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.