Status of Approval for a Zero Withdrawal Sedative for Aquaculture and Fishery Management Use

Isoeugenol (the active ingredient in AQUI-S®) has been under evaluation by the National Toxicology Program (NTP), an interagency program whose mission is to evaluate chemical agents for potential public health risks. Initial results reported from the NTP studies resulted in cessation of drug approval efforts for AQUI-S® by the federal partners on the Association of Fish and Wildlife Agencies (AFWA) Drug Approval Working Group (DAWG) on April 27, 2007. On February 28, 2008, the NTP peer review panel confirmed that there is clear evidence of isoeugenol carcinogenicity in male mouse livers; there was no or equivocal evidence of carcinogenicity for the female mouse and male and female rat. Finding clear evidence of carcinogenicity in the male mouse triggered the Delaney Clause, a 1958 amendment to the Food, Drugs, and Cosmetic Act (FDCA). The clause states that "the Secretary of the Food and Drug Administration shall not approve for use in food any chemical additive found to induce cancer in man, or, after tests, found to induce cancer in animals". The Center for Veterinary Medicine (CVM) recently stated that it was “very, very unlikely” that a zero withdrawal period could be gained for isoeugenol based on the NTP interpretation of the results of the male mouse study and the application of the Delaney Clause to the FDCA. 

The DAWG met on March 26-28, 2008 to discuss the available options for, and limitations to, an isoeugenol approval and to formulate plans to identify an alternative sedative. The DAWG presented information on the status of isoeugenol and the potential to develop other candidate sedatives to the AFWA Multi-State Conservation Grants (MSCG) committee so the MSGC committee could determine the disposition of the MSGC funds initially allocated to develop residue chemistry and animal safety data to support the approval of AQUI-S® as a zero-withdrawal anesthetic. The MSCG committee directed the DAWG to identify a new candidate sedative to which the remaining MSGC funds (~$190,000) could be allocated and report back to the MSGC committee on the selection by June 2, 2008. If a candidate sedative is not identified, the MSCG funds would revert to the AFWA general fund and AFWA efforts to develop a zero-withdrawal sedative would stop.

The DAWG members are in the process of gathering information on the use patterns and data requirements for candidate sedatives and working with potential sponsors to determine their interest in supporting a U.S. approval of their sedative.  Currently the top candidates include benzocaine, eugenol, metomidate, and tricaine methanesulfonate, however each will need development of at least some mammalian safety and residue chemistry data to support an approval.