IV.222 In conclusion, the European Communities submitted that almost all the arguments that were made above (paragraphs 4.151 to 4.209), especially the possible carcinogenic effects and the risks which might arise from an administration of hormones not in accordance with good veterinary practice, were equally applicable to animals.

IV.223 Canada argued that it emerged from the definition of sanitary measures in Annex A of the SPS Agreement that a sanitary measure was taken to protect human or animal life or health within the territory of the Member. The EC prohibition on the importation of hormone-treated beef did not protect the health or life of cattle in the territory of the European Community. Thus, the European Communities' references to animal health issues were irrelevant to this dispute and should be given no consideration. Moreover, Canada's complaint was limited to the nullification and impairment of benefits accruing to Canada pursuant to the WTO Agreements respecting market access for meat, and more specifically for beef. Canada exported livestock to the European Communities for breeding purposes only and, since this type of livestock was not treated with hormones for growth promotion, Canada's exports to the European Communities were not affected by the EC measures at issue.

(j) Article 5.4

IV.224 The European Communities noted that Article 5.4 stated that, in choosing the appropriate level of protection, Members "should ... take into account the objective of minimizing negative trade effects". An early draft of this provision required countries to consider the effect on trade of the level they chose, but in the final version of the text the mandatory language had been rejected. A comparison of Articles 5.2 and 5.3 of the SPS Agreement also made it clear that with respect to human health risks, economic factors were irrelevant to risk assessment or the determination of the appropriate measures to be used to protect against such risks.

(k) Article 5.5

IV.225 Canada recalled that Article 5.5 of the SPS Agreement required that "... each Member shall avoid arbitrary or unjustifiable distinctions in the levels it considers to be appropriate in different situations, if such distinctions result in discrimination or a disguised restriction on international trade". Canada claimed, however, that the EC level of sanitary protection for growth promoting hormones was significantly higher than the EC level for antimicrobial growth promoters and other veterinary drugs, resulting in discrimination and a disguised restriction on international trade.

IV.226 Canada noted that a veterinary drug was "[a]ny substance applied or administered to any food-producing animal, such as meat or milk producing animals, poultry, fish or bees, whether used for therapeutic, prophylactic, or diagnostic purposes, or for modification of physiological functions or behaviour".¹⁶¹ A large number of veterinary drugs were used in farm animals and could be categorized into a number of classes, including antimicrobials (e.g., antibiotics), anthelmintics, pesticides, antiprotozoals (e.g., coccidiostats) and hormones. The fate of these veterinary drugs within the animal body was highly variable. Some compounds were metabolized or eliminated quickly, while others, such as some antibiotics, were much more persistent. Hormones were only one type of veterinary drug used for growth promotion. Antimicrobial feed additives were also commonly used as growth promoters in a number of animal species, including cattle. Growth promoters such as ionophores (e.g., monesin) and non-ionophore antibiotics (e.g., avoparcin, carbadox, olaquindox) were used extensively as feed additives in all EC member States.¹⁶²

IV.227 Canada argued that the EC measures must be considered in the context of the European Communities' regulation of veterinary drugs in general. The European Communities regulated veterinary drugs under two schemes: products intended for therapeutic use or for the alteration of physiological function¹⁶³ and those added to feed for prophylaxis and growth promotion.¹⁶⁴ Canada noted that there appeared to be notable differences between the two schemes. Veterinary drugs governed by the Veterinary Medicines Directives were subject to authorization procedures and Maximum Residue Limit ("MRL") requirements¹⁶⁵ ("MRLs Regulation") and to the residues monitoring requirements.¹⁶⁶ This implies that there was an accepted level of risk in the use of each of these compounds. In contrast, veterinary drugs governed by the Feed Additives Directives did not appear to be subject to these provisions. MRLs were not established for these other products, despite the fact that they posed some human health risks. The three natural hormones at issue - oestradiol-17b, progesterone and testosterone - could only be used for therapeutic and zootechnical purposes in the European Communities. Their use was governed by the Veterinary Medicines Directives, and they were subject to the authorization procedures and MRL requirements set out in the EC MRLs Regulations, and the monitoring requirements set out in Directives 85/348/EEC and 96/23/EC.

IV.228 Canada indicated that the EC Veterinary Medicines Directives laid down rules for marketing authorization and distribution of veterinary medicinal products. An application for authorization required studies of toxicity, pharmacological properties, residues and their effects, and data on the emergence of resistant organisms in the case of products used for the prevention or treatment of infectious disease in animals. The Committee for Veterinary Medicinal Products¹⁶⁷ gave opinions on whether a particular medicinal product complied with the Directive's requirements.

