Scientific Opinion on re-evaluation of copper complexes of chlorophylls (E 141(i)) and chlorophyllins (E 141(ii)) as food additives

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Article
Panel on Food Additives and Nutrient Sources Added to Food
EFSA Journal
EFSA Journal 2015;13(6):4151 [60 pp.].
doi
10.2903/j.efsa.2015.4151
Panel members at the time of adoption
Fernando Aguilar, Riccardo Crebelli, Alessandro Di Domenico, Birgit Dusemund, Maria Jose Frutos, Pierre Galtier, David Gott, Ursula Gundert-Remy, Claude Lambré, Jean-Charles Leblanc, Oliver Lindtner, Peter Moldeus, Alicja Mortensen, Pasquale Mosesso, Agneta Oskarsson, Dominique Parent-Massin, Ivan Stankovic, Ine Waalkens-Berendsen, Rudolf Antonius Woutersen, Matthew Wright and Younes Maged.
Acknowledgements

The Panel wishes to thank the members of the former Working Group “A” Food Additives and Nutrient Sources (2011–2014) and the members of the Standing Working Group on the re-evaluation of food colours, Fernando Aguilar, Riccardo Crebelli, Alessandro Di Domenico, Maria Jose Frutos, Pierre Galtier, David Gott, Claude Lambré, Jean-Charles Leblanc, Agneta Oskarsson, Jeanne Stadler, Paul Tobback, Ine Waalkens-Berendsen and Rudolf Antonius Woutersen, for the preparatory work on this scientific opinion and EFSA staff members: Federica Lodi, Ana Maria Rincon and Alexandra Tard for the support provided to this scientific opinion. The ANS Panel wishes to acknowledge all European competent institutions, Member State bodies and other organisations that provided data for this scientific output.

Contact
Type
Opinion of the Scientific Committee/Scientific Panel
On request from
European Commission
Question Number
EFSA-Q-2011-356
EFSA-Q-2011-372
Adopted
9 June 2015
Published
30 June 2015
Affiliation
European Food Safety Authority (EFSA), Parma, Italy
Note
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Abstract

Copper complexes of chlorophylls (Cu-chlorophylls) (E 141(i)) and copper complexes of chlorophyllins (Cu-chlorophyllins) (E 141(ii)) are prepared from sources that could not be regarded as edible plant material or food (grass, lucerne, nettle) for humans. Considering their manufacturing process, these compounds cannot be regarded as natural compounds. The Panel noted that very few studies have been conducted using Cu-chlorophylls, which hampered assessment of their safety. In contrast to (non-copper) chlorophylls and chlorophyllins, the available data showed that some components of Cu-chlorophyllins can be absorbed and distributed systematically. Given the differences in purity, chemical properties, stability and manufacturing process, the Panel considered that it was not possible to use Cu-chlorophyllins (E 141(ii)) data for read-across for Cu-chlorophylls (E 141(i)). The available data were considered inadequate by the Panel to evaluate the genotoxic potential of Cu-chlorophyllins. The Panel considered that, given the discrepancies and uncertainties in the available data concerning the carcinogenic potential of Cu-chlorophyllins, further and adequate evaluation of the possible carcinogenicity of Cu-chlorophyllins was needed. Finally, the Panel concluded that reliable data on absorption, distribution, metabolism and excretion (ADME), genotoxicity, (chronic) toxicity, carcinogenicity, and reproductive and developmental toxicity of Cu-chlorophylls (E 141(i)) and Cu-chlorophyllins (E 141(ii)) were lacking. Therefore, their safety of use as food additives cannot be assessed and the current Acceptable Daily Intake (ADI) should be withdrawn. In addition, the Panel considered that the specifications should be updated to include information on the non-chlorophyll components of E 141(i), which may represent up to 90 % of the extract, together with the precise identification of the various compounds that are present in the food additives E 141(i) and E 141(ii).

Summary

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 copper complexes of chlorophylls (Cu-chlorophylls) (E 141(i)) and copper complexes of chlorophyllins (Cu-chlorophyllins) (E 141(ii)) when used as food additives.

The Panel was not provided with a newly submitted dossier and based its evaluation on previous evaluations and additional literature that has become available since then. No new toxicological or biological information was submitted to the Panel for the re-evaluation of Cu-chlorophylls (E 141(i)) and Cu-chlorophyllins (E 141(ii)) following European Food Safety Authority (EFSA) public calls for data. The Panel noted that not all of the original studies on which previous evaluations were based were available for this re-evaluation. To assist in identifying any emerging issue or any information relevant for the risk assessment, EFSA outsourced a contract to deliver an updated literature review on toxicological endpoints, dietary exposure and occurrence levels of Cu-chlorophylls (E 141(i)) and Cu-chlorophyllins (E 141(ii)), which covered the period up to the end of 2014. A further update has been performed by the Panel.

