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.
See Also: Toxicological Abbreviations