Evaluation E535, E536, E538 as food additives

Abstract

The Panel on Food Additives and Nutrient Sources added to Food (ANS) provided a scientific opinion re-evaluating the safety of sodium ferrocyanide (E 535), potassium ferrocyanide (E 536), and evaluating the safety of calcium ferrocyanide (E 538) as food additives. The Panel considered that adequate exposure and toxicity data were available.

Ferrocyanides (E 535–538) are solely authorised in two food categories as salt substitutes. To assess the dietary exposure to ferrocyanides (E 535–538) from their use as food additives, the exposure was calculated based on regulatory maximum level exposure assessment scenario (maximum permitted level (MPL)) and the refined exposure assessment scenario. Dietary exposure to ferrocyanides was calculated based on mean and high levels consumption of salts in both the regulatory maximum level and the refined scenario.

In the MPL scenario, the exposure to ferrocyanides (E 535–538) from their use as a food additive was up to 0.009 mg/kg body weight (bw) per day in children and adolescents. In the refined estimated exposure scenario, the exposure was up to 0.003 mg/kg bw per day in children and adolescents.

Absorption of ferrocyanides is low and there is no accumulation in human. There is no concern with respect to genotoxicity and carcinogenicity. Reproductive studies were not available, but a no observed adverse effect level (NOAEL) of 1,000 mg sodium ferrocyanide/kg bw per day (highest dose tested) was identified from a prenatal developmental toxicity study. The kidney appeared to be the target organ for ferrocyanides toxicity and 4.4 mg sodium ferrocyanide/kg bw per day was identified as the NOAEL for the renal effects in a chronic (2-year) study in rats.

Assuming that the toxicity of this compound is due to the ferrocyanide ion only, the Panel established a group acceptable daily intake (ADI) for sodium, potassium and calcium ferrocyanide of 0.03 mg/kg bw per day expressed as ferrocyanide ion. The Panel concluded that ferrocyanides (E 535–538) are of no safety concern at the current authorised use and use levels.

Summary

The present opinion deals with the re-evaluation of the safety of sodium ferrocyanide (E 535), potassium ferrocyanide (E 536), and evaluation of the safety of calcium ferrocyanide (E 538) as food additives.

Sodium, potassium and calcium ferrocyanides (E 535, E 536 and E 538) are authorised as food additives in the European Union (EU) in accordance with Annex II to Regulation (EC) No 1333/2008 on food additives and specific purity criteria have been defined in the Commission Regulation (EU) No 231/20121.

In the EU, sodium and potassium ferrocyanide, used as food additives, were previously evaluated by the Scientific Committee on Food (SCF) in 1990. In that evaluation, the SCF agreed with the acceptable daily intake (ADI) of 0.025 mg/kg body weight (bw) per day (calculated as sodium ferrocyanide) established by the Joint FAO/WHO Expert Committee on Food Additives (JECFA) for sodium and potassium ferrocyanide.

Sodium, potassium and calcium ferrocyanide were evaluated by JECFA in 1969, 1973 and 1974. A temporary acceptance of 0–0.00125 mg/kg bw per day was established in 1969 based on a dietary level of 0.05% sodium ferrocyanide and subsequently a temporary ADI of 0–0.025 mg/kg bw per day was established. In 1974, the temporary ADI of 0–0.025 mg/kg per bw (calculated as sodium ferrocyanide) was confirmed. A larger uncertainty factor (1,000) than the generally one employed was used to compensate for the absence of a long-term feeding study.

Potassium and sodium ferrocyanide were evaluated by the UK Committees on the Toxicity of Chemicals in Food, Consumer Products and the Environment (COT) in 1994 and set a group ADI for ferrocyanides of 0–0.05 mg/kg bw per day.

The Scientific Committee for Animal Nutrition (SCAN) evaluated the safety for the target animals, the users, the workers, the consumers and the environment of sodium and potassium ferrocyanide used as anticaking agents. It was concluded that sodium and potassium ferrocyanide in salt for feed use (20, 80 and 100 mg/kg in salt for man, poultry and livestock, respectively) is acceptable in regard to the safety for target animals and human consumers.

Sodium, potassium and calcium ferrocyanide were evaluated by a working group established by the Nordic Council of Ministers in 2000. Sodium, potassium and calcium ferrocyanide were not considered to cause a safety problem due to the very small quantities consumed.

