Reaction mass of ethane-1,2-diol and 2-hydroxyethyl formate and ethylene diformate

Endpoint summary

Description of key information

The components of the reaction mass hydrolyse quickly to formic acid and ethane-1,2 -diol.

- Absorption

Due to the low molecular weight, high water solubility and negative log Pow, an effective absorption can be assumed.

- Distribution

Based on the physical-chemical properties of the components, a thourough distribution in the body can be expected.

- Metabolism and excretion

Metabolism occurrs mainly through hydrolysis and the endproducts of the metabolism are excreted in the urine or exhaled.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

The reaction mass consists of ethane-1,2-diol, 2-hydroxyethyl formate and ethylene diformate, the latter two substances being the main components. The esters present in the reaction mass hydrolyse rapidly under physiological conditions releasing formic acid and ethane-1,2-diol (see below). Thus, all components of the reaction mass as well as its biotransformation products are considered in the toxicokinetic assessment.

 

Biotransformation

The biotransformation of the reaction mass was investigated in an intestinal-fluid simulant (Infrapark Baselland Ltd, 2016). The reaction mass was incubated at 37°C and pH 7.5 for 4 hours. After 0, 1, 2 and 4 hours of incubation the concentration of ethane-1,2-diol, 2-hydroxyethyl formate and ethylene diformate were determined. After the 4-hour incubation period only negligible levels of ethylene diformate (i.e. <0.5% of the initial amount) remained. The half-life (t1/2) was 0.35 h for ethylene diformate and 2.40 h for 2-hydroxyethyl formate.

The results of the study demonstrate rapid transformation of ethylene diformate under physiological conditions into 2-hydroxyethyl formate and formic acid and further transformation of 2-hydroxyethyl formate into ethane-1,2-diol and formic acid.

 

Absorption

Oral absorption

Since all components as well as the transformation products of the reaction mass are low molecular weight substances, highly water soluble (miscible with water at any ratio) and have a negative log Pow value it can be assumed that the substances pass through biological membranes and will be effectively absorbed from the gastrointestinal tract. For ethane-1,2-diol an oral absorption of 90 -100% has been reported in rats and mice (WHO, 2002). Oral absorption (not further specified) has also been described for formic acid by MAK (2003). The actual amount absorbed will be low in the case of the mono- and diformate of ethane-1,2-diol because of rapid hydrolysis in the gastrointestinal tract.

Dermal absorption

Since the reaction mass is corrosive, a high dermal absorption is likely because of the destruction of the skin barrier. Due to the rapid hydrolysis of the di- and monoformate of ethane-1,2-diol it is assumed that the amount of both substances which becomes systemically available after dermal contact is low. With intact skin barrier, a low dermal absorption is assumed as substances with water solubility above 10 g/L and low Pow value below 0 are too hydrophilic to cross the lipid rich environment of the stratum corneum. For ethane-1,2–diol the dermal bioavailability within the first 6 h following dermal exposure was only 20–30% and 5% in rats and mice, respectively (WHO, 2002).

Inhalation absorption

In general, vapours of hydrophilic substances such as the reaction mass are effectively removed from the air in the upper respiratory tract, thus restricting the absorption through the gas exchange region. The rate of systemic uptake may be limited by the rate at which the substance partitions out of the aqueous fluids (mucus) lining the respiratory tract and into the blood. Due to the low molecular weight, absorption through aqueous pores is possible. Alternatively the substance may be retained in the mucus, transported out of the deposition region with the mucus and subsequently swallowed. The corrosive property of the reaction mass is assumed to enhance absorption via inhalation. In the case of ethane-1,2-diol approximately 60% of the inhaled dose was absorbed into the systemic circulation of rats (WHO, 2002). Absorption following inhalation has also been described for formic acid. However, the amount of formic acid taken up during inhalation exposure is too small to cause metabolic acidosis, as described after ingestion of large amounts of formic acid (MAK, 2003). Due to the rapid hydrolysis of the di- and monoformate of ethane-1,2-diol it is assumed that the amount of both substances which becomes systemically available after inhalation is low.

 

Distribution

Due to the high water solubility and low log Pow of the constituents and degradation products of the reaction mass distribution throughout the body via the extracellular aqueous compartment seems likely. Furthermore, a bioaccumulation potential can be excluded.

After oral administration ethane-1,2-diol is rapidly cleared from the blood following absorption into the systemic circulation, with reported plasma half-lives in rodents, monkeys, and dogs (receiving 1–1000 mg/kg body weight) ranging from 1 to 4 h (WHO, 2002).

 

Metabolism and excretion

The metabolism of the reaction mass is characterised by hydrolysis of 2-hydroxyethyl formate and ethylene diformate to ethane-1,2-diol and formic acid. Formic acid is metabolised to and excreted as carbon dioxide and water (US EPA, 2001). Only partially the non-metabolised formic acid is excreted (US EPA, 2001). The biological half-life, depending on the main route of elimination, the species of animal and amount taken up, is between 15 minutes and 1 hour; for man a value of 2.5 hours was reported in a case of intoxication (MAK, 2003). Ethane-1,2-diol is oxidized in experimental animals and in humans in successive steps, first to glycolaldehyde (in a reaction catalysed by alcohol dehydrogenase), then to glycolic acid, glyoxylic acid and oxalic acid (WHO, 2002). Glyoxylic acid is metabolized in intermediary metabolism to malate, formate, and glycine. Ethane-1,2-diol, glycolic acid, calcium oxalate, and glycine (and its conjugate, hippurate) are excreted in urine (WHO, 2002).

 

References:

MAK (2002). Formic acid. Published Online: 31 JAN 2012 DOI: 10.1002/3527600418.mb6418e0019

US EPA (2001). High Production Volume (HPV) Challenge Program's Robust Summaries and Test Plans. Formates

WHO (2002). Ethylene glycol: human health aspects. Concise International Chemical Assessment Document 45.