Following a request from the European Commission (EC), the Panel on Food Additives and Nutrient Sources added to Food (ANS) was asked to deliver a scientific opinion re-evaluating the safety of silver (E 174) when used as a food additive.
The Panel based its evaluation on previous evaluations and on the additional literature that became available since then and the data available following a public call for data. The Panel noted that not all original studies on which previous evaluations were based were available. To assist in identifying any emerging issue or any relevant information for the risk assessment, the European Food Safety Authority (EFSA) has outsourced a contract to deliver an updated literature review on toxicological endpoints, dietary exposure and occurrence levels of silver (E 174) which covered the period up to the end of 2014. Further update has been performed by the Panel.
E 174 is authorised as a food additive in the European Union (EU) in accordance with Annex II to Regulation (EC) No 1333/2008. E 174 has been previously evaluated by the EU Scientific Committee for Food (SCF) in 1975 (SCF, 1975) and by the Joint FAO/ WHO Expert Committee on Food Additives (JECFA) in 1977 (JECFA, 1977; 1978). Both committees did not establish an acceptable daily intake (ADI) due to inadequate data.
Silver in food additive E 174 is present in its elemental form. Specifications for E174 have been defined in the EU in Commission Regulation (EU) No 231/2012. The purity is specified to be not less than 99.5% for silver-coloured powder or tiny sheets. Silver can also occur in crystalline form as a white metal.
During the last call for data, a study on confectionery pearls coated with E 174 was performed, finding that a 20% of the mean total silver concentration in the pearls was released as particles after the water treatment of the pearls (Verleysen et al., 2015).
The Panel noted that in Commission Regulation (EU) No 231/2012, no information is included regarding the particle size of silver powder. According to the Panel, the characterisation of the particle size in the powder of E 174 should be included in the specifications. The full characterisation should include the particles size distribution together with determination and quantification of any nanoparticulate material.
The Panel noted that silver nanoparticles (AgNPs) are released from confectionary pearls (Verleysen et al., 2015) and nanosilver is unstable and releases ions. The Panel was aware of the extensive database on ionic silver or AgNPs, however, the relevance of these data to the evaluation of E 174 was not apparent. Therefore, the Panel considered these data could not be directly applied to the evaluation of the food additive.
In this opinion, only data with non-capped nanoparticles are included. However, when corresponding capped nanoparticles have been studied in the same experiments, also those data are included.
Following oral exposure of animals to ionic silver or AgNPs, it is systemically available. Silver concentrations in the organs were highly correlated to the size of the nanoparticles concentrations being higher in animals exposed to smaller nanoparticles and to the amount of silver ions released from the AgNPs. Bioavailability seems to be in the range of 2–20% depending on many factors including the animal species.
However, the Panel noted that, due to the many variables involved, the conversion rate of metal silver from nanoparticles to silver ions in biological systems is unknown. Moreover, the formation of reactive oxygen species (ROS) from the fraction of AgNPs which may be present in the food additive has not been determined. The rate of both processes depends on the size of particles and their relative surface.
Silver distribution has been reported to all organs and tissues in animals. Silver distribution to the brain following oral exposure has been described in several studies, which is in contrast to the conclusions of previous studies with silver nitrate or lactate, that silver would not cross the blood–brain barrier (van Breemen and Clemente, 1955). However, it is also in the recent studies not clear whether silver is present in the brain endothelial cells or in the brain tissue. Silver ions were also detected in the milk of rat dams receiving a daily oral administration of silver chloride, and in the liver and in the brain of the pups. In rodents, silver is primarily excreted via the bile and faeces, but a small amount is also excreted via the urine.
The Panel noted that only one study described the fate of microsized silver particles in animals (Park et al., 2010). In this study, it was not detected in any of the tissues of mice given an oral administration of microsized silver particles (323 nm), whereas it was present in tissues of mice receiving a similar administration of nanosized particles (21 to 71 nm).
