identify all possible sites for phase I and II reactions, the molecular structure of 1,2,3-propanetriol, glycidyl ethers was investigated in detail. The epoxide-groups can be subject to hydrolysis mediated by microsomal or soluble epoxide-hydrolases (Seidegard and Ekström, 1997), leading after addition of water to the epoxides to the formation of R-CHOH-CH3, or RCH2-CH2OH (possibly subject to further modification by alcohol dehydrogenase). The formation of diols was also predicted by the “Rat liver S9 metabolism simulator” and “Hydrolysis simulator” of the OECD QSAR Toolbox (v. 3.3., 2014) (please see Annex). It should be noted that the predicted metabolites and hydrolysis products at neutral and basic conditions are the same while hydrolysis products at acidic conditions are oxidation derivatives of the formed diols. Acidic condition facilitate a further degradation to glycerin, dihydroxypropoxy derivatives of glycerine and (mono)propanediol ether of glycerine. In addition, it is possible that after oral ingestion the epoxide-groups are subject to reduction by bacteria of the gastrointestinal flora, which would lead to the formation of alkenes. Those would probably be reduced to alkanes. However, these intermediates will be either subject to modifications by esterases (hydrolysis at the oxygen within the chain) or subject to oxidative dealkylations by Cytochrome P450s (hydroxylation at the oxygen within the chain). Regarding the chlorinated 1,2,3-propanetriol, glycidyl ethers, this can be subject to reduction, where the chlorine atom is replaced by a hydrogen atom. This reaction can either be mediated by intestinal bacteria or by mammalian reductases. The existing or newly introduced functional groups will react in phase II of the biotransformation with different molecules, leading to the formation of conjugations. For the hydroxyl-groups it is most likely that they conjugate to glucuronic acid, activated sulphate or activated methionine. This however, is not very likely as the substance / metabolites is / are already very water soluble and of low molecular weight. Nevertheless, it has to be kept in mind, that metabolites conjugated to glucuronic acid, can be subject to entero-hepatic recycling, and therefore re-enter the system. There are published data available for the metabolism of epoxy compounds. Epoxyde hydrolases, presented in mammalian species, reduce glycidyl ethers to their corresponding diols (Oesch, 1972; NIOSH, 1978; Seidegard and Ekström, 1997; Chen et al., 2007). They can be further oxidised or conjugated with glutathione (Glatt et al., 1983, Boogard et al., 2000).

In conclusion, it is likely that the substance of interest will be subject to metabolism by esterases, Cytochrome P450 enzymes or alcohol dehydrogenase and theoretically subsequent glucuronidation or binding with glutathione. Concerning the possibility of protein binding of 1,2,3-propanetriol, glycidyl ethers, this cannot be ruled out due to the epoxy moieties which are known to bind to proteins via SN2 mechanism. The non-enzymatic reactions of epoxides like covalent binding to proteins and to DNA have been reported in literature (Oesch, 1972; NIOSH, 1978).

In conclusion, it is likely that the substance of interest will be subject to metabolism by esterases, Cytochrome P450 enzymes or alcohol dehydrogenase and theoretically subsequent glucuronidation or binding with glutathione. Concerning the possibility of protein binding of 1,2,3-propanetriol, glycidyl ethers, this cannot be ruled out due to the epoxy moieties which are known to bind to proteins via SN2 mechanism. The non-enzymatic reactions of epoxides like covalent binding to proteins and to DNA have been reported in literature (Oesch, 1972; NIOSH, 1978).

Excretion:

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 mainly excreted via 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). They have generally 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 and more lipid soluble molecules that can then be reabsorbed from the gastrointestinal tract (GIT). Those substances less likely to recirculate are substances having strong polarity and high molecular weight. Other substances excreted in the faeces are those that have diffused out of the systemic circulation into the GIT 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 by skin cells.

For 1,2,3-propanetriol, glycidyl ethers no data is available concerning its elimination. Taking into account its chemical structure, its molecular weight and the above mentioned behaviour predicted for its metabolic fate, it is very likely that the parent substance will be excreted unchanged or in form of diols via the urine.