Cu-chlorophylls (E 141(i)) and Cu-chlorophyllins (E 141(ii)) are authorised as food additives in the European Union (EU) in accordance with Annex II to Regulation (EC) No 1333/2008.

The Panel noted that the name “copper complex of chlorophylls” is meaningless on a chemical basis, and should be “copper complex of phaeophytins”. Cu-chlorophylls (E 141(i) and Cu-chlorophyllins (E 141(ii)) are obtained from sources that could not be regarded as edible plant material or food (grass, lucerne, nettle) for humans. In addition, owing to their manufacturing process, the food additives Cu-chlorophylls E 141(i) and Cu-chlorophyllins E 141(ii) cannot be considered as natural compounds. The Panel considered that the raw material should fulfil the conditions of the current regulation as regards maximum levels of possible contaminants, including pesticides residues applied during cultivation and mycotoxins.

The Panel considered that the specifications do not sufficiently cover Cu-chlorophylls, which are processed from extracts from plants that do not have a long-term history of food use, and that, consequently, the specifications should be updated to include the information on the non-chlorophyll components of E 141(i), which may represent up to 90 % of the extract.

The Panel noted that, according to industry, Cu-chlorophylls (E 141(i)) is not used to produce an aluminium lake and that Cu-chlorophyllins (E 141(ii)) can be transformed into the corresponding aluminium lake.

There is great confusion in the literature. In many publications, the study material, usually named “chlorophyllin”, was quite often, if not always, a sodium and/or potassium salt of Cu-chlorophyllins (E 141(ii)). Scotter (2011) stated that: “It is important to consider that despite a joint initiative introduced by the International Union of Pure and Applied Chemistry and the International Union of Biochemistry, a substantial body of long-established trivial names for chlorophyll and its analogues remains in popular use by both the food colour industry and scientific researchers. The term ‘chlorophyllin’ covers a range of compounds identical to, or structurally related to the porphyrins”.

The Panel considered that the maximum limits for the impurities of toxic elements (arsenic, lead, mercury and cadmium) in the EC specification for Cu-chlorophylls (E 141(i)) and Cu-chlorophyllins (E 141(ii)) should be revised to ensure that their use as food additives will not be a significant source of exposure to these toxic elements in foods.

Cu-chlorophyllins (E 141(ii)) have been previously evaluated by the Joint Food and Agriculture Organization of the United Nations (FAO)/World Health Organization (WHO) Expert Committee on Food Additives (JECFA) in 1969 and 1974 (JECFA, 1970, 1975). In 1975, the Scientific Committee on Food (SCF) evaluated Cu-chlorophylls (E 141(i)) and Cu-chlorophyllins (E 141(ii)) (SCF, 1975). Based on a No Observed Adverse Effect Level (NOAEL) of 1 500 mg Cu-chlorophyllins/kg body weight (bw)/day derived from the long-term and reproduction study by Harrisson et al. (1954), JECFA (1975) set a temporary Acceptable Daily Intake (ADI) of 0–15 mg/kg bw/day to Cu-chlorophyllins. In addition, in its evaluations of 1970 and 1975, JECFA described a study by Reber and Willigan (1954) in which Cu-chlorophyllins exhibited significant adverse effects on rat survival after oral exposure to 500 mg/kg bw/day for 19 weeks. The Panel noted that the reason why JECFA did not take into account these findings for the calculation of the ADI was unclear. SCF (1975) allocated a group ADI of 15 mg/kg bw/day to the sum of both complexes and stated that “Cu-chlorophylls and Cu-chlorophyllins are two distinct food colours and recommends separate listing of the two colours; accordingly, the Community Directive specification requires amendment”. The Panel noted that no subsequent actions appear to have been taken following this recommendation.

Based on the same NOAEL of 1 500 mg/kg bw/day identified from the Harrisson et al. (1954) study, but by applying a safety factor of 200 instead of 100 for the JECFA and the SCF evaluations, the United States Food and Drug Administration (US FDA) allocated an ADI of 7.5 mg/kg/day for sodium–copper chlorophyllins (FDA, 2002). The US FDA has recommended that sodium–copper chlorophyllins can be taken orally as a deodorant, generally at 100–200 mg/day. In some cases an additional 100 mg/day may be required, but the total daily dose should not exceed 300 mg/day (FDA, 1990).

