Triethyl citrate

Endpoint summary

Description of key information

Short description of key information on bioaccumulation potential result: 
1) Toxicokinetic statement, Chemservice S.A., 2012
2) Prediction - Toxtree Chemservice S.A., 2011
Short description of key information on absorption rate: 
1) Toxicokinetic statement, Chemservice S.A., 2012

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

Conclusion on absorption, distribution, metabolism and excretion

Based on physicochemical properties and experimental data for triethyl citrate and for its structural analogues, triethyl citrate is expected to be well absorbed via the oral and dermal exposure route (for a detailed argumentation please refer to read-across statement and the toxicokinetik statement attached to the IUCLID file). Due to the low vapour pressure of triethyl citrate, inhalation is considered not to be a relevant route of exposure. The substance will be extensively distributed in the circulatory system of the body where it will be rapid metabolised forming citric acid and ethanol, substances which are known to be of low toxicity and can either be excreted or further be involved into intermediary metabolism.

Discussion on bioaccumulation potential result:

Toxicokinetic statement for triethyl citrate

Triethyl citrate was evaluated regarding its toxicokinetic behaviour. Due to its physico-chemical properties it is reasonable to assume, that it is expected to be absorbed very well. The substance is expected to be poorly available after inhalation but avaailable after dermal exposure. Triethyl citrate is expected to be distributed throughout the body mostly in the circulatory system. No significant potential for accumulation was identified. Triethyl citrate is expected to be extensively metabolised by esterases and cytochrome P450 enzymes and break-down in the beta-oxidation or citric acid cycle or in cases subsequent glucuronidation. Excretion (if not metabolised completely in beta-oxidation and citric cycle) is predicted to occur as metabolites (i.e. conjugates with glucuronic acid) via urine and to a lower extent via bile.

Data on metabolism of triethyl citrate and its structural analogues

Triethyl citrate (TEC) and triethyl-O-acetylcitrate (ATEC) were subjected to a detailed investigation of their toxicological properties (Finkelstein and Gold, 1959). Poisoning pattern in treated animals during acute and repeated oral toxicity studies elucidated the mechanism of toxic action of the substance. Doses ranging from 5 to 15 gram per kilogram were administered by stomach tube to rats and 1 - 9.5 gram per kilogram were given by stomach tube to cats. The effects of the two compounds were indistinguishable and similar in treated animal species. The absorption of the two substances was fairly rapid; signs, depending on the dose, appeared within a few minutes. The course of their poisoning was also fairly rapid, progressing to advanced stages within approximately one hour and terminating either in death (occurrence between 2 hours to 2-3 days after administration) or in apparent recovery. The disappearance of manifest signs of poisoning can be deceptive, since the poisoning persisted for a much longer time. TEC appeared to be approximately twice as potent as ATEC in the cat. According to the authors the toxic effects and the course of TEC and ATEC poisoning resemble those of the citrate ion, which when introduced into the circulation, results in deionization of calcium and therefore effects of hypocalcaemia. In this way, a rapid hydrolysis of citrates forming citric acid and ethanol was suggested (Finkelstein and Gold, 1959).

Bruns and Werners verified the assumptions of Finkelstein and Gold in an in vitro study where TEC and ATEC were investigated for their potential to hydrolyse by liver homogenates and by blood serum (Bruns and Werners, 1962, also cited in TNO BIBRA, 1998). The substances were hydrolysed by liver homogenate of human, rat and mouse origin, and by blood serum to citric acid and ethanol (in case of TEC) or acetic acid, citric acid and ethanol (in case of ATEC). Per mole of triethyl citrate 1 mol of citric acid and 3 moles of ethanol were formed during complete hydrolysis. In case of triethyl-O-acetylcitrate a further 1 mol of acetic acid was build. These three metabolites are known to be of low toxic potential and appear in intermediary metabolism, where they are oxidized in well-defined paths in the organism to CO2 and H20 (Bruns and Werners, 1962; CSTEE, 1999).

Further, triethyl citrate was reported to be rapidly hydrolysed (within 15 minutes) by freshly collected rat serum, and at a much slower rate (hydrolyses was not complete after 4 hr) by freshly collected human serum (Figdor & Ballinger, 1981, cited in TNO BIBRA, 1998; CSTEE, 1999).

Prediction using TOXTREE

The chemical structure of triethyl citrate was assessed by Toxtree (v.2.5.0) modelling tool for possible metabolism. SMART Cyp is a prediction model, included in the tool, which identifies sites in a molecule that are labile for the metabolism by Cytochromes P450.

Triethyl citrate, containing the structural alerts: carbonyl compound: aldehyde or ketone, alcohol, tertiary alcohol, ether, dialkyl ether, carboxylic acid derivative, carbonic acid ester and carbonic acid diester, is expected to be well metabolized by the Cytochrome P450 group of drugs metabolizing enzymes. The primary, secondary and tertiary sites of metabolism are predicted to be subject to aliphatic hydroxylation. The primary sites are predicted to be the centred carbon atoms, the secondary and tertiary sites of metabolism are predicted to be the carbon-atoms of the collateral chains.

Discussion on absorption rate:

Toxicokinetic statement

Absorption following dermal exposure

In order to cross the skin, a compound must first penetrate into the stratum corneum and may subsequently reach the epidermis, the dermis and the vascular network. The stratum corneum provides its greatest barrier function against hydrophilic compounds, whereas the viable epidermis is most resistant to penetration by highly lipophilic compounds. Substances with a molecular weight (MG) below 100 are favourable for penetration of the skin and substances with a MG > 500 are normally not able to penetrate. The substance must be sufficiently soluble in water to partition from the stratum corneum into the epidermis. Therefore if the water solubility is below 1 mg/L, dermal uptake is likely to be low. Additionally LogPow values between 1 and 4 favour dermal absorption (values between 2 and 3 are optimal). Above 4, the rate of penetration may be limited by the rate of transfer between the stratum corneum and the epidermis, but uptake into the stratum corneum will be high. Above 6, the rate of transfer between the stratum corneum and the epidermis will be slow and will limit absorption across the skin. Uptake into the stratum corneum itself may be slow. Moreover vapours of substances with vapour pressures below 100 Pa are likely to be well absorbed and the amount absorbed dermally may be more than 10% of the amount that would be absorbed by inhalation. If the substance is a skin irritant or corrosive, damage to the skin surface may enhance penetration. During the whole absorption process into the skin, the compound may be subject to biotransformation.

In case of triethyl citrate, the molecular weight is above 100 and below 500, which indicates a low potential to penetrate the skin. Because the water solubility of triethyl citrate is fairly high, absorption through the lipophilic stratum corneum is possible. The LogPow value for this substance is not optimal (values 2-3), but still favours absorption via the skin (between 1 and 4). The amount of substance, which is absorbed following dermal exposure into the stratum corneum is however unlikely to be transferred into the epidermis, due to its molecular weight and LogPow. The systemic toxicity via the skin is assumed to be low and this has been proven with the results of the acute dermal toxicity study, which showed no mortality after dermal application of 5000 mg/kg bw in rabbits.

Conclusion

In order to assess the toxicological behaviour of triethyl citrate, the available experimental and predicted physico-chemical data have been evaluated. Triethyl citrate is expected to be absorbed following dermal exposure into the stratum corneum and to a certain extent into the epidermis, due to its molecular weight of 276.283 g/mol and its LogPow of 1.17. In addition, the systemic toxicity via the skin is assumed to be low and this has been proven with the results of the acute dermal toxicity study with the acute dermal study with triethyl citrate, in which a LD₅₀of 5000 mg/kg bw has been obtained.