U. S. Food and Drug Administration
Center for Food Safety and Applied Nutrition
FDA Prime Connection

FEDERAL REGISTER NOTICE Decomposition and Histamine for Seafood
 
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 DEPARTMENT OF HEALTH AND HUMAN SERVICES
 FOOD AND DRUG ADMINISTRATION
 
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 Decomposition and Histamine-Raw, Frozen Tuna and Mahi-Mahi;
 Canned Tuna; and Related Species; Revised Compliance Policy
 Guide; Availability
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 Notice.
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 SUMMARY: The Food and Drug Administration (FDA) is announcing
 the availability of revised Compliance Policy Guide (CPG) 7108.24,
 entitled ``Decomposition and Histamine-Raw, Frozen Tuna and
 Mahi-Mahi; Canned Tuna; and Related Species.'' Revised CPG 7108.24
 lowers the histamine level at which FDA may consider the fish
 subject to action under the Federal Food, Drug, and Cosmetic
 Act (the act) and states that the histamine defect action level
 (DAL) and the histamine action level (AL) now apply to raw,
 frozen tuna and mahi-mahi in addition to canned tuna. Furthermore,
 the revised CPG 7108.24 states that the AL also applies to related
 species of raw, frozen, and canned fish implicated in instances
 of histamine poisoning, such as bluefish, amberjack, and mackerel,
 in addition to tuna and mahi-mahi. Additionally, for these related
 species, levels of histamine less than the AL may be considered
 as evidence of decomposition on a case-by-case basis when supported
 by additional scientific data. The title of the revised CPG
 reflects these changes.
 
 DATES: Written comments by September 5, 1995.
 
 ADDRESSES: Submit written requests for single copies of CPG
 7108.24, ``Decomposition and Histamine-Raw, Frozen Tuna and
 Mahi-Mahi and Canned Tuna; and Related Species,'' and Laboratory
 Information Bulletin no. 3794 to the Director, Office of Constituent
 Operations, Industry Activities Staff (HFS-565), Food and Drug
 Administration, rm. 5827, 200 C St. SW., Washington, DC 20204.
 Send two self-addressed adhesive labels to assist that office
 in processing your requests. Submit written comments on CPG
 7108.24, ``Decomposition and Histamine-Raw, Frozen Tuna and
 Mahi-Mahi; Canned Tuna; and Related Species,'' to the Dockets
 Management Branch (HFA-305), Food and Drug Administration, rm.
 1-23, 12420 Parklawn Dr., Rockville, MD 20857. Requests and
 comments should be identified with the docket number found in
 brackets in the heading of this document. A copy of revised
 CPG 7108.24, ``Decomposition and Histamine-Raw, Frozen Tuna
 and Mahi-Mahi; Canned Tuna; and Related Species,'' the Official
 Methods of Analysis of the Association of Official Analytical
 Chemists 15th Ed. (1990), section 977.13, and Laboratory Information
 Bulletin no. 3794, and received comments are available for public
 examination in the Dockets Management Branch between 9 a.m.
 and 4 p.m., Monday through Friday.
 
 FOR FURTHER INFORMATION CONTACT: Mary I. Snyder, Office of Seafood
 (HFS-416), Center for Food Safety and Applied Nutrition, Food
 and Drug Administration, 200 C St. SW., Washington, DC 20204,
 202-418-3160.
 
 SUPPLEMENTARY INFORMATION: Histamine is a chemical compound
 that forms postmortem in the muscle of scombroid fish, such
 as tuna, and in other species, such as mahi-mahi, by the action
 of certain bacteria that are common in fish. Bacteria that have
 the ability to form histamine do so by the decarboxylation of
 L-histidine, an amino acid found in the fish muscle. The decarboxylation
 reaction is catalyzed by an enzyme, histidine decarboxylase,
 produced by the bacteria. Fish species that are particularly
 vulnerable to the development of histamine are those with high
 levels of free L-histidine in their muscle tissues. Additional
 histidine may be released during decomposition and spoilage
 by proteolysis, whereby the protein structure is degraded, and
 amino acids are liberated (Ref. 1). The level of histamine produced
 in scombroid or other histidine-containing fish by these processes
 serves as an indicator of the decomposition that has occurred.
 When present at higher levels, histamine represents a health
 hazard. Therefore, FDA uses histamine to indicate that these
 fish are adulterated within the meaning of section 402(a)(1)
 and (a)(3) of the act (21 U.S.C. 342(a)(1) and (a)(3)).
 