Potassium ferrocyanide is absorbed to a limited extent from the gastrointestinal tract following oral administration to rats and in humans absorption is low (0.25–0.42%). Potassium ferrocyanide is of low acute oral toxicity. Based on the available data, the Panel considered that the use of ferrocyanides as food additives is not of genotoxic concern and that ferrocyanides are not carcinogenic. Reproductive studies were not available, but a no observed adverse effect level (NOAEL) of 1,000 mg sodium ferrocyanide/kg bw per day (highest dose tested) was identified from a prenatal developmental toxicity study.

In a 2-year study, animals frequently showed a higher cell excretion rate in urine samples compared to controls. Since the kidney is known to be the target organ for ferrocyanide toxicity, the Panel considered the increased cell excretion rate indicative for occasional, transient kidney toxicity and identified a NOAEL of 4.4 mg/kg bw per day. Based on this NOAEL of 4.4 mg sodium ferrocyanide/kg bw per day for male rats, the Panel derived an ADI of 0.044 mg sodium ferrocyanide/kg bw per day. Assuming that the toxicity of this compound is due to the ferrocyanide ion only, the Panel established a group ADI for sodium, potassium and calcium ferrocyanide of 0.03 mg/kg bw per day expressed as ferrocyanide ion. The Panel noted that at this ADI the potential amount of free cyanide released would not be of safety concern.

To assess the dietary exposure to ferrocyanides (E 535–538) from their use as food additives, the exposure was calculated based on (1) maximum permitted level (MPL) in FC 12.1.1 ‘Salt’ set out in the EU legislation (defined as the regulatory maximum level exposure assessment scenario) and (2) the mean reported use levels of salt (defined as the refined exposure assessment scenario).

The Panel decided to use salt intake data from urinary excretion studies for the assessment of exposure to ferrocyanides (E 535–538) instead of the food consumption data from the EFSA Comprehensive European Food Consumption Database as dietary surveys are commonly not considered as a good source of information in the estimation of salt intake while a more accurate way of estimation of the salt intake is a calculation from the urinary excretion of sodium.

Dietary exposure to ferrocyanides was calculated based on mean and high levels consumption of salts in both the regulatory maximum level and the refined scenario.

In the MPL scenario, the exposure to ferrocyanides (E 535–538) from their use as a food additive was up to 0.009 mg/kg bw per day in children and adolescents. In the refined estimated exposure scenario, the exposure was up to 0.004 mg/kg bw per day in children and adolescents. Considering that the majority of the use levels in salt reported by Industry were for sodium ferrocyanide (E 535), these exposures would correspond approximately to 0.003 mg ferrocyanide ion/kg bw per day in children and adolescents in the refined exposure scenario.

The Panel considered that the uncertainties identified indicate an overestimation of the exposure to ferrocyanides (E 535–538) as food additives.

Considering that:

• in the refined exposure scenario estimated exposure to ferrocyanides (E 535–538) would correspond approximately to 0.003 mg ferrocyanide ion/kg bw per day in children and adolescents;
• absorption of ferrocyanides from the gastrointestinal tract was low, and there is no accumulation in human;
• ferrocyanides are of low acute toxicity and not mutagenic or carcinogenic;
• reproductive studies were not available, but a NOAEL of 1,000 mg sodium ferrocyanide/kg bw per day (highest dose tested) was identified from a prenatal developmental toxicity study;
• the kidney is the target organ for ferrocyanides toxicity as characterised by the high number of cells excreted in the urine in rats;
• 4.4 mg sodium ferrocyanide/kg bw per day was identified as the NOAEL for this effect in a chronic (2-year) study in rats;
• assuming that the toxicity of this compound is due to the ferrocyanide ion only, the Panel established a ADI for ferrocyanide ion of 0.03 mg/kg bw per day;
• ferrocyanides (E 535–538) are only permitted as food additives in two food categories.

The Panel concluded that ferrocyanides (E 535–538) are of no safety concern in these current authorised use and use levels.

The Panel further concluded that the available data give reason to revise the ADI of 0.025 mg sodium ferrocyanide/kg bw per day (equivalent approximately to 0.02 mg ferrocyanide ion/kg bw per day) based on a subchronic study, to a group ADI for sodium, potassium and calcium ferrocyanide of 0.03 mg/kg bw per day expressed as ferrocyanide ion.