Citric acid

Endpoint summary

Description of key information

There are no reliable 28-day or 90-day studies available, so this endpoint is waived. Numerous studies have been reported in the literature and are discussed below. The most reliable studies are 10-day studies in rats and mice, with the following results:

NOAEL (10 d) 4000 mg/kg bw/day rats (unidentified gender)  

LD50 (10 d) 5660 (+/- 0.44) mg/kg bw/day rats (unidentified gender)

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

There are numerous repeat dose studies that have been conducted. Although they do not meet current testing requirements, they still indicate a lack of any significant toxicological effects under the test conditions that were used. A reliable five-day feeding study in rats gave a NOAEL value of 4000 mg/kg (Bachtold, 1976a); and a 10-day feeding study in mice and rats gave NOAEL (mortality) values of 1000 mg/kg and 4000 mg/kg respectively (Bachtold, 1978a).

Additionally, there are a number of published studies using mice, rabbits, dogs, guinea pigs and pigs with various doses of citric acid or sodium citrate and various dosing periods. Most of the studies report no adverse effects, although some effects that were mentioned are reduced zinc levels, increased zinc excretion and erosion of the tooth enamel: effects attributable to zinc and calcium complexation. Very high doses (5%) of citric acid in the diet administered to male albino mice throughout most of their lives were shown to depress the mean body weight at 14 months by 9.9% (sexually immature animals) and 18.7% (sexually mature animals). This treatment also reduced the mean survival time from 16.7 to 12.7 months and from 16.4 to 10.8 months respectively in the same two groups (Wright and Hughes, 1976b).

A shorter timescale (60 day) feeding study with 5% citric acid in the diet of guinea pigs and rats by the same authors showed no such effect on body weight (Wright and Hughes, 1976a). It was estimated that the dietary uptake of citric acid in both rat and guinea pig studies was 3000 mg/kg/d. There was no increase in tissue concentrations of citric acid, indicating a very efficient homeostasis mechanism due to its rapid metabolism, neither was there any effect on serum alkaline phosphatase: an indicator of tissue damage and specifically liver damage.

In a feeding study in rats, daily oral administration of 1.2, 2.4 and 4.8 % fermentation citric acid in the diet for 6 weeks produced no physiological or behavioural abnormalities, except a slight depression of body weight gain and daily food-intake. Morphological and biochemical examinations of the blood and urine demonstrated mild abnormal findings; however, many of the findings could not be ascribed to the toxic effect of citric acid (Silverstein et al. 1989).

Citric acid plays a central role in cellular metabolism, is naturally present in common fruit and vegetables, which means there is a long history of human exposure; it has been estimated that maximum daily intake of citric acid can reach up to 500 mg/kg/day (OECD SIDS 2001). In addition, citric acid has well established and documented metabolic pathways in humans (JECFA, 1973). It is also added to processed food and beverages, (HERA, 2005); it is a permitted EU Food Additive and, according to the JECFA (Joint Expert Committee on Food Additives of the WHO/ FAO), these products may be used without limitation, according to Good Manufacturing Practice (JECFA, summary of evaluations, citric acid, 1973). The US Food and Drug Administration also classifies citric acid as GRAS (Generally Recognized as Safe) food ingredients (www.accessdata.fda.gov, 2018).

No repeat dose dermal or inhalation animal studies related to citric acid were located. This is probably because citric acid is commonly used as a food additive and therefore the oral route is the most significant (and therefore studied) route of exposure. Similarly, the low vapour pressure of citric acid means that it is unlikely to be inhaled unless used in a spray, or in a powder form containing particles of a respirable size.

Public and private usage of the liquid form indicates that exposure by the dermal route would be the most significant. However, based on the chemical structure of citric acid (hydrophilic, ionisable), it is unlikely that citric acid would penetrate the stratum corneum of the skin. If it did, two sub-cutaneous toxicity studies (Yokotani 1971) indicate a low toxicity (>2500 mg/kg bw).

In humans, the most common adverse effects of taking large doses of citric acid or citrate salts are mild gastrointestinal symptoms (diarrhoea, indigestion and nausea) such as reported in a study in which potassium citrate was administered as a treatment for kidney stones (Pak 1987). However, doses of up to 15 g/d of potassium or sodium citrate have been reported as producing no adverse effects (JECFA, 1974).  

Humans have been historically exposed to citric acid and it has been estimated that maximum daily intake of citric acid can reach up to 500 mg/kg/day. (OECD SIDS, 2001).

References

HERA (2005). Human & Environmental Risk Assessment on Ingredients of Household Cleaning Products. Guidance Document Methodology.

JECFA, 1973. Toxicological evaluation of some food additives including anticaking agents, antimicrobials, antioxidants, emulsifiers and thickening agents. WHO FOOD ADDITIVES SERIES NO. 5. CITRIC ACID AND ITS CALCIUM, POTASSIUM AND SODIUM SALTS. http://www.inchem.org/documents/jecfa/jecmono/v05je24.htmJ

ECFA (1974). Report of the Joint FAO/WHO Expert Committee on Food Additives. WHO Food Additives Series No. 5.

Kim, H. M., Shim, I. S., Baek, Y. W., Han, H. J., Kim, P. J., & Choi, K. (2013). Investigation of disinfectants for foot-and-mouth disease in the Republic of Korea. Journal of infection and public health, 6(5), 331-338.

OECD SIDS (2001). SIDS Initial Assessment Report for 11th SIAM (Orlando, Fla., January 2001), for CAS 77-92-9, Citric acid.

Pak, CYC (1987). Citrate and Renal Calculi Mineral Electrolyte Metab. 13, 257-266.

Wright, E., Hughes, R.E., (1976a). Some Effects of Dietary Citric Acid in Small Animals Food and Cosmetics Toxicology 14, 561-564.

Wright and Hughes (1976b). The influence of a dietary citric acid supplement on the reproduction and survival time of mice and rats (publication), Nutr. Rep. Int. 13: 563,. Report date:

Justification for classification or non-classification

Based on the available supporting data, the long history of safe use in food and cosmetics, and the central role played by citric acid in metabolism, no classification is required according Regulation (EC) No 1272/2008.