    In the fishing industry, decomposition and bacterial histamine
 production are controlled primarily by the use of low temperature
 storage (Ref. 2). Significant decomposition and histamine formation
 can be avoided by good fish handling practices including icing
 or rapid immersion of the catch in water chilled to -1 degs.C (30
 degs.F), followed by uninterrupted frozen storage. Under high temperature
 storage conditions, histamine may form before other indicators
 of decomposition are evident, especially the odor and appearance
 of decomposed fish (Ref. 3).
     Histamine also may form during low temperature storage conditions.
 However, in low temperature storage, the rate of histamine formation
 is slower, and it is usually accompanied by the typical odor
 of decomposition. Research sponsored by the Department of Health
 and Human Services has suggested that freezing may be more damaging
 to histamine-forming bacteria than it is to nonhistamine producing
 spoilage bacteria (Ref. 4).
     Canned fish is frequently prepared from fish preserved by
 frozen storage before delivery to canneries. These fish are
 thawed before processing and are subjected to additional handling
 that may result in histamine levels in canned fish being somewhat
 higher than the levels observed in raw, freshly caught fish.
     Histamine is generally not uniformly distributed in a decomposed
 fish. A level of less than 50 parts per million (ppm) in one
 section may accompany a level in excess of 1,000 ppm elsewhere
 in the same fillet (Ref. 3). The anterior section of an individual
 fish generally is higher in histamine content than the posterior
 section, because the intestine, which is located in the forward
 end, is apparently the major source of the
 
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 bacteria responsible for histamine formation. Postmortem disintegration
 of the intestine releases the microbial contents of the intestine
 which contaminate the anterior muscle tissue, making these sites
 particularly vulnerable to an accumulation of the amine (Refs.
 5 and 6). The preponderance of scientific evidence demonstrates
 that the presence of histamine equal to or greater than 50 ppm,
 in a sample, is evidence that the fish is in a state of decomposition
 (Refs. 3, 5, and 6).
 
