Urea, reaction products with diethylene glycol, formaldehyde and glyoxal

Endpoint summary

Description of key information

The physicochemical properties of the various reaction products obtained from the controlled condensation of urea, formaldehyde, glyoxal and diethylene glycol will ultimately determine the likelihood of uptake into the systemic circulation following oral and dermal administration. 
Experimental data available for the common base structure 4,5-dihydroxy-1,3-bis(hydroxymethyl)imidazolidin-2-one provides evidence that the substance is well absorbed after oral intake and will be distributed to various body tissues before being predominantly excreted within the urine in its unchanged form. Similarly, diethylene glycol will become bioavailable following oral intake. Once within the systemic circulation, diethylene glycol will be readily metabolised and excreted from the body. The absence of any systemic effects in the comprehensive toxicological investigation indicates that no toxicologically relevant concentrations of the reaction products and its unreacted educts will reach the systemic circulation. Based on the physicochemical properties and the results obtained from the experimental data neither the reaction products nor its cleavage products nor diethylene glycol  are considered to be bioaccumulative.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

1 Physicochemical Data on the reaction product of urea, formaldehyde, glycoxal and diethylene glycol

The complex reaction product was obtained from the controlled condensation of urea, formaldehyde, glyoxal and diethylene glycol. The condensation reaction yielded in the formation of various cyclic urea derivate structures based on the poly-hydroxylated 2-imidazolidinone compound 4,5-dihydroxy-1,3-bis(hydroxymethyl) imidazolidin-2-one.

The molecular weight (Mw) was analysed with gel permeation chromatography revealing that the majority of the reaction products have a Mw in the range of 106 to 426 Da. The product also contains diethylene glycol with has a Mw of 106.12 Da.

The reaction product appears as a viscous, cloudy yellow liquid of low viscosity at standard ambient temperature and pressure. The dynamic viscosity was determined to be 21300 mPa s at 20°C. At standard ambient pressure, the reaction product has a glass transition temperature of -52°C while the boiling point could not be determined due steadily increasing vapour pressures above 80 °C caused by a limited stability of the compound.

The product is very water soluble as indicated by the measured water solubility value of 1000 g/L at 20°C. The empirically measured logPow (HPLC method) was determined to be < 0.3 at 23°C. The substance has a relatively low vapour pressure of 5.2 hPa at 20°C. Since the final product contains a considerable amount of water, it can be concluded that no further hydrolysis reactions occur. 

2 Toxicokinetic analysis of the reaction product of urea, formaldehyde, glycoxal and diethylene glycol

Absorption

Oral route:

Due to the favourable physicochemical properties of the 2-imidazoline based reaction products, absorption into the systemic circulation following oral intake can be assumed. Especially the reaction products with a molecular weight below 500 Da are prone to be absorbed via the gastro intestinal (GI) tract. A toxicokinetic study conducted on rats by Jeffcoat (1985) with a comparable reaction product containing high amounts ofpoly-hydroxylated 2-imidazolidinone compounds revealed that intestinal absorption of such substances takes place and is directly related to the amount administered i. e., the higher the amount orally administered, the higher the percentage of intestinal absorption. Also it is commonly accepted that diethylene glycol can be readily absorbed within the GI-tract.

With regards to available toxicological data, an acute oral systemic toxicity study in rats (OECD 423) determined the LD50 value to be higher than 2000 mg/kg bw (limit dose). Here the lack of any adverse effects indicated that the formed reaction products have a limited potential to cause acute systemic toxicity following a single oral administration.

Similarly, no signs of systemic toxicity were observed in a subacute combined repeated dose toxicity study with the reproduction and developmental toxicity screening test (OECD 422). The respective NOAELs for systemic toxicity, reproductive performance and developmental toxicity were determined to be 1000 mg/kg bw/day (limit dose). It has however to be noted that due to the content of diethylene glycol, damage to the kidneys can’t be excluded in humans after prolonged or repeated oral exposure as humans are far more susceptible to the effects of diethylene glycol than rats.

Also, no genotoxic and no systemic toxic effects were observed in anin vivomouse micronucleus assay in bone marrow cells of mice (OECD 474). Overall, the lack of systemic toxicity is most likely due to the fact that the reaction product is of low toxicity.

Dermal route:

Based on physicochemical properties such as logPow and water solubility, parts of the reaction products with a molecular weight below 426 Da may be able to reach the systemic circulation following topical application. Jeffcoat (1985) showed that if 4,5-dihydroxy-1,3-bis(hydroxymethyl) imidazolidin-2-one is openly applied to the rat’s skin for 144 hours up to 5 % of the applied amount will reach systemic circulation. Also for diethylene glycol transdermal absorption is likely to a certain extend.

