INTERNATIONAL PROGRAMME ON CHEMICAL SAFETY
WORLD HEALTH ORGANIZATION
TOXICOLOGICAL EVALUATION OF CERTAIN
VETERINARY DRUG RESIDUES IN FOOD
WHO FOOD ADDITIVES SERIES 34
Prepared by:
The forty-third meeting of the Joint FAO/WHO Expert
Committee on Food Additives (JECFA)
World Health Organization, Geneva 1995
The International Programme on Chemical Safety (IPCS) is a
joint venture of the United Nations Environment Programme, the
International Labour Organisation, and the World Health Organization.
The main objective of the IPCS is to carry out and disseminate
evaluations of the effects of chemicals on human health and the
quality of the environment. Supporting activities include the
development of epidemiological, experimental laboratory, and risk-
assessment methods that could produce internationally comparable
results, and the development of manpower in the field of toxicology.
Other activities carried out by the IPCS include the development of
know-how for coping with chemical accidents, coordination of
laboratory testing and epidemiological studies, and promotion of
research on the mechanisms of the biological action of chemicals.
CONTENT
Preface
ß-Adrenoceptor-blocking agent
Carazolol
Antimicrobial agents
Dihydrostreptomycin
Streptomycin
Enrofloxascin
Gentamicin
Neomycin
Spiramycin
Tranquillizing agent
Azaperone
Annexes
Annex 1 Reports and other documents
resulting from previous meetings
of the Joint FAO/WHO Expert
Committee on Food Additives
Annex 2 Abbreviations used in the
Monographs
Annex 3 Joint FAO/WHO Expert Committee
on Food Additives, Geneva,
15-24 November 1994
Annex 4 Recommendations on compounds
on the agenda
Annex 5 Corrigenda
PREFACE
The monographs contained in this volume were prepared by the
forty-third Joint FAO/WHO Expert Committee on Food Additives (JECFA),
which met in Geneva, Switzerland, 15-24 November 1994. These
monographs summarize the safety data on selected veterinary drug
residues reviewed by the Committee. The data reviewed in these
monographs form the basis for acceptable daily intakes (ADIs)
established by the Committee.
The forty-third report of JECFA will be published by the World
Health Organization in the WHO Technical Report Series. The
participants in the meeting are listed in Annex 3 of the present
publication and a summary of the conclusions of the Committee is
included as Annex 4.
Residue monographs on the veterinary drugs that were evaluated at
the forty third meeting of JECFA will be issued separately by FAO as
FAO Food and Nutrition Paper No. 41/7. These toxicological monographs
should be read in conjunction with the residue monographs and the
report.
Reports and other documents resulting from previous meetings of
JECFA are listed in Annex 1.
JECFA serves as a scientific advisory body to FAO, WHO, their
Member States, and the Codex Alimentarius Commission, primarily
through the Codex Committee on Food Additives and Contaminants and the
Codex Committee on Residues of Veterinary Drugs in Foods, regarding
the safety of food additives, residues of veterinary drugs, naturally
occurring toxicants, and contaminants in food. Committees accomplish
this task by preparing reports of their meetings and publishing
specifications or residue monographs and toxicological monographs,
such as those contained in this volume, on substances that they have
considered.
The toxicological monographs contained in this volume are based
upon working papers that were prepared by Temporary Advisers. A
special acknowledgement is given at the beginning of each monograph to
those who prepared these working papers.
Many proprietary unpublished reports are referenced. These were
voluntarily submitted to the Committee by various producers of the
veterinary drugs under review and in many cases these reports
represent the only safety data available on these substances. The
Temporary Advisers based the working papers they developed on all the
data that were submitted, and all these studies were available to the
Committee when it made its evaluations.
From 1972 to 1975 the toxicology monographs prepared by JECFA
were published in the WHO Food Additives Series; after 1975 this
series was available in the form of unpublished WHO documents provided
upon request to the Organization. WHO Food Additives Series No. 20,
which was prepared by the twenty-ninth Committee in 1985, through WHO
Food Additives Series No. 24, which was prepared by the thirty-third
Committee in 1988, were published by the Cambridge University Press.
Beginning with WHO Food Additives Series No. 25, which was prepared by
the thirty-fourth Committee, WHO has been producing these volumes as
priced documents.
The preparation and editing of the monographs included in this
volume have been made possible through the technical and financial
contributions of the Participating Institutions of the International
Programme on Chemical Safety (IPCS), which supports the activities of
JECFA. IPCS is a joint venture of the United Nations Environment
Programme, the International Labour Organisation, and the World Health
Organization, which is the executing agency. One of the main
objectives of the IPCS is to carry out and disseminate evaluations of
the effects of chemicals on human health and the quality of the
environment.
The designations employed and the presentation of the material in
this publication do not imply the expression of any opinion whatsoever
on the part of the organizations participating in the IPCS concerning
the legal status of any country, territory, city, or area or its
authorities, or concerning the delimitation of its frontiers or
boundaries. The mention of specific companies or of certain
manufacturers' products does not imply that they are endorsed or
recommended by those organizations in preference to others of a
similar nature that are not mentioned.
Any comments or new information on the biological or
toxicological data on the compounds reported in this document should
be addressed to: Joint WHO Secretary of the Joint FAO/WHO Expert
Committee on Food Additives, International Programme on Chemical
Safety, World Health Organization, Avenue Appia, 1211 Geneva 27,
Switzerland.
ANTIMICROBIAL AGENTS
ADIs based on in vitro experiments using relevant human gut
microflora to identify MICs were derived for some of the antimicrobial
agents that were reviewed. The equation used for deriving these ADIs
is based on Annex 5 of the report of the thirty-eighth meeting of the
Committee (Annex 1, reference 97), in which an equation was provided
for the derivation of temporary ADIs. At the forty-second meeting
(Annex 1, reference 110) the Committee concluded that this approach
could also be used for the establishment of final ADIs.
The upper limit of the ADI is derived as follows:
Concentration without
effect on human gut x Daily faecal bolus (g)
Upper limit of flora (µg/ml)
ADI (µg/bw) =
Fraction of
oral dose x Safety x Weight of human (60 kg)
bioavailable factor
The concentration without effect on human gut flora, the
fraction of oral dose bioavailable, and the safety factor may
vary, depending upon the circumstances relating to the particular
veterinary drug under consideration. The reasons for using particular
factors are given in the individual evaluations.
The average weight of the daily faecal bolus is known to vary
widely among individuals between 150 to greater than 400 g per day;
additionally, concentrations of substances in the rectum are greater
than in the more proximal portions of the colon. In the estimations
of the ADIs in this report, a very conservative estimate of 150 g was
selected for the weight of the daily faecal bolus.
The body weight was taken to be 60 kg in the calculations in
these evaluations.