 Defect Action Level for Decomposition
 
     Results of research conducted in the 1970's by FDA in cooperation
 with major universities, industry research associations, individual
 canners, and the National Marine Fisheries Service demonstrate
 that histamine levels in freshly caught tuna and mahi-mahi are
 less than 1 ppm. Acceptable commercial fish generally contain
 about 5 ppm and rarely as much as 20 ppm histamine (Ref. 3).
 In a notice published in the Federal Register of September 14,
 1982 (47 FR 40487), FDA stated that histamine levels in tuna
 that are judged to be of acceptable quality, based on organoleptic
 and physical analyses, are on the order of 10 to 20 ppm. FDA
 data from 1990 to 1992 show that the average histamine levels
 in acceptable commercial raw frozen fish (number of samples
 in parentheses) are 2 ppm for mahi-mahi (4), 4 ppm for albacore
 tuna (7), 2 ppm for yellowfin tuna (10), and 2 ppm for skipjack
 tuna (10) (Ref. 3). Other investigators also have reported that
 raw freshly caught scombroid fish contain very little histamine
 (Refs. 5 and 6).
     FDA conducted workshops in 1974 and 1976 in association
 with the Tuna Research Foundation. Test packs of canned tuna
 were prepared by the industry and classified by FDA experts
 using organoleptic evaluation. The average levels of histamine
 in the packs of canned tuna (numbers of cans in parentheses)
 found to be acceptable by organoleptic evaluation were 22 ppm
 for albacore (36), 12 ppm for skipjack (112), and 11 ppm for
 yellowfin (82). The average histamine level for all 230 samples
 was 13 ppm. These tuna packs were not authentic packs but confirmed
 that commercially canned tuna of acceptable quality does not
 contain high levels of histamine. Similarly, commercially canned
 tuna collected from retail stores, in a survey conducted in
 1981, was found to contain an average of approximately 6 ppm
 histamine (Ref. 3).
     The provisions of the current CPG 7108.24 announced in the
 September 14, 1982, notice, established a DAL of 200 ppm histamine
 for canned albacore, skipjack, and yellowfin tuna. The agency
 also stated that it would consider regulatory action against
 any canned tuna found to contain between 100 and 200 ppm histamine
 when a second indicator of decomposition (e.g., spoilage odors
 or honeycomb formation) is present.
     Since the studies on which the previous histamine DAL was
 based were conducted, the analytical methodology available for
 determination of histamine to 5 ppm levels has become standard
 practice. The official method for histamine detection published
 in 1977 (Ref. 7) was refined in 1993 (Ref. 8). The 1993 methodology
 has successfully undergone collaborative evaluation and testing.
 Refinement in the methodology for histamine determination and
 experience in using the methodology have made the determination
 of 50 ppm histamine levels a routine practice.
     Given the findings of these studies (Refs. 3, 5, and 6);
 the research that shows that the histamine levels in freshly
 caught fish are less than 2 ppm; the fact that commercially
 canned tuna classified as acceptable by FDA averages 6 ppm histamine;
 and the fact that levels at or above 50 ppm are only found in
 samples classified as decomposed by FDA organoleptic expert
 examination, the presence of 50 ppm histamine is evidence that
 raw, frozen, or canned tuna, and raw or frozen mahi-mahi, are
 in a state of decomposition. See United States v. 1,200 Cases,
 Pasteurized Whole Eggs, 339 F. Supp. 131, 137 (N.D. Ga. 1972).
 Therefore, when 50 ppm or more histamine is found in these types
 of fish, the agency may recommend regulatory action against
 the fish under section 402(a)(3) of the act.
     In the past two decades both industry and government have
 used organoleptic analysis of volatile odors for the detection
 of decomposition in raw and thermally processed fishery products.
 This analytical technique is acquired through extensive training
 and experience on samples and requires the analyst be periodically
 standardized in the application and performance of the analytical
 technique. However, organoleptic analysis is not quantifiable,
 and its application to stored and thermally processed commercial
 products, such as canned tuna, is difficult because the usual
 odors of decomposition found in raw product are often removed
 or altered during thermal processing. Unlike odors of decomposition,
 nonvolatile spoilage compounds such as histamine remain in the
 product and can be reliably measured by chemical analysis (Ref.
 3). Therefore, confirmatory organoleptic examination for decomposition
 in regulatory samples would not be necessary when histamine
 levels at or above 50 ppm are detected by chemical analysis.
     Although the agency intends to use this DAL in deciding
 whether to recommend regulatory action, it does not consider
 that the fact that a fish or fishery product has a histamine
 level below 50 ppm establishes that the fish or fishery product
 is acceptable. Other spoilage mechanisms are possible that do
 not result in the formation of histamine. Thus a finding of
 histamine levels between 20 and 50 ppm should be viewed as indicating
 that the fish or fishery product has deteriorated and should
 cause a producer to further evaluate or test the product.
 
 Histamine Formation in Species Other Than Tuna and Mahi-Mahi
 
    The agency's use of histamine level as a reliable indicator
 of decomposition is based primarily on agency experience with
 tuna and mahi-mahi. However, other species have been implicated
 in a significant number of incidents of histamine poisoning.
 These other species also contain high levels of free L-histidine
 in their muscle tissue and are known to form histamine as they
 decompose. Therefore, on a case-by-case basis, when these other
 species contain levels of histamine equal to or greater than
 50 ppm, the agency may determine that these fish are decomposed
 particularly when such a judgment is supported by other scientific
 data, including the presence of other amines associated with
 decomposition in these fish.
 
