Reaction mass of glycerol, glycerol 1-formate, glycerol 2-formate, glycerol 1,2-diformate, glycerol 1,3-diformate and glycerol triformate

Endpoint summary

Description of key information

Based on considerations of the physico-chemical properties and the toxicologically insignificant pathological findings from the various in vivo studies, propane-1,2,3-triol and its esterification products with formic acid would be expected to be absorbed following oral, dermal and inhalation exposure. Conservative absorption rates for this substance are set at 100% for all routes of exposure.

Gross pathological observations and the physico-chemical properties of the substance suggest that there will be distribution of the substance and the subsequent transformation products throughout the body. The substance is expected to rapidly transform via hydrolysis and metabolism to its ultimate products of free glycerol and formic acid. The glycerol will be utilized by the body during endogenous anabolism and the formic acid will be metabolised to carbon dioxide and water. Based on the available data the target substance is expected to have a no potential to bioaccumulate.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Absorption rate - oral (%):

100

Absorption rate - dermal (%):

100

Absorption rate - inhalation (%):

100

Additional information

To date, no relevant analytical toxicokinetic testing data has been generated for propane-1,2,3-triol and its esterification products with formic acid, hereafter referred to as the target substance. However, toxicological information following exposure to the target substance and/or transformation substances and information on the physico-chemical properties can be used as a basis for the assessment of toxicokinetics.

Absorption

Absorption information provides details on how, how much and how fast the substance enters the body. The diffusion of a substance across biological membranes in a test species is governed by the physico-chemical properties of the substance, particularly its molecular size, Log P, and water solubility (ECHA, 2017).

Oral

Upon oral administration, the target substance is expected to undergo stepwise transformation by gastrointestinal esterases in which the triformate constituent is converted into diformate constituents, diformate constituents are converted to monoformate constituents, and monoformate constituents to free glycerol, with formic acid being released at each step. Thus, the predictions based on physico-chemical characteristics of the parent substance may not apply, rather the transformation products glycerol and formic acid are more applicable. As the target substance and the source substances (glycerol (SS1), sodium formate (SS2), potassium formate (SS3), potassium diformate (SS4), calcium formate (SS5), ethylene diformate (SS6), ethylene glycol (SS7) and formic acid (SS8)) are relatively small with molecular weights of less than 130 g/mol, highly water soluble (≥128.5 g/L) and have Log P values of less than 0, there is the possibility of passive absorption of both the target substance and transformation substances through aqueous pores or through the epithelial barrier by bulk transport of water.

The chronic repeated dose studies with some of the source substances suggest systemic absorption of the breakdown products followed oral exposure as small changes of no significant toxicological importance were reported in clinical biochemistry, hematology, etc. Based on consideration of the target substance’s physico-chemical properties and the available oral toxicity studies, a conservative default value for oral absorption of the target substance is set as 100%.

Inhalation

The low measured vapour pressure (< 0.4 kPa at 25 °C) and measured boiling point (132 °C) of the target substance would suggest it possesses moderate to low volatility. Therefore, under normal use and handling conditions, inhalation exposure and thus availability for respiratory absorption of the target substance in the form of vapours, gases, or mists is not significant. However, if the formulated product is sprayed, the target substance may be available for respiratory absorption after inhalation of aerosols.

Due to the hydrophilicity of the target substance it is anticipated to readily diffuse/dissolve into the mucus lining the respiratory tract. The target substance is then expected to undergo stepwise transformation by hydrolysis to the ultimate transformation products of glycerol and formic acid as detailed in the oral absorption section. Absorption through aqueous pores of either the parent target substance or the transformation products is anticipated to be high due to the low molecular weight and the Log P values of less than 0. Based on a consideration of the physico-chemical properties and the available oral toxicity studies, a conservative default value for inhalation absorption of the substance is set as 100%.

Dermal

The very hydrophilic nature of the target substance would suggest that it would not cross the lipid rich environment of the stratum corneum. This is supported by the lack of clinical signs of toxicity following the acute dermal toxicity study where 2000 mg/kg bw were applied under semi-occlusive conditions according to OECD Test Guideline 402 (Envigo Research, 2017). As the molecular mass of the target substance and potential transformation products are less than 500 g/mol, indicating there is a possibility for dermal absorption and due to a lack of formal assessment of the potential for dermal absorption, the default value of 100% skin absorption is selected.

Distribution

Distribution information provides details on the reversible transfer of substances between various parts of the organism. As the target substance and the transformation substances are small water-soluble molecules they are anticipated to diffuse through the aqueous channels and pores of cellular membranes following absorption. While there were no toxicologically significant gross pathological findings following oral exposure to the transformation substances, small changes of no significant toxicological importance were reported in clinical biochemistry, hematology, etc. which supports distribution throughout the animal system.

Metabolism

Metabolism information provides details on the enzymatic or non-enzymatic transformation of the substance of interest into structurally different substances. The substance is expected to undergo abiotic hydrolysis and transformation by esterases in which the triformate constituent is converted into diformate constituents, diformate constituents are converted to monoformate constituents, and monoformate constituents to free glycerol, with formic acid being released at each step.

The resulting glycerol serves as one of the substrates for gluconeogenesis in the liver which further increases glycogen and circulating glucose (Klaassen, 2018). Under physiological conditions, the resulting formic acid dissociates to formate which is further metabolised to the excretion products carbon dioxide and water. Oxidation of formate to carbon dioxide is mainly driven by a tetrahydrofolate-dependent pathway while a small percentage of formate is excreted directly with the urine (Klaassen, 2018).

Excretion

Excretion information provides details on the physical loss of the parent substance and/or its metabolites. The transformation products of the target substance will be metabolised in the body with the glycerol being used in endogenous anabolism and the formic acid being metabolised to the ultimate excretion products of carbon dioxide and water. Formic acid may also be excreted in the urine unchanged.

Based on the available data, in particular the log P value, high water solubility and ultimate excretion, the target substance is expected to have a no potential to bioaccumulate in animals and humans.

REFERENCES

ECHA (2017). Guidance on information requirements and chemical safety assessment. Chapter R.7c: Endpoint specific guidance. Volume 3.0, June 2017. Available at: https://echa.europa.eu/documents/10162/13632/information_requirements_r7c_en.pdf/e2e23a98-adb2-4573-b450-cc0dfa7988e5

 

Klaassen C, editor (2018). Casarett & Doull's Toxicology: The Basic Science of Poisons, 9th edition. New York (NY) / Toronto (ON): McGraw-Hill, Medical Publishing Division