IV.229 Canada stated that EC member States were obliged to take regulatory measures to control the distribution of veterinary drugs in accordance with the Veterinary Medicines Directives. Canada noted that, nonetheless, implementation differed among EC member States, with some permitting certain veterinary medicines for use in food animals to be available without prescription¹⁶⁸, while others made it subject to a prescription. There were also divergent views on when it was necessary for a veterinarian to administer a prescribed drug.¹⁶⁹ Although EC Directives dictated that only a veterinarian can administer the three natural hormones, it appeared that the European Communities did not extend that requirement to cover other drugs, such as general anaesthetics, narcotics or psychotropics.¹⁷⁰ In practice, farmers might be administering prescribed veterinary drugs without the veterinarian even seeing the animals being treated.¹⁷¹

IV.230 Canada noted that under the EC MRLs Regulations, no new veterinary medicinal product might be authorized for use in EC member States until a Community-wide MRL had been set, and MRLs for existing products were to be established before the end of 1997. All pharmacologically active substances considered must be entered into one of the annexes to the Regulation¹⁷², which were as follows:

(i) substances for which MRLs have been fixed;

(ii) substances not subject to MRLs;

(iii) substances for which provisional MRLs have been fixed;

(iv) substances for which no MRLs can be fixed.

IV.231 Substances were included in Annex II where, "... following an evaluation ... it appears that it is not necessary for the protection of public health to establish a maximum residue limit". For substances contained in Annex III, a provisional MRL had been established for a defined period of time "... provided that there are no grounds for supposing that residues of the substance concerned at the level proposed present a hazard to the health of the consumer". Substances were entered in Annex IV where it appeared that a MRL could not be established because residues of the substance, at whatever limit, in foodstuffs constituted a hazard to the health of the consumer. The administration of these substances were prohibited in the European Communities for use in food-producing species. Of the three natural hormones at issue in this dispute, only one appeared to have been considered under this Regulation, oestradiol-17b, which had been included in Annex II. The European Communities had decided that it need not be subject to a MRL.

IV.232 Canada indicated that the European Communities had established requirements for the examination of animals and fresh meat for the presence of veterinary drug residues¹⁷³ which, with respect to hormones, supplemented requirements¹⁷⁴ setting out rules on the detection and monitoring of substances having a hormonal or thyrostatic action. EC member States were required to test for the presence of veterinary drug residues under a "National Plan". EC Reference Laboratories and National Laboratories provided surveillance testing of meat samples. Where an examination of a sample revealed the presence of residues of prohibited substances or quantities of authorized substances exceeding the levels set by EC law or, in their absence, national levels, competent authorities were required to follow up with an investigation and appropriate measures. Canada added that as of 1 July 1997, Council Directive 96/23/EC, would replace the present legislation, setting out measures to monitor listed substances and groups of residues. This Directive appeared to broaden the scope of the repealed Directives "to cover other substances which are used in stockfarming to promote growth and productivity in livestock or for therapeutic purposes and which may prove dangerous to the consumer on account of their residues".¹⁷⁵

IV.233 Canada recalled that the European Communities regulated feed additives differently than other veterinary drugs. However, antimiciobial feed additives were among those animal husbandry drugs, called growth promoters, used for improving animal production without a primary therapeutic objective. Better weight gain and/or feed efficiency were the main goals.¹⁷⁶ Antimicrobial feed additives were antimicrobial compounds which changed the population of microorganisms in the alimentary tract of healthy animals, resulting in improved feed conversion efficiency and hence growth rate.¹⁷⁷ Hormones, in contrast, exerted their effects as chemical messengers which bound to specific receptors.¹⁷⁸

IV.234 There were a number of growth promoting antimicrobial compounds that were administered in the feed at low dose rates. These compounds could be sub-divided into categories of ionophore antibiotics (e.g., monesin, lasalocid), non-ionophore antibiotics (e.g., carbadox, avoparcin) and gut active growth promoters (e.g., probiotics, enzymes). The ionophore antibiotics altered digestion, whereas the non-ionophore antibiotics might favourably modify the quantity and quality of nutrients entering the body.¹⁷⁹ Coccidiostats were another group of antimicrobial feed additives used for prophylaxis purposes. Coccidiosis was a highly contagious infection of an animal caused by parasitic microbial organisms (i.e., protozoa) collectively known as coccidia. This disease affected mainly poultry, but also cattle, pigs, sheep and game birds. As many of the antimicrobial feed additives were fed to the animals throughout their lives, it was possible that other veterinary drugs would be administered in combination, or at the same time, as the feed additives were being administered.

