Chapter 22: Aquaculture Drugs

Updated: 9/21/00

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Potential Food Safety Hazard

Unregulated/unapproved drugs administered to aquacultured fish poses a potential human health hazard. These substances may be carcinogenic, allergenic, and/or may cause antibiotic resistance in man.

Incentives for the use of animal drugs in aquatic animal species include the need to:
  1. Treat and prevent disease;
  2. Control parasites;
  3. Affect reproduction and growth; and,
  4. Tranquilization (e.g., during transit).

Relatively few drugs have been approved for aquaculture. As a result, aquaculture growers may use unapproved drugs, general-purpose chemicals that are not labeled for drug use, and approved drugs in a manner that deviates from the labeled instructions (FDA, 1998).

When a drug is approved by the Food and Drug Administration's Center for Veterinary Medicine, the conditions of the approval are listed on the label of the product. These will include the species the drug is approved for, dosage, route of administration, frequency, and indications for use. The only person(s) who can legally prescribe or use a drug for a condition not on the label are licensed veterinarians. The conditions under which this can be done are explained in 21 CFR 530. Any extra-label use that does not comply with 21 CFR 520 can be considered a violation of the Animal Medicine Drug Use Clarification Act (AMDUCA).

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Control Measures

To control this hazard in food animals, all drugs, whether for direct medication or for addition to feed, must be approved by FDA. Under certain conditions authorized by FDA, unapproved new animal drugs may be used in conformance with the terms of an Investigational New Animal Drug (INAD) application.

Labels of approved drugs list mandatory withdrawal times, where applicable. These withdrawal times must be observed to ensure that the edible tissue is safe when it is offered for sale. Tissue residue tolerances have been established for some drugs.

Control measures for approved aquaculture drugs used in aquaculture operations can include any combination of the following:

  1. On-farm visits to review drug usage (other than Investigational New Animal Drugs (INADs)) before receipt of the product, coupled with a supplier's lot-by-lot certificate that any INADs used were used in conformance with the application requirements;
  2. Receipt of supplier's lot-by-lot certification of proper drug usage, coupled with appropriate verification;
  3. Review of drug usage records (other than INADs) at receipt of the product, coupled with a supplier's lot-by-lot certificate that any INADs used were used in conformance with the application requirements;
  4. Drug residue testing.
  5. Receipt of evidence (e.g., third party certificate) that the producer operates under a third party-audited Quality Assurance Program for aquaculture drug use.

Note: The use of Investigational New Animal Drugs (INAD) is confidential unless an exception is made by the sponsor of the drug research. Thus, review of INAD drug usage records by the processor may not be practical in certain situations. Written certification from the grower to the processor stating that any INAD drug usage is in accordance with authorizations from FDA/Center for Veterinary Medicine, will be acceptable on a lot-by-lot basis.

Control measures for aquaculture drugs used during the holding of live fish (e.g., lobster pounds) can include controlled application of animal drugs in a manner consistent with:

  1. The established withdrawal times;
  2. The labeled instructions for use;
  3. Extra-label use of FDA-approved drugs, under a veterinarian's supervision in accordance with FDA regulations and guidelines;
  4. The conditions specified in the FDA "low regulatory priority aquaculture drug" list;
  5. The conditions of an INAD application.
(FDA, 1998).

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FDA Guidelines

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FDA approved aquaculture drugs

FDA approved aquaculture drugs with their approved sources, species and withdrawal times are listed below. Additional details on conditions of use (e.g., disease conditions and dosage levels) can be obtained from: the Code of Federal Regulations as cited below; the labeling for the product; the FDA Center for Veterinary Medicine; or "Guide to Drug, Vaccine, and Pesticide Use in Aquaculture," Texas Agricultural Extension Service, Publication B-5085 (FDA, 1998).

