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Scientific Opinion on the reconsideration of the ADI and a refined exposure assessment of β-apo-8′-carotenal (E 160e)

EFSA Journal 2014;12(1):3492[30 pp.]. doi:10.2903/j.efsa.2014.3492
  EFSA Panel on Food Additives and Nutrient Sources added to food (ANS) Panel Members Fernando Aguilar, Riccardo Crebelli, Birgit Dusemund, Pierre Galtier, David Gott, Ursula Gundert-Remy, Jürgen König, Claude Lambré, Jean-Charles Leblanc, Pasquale Mosesso, Alicja Mortensen, Agneta Oskarsson, Dominique Parent-Massin, Martin Rose, Ivan Stankovic, Paul Tobback, Ine Waalkens-Berendsen, Ruud Woutersen and Matthew Wright. Acknowledgment The Panel wishes to thank the members of the Working Group B on Food Additives and Nutrient Sources added to Food: Fernando Aguilar, Riccardo Crebelli, Birgit Dusemund, David Gott, Torben Hallas-Møller, Jürgen König, Oliver Lindtner, Daniel Marzin, Inge Meyland, Alicja Mortensen, Agneta Oskarsson, Iona Pratt, Paul Tobback, Ine Waalkens-Berendsen and Ruud Woutersen for the preparatory work on this scientific opinion and EFSA staff: Anna Christodoulidou, Petra Gergelova and Stavroula Tasiopoulou for the support provided to this scientific opinion. Contact
Type: Opinion of the Scientific Committee/Scientific Panel On request from: European Commission Question number: EFSA-Q-2012-01001 Adopted: 03 December 2013 Published: 22 January 2014 Last updated: 24 March 2014. This version replaces the previous one/s. Affiliation: European Food Safety Authority (EFSA), Parma, Italy

The Panel on Food Additives and Nutrient Sources added to Food (ANS) has previously provided a scientific opinion re-evaluating the safety of β-apo-8′-carotenal (E 160e) as a food additive in the EU and establishing an acceptable daily intake (ADI) of 0.05 mg/kg body weight (bw)/day (EFSA ANS Panel, 2012). Following a request by the European Commission, the ANS Panel was asked to consider newly submitted information on the interpretation of the 13-week study in rats used as a basis to establish the ADI, to clarify its impact on that ADI and to carry out the refined exposure assessment of β-apo-8′-carotenal. The new information comprised an evaluation of all of the original kidney section slides from the 13-week toxicological study under improved visualisation conditions. The ANS Panel has considered that the supplementary information provided by the Commission and the present toxicological database on β-apo-8′-carotenal provides a basis to revise the established ADI and concluded that, based on the NOAEL of 30 mg/kg bw/day from the 13-week study in rats and an uncertainty factor of 100, a new ADI for β-apo-8′-carotenal of 0.3 mg/kg bw/day can be established. The Panel concluded that using data provided by the food industry, which are based only on a limited number of regulated categories, the reported uses and use levels of β-apo-8’-carotenal (E 160e) would not be of safety concern.

© European Food Safety Authority,2014


Following a request from the European Commission (EC) to the European Food Safety Authority (EFSA), the EFSA Panel on Food Additives and Nutrient Sources added to Food (ANS) delivered a scientific opinion reevaluating the safety of β-apo-8′-carotenal (E 160e) when used as a food colour (EFSA ANS Panel, 2012). In this re-evaluation, the ANS Panel used a 13-week study in rats to establish an acceptable daily intake (ADI) of 0.05 mg/kg body weight (bw)/day for β-apo-8′-carotenal (E 160e).

After the publication of the EFSA opinion, the European Commission received new information concerning the interpretation of kidney data from this 13-week study in rats and considered that EFSA implemented new methodology in its exposure assessment. Therefore, the European Commission requested EFSA to reconsider the established ADI and to refine the exposure assessment of its previous opinion.

The Panel was provided with supplementary information on the evaluation of the significance of kidney changes (Hard, 2012), previously observed by Edwards et al (2007) and Perry and Shearer (2008). The Panel evaluated the new report (Hard, 2012) reviewing the significance of eosinophilic droplets in the kidneys of rats of both sexes observed at all dose levels of β-apo-8’-carotenal active ingredient/kg bw/day. The material was most prominent in the cortical tubules of female rats exposed to 100 mg/kg bw/day. Hard (2012) suggested that it was very likely that the eosinophilic material represented accumulation of the test compound or a derivative during normal renal processing. The persistence of a reduced amount of the accumulating material in proximal convoluted tubule cells of the kidneys at the end of the 4-week recovery period indicated that the material was eliminated, but at a relatively slow rate (Hard, 2012). At the high dose of 100 mg/kg bw/day, a rare condition of cell detachments was suspected, accompanied by very occasional mitotic figures, which suggested that the normal ability of the proximal tubule to repair proximal convoluted tubule cells affected by the accumulated material might have marginally been exceeded at this dose. Based on these observations, the author concluded that 30 mg/kg bw/day represented a no observed adverse effect level (NOAEL), since no microscopic evidence of tubule injury was observed at this dose. The Panel agreed with this conclusion.

The Panel concluded that based on the NOAEL of 30 mg/kg bw/day from the 13-week study in rats, in which tubular cell injury was observed at 100 mg/kg bw/day, and using an uncertainty factor of 100, an ADI for β-apo-8’-carotenal of 0.3 mg/kg bw/day was established. The Panel considered an uncertainty factor of 100 as sufficient, not needing an extra adjusting factor due to the pivotal study being a subchronic study (and not a chronic study), given the fact that tubular injury was not observed in the two-year study at 40 mg/kg bw/day, the single dose tested.

Scenarios used for the exposure assessment based on the MPLs or use levels in reported food categories combined with the MPLs for other categories led to an exceedance of the ADI up to 10-20 fold in all population groups, both at mean and high level exposure.

However, a further refined exposure scenario was based only on the limited number of categories where industry reported use levels and analytical data. Exposure estimates using this scenario were below the ADI at the mean level for all population groups. At high level of exposure, the ADI was exceeded for toddlers and children, and the exposure for adolescents was at about the ADI. The Panel considered that this high level exposure estimate was still conservative and concluded that these exceedances are unlikely to occur. The Panel concluded that the uses and use levels of β-apo-8’-carotenal (E 160e), as reported by the food industry, would not be of safety concern.


β-apo-8′-carotenal, E 160e, CAS Registry Number 1107-26-2, food colour, refined exposure, ADI