Investigations on the Metabolism and Potentially Adverse Effects of Ethoxyquin Dimer, a Major Metabolite of the Synthetic Antioxidant Ethoxyquin in Salmon Muscle

Abstract

The feed additive ethoxyquin (EQ) is a commonly used synthetic antioxidant preservative in animal feeds. In farmed Atlantic salmon fillets, EQ residues are present, both as the parent compound and as EQ derivatives. One of the main EQ derivates in fish muscle is an ethoxyquin dimer (EQDM), and the potential toxicity of this metabolite is not known. The aim of this study was to evaluate the metabolism and potentially toxicological effects of EQDM. A 90-day subchronic exposure study with repeated dietary exposure to EQDM at 12.5 mg/kg of body weight per day was performed with male F344 rats. Hepatic Cyp1a1 mRNA was significantly reduced to <3% of the control in rats fed EQDM, and hepatic Cyp2b1 mRNA was increased to 192%. EQDM increased Gstpi1 mRNA expression to 144% that of the control, but the activity level of this phase II enzyme was reduced. Biomarkers of liver and kidney function did indicate adverse effects of EQDM when F344 rats were fed 12.5 mg/kg of body weight per day. The present study revealed that EQDM produces responses that are comparable to those produced by the parent compound (EQ) in terms of activating the same enzyme systems.

Applicability of a food chain analysis on aquaculture of Atlantic salmon to identify and monitor vulnerabilities and drivers of change for the identification of emerging risks

“…The occurrence of such residues and their transfer to edible tissues of salmon may therefore be a new phenomenon, constituting a novel route of exposure (or increased exposure) to consumers Feed production Growing Lack of residue and safety data on certain metabolites of contaminants (e.g. newly discovered metabolites of ethoxyquin, leuco dyes, pesticides, etcetera, or residues not commonly included in residue monitoring) (Ørnsrud et al, 2011;Chan et al, 2012)…”

“…Until 2009, it was also authorised in the EU as pesticide (2015b). In the fish, ethoxyquin is converted to an ethoxyquin dimer, which has been detected in liver and muscle from Atlantic Salmon (Ørnsrud et al, 2011;EFSA, 2015b). Although ethoxyquin is commonly used as feed additive, it is not authorized as a food additive in the EU (Ornsrud et al, 2011).…”

“…In the fish, ethoxyquin is converted to an ethoxyquin dimer, which has been detected in liver and muscle from Atlantic Salmon (Ørnsrud et al, 2011;EFSA, 2015b). Although ethoxyquin is commonly used as feed additive, it is not authorized as a food additive in the EU (Ornsrud et al, 2011). Due to an overall lack of data to assess the safety of ethoxyquin and its metabolites, EFSA does not conclude on the safety as a feed additive for animals (salmonids), consumers or the environment (EFSA, 2015b).…”

Synthesis and Crystal Structures of Methyl 3,4,5-Trimethoxybenzoate and 1,2-Dihydro-2,2,4-Trimethylquinoline Derivatives

“…They are also known to display a wide range of biological and pharmaceutical properties including antioxidant [16,17], anti-inflammatory [18] and hormone receptor modulating [19] properties. Furthermore, ethoxyquin (6-ethoxy-1,2-dihydro-2,2,4-trimethylquinoline) is a powerful antioxidant approved by the Food and Drug Administration (FDA) and authorized in the European Union for use as additives in animal foods [17,20]. However, despite its potent radical scavenger activity, the significant hypothermic effect of ethoxyquin in rodents [21] has precluded its potential use for central nervous system protection in human [22].…”

C–N Coupling of 1,2‐Dihydro‐2,2,4‐trimethylquinoline Derivatives via a Silver(I)‐Catalyzed Direct Functionalization of a C–H Bond

“…However, the use of ethoxyquin as a food additive for human consumption is prohibited. Although the effects of the presence of this ethoxyquin dimer in human through a carryover from edible fish parts have not been studied [7,11,12], this compound was shown to be associated with the modulation of hepatic detoxifying enzymes [13] and the alteration in gene and protein expression patterns in fish [11,12] and in male F344 rats [7]. In fact, the study of the muscles of Atlantic salmons fed with ethoxyquin-preserved feedstock has indicated that 6-ethoxy-1-(6-ethoxy-1,2-dihydro-2,2,4-trimethylquinolin-8-yl)-1,2-dihydro-2,2,4-trimethylquinoline, one of the C,N-linked ethoxyquin dimers described in this report, was the main and ubiquitous metabolite of dietary ethoxyquin in fish [2,6,11,12].…”