Formalin solution, supplied by Natchez Animal Supply Co., Natchez, MS or Argent Laboratories, Redmond, WA, may only be used in salmon, trout, catfish, largemouth bass, and bluegill for the treatment of protozoa and for control of fungi of the family Saprolegniaceae on the eggs of salmon, trout and pike (esocids), (21 CFR 529.1030);

Formalin solution, supplied by Western Chemical, Inc., Ferndale, WA, may be used to control: external parasites on all fish species, external protozoan parasites on shrimp, and fungi of the family Saprolegniaceae on the eggs of all fish species, (21 CFR 529.1030);

Tricaine methanesulfonate (MS-222), supplied by Argent Laboratories, Redmond, WA, and Western Chemical, Inc., Ferndale, WA, may only be used in the families Ictaluridae (catfish), Salmonidae (salmon and trout), Esocidae (pike), and Percidae (perch). It may not be used within 21 d of harvest. In other fish and cold blooded animals the drug should be limited to use in hatcheries or laboratories, (21 CFR 529.2503);

Oxytetracycline, for feed use, supplied by Pfizer, Inc., may only be used in salmonids, catfish, and lobster. Withdrawal times are: marking in pacific salmon, 7 d; disease control in salmonids, 21 d; catfish, 21 d; lobster, 30 d (21 CFR 558.450). Oxytetracycline tolerance in the flesh is 2.0 ppm, (21 CFR 556.500).

Sulfamerazine, supplied by American Cyanamid, may only be used in trout. It may not be used within 21 d of harvest (21 CFR 558.582). Sulfamerazine tolerance in the flesh is zero, (21 CFR 556.660). Note: this product is currently not marketed.

Sulfadimethoxine/ormetoprim combination, supplied by Hoffmann-LaRoche, may only be used in salmonids and catfish. Withdrawal times are: salmonids, 42 d; catfish, 3 d (21 CFR 558.575). Sulfadimethoxine/ormetoprim combination tolerance in the flesh is 0.1 ppm for both drugs, (21 CFR 556.640).

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FDA low regulatory priority aquaculture drugs (FDA, 1998)

FDA's Center for Veterinary Medicine has identified a number of "low regulatory priority aquaculture drugs." The following list identifies these compounds and provides their indicated use and usage levels. These compounds have undergone review by the Food and Drug Administration and have been determined to be new animal drugs of low regulatory priority. Additional information on this subject can be obtained from the FDA Center for Veterinary Medicine; or "Guide to Drug, Vaccine, and Pesticide Use in Aquaculture," Texas Agricultural Extension Service, Publication B-5085 (FDA, 1998).

Acetic Acid. Used in a 1000 to 2000 ppm dip for 1 to 10 min as a parasitide for fish.

Calcium Chloride. Used to increase water calcium concentration to insure proper egg hardening. Dosages used would be those necessary to raise calcium concentration to 1-20 ppm CaCO3. Used up to 150 ppm indefinitely to increase the hardness of water for holding and transporting fish in order to enable fish to maintain osmotic balance.

Calcium Oxide. Used as an external protozoacide for fingerlings to adult fish at a concentration of 2000 mg/L for 5 s.

Carbon Dioxide Gas. Used for anesthetic purposes in cold, cool, and warm water fish.

Fuller's Earth. Used to reduce the adhesiveness of fish eggs to improve hatchability.

Garlic (whole form). Used for control of helminth and sea lice infestations of marine salmonids at all life stages.

Hydrogen Peroxide. Used at 250-500 mg/L to control fungi on all species and life states of fish, including eggs.

Ice. Used to reduce metabolic rate of fish during transport.

Magnesium Sulfate. Used to treat external monogenic trematode infestations and external crustacean infestations in fish at all life stages. Used in all freshwater species. Fish are immersed in a 30,000 mg MgSO4/L and 7000 mg NaCl/L solutions for 5 to 10 min.

Onion (whole form). Used to treat external crustacean parasites, and to deter sea lice from infesting external surface of salmonids at all life stages.

Papain. Used in a 0.2% solution to remove the gelatinous matrix of fish egg masses in order to improve hatchability and decrease the incidence of disease.

Potassium Chloride. Used as an aid in osmoregulation; relieves stress and prevents shock. Dosages used would be those necessary to increase chloride ion concentration to 10-2000 mg/L.

Povidone Iodine. Used in a 100 ppm solution for 10 min as an egg surface disinfectant during and after water hardening.

Sodium Bicarbonate. Used at 142 to 642 ppm for 5 min as a means of introducing carbon dioxide into the water to anesthetize fish.

