Citric acid

Endpoint summary

Additional information

Since citric acid plays a central role in cellular metabolism, has been used as a food additive over a long period and is also present in natural foods, the standard approach to toxicokinetics is not relevant. The following section covers both human and non-human information as citrates are key to cellular metabolism across the animal and plant kingdoms.

 

Absorption

Oral absorption

Citric acid is readily absorbed from the digestive tract and is known to enhance the uptake of other substances such as iron.

Dermal absorption

Dermal uptake is being considered separately since this is necessary for the risk assessment.

Dermal uptake limitations

Dermal uptake of aqueous substances with low affinity for lipids (evidenced by log Kow values <3) is known to be limited. However, some chemical types particularly with alcohol functionality are known to have non-standard behaviour in this respect. Citric acid has an alcohol functionality, therefore calculations based on log Kow may be misleading, however, citric acid is known to inhibit the dermal absorption of viprostol (Cosmetic Ingredient Review, 2012). The dermal absorption of citric acid has been reported as 3.2% and 6.0% of the dose from cosmetic formulations, and 13.8% of the dose from aqueous formulation absorbed (SCCS, 2009). There were limitations to this study, but the conclusion of low dermal uptake was accepted by the Scientific Committee on Consumer Product (SCCS, 2009).

Metabolism

Tricarboxylic acid cycle

The TCA cycle is a central biochemical cycle, of almost universal occurrence in aerobic organisms. In eukaryotes it occurs within the mitochondria. Glucose (derived directly from sugars and starches in the diet and indirectly from protein and fat) is broken down by glycolysis, an enzyme regulated pathway, which converts glucose to pyruvate from which acetyl-CoA is formed. Acetyl-CoA undergoes a condensation reaction (an aldol condensation catalysed by the enzyme citrate synthase) with oxaloacetate to form citrate, which is the first intermediate of the TCA cycle. This reaction is the primary control point of the cycle. Subsequent reactions of the TCA cycle liberate carbon dioxide and four pairs of hydrogen atoms that enter electron transport pathways. The last stage of the cycle is the regeneration of oxaloacetate.

 

This physiological pathway can process very high amounts of citric acid as long as the steady state concentration within the cell remains low. In adult humans, approximately 2000 g per day of citric acid are formed and further metabolised as an intermediate of the TCA cycle (OECD, 2001 citing Römpp, 1989). However, the turnover is dependent upon the metabolic rate and rate of exercise and the values of both citric acid concentration and flux increase with exercise (Gibala 1998).

Circulation and excretion

Quantities of citric acid ingested from natural sources and food additives may exceed 500 mg/kg per day. This forms only a part of the citric acid in the circulation, which is mainly derived from metabolism. Part of the circulating substance is excreted in urine, with approximately 0.29-0.71 g of citric acid excreted per person per day (OECD, 2001). Citric acid acts as a naturally-occurring inhibitor of urinary crystallisation, and low concentrations of citrate in the urine are associated with a tendency to develop calcium uroliths (bladder and kidney stones) (Gul, 2014; Han, 2015). Consequently, drinking large amounts of citric acid containing drinks such as fresh lemonade and orange drinks is frequently recommended as a prophylaxis for individuals susceptible to calcium oxalate stones.

The pharmacokinetics of citrate after intravenous administration has been measured in a study conducted to predict the accumulation of citrate in humans in assessing the use of citrate in treatment (Zheng et al., 2013). 12 healthy volunteers were administered trisodium citrate at a dose of 3.7 mmol/L of plasma flow. Blood samples were taken before, during 120 minutes of infusion and up to 120 minutes after infusion, and the level of citrate in plasma was determined using HPLC. The maximum level of citrate in the plasma was 0.56 ± 0.45, and the total dose of citrate 57.1 ±. 10.5 Total body clearance was 686.64 ± 353.60 L/min.

