Safety and efficacy of ethoxyquin (6-ethoxy-1,2-dihydro-2,2,4-trimethylquinoline) for all animal species

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Article
Panel on Additives and Products or Substances used in Animal Feed
EFSA Journal
EFSA Journal 2015;13(11):4272 [58 pp.].
doi
10.2903/j.efsa.2015.4272
Panel members at the time of adoption
Gabriele Aquilina, Vasileios Bampidis, Maria de Lourdes Bastos, Georges Bories, Andrew Chesson, Pier Sandro Cocconcelli, Gerhard Flachowsky, Jürgen Gropp, Boris Kolar, Maryline Kouba, Secundino López Puente, Marta López-Alonso, Alberto Mantovani, Baltasar Mayo, Fernando Ramos, Guido Rychen, Maria Saarela, Roberto Edoardo Villa, Robert John Wallace and Pieter Wester.
Acknowledgements

The Panel wishes to thank the members of the Working Group on Technological Additives, including Mikolaj Gralak, Anne-Katrine Lundebye, Carlo Nebbia and Derek Renshaw for the support provided to this scientific output.

Contact
feedap@efsa.europa.eu
Type
Opinion of the Scientific Committee/Scientific Panel
Question Number
EFSA-Q-2010-01224
Adopted
21 October 2015
Published
18 November 2015
Affiliation
European Food Safety Authority (EFSA), Parma, Italy
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Abstract

The additive ethoxyquin contains ≥ 91 % ethoxyquin, ≤ 8 % ethoxyquin polymers and ≤ 3 % p-phenetidine. It is intended for use in all animal species as an antioxidant at a maximum content of 50 mg/kg complete feed. Ethoxyquin is rapidly absorbed after oral administration. Ethoxyquin oxidation in feed materials and in animals leads to four main compounds: 2,4-dimethyl-6-ethoxyquinoline, ethoxyquin N-oxide, ethoxyquin quinone imine, and ethoxyquin dimer (detected only in fishmeal and in salmon). Ethoxyquin itself is not genotoxic or carcinogenic, and does not cause developmental toxicity. The lowest NOAEL (based on studies in rats and dogs) is 2 mg/kg body weight per day. The genotoxic profile of the dimer reflects that of ethoxyquin. Ethoxyquin quinone imine shows structural alerts for mutagenicity, carcinogenicity and DNA binding; no conclusion on the absence of genotoxicity of ethoxyquin quinone imine is possible. p-Phenetidine is a recognised possible mutagen. Concentrations of 50 mg ethoxyquin/kg and 11 mg ethoxyquin/kg complete feed might be considered as potentially safe for chickens and breeders and for dogs, respectively. No conclusion on potential safe levels for other poultry, pigs, ruminants, fish and cats is possible. Overall, when considering the presence of p-phenetidine in the additive, no conclusion on any safe level of the additive for target animals can be drawn. An assessment of safety for the consumer is prevented by the lack of exposure data, the absence of a safe level of exposure and the presence of p-phenetidine in ethoxyquin. The respirable mist of ethoxyquin is of low toxicity. Ethoxyquin is not a dermal irritant, but is considered a potential irritant to eyes and other mucous membranes and a skin sensitiser. No conclusion on the safety for the environment can be made. Ethoxyquin is a potent antioxidant; however, no data confirm its efficacy at the proposed use level.

Summary

Following a request from the European Commission, the Panel on Additives and Products or Substances used in Animal Feed (FEEDAP) was asked to deliver a scientific opinion on ethoxyquin for all animal species.

The additive ethoxyquin contains at least 91 % ethoxyquin, ≤ 8 % ethoxyquin polymers, ≤ 3 % p-phenetidine. and ≤ 0.02 % acetone. It is intended to be used in feed for all animal species with a maximum content of 50 mg/kg complete feed.
Ethoxyquin is rapidly absorbed after oral administration. Ethoxyquin oxidation in feed materials and in animals leads to four main compounds: 2,4-dimethyl-6-ethoxyquinoline, ethoxyquin N-oxide, ethoxyquin quinone imine, and ethoxyquin dimer (detected only in fishmeal and in salmon).

Ethoxyquin itself is not carcinogenic, and it does not cause developmental toxicity in the offspring. The lowest no observed adverse effect level (NOAEL) observed in the available studies on rats and dog is 2 mg/kg body weight (bw) per day. Ethoxyquin showed positive results in some in vitro studies on cultured mammalian cells; however these outcomes were not confirmed in vivo. The FEEDAP Panel concludes that ethoxyquin itself is not genotoxic. The toxicological profile of the ethoxyquin dimers, present in feed and animal tissues, is considered to reflect that of the precursor monomers. No conclusion on the absence of genotoxicity of ethoxyquin quinone imine is possible.

Ethoxyquin quinone imine shows structural alerts for mutagenicity, carcinogenicity and DNA binding. Ethoxyquin quinone imine is negative in a bacterial reverse mutation assay but the results of an in vitro micronucleus assay do not allow the exclusion of clastogenicity. Consequently, no conclusion on the absence of genotoxicity of ethoxyquin quinone imine is possible.

p-phenetidine., an impurity of the additive ethoxyquin, is a possible mutagen. The few available toxicological studies do not allow the identification of an overall NOAEL for p-phenetidine..

Considering the dietary levels of ethoxyquin apparently tolerated by growing chickens and breeders reported in the literature (500–750 mg/kg feed), the proposed maximum concentration of 50 mg ethoxyquin/kg might be considered as potentially safe for chickens and breeders. Since no studies comparable to a tolerance study were available, an extrapolation to other poultry (including laying hens) is not possible. The safety of the use of ethoxyquin in feed for piglets is not demonstrated by a tolerance study. No conclusion on the safety of EQ for other pigs is possible. Owing to the absence of data, no conclusions can be made on the safety of ethoxyquin for calves, cattle for fattening, dairy cows, sheep and goats. Considering the data gaps in the available studies, no safe dietary level for fish, including salmonids, can be derived. Using default values for body weight and feed intake and applying an uncertainty factor of 10 (for individual and breed variability) to the NOAEL of 2 mg ethoxyquin/kg bw per day from a chronic dog study, 11 mg ethoxyquin/complete feed is derived as the maximum potentially safe ethoxyquin concentration in complete feed for dogs. No data were available for cats.
Considering that the additive ethoxyquin contains p-phenetidine., a possible mutagen, the FEEDAP Panel cannot conclude on any safe level of ethoxyquin in feed for target animals.

An estimate of consumer exposure to ethoxyquin-related residues in tissues and products from animals treated with ethoxyquin is not possible owing to considerable data gaps. An assessment of the safety for the consumer is prevented by the lack of a safe level of exposure and the presence of p-phenetidine. in the currently measured quantities in the additive.

The user may be exposed by inhalation to a mist of the additive. However, the respirable mist of ethoxyquin is of low toxicity. Ethoxyquin is not a dermal irritant, but should be considered as a potential irritant to eyes and other mucous membranes and as a skin sensitiser.
Since the ecotoxicity of ethoxyquin to the soil and the sediment compartments cannot be assessed owing to lack of data, no conclusion on the safety for the environment resulting from the use of ethoxyquin as a feed additive for all animal species can be drawn.

Ethoxyquin is a potent antioxidant; however, the studies presented do not confirm its efficacy at the proposed use level of 50 mg/kg complete feed.

Keywords
ethoxyquin, p-phenetidine, ethoxyquin quinone imine, antioxidant, genotoxicity, toxicity, safety
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Number of Pages
58