Sodium Chloride. Used in a 0.5% to 1.0% solution for an indefinite period as an osmoregulatory aid for the relief of stress and prevention of shock; and 3% solution for 10 to 30 min as a parasitide.

Sodium Sulfite. Used in a 15% solution for 5 to 8 min to treat eggs in order to improve their hatchability.

Thiamine Hydrochloride. Used to prevent or treat thiamine deficiency in salmonids. Eggs are immersed in an aqueous solution of up to 100 ppm for up to 4 h during water hardening. Sac fry are immersed in an aqueous solution of up to 1,000 ppm for up to 1 h.

Urea and Tannic Acid. Used to denature the adhesive component of fish eggs at concentrations of 15 g urea and 20 g NaCl/5L of water for approximately 6 min, followed by a separate solution of 0.75 g tannic acid/5L of water for an additional 6 min. These amounts will treat approximately 400,000 eggs.

FDA is unlikely to object to the use of low regulatory priority substances if the following conditions are met:

  1. The substances are used for the stated indications;
  2. The substances are used at the prescribed levels;
  3. The substances are used according to good management practices;
  4. The product is of an appropriate grade for use in food animals; and,
  5. There is not likely to be an adverse effect on the environment.

FDA's enforcement position on the use of these substances should not be considered an approval, nor an affirmation of their safety and effectiveness. FDA reserves the right to take a different position on the use of any or all of these substances at some time in the future.

Classification of these substances as new animal drugs of low regulatory priority does not exempt facilities from complying with other Federal, State, and local environmental requirements. For, example, facilities using these substances would still be required to comply with National Pollutant Discharge Elimination System (NPDES) requirements (FDA, 1998).

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FDA approved flesh color enhancers

Astaxanthin. Used as a feed additive at no more than 80 mg/kg (72 g/ton [907 kg]) of finished feed to enhance the pink to orange-red color of the flesh of salmonid fish (21 CFR 73.35).

Canthaxanthin. Used as a feed additive at no more than 80 ppm to enhance the pink to orange-red color of the flesh of salmonid fish (21 CFR 73.75).

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Analytical Procedures

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Acetic Acid

  • Fatty Acids (Volatile) in Seafood: Chromatographic Separation of C2 to C4 Saturated Fatty Acids (AOAC, 1995b).

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Chloramphenicol

  • Chloramphenicol ELISA (Neogen, 1997)

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Oxytetracycline

  • Chlortetracycline, Oxytetracycline and Tetracycline in Edible Animal Tissues: Liquid Chromatographic Method (AOAC, 1995a).
  • Oxytetracycline in Feeds (AOAC 1995c).

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Sodium sulfite

  • Alert for Sulfites Kit (Neogen, 1998)
  • Sulfites in foods, Optimized Monier-Williams method (AOAC, 1995j).
  • EM Quant Sulfitest Strips (Center Laboratories, Port Washington, New York; Nordlee et al., 1988).
  • Ion chromatography (Cooper et al., 1985).
  • Ion chromatography (Cooper et al., 1986).
  • Alkali titration method (Yamagata and Low, 1992a).
  • Colorimetric method (Yamagata and Low, 1992b).
  • Determination of sulphites and borates in imported frozen prawns, frozen shrimps and salted jelly fish (Ogawa et al., 1978).
  • Comparison of sulfite methods (DeWitt and Finne, 1985).

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Sodium chloride

  • See Chapter 1
  • Salt (chlorine as sodium chloride) in seafood: Volumetric method (AOAC, 1995g).
  • Salt (chlorine as sodium chloride) in seafood: Potentiometric method (AOAC, 1995h).
  • Salt (chlorine as sodium chloride) in seafood: Indicating strip method (AOAC, 1995i).
  • Salt content (Woyewoda et al., 1986b).

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Sulfadimethoxine

  • Sulfadimethoxine in Feeds: Colorimetric Method. (AOAC, 1995d).

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Sulfamerzine

  • Sulfonamides in Feeds: Spectrophotometric Method (AOAC, 1995e).
  • Sulfonamides in Feeds: Thin Layer Chromatographic Method (AOAC, 1995f).