During an acute dermal toxicity study with the reaction products performed on rats (OECD 402) no systemic effects or local effects were observed and the LD50 was determined to be > 2000 mg/kg bw (limit dose). Also, no immunological response was observed in a Murine Local Lymph Node Assay (LLNA) (OECD 429). Overall, the results from the acute dermal toxicity and sensitisation testing do not suggest that toxicological relevant amounts of the reaction product are absorbed and become systemically available.

Inhalation route:

Considering the low vapour pressure, the resulting low volatility and the results obtained in the oral and dermal toxicity testing, it is unlikely that relevant amounts of the substance will reach the systemic circulation via the inhalation route when handled at room temperature.

Distribution

Considering the physicochemical properties including the high water solubility and logPow, it is expected that absorbed fractions of the reaction product are distributed to the whole body with the blood stream before being readily excreted with the urine. Toxicokinetic studies performed by Jeffcoat (1985) show that once the base compound 4,5-dihydroxy-1,3-bis(hydroxymethyl) imidazolidin-2-one is absorbed into the systemic circulation, it will reach several body tissue including skin, muscle, blood, liver, and kidney before being excreted.

Similarly, after reaching the systemic circulation diethylene glycol will be distributed within the blood stream.

Metabolism and excretion

Depending on the molecular structure of the various reaction products, enzymatically meditated reactions aiming to break down the chemicals towards the base structure 4,5-dihydroxy-1,3-bis(hydroxymethyl) imidazolidin-2-one are likely to occur. Once being degraded to 4,5-dihydroxy-1,3-bis(hydroxymethyl) imidazolidin-2-one or a similar product, further metabolism or appreciable degradation is not expected (Jeffcoat, 1985). Moreover, Jeffcoat (1985) demonstrated that within 72 hours of administration to rats the vast majority of 4,5-dihydroxy-1,3-bis(hydroxymethyl) imidazolidin-2-one will be excreted via the urine in its unmodified form. Only minor amounts are excreted within the faeces. No evidence of bioaccumulation was observed in this study.

For diethylene glycol (DEG) metabolism occurs principally in the liver and any residues of the parent substance and its metabolite (2-hydroxyethoxyacetic acid [HEEA]) are rapidly eliminated via the kidneys (Schepet al.,2009). It is suggested that un-metabolized DEG and HEAA are partially reabsorbed throughglomerular filtration. As a consequence, the concentrations of the weak acid HEAA and other metabolites may cause renal delay, leading tometabolic acidosisand further kidney damage in humans.

 

3 Summary

The physicochemical properties of the various reaction products obtained from the controlled condensation of urea, formaldehyde, glyoxal and diethylene glycol will ultimately determine the likelihood of uptake into the systemic circulation following oral and dermal administration.

Experimental data available for the common base structure 4,5-dihydroxy-1,3-bis(hydroxymethyl) imidazolidin-2-one provides evidence that the substance is well absorbed after oral intake and will be distributed to various body tissues before being predominantly excreted within the urine in its unchanged form. Similarly, diethylene glycol will become bioavailable following oral intake. Once within the systemic circulation, diethylene glycol will be readily metabolised and excreted from the body. The absence of any systemic effects in the comprehensive toxicological investigation indicates that no toxicologically relevant concentrations of the reaction products and its unreacted educts will reach the systemic circulation. Based on the physicochemical properties and the results obtained from the experimental data neither the reaction products nor its cleavage products nor diethylene glycol are considered to be bioaccumulative.

 

4 References

ECHA (2008), Guidance on information requirements and chemical safety assessment, Chapter R.7c: Endpoint specific guidance.

Jeffcoat A. R. (1985): Adsorption, Disposition, Metabolism and Excretion of 1,3-Dimethylol-4,5-dihydroxy-2-imidazolidinone (DMDHEU). Contract No. N01-ES-1-5007, National Institute of Environmental Health Sciences, Research Triangle Institute.

Marquardt H., Schäfer S. (2004). Toxicology. Academic Press, 2nd Edition 688-689.

Mutschler E., Schäfer-Korting M. (2001) Arzneimittelwirkungen. Lehrbuch der Pharmakologie und Toxikologie. Wissenschaftliche Verlagsgesellschaft, Stuttgart.

Rozman K. K., Klaassen C. D. (1996) Absorption, Distribution, and Excretion of Toxicants. In Klaassen C. D. (ed.) Cassarett and Doull's Toxicology: The Basic Science of Poisons. McGraw-Hill, New York.

Schep L. P., Slaughter R. J., Temple W. A., Beasley D. M. (2009) Diethylene glycol poisoning. Clinical Toxicology (Philadelphia, PA). 47(6):525-35