IV.235 Antimicrobial agents were added to animal feeds for two purposes: (1) growth promotion, or (2) to cure or prevent outbreaks of disease. One EC scientist had indicated that "[i]t has been estimated that approximately one-third of all UK feeding stuffs contain medicinal compounds licensed for inclusion without a veterinary prescription, whilst only 5 per cent of feeds contain medicaments for therapeutic use".¹⁸⁰ The primary uses thus were for prophylaxis purposes, that is, to prevent disease outbreaks, or for growth promoting purposes.¹⁸¹

IV.236 Canada argued that the distinctions made between the EC regulatory schemes governing veterinary drugs on the one hand, and feed additives on the other, were anomalous.¹⁸² At a joint meeting of EC Commission DGIII and DGVI held under the auspices of the Scientific Committee on Animal Nutrition (SCAN)¹⁸³, one EC scientist had commented that:

"SCAN ... has seen certain benefits in following the MRL route in assuring consumer safety. Not least among these are the use of the MRL for establishing withdrawal periods for 70/524/EEC candidate compounds and for residues surveillance.


This is important now as the JECFA system makes no distinction between veterinary medicines and medicinal feed additives and it recently assessed two drugs, carbadox and olaquindox, currently regulated in the Community under 70/524/EEC and so not subject to MRLs under 2377/90. In doing so it established an MRL for carbadox and identified further work on olaquindox. (...) In viewing MRLs within the Community, it seems only sensible to view medicines as one distinct group - rather than to see them, as is currently the case, largely as therapeutics and feed additives - and to establish MRLs for all. This would introduce some degree of harmonisation on this front with the JECFA/Codex Alimentarius system.¹⁸⁴

Thus, Canada wondered whether residues in meat arising from the misuse or abuse of substances found in feed additives would be detected under the current EC regulatory scheme.

IV.237 Canada also claimed that the EC regulation of the six hormones at issue was also anomalous. In contrast to the prohibition imposed on the three synthetic hormones, some veterinary drugs such as ivermectin and benzylpenicillin were available over-the-counter without a prescription. Similarly, in comparison with the strict control maintained over the administration of the three natural hormones, many classes of prescription drugs might be administered by the farmer, in some instances without the veterinarian even seeing the animals being treated.

IV.238 The European Communities responded that Canada did not explain the strict conditions under which the use of the three natural hormones for therapeutic and zootechnical use was allowed in the European Communities. The three hormones might be administered only by a veterinarian, only by injection or vaginal spiral (to the exclusion of implantation) and only to farm animals which had been clearly identified. Such treatments must be registered by the veterinarian and these animals could not be slaughtered for meat production before a waiting period long enough to ensure that no residues were present in their meat. All these conditions ensured that the hormones were not administered improperly and that no residues of hormones, other than those naturally produced by the animals themselves, were present in the meat destined for human consumption. The JECFA itself had recognized the need for a clear distinction to be drawn between the use of hormones for therapeutic or zootechnical reasons and animal growth promotion. when it stated:

"The Committee recognized that certain hormonally active substances employed as growth promoters are used in animals for other purposes as well. The Committee concluded that residues left after the use of a drug for growth promotion should be considered separately from residues left after the use of that drug for other purposes, because in the latter case (a) the administration of the drug might be by a different route and (b) a different withdrawal period in conformity with good veterinary practice might first have to be established and observed. The Committee therefore did not consider residues of hormonally active drugs used for purposes other than growth promotion" (page 16, emphasis added).

IV.239 The European Communities indicated that the basic provisions in EC law which regulated, at European Community level, the additives in feedingstuffs was Council Directive 70/524/EEC¹⁸⁵ as subsequently amended. In general three types of additives might be used by EC member States in feedingstuffs: antibiotics, growth promoters, coccidiostats and other medicinal substances. The use of any of the three types of additives required advanced authorization by the EC Commission after consultation with the Standing Committee for Feedingstuffs. There were two types of authorizations:

(i) definitive authorization, in which case the additive was placed in Annex I of the Directive and might be used in all EC member States in accordance with the conditions fixed in the authorization; and


(ii) provisional authorization, in which case the additive was placed in Annex II of the Directive. A provisional authorization was valid for a maximum period of five years.