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References

21 CFR 73.35. 1999. Astaxanthin. Title 21, part 73, subpart A, sec. 35, Code of Federal Regulations, U.S. Government Printing Office, Washington, DC.

21 CFR 73.75. 1999. Canthaxanthin. Title 21, part 73, subpart A, sec. 75, Code of Federal Regulations, U.S. Government Printing Office, Washington, DC.

21 CFR 529.1030. 1999. Formalin solution. Title 21, part 529, sec. 1030, Code of Federal Regulations, U.S. Government Printing Office, Washington, DC.

21 CFR 529.2503. 1999. Tricaine methanesulfonate. Title 21, part 529, sec. 2503, Code of Federal Regulations, U.S. Government Printing Office, Washington, DC.

21 CFR 556.500. 1999. Oxytetracycline. Title 21, part 556, subpart B, sec. 500, Code of Federal Regulations, U.S. Government Printing Office, Washington, DC.

21 CFR 556.600. 1999. Sulfadimethoxine. Title 21, part 556, subpart B, sec. 600, Code of Federal Regulations, U.S. Government Printing Office, Washington, DC.

21 CFR 556.640. 1999. Sulfadimethoxine. Title 21, part 556, subpart B, sec. 640, Code of Federal Regulations, U.S. Government Printing Office, Washington, DC.

21 CFR 558.450. 1999. Oxytetracycline. Title 21, part 558, subpart B, sec. 450, Code of Federal Regulations, U.S. Government Printing Office, Washington, DC.

21 CFR 558.575. 1999. Sulfadimethoxine, ormetoprim. Title 21, part 558, subpart B, sec. 575. Code of Federal Regulations, U.S. Government Printing Office, Washington, DC.

21 CFR 558.582. 1999. Sulfamerazine. Title 21, part 558, subpart B, sec. 582, Code of Federal Regulations, U.S. Government Printing Office, Washington, DC.

AOAC. 1995a. Chlortetracycline, oxytetracycline and tetracycline in edible animal tisues: Liquid chromatographic method. Sec. 23.1.17, Method 995.09. In Official Methods of Analysis of AOAC International, 16th ed., P.A. Cunniff (Ed.), p. 19-23. AOAC International, Gaithersburg, MD.

AOAC. 1995b. Fatty acids (volatile) in seafood: Chromatographic separation of C2 to C4 saturated fatty acids. Sec. 35.1.28, Method 945.52. In Official Methods of Analysis of AOAC International, 16th ed., P.A. Cunniff (Ed.), p. 13-14. AOAC International, Gaithersburg, MD.

AOAC. 1995c. Oxytetracycline in feeds. Sec. 5.3.19, Method 968.50. In Official Methods of Analysis of AOAC International, 16th ed., P.A. Cunniff (Ed.), p. 47-48. AOAC International, Gaithersburg, MD.

AOAC. 1995d. Sulfadimethoxine in feeds: Colorimetric method. Sec. 5.1.48, Method 970.88. In Official Methods of Analysis of AOAC International, 16th ed., P.A. Cunniff (Ed.), p. 23-24. AOAC International, Gaithersburg, MD.

AOAC. 1995e. Sulfonamides in feeds: Spectrophotometric method. Sec. 5.1.53, Method 974.46. In Official Methods of Analysis of AOAC International, 16th ed., P.A. Cunniff (Ed.), p. 27. AOAC International, Gaithersburg, MD.

AOAC. 1995f. Sulfonamides in feeds: Thin layer chromatographic method. Sec. 5.1.54, Method 974.47. In Official Methods of Analysis of AOAC International, 16th ed., P.A. Cunniff (Ed.), p. 27-28. AOAC International, Gaithersburg, MD.

AOAC. 1995g. Salt (chlorine as sodium chloride) in seafood: Volumetric method. Sec. 35.1.18, Method 937.09. In Official Methods of Analysis of AOAC International, 16th ed., P. Cunniff (Ed.), p. 7. AOAC International, Gaithersburg, MD.

AOAC. 1995h. Salt (chlorine as sodium chloride) in seafood: Potentiometric method. Sec. 35.1.19, Method 976.18. In Official Methods of Analysis of AOAC International, 16th ed., P. Cunniff (Ed.), p. 8. AOAC International, Gaithersburg, MD.

