1,2,3-Propanetriol, mono- and diformates

Endpoint summary

Description of key information

1,2,3-Propanetriol, mono- and diformate is considered to readily decompose into 1,2,3-propanetriol (glycerol) and formic acid. This assumption is supported by data on hydrolysis (chapter 5.1.2) and fast enzymatic degradation (Chapter 7.1.1). 

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

Basic toxicokinetics

No studies are available on the toxicokinetic behaviour of 1,2,3-Propanetriol, mono- and diformates. Therefore, in accordance with Annex VIII, Column 1, Item 8.8, of Regulation (EC) No 1907/2006, and with the "Guidance on information requirements and chemical safety assessment Chapter R.7c: Endpoint specific guidance (ECHA, 2008)", assessment of the toxicokinetic behaviour of the substance was conducted to the extent that can be derived from the relevant available information on physico-chemical and toxicological properties.

Absorption

Oral:

When assessing the potential of 1,2,3-Propanetriol, mono- and diformates to be absorbed in the gastrointestinal (GI) tract, it has to be considered that esters like formates can undergo hydrolysis to a high extent by ubiquitous expressed GI enzymes (Long, 1958; Lehninger, 1970; Mattson and Nolen, 1972). An in vitro hydrolysis test with 1,2,3-Propanetriol, mono- and diformates confirmed rapid hydrolysis using simulated intestinal fluid. The degradation products are glycerol and formic acid (Strauhal, 2013). In addition, 1,2,3-Propanetriol, mono- and diformates are rapidly degraded in gastric fluid (pH 1.2: t ½ = 0.5 h, Möller 2013). Thus, the predictions based on physico-chemical characteristics of the parent substance may not apply but the breakdown products glycol and formic acid have to been taken into account.

As the parent compound and the breakdown products are highly water-soluble, the substances will readily dissolve in GI fluids. Due to their low molecular weights, the breakdown products and the intact parent substance may pass through aqueous pores or may be carried through the epithelial barrier by the bulk passage of water. Furthermore, the small log Pow of the substances (1,2,3-Propanetriol, mono- and diformates: log Pow = -1.7; formic acid: log Pow= -0.54; glycerol: log Pow= -1,85) favours absorption by passive diffusion facilitating absorption in the GI tract (ATSDR, 2010; ICPS, 2001; NTP, 1992; Hanzlik, 2005).

Dermal:

No data are available on dermal absorption or on acute dermal toxicity of 1,2,3-Propanetriol, mono- and diformates. Regarding the molecular weight of both the parent substance (120 - 148 g/mol) and the hydrolytical breakdown products (62.07 and 46.03 g/mol) dermal uptake is anticipated to be high. However, regarding the calculated octanol/water partition coefficient of the parent substance of -1.7 and the high water solubility, the intact substance may be too hydrophilic to cross the lipid rich environment of the stratum corneum. QSAR calculation using DERMWIN showed a dermal absorption potential with a permeability constant (pK) of 2.15E-05 cm/h and an estimated dermal absorbed dose of approx. 3 mg/kg/d. However, it is important to note that 1,2,3-Propanetriol, mono- and diformates is considered to show corrosive properties, thus the damage to the skin surface may enhance penetration of the breakdown products.

Inhalation:

1,2,3-Propanetriol, mono- and diformates has a vapour pressure of 0.0985 Pa at 20 °C thus being of low volatility. Therefore, under normal use and handling conditions, inhalation exposure and thus availability for respiratory absorption of the substance in the form of vapours, gases, or mists is not significant. However, the substance may be available for respiratory absorption in the lung after inhalation of aerosols, if the formulated substance is sprayed.

Due to the hydrophilicity of 1,2,3-Propanetriol, mono- and diformates, deposition in the mucus is possible. A hydrolysis test in vitro is available indicating rapid hydrolysis of the ester. Thus, the parent compound may only be present in the respiratory tract for a limited period of time. Absorption of deposited material is anticipated to be high, due to the low molecular weight and the moderate log Pow of the parent substance and the hydrolysis products as discussed in the oral absorption section.

Distribution and accumulation:

Distribution of a compound within the body depends on the physicochemical properties of the substance especially the molecular weight, the lipophilic character and the water solubility. In general, the smaller the molecule, the wider is the distribution (ECHA, 2008). Based on the small size and the high hydrophilicity it is concluded that parent compound and breakdown products will be readily distributed. 1,2,3-Propanetriol, mono- and diformates, glycol and formic acid do not have the potential to accumulate in adipose tissue due to their low log Pow. In addition, the intact parent compound is not assumed to accumulate as hydrolysis to glycol and formic acid is anticipated to take place to a high extent before absorption or during metabolism.

In summary, the available information on 1,2,3-Propanetriol, mono- and diformates indicate that no significant bioaccumulation of the parent substance or the breakdown products of hydrolysis in adipose tissue is expected. The parent substance and the breakdown products will be distributed in the organism.

Metabolism:

Metabolism of 1,2,3-Propanetriol, mono- and diformates occurs initially via enzymatic hydrolysis of the ester resulting in glycol and formic acid. The hydrolysis of the ester was confirmed by an in-vitro study using simulated intestinal fluid (Strauhal, 2013). In this study, rapid ester hydrolysis was confirmed with a half live of 1.57 h. Furthermore, in-vivo studies in rats with esters containing one, two or three ester groups showed that they are rapidly hydrolysed by ubiquitously expressed esterases and almost completely absorbed (Mattson and Volpenheim, 1968; Mattson and Nolen, 1972).

The resulting Glycerol is a precursor for synthesis of triacylglycerols and of phospholipids in the liver and adipose tissue. Formic acid is primarily oxidized in the liver (NTP, 1992). Under physiological conditions, formic acid dissociates to formate which is further metabolised to the excretion products CO2 and H2O (Bouchard, 2001). Oxidation of formate to carbon dioxide is mainly driven by a tetrahydrofolate-dependent multistep pathway while a small percentage of formate is excreted directly with the urine (Bouchard, 2001).

Excretion:

Based on the metabolism described above, the breakdown products of 1,2,3-Propanetriol, mono- and diformates will be metabolised in the body to a high extent. Glycerol will be used in endogenous anabolism. Formic acid will be metabolised and mainly excreted via exhaled air as CO2 (Bouchard, 2001; NTP 1992).

A detailed reference list is provided in the technical dossier (see IUCLID, section 13) and within the CSR.