ANTIMICROBIAL AGENTS

    NEOMYCIN

    First draft prepared by
    Dr K.N. Woodward
    Veterinary Medicines Directorate
    Ministry of Agriculture, Fisheries and Food
    Addlestone, Surrey, United Kingdom

    1.   Explanation

    2.   Biological data
         2.1   Toxicological studies
               2.1.1   Special studies on genotoxicity

    3.   Comments

    4.   Evaluation

    5.   References

    1.  EXPLANATION

         Neomycin is an aminoglycoside antibiotic that was previously
    evaluated at the forty-third meeting of the Committee (Annex 1,
    reference 113). At that time the Committee established a temporary ADI
    of 0-30 µg/kg bw based on the NOEL of 6 mg/kg bw per day for
    ototoxicity in a 90-day study on the guinea-pig and a safety factor of
    200. The ADI was made temporary in view of deficiencies in the
    genotoxicity data.

         The  in vitro genotoxicity data available at the forty-third
    meeting indicated that neomycin causes chromosomal aberrations, but
    only a limited number of studies were available and these had been
    poorly performed.

         This monograph addendum summarizes the data that have become
    available since the previous evaluation.

    2.  BIOLOGICAL DATA

    2.1  Toxicological studies

    2.1.1  Special studies on genotoxicity

         The results of the further genotoxicity studies with neomycin are
    summarized in Table 1.

         Neomycin was negative in the Ames  Salmonella typhimurium
    reverse mutation assay, although the maximum concentration used was
    limited to 75 µg/plate, owing to cytotoxicity. Similarly, a negative
    result was obtained in a reversion assay with  Escherichia coli
    WP2 uvrA, but again the maximum concentration was limited by
    cytotoxicity to 75 µg/plate. However, in a test for point mutations
    using Chinese hamster ovary cells (HGPRT locus), negative results were
    obtained with concentrations of up to 5000 µg/ml. A negative result
    was obtained in a cytogenetics test in mice where animals were given
    repeated intraperitoneal doses of up to 200 mg/kg bw per day. No
    studies were presented to show that neomycin distributes to bone
    marrow, but aminoglycosides are widely distributed in the body
    following absorption and it is highly likely, taking into account
    vascular perfusion of bone marrow, that the drug reached the target
    cells.

         The data indicate that neomycin is not genotoxic.

        Table 1.  Results of genotoxicity studies on neomycin
                                                                                                             

    Test system            Test object                 Concentration       Results       Reference
                                                                                                             

    Reverse                Salmonella typhimurium      0.93-75             -             Mayo et al.,
      mutation1            TA97A, TA98, TA100,         µ/plate                           1995
                           TA1535

                           Escherichia coli            0.93-75             -             Mayo et al.,
                           WP2 uvrA                    µg/plate                          1995

    Forward                Chinese hamster             0-5000              -             Mayo &
      mutation1            ovary cells,                µg/ml                             Aaron, 1995a
                           HGPRT locus

    In vivo                mouse bone                  0-200/250           -             Mayo &
     cytogenetics test     marrow                      mg/kg bw                          Aaron, 1995b
                                                       per day
                                                                                                             

    1    with and without rat liver metabolic activation (S9)
    
    3.  COMMENTS

         The new data on genotoxicity considered by the Committee
    consisted of the results of a reverse mutation assay using  Salmonella
     typhimurium and  Escherichia coli, a forward mutation assay in
    Chinese hamster ovary cells, and an  in vivo bone marrow cytogenetic
    assay in mice. All gave negative results.

         The Committee concluded from these results that neomycin is not
    genotoxic.

    4.  EVALUATION

         The Committee established an ADI of 0-60 µg/kg bw, based on the
    NOEL of 6 mg/kg bw per day for ototoxicity in the guinea-pig and a
    safety factor of 100.

    5.  REFERENCES

    Mayo, J.K. & Aaron, C.S. (1995a). U-4567 (Neomycin Sulfate):
    Evaluation of U-4567 (Neomycin sulfate) in the ASA52/XPRT mammalian
    cell mutation assay with and without metabolic activation. Unpublished
    report No. 7228-95-125. Submitted to WHO by Pharmacia and Upjohn
    Company, Kalamazoo, MI, USA.

    Mayo, J.K. & Aaron, C.S. (1995b). U-4567 (Neomycin sulfate):
    Evaluation of U-4567 (Neomycin sulfate) in the acute test for chemical
    induction of chromosome aberration in mouse bone marrow cells
     in vivo. Unpublished report No. 7228-95-130. Submitted to WHO by
    Pharmacia and Upjohn Company, Kalamazoo, MI, USA.

    Mayo, J.K., Smith, A.L, & Aaron, C.S. (1995). Neomycin sulfate
    (U-4567): Evaluation of neomycin sulfate (U-4567) in the preincubation
    mutagenesis assay in bacteria (Ames Assay). Unpublished report
    No. 7228-94-133. Submitted to WHO by Pharmacia and Upjohn Company,
    Kalamazoo, MI, USA.
    

    See Also:
       Toxicological Abbreviations
       Neomycin (JECFA Food Additives Series 51)
       Neomycin (WHO Food Additives Series 34)
       NEOMYCIN (JECFA Evaluation)