AOAC. 1995i. Salt (chlorine as sodium chloride) in seafood: Indicating strip method. Sec. 35.1.20, Method 976.19. In Official Methods of Analysis of AOAC International, 16th ed., P. Cunniff (Ed.), p. 8. AOAC International, Gaithersburg, MD.

AOAC. 1995j. Sulfites in foods, optimized Monier-Williams method. Vol. 2, Ch. 47, Official Method 990.28, Sec. 47.3.43. In Official Methods of Analysis of AOAC, 16th ed. P. Cunniff (Ed.), p. 29-31. AOAC International, Gaithersburg, MD.

Cooper, P.L., Marshall, M.R., Gregory, J.F., and Otwell, W.S. 1985. Preliminary study on the use of ion chromatography to measure residual sulfite levels in shrimp. In Proceedings of the Tropical and Subtropical Fisheries Technical Conference, p. 141-147. Florida Sea Grant Program, University of Florida, Gainsville, FL.

Cooper, P.L., Marshall, M.R., Gregory, J.F., and Otwell, W.S. 1986. Ion chromatography for determining residual sulfite on shrimp. J. Food Sci. 51(4):924-927.

DeWitt, B.J. and Finne, G. 1985. A comparison of methods for determining sulfur dioxide in shrimp. In Proceedings of the Tropical and Subtropical Fisheries Technical Conference, p. 135-140. Florida Sea Grant Program, University of Florida, Gainsville FL.

FDA. 1998. Aquaculture drugs. Ch. 11. In Fish and Fishery Products Hazards and Controls Guide. 2nd ed., p. 115-132. Department of Health and Human Services, Public Health Service, Food and Drug Administration, Center for Food Safety and Applied Nutrition, Office of Seafood, Washington, DC.

Larocque, L., Schnurr, M., Sved, S., and Weninger, A. 1991. Determination of oxolinic acid residues in salmon muscle tissue by liquid chromatography with fluorescence detection. J. AOAC 74(4):608-611.

Munns, R.K., Holland, D.C., Royball, J.E., Storey, J.M., Long, A.R., Stehly, G.R., and Plakas, S.M. 1994. Gas chromatographic determination of chloramphenicol residues in shrimp: Interlaboratory study. J. AOAC. 77(3):596-601.

Neogen. 1997. Chloramphenicol ELISA Test Kit. http://www.neogen.com/chloram.html, Neogen Corporation, Lexington, KY.

Neogen. 1998. Alert for sulfites kit. Neogen Corporation, Lexington, KY.

Nordlee, J.A., Naidu, S.G., and Taylor, S.L. 1988. False positive and false negative reactions encountered in the use of sulfite test strips for the detection of sulfite-treated foods. J. Allergy Clin. Immunol. 81:537-541.

Ogawa, S., Toyoda, M., Ito, Y., and Iwaida, M. 1978. Determination of sulphites and borates in imported frozen prawns, frozen shrimps and salted jelly fish. Bull. National Institute of Hygienic Sciences 96:130-132.

Woyewoda, A.D., Shaw, S.J., Ke, P.J., and Burns, B.G. 1986b. Salt content. In Recommended Laboratory Methods for Assessment of Fish Quality. Canadian Technical Report of Fisheries and Aquatic Sciences No. 1448, p. 28-31. Fisheries and Oceans, Halifax, Nova Scotia.

Yamagata, M. and Low, L.K. 1992a. Determination of sulphur dioxide by Rankine method (Alkali titration method). In Laboratory Manual on Analytical Methods and Procedures for Fish and Fish Products, Katsutoshi Miwa and Su Ji Lim (Eds.), D-9.1 to D-9.5. Marine Fisheries Research Department, Southeast Asian Fisheries Development Center.

Yamagata, M. and Low, L.K. 1992b. Determination of sulphur dioxide by Rankine method (Colorimetric method). In Laboratory Manual on Analytical Methods and Procedures for Fish and Fish Products, Katutoshi Miwa and Su Ji Lim (Eds.), D-10.1 to D-10.6. Marine Fisheries Research Department, Southeast Asian Fisheries Development Center.