 Action Level for Health Hazard
 
     In addition to being an indicator of decomposition, when
 ingested at sufficiently high levels histamine causes scombroid
 poisoning. The term ``scombroid fish poisoning'' developed because
 fish of the families Scombridae and Scomberesocidae are commonly
 implicated in instances of histamine poisoning deriving from
 advanced stages of decomposition in these fish. Tuna and mackerel
 are most frequently involved in instances of histamine poisoning,
 but this fact is attributable, in part, to the large amounts
 of these species that are consumed worldwide (Ref. 9).
     Nonscombroid fish, such as mahi-mahi (Coryphaena hippurus),
 is also involved in histamine poisoning. Bluefish (Pomatomus
 saltatrix) has been responsible for several scombroid poisoning
 outbreaks in the United States
 
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 and has caused at least one outbreak in Australia. Pink salmon,
 redfish, yellowtail, marlin, and amberjack have also been implicated
 in scombroid poisoning outbreaks that have occurred in the United
 States. Outside the United States, pilchards, herring, anchovies,
 bluefish, and sardines have been involved in a number of cases.
 Sardines and pilchards have become a major source of histamine
 poisoning in Great Britain. Japan had an outbreak associated
 with black marlin, and anchovies have been implicated in single
 incidents in Japan, the United States, and Great Britain (Ref.
 9).
     From 1977 to 1981 there were 68 outbreaks of scombroid poisoning
 involving 461 illnesses (Ref. 10). In March 1980, the Centers
 for Disease Control and Prevention reported that mahi-mahi accounted
 for 40 percent of the scombroid poisoning outbreaks reported
 in the United States. Since 1980, FDA has placed most shipments
 of mahi-mahi offered for entry into the United States on automatic
 detention because of the frequent occurrence of histamine levels
 exceeding 500 ppm (Ref. 11).
     Histamine is a poisonous or deleterious substance under
 section 402 (a)(1) of the act because, when ingested at sufficiently
 high levels, it is known to cause scombroid poisoning (Ref.
 12). In the September 14, 1982, notice, the agency established,
 on an interim basis, an AL of 500 ppm histamine in canned tuna
 (47 FR 40487). At this level, the agency considers histamine
 to present a hazard to public health. The agency is not changing
 the 500 ppm AL at this time because the threshold toxic dose
 of histamine is not known. However, the action level for canned
 tuna of 500 ppm will also apply to other species of raw, frozen,
 and canned fish, such as mahi-mahi, bluefish, amberjack, and
 mackerel, all fish that have been implicated in histamine poisoning
 outbreaks. Furthermore, the presence of other amine decomposition
 products in fish may have a synergistic effect on histamine
 toxicity. This synergism may dramatically lower the threshold
 toxic dose (Refs. 9 and 10).
    Therefore, FDA is revising its histamine policy and announcing
 the availability of revised CPG 7108.24 ``Decomposition and
 Histamine-Raw, Frozen Tuna and Mahi-Mahi; Canned Tuna; and Related
 Species,'' which: (1) Includes a lower histamine DAL for decomposition,
 50 ppm histamine rather than 100 ppm; (2) extends the application
 of the DAL of 50 ppm (5 mg per 100g) histamine for decomposition
 to raw and frozen tuna and mahi-mahi; (3) eliminates the provision
 that findings of less than 200 ppm histamine need to be confirmed
 by organoleptic evaluation; (4) states that, on a case by case
 basis, histamine levels equal to or greater than 50 ppm, but
 less than 500 ppm, may be used as evidence of decomposition
 in other species commonly implicated in instances of histamine
 poisoning when supported by other scientific data; and (5) states
 that the AL of 500 ppm histamine now applies to other species
 of fish that have been implicated in histamine poisoning outbreaks.
 