The Panel noted that both JECFA and FDA have used the Harrisson et al. (1954) study to establish an ADI. This is an old study not carried out in accordance with the Organisation for Economic Co-operation and Development (OECD) guidelines, and which did not include the usual endpoints for reproductive and developmental toxicity and used a small number of animals. Therefore, the Panel considered that, based on current standards, this study was inadequate to identify a NOAEL from which a reliable ADI could be derived.

Most of the available toxicity data were for Cu-chlorophyllins, whereas very few studies have been conducted using Cu-chlorophylls, which hampered their safety assessment. Given the differences in purity, chemical properties, stability and manufacturing process, the Panel considered that it was not possible to use Cu-chlorophyllins (E 141(ii) data for read-across for Cu-chlorophylls (E 141(i)). The Panel noted that the amount of copper-containing material that is absorbed, as well as the full metabolic fate and bioavailability of copper, are not known. Because some reports have shown tissue distribution of copper-containing materials after ingestion of Cu-chlorophyllins, the Panel considered that this might deserve further investigations.

In a study in which the rats were fed a diet containing Cu-chlorophyllins for 19 weeks (Reber and Willigan, 1954), a NOAEL of 500 mg/kg bw/day (the only dose used) could be determined. The Panel noted that this NOAEL was not considered by either the JECFA or the SCF for their evaluations.

No genotoxicity data for Cu-chlorophylls were available, while data on Cu-chlorophyllins were considered by the Panel as inadequate to evaluate its genotoxic potential.

The Panel considered that given the discrepancies and uncertainties in the available data concerning the carcinogenic potential of Cu-chlorophyllins, further and adequate evaluation of the possible carcinogenicity of Cu-chlorophyllins is needed.

The Panel noted that the available studies for the evaluation of the reproductive and developmental toxicity of Cu-chlorophyllins (E 141(ii)) were inadequate and that no study on the reproductive and developmental toxicity of Cu-chlorophylls (E 141(i)) was available.

In the refined exposure assessment scenario, the Panel used to use only maximum concentration values (maximum reported use levels) available for each authorised food category. However, given the range of data that have been made available, the Panel considered that all data should be used in additional scenarios of the exposure assessment approach intended to provide more realistic exposure estimates. For Cu-chlorophylls (E 141(i)) and Cu-chlorophyllins (E 141(ii)), only usage levels were available for the refined exposure assessment scenario. Based on these data, and the maximum level exposure assessment scenario, the Panel calculated two refined exposure estimates based on different assumptions: a “brand-loyal scenario” and a “non-brand-loyal scenario”.

The Panel noted that the refined exposure estimates will not cover future changes in the level of use of Cu-chlorophylls (E 141(i)) or Cu-chlorophyllins (E 141(ii)). Only use levels were reported by industry; no analytical data were provided to EFSA. These data covered the main food categories in which Cu-chlorophylls (E 141(i)) and Cu-chlorophyllins (E 141(ii)) are authorised. The Panel noted that some data providers did not distinguish between Cu-chlorophylls (E 141(i)) and Cu-chlorophyllins (E 141(ii)) and therefore, there was uncertainty whether some usage data refer to Cu-chlorophylls (E 141(i)) or Cu-chlorophyllins (E 141(ii)).

The Panel concluded that adequate data on absorption, distribution, metabolism and excretion (ADME), genotoxicity, (chronic) toxicity, carcinogenicity, and reproductive and developmental toxicity of Cu-chlorophylls (E 141(i)) and Cu-chlorophyllins (E 141(ii)) are lacking. Therefore, their safety of use as food additives cannot be assessed and the ADI should be withdrawn.

The Panel also concluded that the specifications do not adequately cover Cu-chlorophylls (E 141(i)) and Cu-chlorophyllins (E 141(ii)) and recommended that the components that are present in the commercial food additives Cu-chlorophylls (E 141(i)) and Cu-chlorophyllins (E 141(ii)) should be adequately identified and characterised. In addition, the inconsistency in the total copper content currently indicated in the specifications should be clarified.

The Panel recommended that data on the raw material should fulfil the conditions of the current regulation as regards maximum levels for possible contaminants, including residues of pesticides applied during cultivation and mycotoxins.

The Panel recommended that the maximum limits for the impurities of toxic elements (arsenic, lead, mercury and cadmium) in the EC specification for Cu-chlorophylls (E 141(i)) and Cu-chlorophyllins (E 141(ii)) should be revised to ensure that their use as food additives will not be a significant source of exposure to these toxic elements in foods.

Keywords
copper complexes of chlorophylls, E 141(i), copper complexes of chlorophyllins, E 141(ii), food colours
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Number of Pages
60