The Panel was aware that there are many data reporting distribution of silver in various human organs following prolonged exposure to very high doses of silver in different forms. The Panel was also aware that there are numerous data reporting adverse effects of silver due to its use in the medical field (Lansdown, 2010; Maillard and Hartemann, 2013) or as a result of occupational exposure (Drake and Hazelwood, 2005). Overall, the Panel noted that in the case of medical and occupational exposure to silver, the doses and/or the route of exposure (inhalation, no inclusion in a food matrix) were usually irrelevant to the exposure resulting from the use of silver as a food additive.
No toxicity studies were reported on elemental silver.
There are no data available to evaluate the in vivo genotoxicity of ionic silver. Concerning AgNPs, the available studies provide clear evidence of a genotoxic potential in various in vitro test systems. The in vivo oral genotoxicity studies performed provide less conclusive evidence and do not allow a definitive assessment of the possible genotoxic hazard associated with oral exposure to AgNPs. Overall, the Panel concluded that the available data are inadequate to evaluate the genotoxic hazard associated with the use of silver as food additive.
No studies on the carcinogenic potential of either ionic silver compounds or AgNPs have been identified.
In an oral one-generation reproductive toxicity study with silver acetate in drinking water at dose levels of 0, 0.4, 4 or 40 mg silver acetate/kg body weight (bw)/day (0, 0.26, 2.6 or 26 mg ionic silver/kg bw/day) in rats a no-observed-adverse-effect level (NOAEL) for developmental effects (based on an increased number of pups, pup death and decreased weight gain of pups) of 0.4 mg silver acetate/kg bw/day (0.26 mg ionic silver/kg bw/day) was observed (Documentation provided to EFSA No5). The NOAEL for fertility was 4 mg silver acetate/kg bw/day (2.6 mg ionic silver/kg bw/day).
From the maximum level exposure assessment, mean estimates ranged from < 0.01 to 2.6 µg/kg bw/day across all population groups. Estimates based on the high percentile (95th percentile) ranged from 0 to12 µg/kg bw/day across all population groups.
From the refined estimated exposure scenario in the brand-loyal scenario, mean exposure to E 174 from its use as a food additive ranged from < 0.01 µg/kg bw/day for infants to 2.6 µg/kg bw/day in children. The high exposure to E 174 ranged from 0 µg/kg bw/day for infants to 12 µg/kg bw/day in children. In the non-brand-loyal scenario, mean exposure to E 174 ranged from < 0.01 µg/kg bw/day for infants to 1.6 µg/kg bw/day in children. The high exposure ranged from 0 µg/kg bw/day for infants to 3.2 µg/kg bw/day in children.
The exposure from the food additive and the regular diet (ANSES, 2011) could lead to a mean intake for children around 3.5 µg/kg bw/day (non-brand-loyal scenario). On average, exposure from the food additive would represent around 30% of total dietary exposure to silver.
Overall, the Panel noted that there are data gaps and concerns that need to be addressed in order to conduct a risk assessment with respect to the use of silver (E 174) as food additive:
- Data from toxicity studies on elemental silver or the food additive (E 174) are lacking.
- The particle size distribution of the food additive (E 174) is unknown.
- There is evidence of the release of silver ions from elemental silver, which may be of concern. However, the extent of the release of the silver ions, which depends on multiple factors such as pH and particle size, is unknown in the case of E 174 used as food additive.
The Panel concluded that the information available was insufficient to assess the safety of silver as food additive. The major issues included chemical identification and characterisation of E 174 (e.g. quantity of nanoparticles and release of ionic silver) and similar information on the material used in the available toxicity studies. Therefore, the Panel concluded that the relevance of the available toxicological studies to the safety evaluation of food additive E 174 could not be established.
The Panel recommended that the specifications for E 174 should include the mean particle size and particle size distribution (± SD), as well as the percentage (in number) of particles in the nanoscale (with at least one dimension below 100 nm), present in the powder form of E 174 used as a food additive. The methodology applied should comply with the EFSA Guidance document (EFSA Scientific Committee, 2011), e.g. scanning electron microscopy (SEM) or transmission electron microscopy (TEM).
The Panel recommended that additional data in line with the current Guidance document on the evaluation of food additives (EFSA, 2012) would be required.
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