Among the conditions for granting of authorization, particular the European Communities drew attention to those stipulating that the substance must have a favourable effect on the characteristics of those feedingstuffs or on livestock production; that at the level permitted in feedingstuffs, it did not adversely affect human or animal health or the environment, nor harm the consumer by altering the characteristics of livestock products; its presence in feedingstuffs could be controlled; and that at the level permitted in feedingstuffs, treatment or prevention of animal disease was excluded. For the issuance of an authorization to place an additive in Annex I or II, a monograph must be drawn up, indicating the identification process or the criteria for the identification and characterization of the additive, particularly its composition and degree of purity and its physico-chemical and biological properties, taking account of scientific and technical knowledge. A pharmaceutical company applying for the authorization of a substance to be used as an additive in feedingstuffs must provide the information and studies prescribed in Directive 87/153/EEC.¹⁸⁶

IV.240 The European Communities stressed that the fact that a substance was placed in Annex I or Annex II did not necessarily mean that it was used automatically in all EC member States. The EC member States were free to decide which of those substances could be used in feedingstuffs in their territory. The principle in EC law for all substances permitted as additives in feedingstuffs was that there should be no residues of these substances in meat for human consumption.¹⁸⁷ The principle of no residues was achieved with the imposition, if necessary, of appropriate withdrawal periods, as was the case notably for growth-promoting additives, coccidiostats and other medicinal substances. However, when a particular substance was used also as a veterinary medicinal product (i.e. substances administered to food producing animals for medical treatment), the MRLs established in the latter case were also applicable when the substances were used as additives in feedingstuffs. In the European Communities, Council Regulation (EEC) 2377/90 of 26 June 1990¹⁸⁸, laid down the MRLs for veterinary medicinal products which were used in foodstuffs of animal origin. The absence of MRLs for additives in feedingstuffs was explained by the fact that the substances were used in very small quantities and were nearly not absorbed, leaving practically no residues at all in meat destined for human consumption. However, in order to harmonize entirely the EC legislation, the European Commission would shortly propose an amendment to Directive 70/524/EEC, which introduced MRLs also for additives which would need to be established before granting an authorization.

IV.241 The European Communities indicated that monesin was permitted to be used as an antibiotic in bovine and as coccidiostat in poultry, in which case a withdrawal period of 3 days was required. As an ionophore, it was assumed to have a certain degree of toxicity (headaches, nausea, nosebleeds, skin rashes). But monesin was not genotoxic nor mutagenic. When used as an additive in feedingstuffs, no MRLs were established. The dosage of Monesin authorized as an additive had been evaluated five times. It was concluded that the fact that it was available as a prepared feedingstuff, the dosage permitted and the withdrawal periods fixed eliminated the risks of residues in meat destined for human consumption. Monesin was allowed to be used in Canada for nutritional purposes and the prevention of coccidiosis. Benzylpenicillin was an antibiotic substance used mainly against gram-negative bacteria. It was one of the longest-used antibiotics. Penicillins had a very low toxicity in terms of direct effects. In connection with therapeutic use, hypersensitivity reactions were by far the most commonly encountered side effects. The small amounts of penicillin which might be present in food products of animal origin were not able to sensitise humans. For those reasons, benzylpenicillin had been included in Annex I of Regulation 2377/90 for all food producing species and an MRL of 50 mg/kg had been established. Ivermectin was an anthelmintic used against various parasites. Its scientific evaluation had shown that it was neither carcinogenic nor mutagenic. It was included in Annex I of Regulation 2377/90 for all food producing animals. MRLs of 100 mg/kg of bovine liver, 40 mg/kg of bovine fat, 15 mg/kg of ovine liver, 20 mg/kg of porcine fat had been established. The European Communities added that for monesin, carbadox and olaquindox, the European Commission would shortly propose MRLs even for feed additives. As feed additives, no veterinary control for their use was required. Monesin was not carcinogenic and avoparcin had been recently withdrawn from use. The European Communities noted that in general, the system of surveillance in force in the European Communities had been maintained under the new Directive 96/23/EC, which would enter into force on 1 July 1997. However, the new Directive clarified and improved the procedures for the detection of residues. It required that controls should be based primarily on targeted and unannounced inspections, with less emphasis on the present system of random sampling.