Citric acid levels in plants and animals

Citric acid is sequestered in much greater than trace amounts in many plants, and as is well known, its concentration in fruits of the genus Citrus are high. Actual concentrations depend on the species and cultivar; however, for lemons and limes it can reach 8% by dry weight (80,000 mg/kg) in the fruit and 57000 mg/l in the juices (Penniston et al., 2008). Citric acid is also produced in large amounts by certain fungi, and indeed it is mostly produced commercially by fungal fermentation, principally using Aspergillus niger (Yigitoglu, 1992). The levels of citric acid are considerably lower in most other plants and actual levels have been shown to be dependent on photosynthetic activity. Concentrations of citric acid in grain flour (wheat, barley, oats etc.) are 100-300 mg/kg and in maize, 2000 mg/kg; however, levels are appreciably higher in the seeds of leguminous plants (peas, beans etc.) with levels from 3,300-20,140 mg/kg being measured. Concentrations increase during seed germination by up to 6-fold and the highest amounts are found in the shoots (Munch-Petersen 1944). In animals, although large amounts of citric acid are processed through the TCA cycle (see above), the steady-state concentrations are generally lower than plants and in the rat were found to be 16-40 mg/kg for most tissues (32-40 in blood, 16-26 in liver and 27-31 in skeletal muscle) with appreciably larger amounts in kidney (61-63 mg/kg) (Orten and Smith, 1939). More modern values are provided by Gibala et al., 1998 with values in human skeletal muscle of 70 mg/kg dry weight at rest, rising to 130 mg/kg dry weight after muscle exhaustion. These numbers are equivalent to about 280 and 520 mg/kg respectively on a fresh weight basis.

Summary

Citric acid is ubiquitous in the animal kingdom. No study which meets current OECD guidelines is available. However, sufficient information exists on the substance as it is part of the metabolic processed in animals and plants. Therefore, pathways for adsorption, distribution and excretion as well as its metabolism are well established, and even essential to all living organisms.

 

References:

Cosmetic Ingredient Review, 2012. On the Safety Assessment of Citric Acid, Inorganic Citrate Salts, and Alkyl Citrate Esters as Used in Cosmetics. Report date: March 27, 2012.

Gibala, M. J., MacLean, D. A., Graham, T. E., & Saltin, B. (1998). Tricarboxylic acid cycle intermediate pool size and estimated cycle flux in human muscle during exercise.American Journal of Physiology-Endocrinology And Metabolism,275(2), E235-E242.

Gul, Z., & Monga, M. (2014). Medical and dietary therapy for kidney stone prevention. Korean journal of urology, 55(12), 775-779.

Han, H., Segal, A. M., Seifter, J. L., & Dwyer, J. T. (2015). Nutritional management of kidney stones (nephrolithiasis). Clinical nutrition research,4(3), 137-152.

OECD (2001).SIDS for Citric acid, 77-92-9, January 2001 citing Römpp 198

Orten, JM and Smith, AH. (1939) On the Site of the Formation of Citric Acid in the Animal OrganismJ. Biol. Chem.128, 101-107

Penniston KL, Nakada SY, Holmes RP, Assimos DG (2008). Quantitative Assessment of Citric Acid in Lemon Juice, Lime Juice and Commercially-Available Fruit Juice Products Journal of Endourology 22, 567-570

SCCS (2009). Scientific Committee on Consumer Safety SCCS Opinion on Citric acid (and) Silver citrate. 13 October 2009. https://ec.europa.eu/health/scientific_committees/consumer_safety/docs/sccs_o_004.pdfU

S EPA, 2008,September 2008, DERMWIN model developed by SRC, published by US EPA as part of EPIWEB 4.0

Yigitoglu, M. U. S. T. A. F. A. (1992). Production of citric acid by fungi. Journal of Islamic Academy of Sciences, 5(2), 100-106.

Zheng Y, Xu Z, Zhu Q, et al. (2013) Citrate pharmacokinetics in critically ill patients with acute kidney injury. PLoS One 2013; 8:e65992.