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Administrative data

Link to relevant study record(s)

Description of key information

DEO is considered to be absorbed via the oral, dermal and inhalation route. Metabolism is characterized by ester hydrolysis to MEO and finally to Oxalic acid and ethanol. Urinary excretion is the main route of elimination.

Key value for chemical safety assessment

Bioaccumulation potential:
no bioaccumulation potential
Absorption rate - oral (%):
50
Absorption rate - dermal (%):
25
Absorption rate - inhalation (%):
100

Additional information

Metabolism

Diethyloxalate (DEO) hydrolyses rapidly to Monoethyloxalate and Oxalate in water as demonstrated in the hydrolysis, acute fish, acute daphnia and algae study (Research Institute for Organic Syntheses Inc., 2011a, 2011d, 2011e and 2011f).

The hydrolysis of DEO is rapid at pH 7 and 9 and only at pH 4 a sufficient recovery for the performance of a hydrolysis study could be identified. At pH 4 and 35°C the half-time t1/2was approx. 0.5 days (Research Institute for Organic Syntheses Inc., 2011a).

Due to the expected hydrolysis in the gastrointestinal tract it can be assumed that DEO decomposes completely into its hydrolysis products during the passage through the stomach (pH<4) and the intestine (pH 6-8).

Oxalic acid and ethanol were found as main degradation products in media used in ecotoxicological studies. Hydrolysis in the body to form Oxalic acid which accounts for the toxicity of the parent molecule has furthermore been reported in the literature (International Labour Office, 1971; David et al., 2012).

Metabolism to Monoethyl oxalate (first step) and to Oxalic acid (second step) has been predicted by the metabolism tool of the QSAR toolbox. Also Metaprint 2D predicted the dealkylation of Diethyl oxalate as the most likely metabolic pathway.

The metabolism to Oxalic acid is also supported by the macroscopical and histological observations in the kidneys (enlarged size of kidneys with changed surface and irreversible severe oxalate nephrolithiasis) in an acute dermal, 28-day oral repeated dose toxicity and reproductive/developmental screening toxicity study with Diethyl oxalate, as the observations are identical with the adverse effects caused by Oxalic acid.

 

Absorption

As described absorption is predominantly in form of the hydrolysis products of DEO.

In general, the low molecular weight and the log Pow (1.38 for DEO, -1.7 for oxalic acid) favour absorption via the oral, dermal and inhalation exposure route.

 

Oral 

In the toxicity studies with oral administration systemic toxicity was seen which demonstrates that the hydrolysis products (or DEO) are orally bioavailable. Furthermore, oxalic acid (and DEO) passes “Lipinski’s rule of 5” indicating good oral bioavailability. It is likely that Diethyl oxalate will be partially cleaved to Monoethyl oxalate and further to Oxalic acid in the gastrointestinal tract i) due to its hydrolytic instability at the pH range present in the intestine and/or ii) by intestinal esterases. An oral bioavailability of 25 % has been reported in rats and up to 20 % in humans for oxalic acid (Bannwart et al., 1979; EMEA, 2003). A significantly higher oral absorption can be assumed for Monoethyl oxalate and Diethyl oxalate due to their lower hydrophilicity. Taking into account all available information it is reasonable to consider an oral absorption value of 50 % for Diethyl oxalate.

 

Dermal

In the acute dermal toxicity study with Diethyl oxalate, findings in the kidneys were observed macroscopically and histologically. This shows that Diethylo xalate or its degradation products are dermally absorbed. However, as no lethality occurred in this study up to the highest dose of 2000 mg/kg bw whereas the acute oral LD50 is reported to be between 400 and 1600 mg/kg bw a significantly lower dermal absorption can be assumed in comparison to oral absorption.

As a proof of concept, dermal permeability can be estimated by the dermal coefficient program (DERMWIN v2.00). The permeability coefficient (Kp) can be estimated by the equation:

log Kp = -2.72 + 0.71(log Kow) – 0.0061(MW)

= -2.72 + 0.71(1.381) -0.0061(144.14 g/mol) = -2.63

In accordance to the DK-EPA heuristics used to classify ranges of Kp values, the resulting Kp of 0.0024 is in the range indicative for low dermal permeability (>=0.001 - <0.005) (EPI Suite Version 4.0 EPA DERMWIN v2.00, 2009).    

Considering the available information, a dermal absorption of 25 % is derived. This corresponds to the default dermal absorption value of 25 % reported in the EFSA Guidance on Dermal Absorption (2012) for active substances.

 

Inhalation

Due to the vapour pressure of 0.55 hPa of the liquid at room temperature and the described exposure scenarios, inhalation exposure is of limited relevance. Nevertheless, if inhalation exposure occurs, resorption of the ester and/or its metabolites is assumed to take place via the lungs (100 % inhalation absorption).

 

Distribution

Based on the results of the toxicity studies, the molecular weight, log Pow and water solubility, distribution of Diethyl oxalate and/or its metabolites through the body can be expected. Diffusion through aqueous channels and pores is assumed. A distribution to the central nervous system is considered to be restricted due to the effective blood/brain barrier. This conclusion is supported by the results obtained in the general toxicity studies performed with Diethyl oxalate, where no CNS related signs of toxicity were observed and human data on the main metabolite Oxalic acid. For the latter compound a wide distribution has been reported in humans (EMEA, 2003) with the highest levels present in kidney and the lowest in brain.

Based on the log Pow of DEO and its metabolites and available data on Oxalic acid a bioaccumulation potential of parent compound and metabolites can be excluded.

 

Excretion

Urinary excretion is the predominant route of excretion of systemically available Diethyl oxalate. This conclusion is based on the low molecular weight (below 300 g/mol) of Diethyl oxalate, the findings in the available toxicity studies and the data on the final metabolite Oxalic acid which is excreted in the urine in rats and humans after oral absorption (Bannwart et al., 1979; EMEA, 2003). 

 

 

References

Bannwart et al., (1979). Absorption of Oxalic Acid in Rats by Means of a 14C Method. Eur. Urol. 5: 276-277

David, RM et al., (2012). Esters of mono-, di-, and tricarboxiylic acids. In Patty`s Toxicology 6th edition, Vol 4. John Wiley and Sons, 2012

EMEA (2003). Summary Report: Oxaclic Acid. EMEA December 2012: EMEA/MRL/891/03-FINAL

EFSA (2012). Scientific opinion: Guidance on Dermal Absorption. EFSA Journal 2012;10(4):2665 [30 pp.].

International Labour Office. Encyclopedia of Occupational Health and Safety. Volumes I and II. New York: McGraw-Hill Book Co., 1971, p. 478

Research Institute for Organic Syntheses Inc., (2010b). Diethyloxalate - Acute Dermal Toxicity. Report number: 10-362

Research Institute for Organic Syntheses Inc., (2011a). Diethyloxalate – Hydrolysis as a function of pH. Report number: 11-163

Research Institute for Organic Syntheses Inc., (2011d). Diethyloxalate – Fish, Acute Toxicity Test: 11-164

Research Institute for Organic Syntheses Inc., (2011e). Diethyloxalate – Daphnia magna, Acute Immobilisation Test: 11-165

Research Institute for Organic Syntheses Inc., (2011f). Diethyloxalate – Alga, Growth Inhibition Test: 11-149