 Title of Revised CPG 7108.24
 
     The title of CPG 7108.24 ``Decomposition and Histamine in
 Canned Albacore, Skipjack, and Yellowfin Tuna'' has been changed
 to ``Decomposition and Histamine-Raw, Frozen Tuna and Mahi-Mahi;
 Canned Tuna; and Related Species'' to more accurately describe
 the contents of the revised CPG.
 
 References
 
     The following references have been placed on display in
 the Dockets Management Branch (address above) and may be seen
 by interested persons between 9 a.m. and 4 p.m., Monday through
 Friday.
     1. Eitenmiller, R. R., and S. C. DeSouza, ``Enzymatic Mechanisms
 for Amine Formation in Fish,'' in Seafood Toxins, edited by
 E. P. Ragelis, American Chemical Society, Washington, DC, pp.
 431-442, 1984.
     2. Behling, A. R., and S. L. Taylor , ``Bacterial Histamine
 Production as a Function of Temperature and Time of Incubation,''
 Journal of Food Science 47:1311-1314, and 1317, 1982.
     3. Memorandum from Division of Science and Applied Technology
 (HFS-425) to Division of Programs and Enforcement Policy (HFS-
 415), CFSAN, FDA, dated August 6, 1992.
     4. Baranowski, J. D., H. A. Frank, P. A. Brust, M. Chongsiriwatana,
 and R. J. Premaratne, ``Decomposition and Histamine Content
 in Mahi-Mahi (Coryphaena Hippurus),'' Journal of Food Protection
 53:217-222, 1990.
     5. Frank, H. A., D. H. Yoshinaga, and W-K. Nip, ``Histamine
 Formation and Honeycombing During Decomposition of Skipjack
 Tuna, Katsuwonus pelamis, at Elevated Temperatures,'' Marine
 Fisheries Review 43:9-14, 1981.
     6. Frank, H. A., and Yoshinaga, ``Histamine Formation in
 Tuna'' in Seafood Toxins, edited by E.P. Ragelis, American Chemical
 Society, Washington, DC, pp. 443-451, 1984.
     7. Staruszkiewicz, W. F., ``Fluorometric determination of
 Histamine in Tuna: Collaborative Study'' in Journal of the Association
 of Official Analytical Chemists 60 (5) pp. 1131-1136, 1977.
     8. Rogers, P. R., and W. F. Staruszkiewicz, ``Modification
 of GLC Method for Putrescine and Cadaverine and the Fluorometric
 Method for Histamine,'' Laboratory Information Bulletin no.
 3794, July 1993.
     9. Stratton, J. E., and S. L. Taylor, ``Scombroid Poisoning,''
 in Microbiology of Marine Food Products, edited by Ward, D.
 R., and C. Hackney, Van Nostrand Reinhold, New York, pp. 333-
 344, 1991.
     10. Taylor, S. L., ``Marine Toxins of Microbial Origin,''
 Food Technology 42(3):94-98, 1988.
     11. Regulatory Procedure Manual, part 9, Imports, Import
 Alert 16-05-``Automatic Detention of Mahi-Mahi Because of Histamine
 and Decomposition,'' August 14, 1991.
     12. Taylor, S. L., J. Y. Hui, and D. E. Lyons, ``Toxicology
 of Scombroid Poisoning,'' in  Seafood Toxins, edited by E. P.
 Ragelis, American Chemical Society, Symposium Series, no. 262,
 pp. 417-430, 1984.
    Interested persons may, on or before September 5, 1995, submit
 to the Dockets Management Branch (address above) written comments
 on the revised CPG 7108.24. Two copies of any comments are to
 be submitted, except that individuals may submit one copy. Comments
 are to be identified with the docket number found in brackets
 in the heading of this document. The revised CPG 7108.24 and
 received comments may be seen in the office above between 9
 a.m. and 4 p.m., Monday through Friday.
 
    Dated: July 26, 1995.
 
 Gary Dykstra,
 Acting Associate Commissioner for Regulatory Affairs.
 
 YFR Doc. 95-19059 Filed 8-2-95; 8:45 am"
 
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