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PMF 005-590 - Human Food Safety Letter

The contact information provided in this letter may no longer be valid due to the passage of time. If you have questions about any of the PMFs in development, please contact AskCVM@fda.hhs.gov.

February 9, 2004

GC 002287 C0001

Dr. Tom Flammang
Acting Director for Research
National Center for Toxicological Research
3900 NCTR Road
Jefferson, AR 72079

Dear Dr. Flammang:

We refer to your submission dated May 16, 1996, to the General Correspondence file (GC 2287) providing for the use of copper in channel catfish via immersion. The submission contained a study report entitled, “Accumulation of copper in edible muscle of channel catfish (Ictalurus punctatus) following exposure to water borne copper sulfate (Technical report no. E06897.01). We have completed our review of your submission and have the following comments.

The report describes a well-conducted GLP study. The data support the conclusion that copper does not accumulate in the muscle of channel catfish exposed to copper sulfate. In addition, the results of the study support the conclusion that copper does not accumulate in the edible tissue of fin fish exposed to copper sulfate. We conclude that the human food safety requirements for copper sulfate in all fin fish have been satisfied for toxicology including human intestinal microflora issue, residue chemistry, and microbial food safety with respect to resistance. We are providing a human food safety technical section complete section for copper sulfate in all fin fish.

Technical Section Complete

The Division of Human Food Safety considers the human food safety technical section to be complete for the purpose of recommending approval of a New Animal Drug Application for copper sulfate in all fin fish. A tolerance, regulatory method, and withdrawal time are not needed for fin fish treated with copper sulfate because copper does not accumulate in the edible tissue of fin fish exposed to copper sulfate.

A final decision on the approval of the application will be made when all the data for all technical sections are viewed as a whole and it is determined that:

  1. the information contained in and referenced by the application supports approval;
  2. the GMP status of each manufacturing facility is current and satisfactory;
  3. if a claim for categorical exclusion was made, conditions for the categorical exclusion are still applicable;
  4. there is no new information that would preclude the approval of the application.

FOI Summary

The following language can be used for the human food safety section of the FOI summary when an NADA is filed:

4. Human Safety

The human food safety of the use of copper sulfate in fin fish has been demonstrated by data from the public literature, a definitive depletion study in channel catfish, and a supporting depletion study in tilapia. All of the data show that copper does not accumulate in the edible tissue of fin fish exposed to copper sulfate. Therefore, a tolerance, regulatory method, and withdrawal time are not needed for fin fish treated with copper sulfate.

Public Literature

The public literature was reviewed to find references on copper accumulation in the edible tissue of fish as a result of exposure to copper sulfate. Selected references are listed below. The data indicate that copper does not accumulate in the edible tissues of fin fish as a result of exposure to copper sulfate but does accumulate in the liver and other inedible organs of fin fish. Also, the data suggest that copper accumulates in shellfish bodies.

  1. Benoit, D. Chronic Effects of Copper on Survival, Growth, and Reproduction of the Bluegill (Lepomis macrochirus). Trans. Amer. Fish. Soc. 1975. 2:353-358.
  2. Phillips, G. and R. Russo. Metal Bioaccumulation in Fishes and Aquatic Invertebrates: A Literature Review. U.S. Environ. Protection Agency, EPA-600/3-78-103. 1978. 100p.
  3. Miller, P., Munkittrick, K., and Dixon, D. Relationship between Concentrations of Copper and Zinc in Water, Sediment, Benthic Invertebrates, and Tissues of White Sucker at Metal-Contaminated Sites. Can. J. Fish. Sci. 1992. 49:978-984.
  4. Wilson, D., Finlayson, B., and Morgan, N. Copper, Zinc, and Cadmium Concentrations of Resident Trout Related to Acid-Mine Wastes. Calif. Fish and Game. 1980. 67(3):176-186.
  5. Anderson, R. Concentration of Cadmium, Copper, Lead, and Zinc in Six Species of Freshwater Clams. 1977. Bull. Env. Contam. Tox. 18(4):492-496.
  6. Ray, S., McLeese, D., and Peterson, M. Accumulation of Copper, Zinc, Cadmium and Lead from Two Contaminated Sediments by Three Marine Invertebrates. 1981. Bull. Env. Contam. Tox. 26:315-322.
  7. Heath, A. Change in Tissue Adenylates and Water Content of Bluegill Exposed to Copper. 1984. J. Fish. Biol. 24:299-309.

Definitive Residue Study in Channel Catfish

A definitive residue study in channel catfish was completed according to Good Laboratory Practices (GLP’s) as described under 21 CFR 58. The in-life portion of the study entitled “Accumulation of Copper in Edible Muscle of Channel Catfish (Ictalurus punctatus) following Exposure to Water Borne Copper Sulfate” (Technical Report No. E06897.01) was conducted at the Harry K. Dupree Stuttgart National Aquaculture Research Center, USDA, ARS in Stuttgart, Arkansas. Quality assurance oversight was provided by the Quality Assurance Unit of the National Center for Toxicological Research (NCTR), Jefferson, Arkansas. Channel Catfish were exposed to 1.7, 2.7, or 3.6 mg/L copper sulfate continuously for 10 weeks. Muscle and liver were sampled and analyzed for copper content at the study start and at two-week intervals throughout the 10 week exposure period. Copper levels increased significantly in the inedible tissue, liver, after 2 weeks of exposure. There was no significant increase in the copper content of muscle collected from the catfish exposed to copper sulfate.

Supporting Residue Study in Tilapia

A supporting residue study in tilapia was completed by Dr. Tom Bell (formerly of CVM/HFV-130). The in-life portion of the study entitled “Copper Residues in the Edible Tissues of market-Size Tilapia (Oreochromis niloticus) Exposed to Therapeutic Copper Sulfate in Simulated Worst-Case Conditions” was completed at the University of Maryland, Aquatic Pathobiologic Center, Baltimore, Maryland. The analytical work was performed at the U.S. Department of Agriculture, Beltsville Human Nutrition Research Center, Beltsville, Maryland. Tilapia were exposed to 365 ppb copper for 9 days. Muscle and liver were sampled and analyzed for copper content on days 0, 3, 6, and 9 post-dosing. Copper levels did not significantly increase in either liver or muscle of the tilapia exposed to copper sulfate.
Future correspondence regarding this submission should be identified by the submission’s correspondence date and our file number, GC 2287 C0001. If you have any questions regarding this correspondence, please contact Dr. Julia A. Oriani, at (301) 827-6976.

Sincerely,

/s/
Mark M. Robinson, Ph.D., DVM
Director, Division of Human Food Safety
Office of New Animal Drug Evaluation
Center for Veterinary Medicine

 
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