IV.242 The European Communities also argued that the argument on consistency which Canada attempted to draw from the fact that oestradiol-17b appeared, as a substance for which no MRL was necessary was misplaced. As stated explicitly in EC Regulation 3059/94, oestradiol-17b was authorized "for therapeutic and zootechnical uses only". This natural hormone (and the other two natural hormones at issue) had to be examined in the context of Regulation 2377/90 because otherwise it could not be used even for therapeutical or zootechnical purposes. No MRL was fixed by the European Communities because it was very difficult to detect such residue limits on a routine basis and without impeding trade. But its administration exclusively for such purposes and under the conditions prescribed in EC Directive 88/299 ensured that there were no residues left in meat destined for human consumption. The European Communities stressed that treatment of animals for therapeutic or zootechnical reasons was necessary in exactly the same way treatment of human beings for therapeutic purposes by doctors was necessary. Although new substances for therapeutic purposes were increasingly used, without therapeutic or zootechnical treatment there would be no meat production. After such treatment was performed, the European Communities noted that it took some time before the veterinarian discovered whether the treatment was effective or not. If, depending on the animal and the therapeutic or zootechnical treatment performed, the veterinarian determined that the animal could not be maintained as a breeding animal, only then the possibility of slaughter was considered. But this meant that, in addition to the strict conditions imposed by EC law for such treatment, there was a lapse of time between such treatment and the slaughter. The percentage of animals receiving such therapeutic or zootechnical treatment and which might be slaughtered did not represent more than 1 per cent of total bovine animals used for human consumption in the European Communities. Therefore, not only the percentage was extremely low but, in addition, the conditions imposed for such treatments and the time which normally lapsed between such treatments and the possibility of slaughtering, guaranteed that there would be no residues of oestradiol-17b left in meat used for human consumption. Therefore, the level of protection of the European Communities was not affected at all. Canada appeared to confuse, as did Dr. Arnold, therapeutic or zootechnical use with use of these hormones for growth promotion. Therapeutic treatment was performed only when the animal was ill. Zootechnical treatment was normally performed only once to an animal. It was not performed every year, as Canada seemed to suggest. Animals treated for both of these purposes could not be slaughtered for human consumption while they were under treatment. Withdrawal periods were also fixed. An animal which at the end of its breeding career was fattened to be slaughtered could not be treated for therapeutic or zootechnical purposes. It was obvious, therefore, that under the conditions prescribed in EC law, there could be no residues of such hormones in meat when the animals were slaughtered for human consumption. Equally, animals treated for therapeutic or zootechnical reasons and meat of such animals from third countries were allowed to be imported under guarantees which were equivalent to those applied for domestic animals and meat from such animals. Therefore, the provisions of EC law applied regardless of the country of origin of the animals or meat of such animals. The European Communities added that benzylpenicilin, carazolol, anaesthetics and ivermectin could be used only under veterinary prescription in the following EC member States: Germany, Netherlands, Sweden, Italy, Finland and the United Kingdom. Invermectin could be used in the United Kingdom without veterinary prescription but only as a feedingstuff additive only. The use of avoparcin had been prohibited in all EC member States since the end of January 1997.

IV.243 Canada noted that there was a degree of risk associated with all veterinary drugs used for animal husbandry and hormones were as safe as, or safer than, many other veterinary drugs commonly used for therapeutic or non-therapeutic purposes. Moreover, many of these veterinary drugs were used for animal husbandry in the European Communities, such as anthelmintics, pesticides, and some antibiotics, and were administered by producers without a veterinary prescription.

IV.244 As one example, Canada noted that monesin was an ionophore¹⁸⁹ that had a dual role both as a coccidiostat in poultry and as a growth promoter in cattle. To ensure minimal residues in meat, a three-day withdrawal period was recommended for poultry. Ionophores such as monesin were capable of disturbing biological membranes and affecting action potentials, which presumably accounted for their high toxicity. Additionally, there were high variations in species toxicity. Workers involved in monesin production or feed compounding had reported adverse reactions, such as, headaches, nausea, nosebleeds and skin rashes.¹⁹⁰ Monesin was administered by producers in the European Communities as a feed additive. The use of monesin was governed by the Feed Additives Directive and it appeared that no MRL or safety limit was established for this compound under the MRLs Regulation.

IV.245 With regard to non-ionophore antiobiotics, Canada indicated that carbadox was a widely available antimicrobial synthetic compound used as a growth promoter in pigs. It was both mutagenic and carcinogenic in animals. Concern had also been expressed about the safety of any residues to the consumer, but evidence suggested that these residues, when present, were devoid of carcinogenic and mutagenic activity, and any risk was likely to be to the workers handling the drugs.¹⁹¹ JECFA had evaluated carbadox in 1990, but because of the genotoxic and carcinogenic nature of carbadox and some of its metabolites, JECFA had not be able to establish an ADI. However, JECFA had been able to complete a qualitative risk assessment and concluded that residues resulting from the use of carbadox in pigs were acceptable, provided that MRLs were not exceeded. JECFA had recommended MRLs of 0.03 mg/kg in liver and 0.005 mg/kg in muscle of pig, based on the levels of, and expressed as, quinoxaline-2-carboxylic acid.¹⁹² The JECFA recommendations for carbadox had been adopted as Codex standards.¹⁹³ Canada noted that in a study commissioned by the European Communities, concluded in 1991, it was reported that "carbadox shows mutagenic effects in short time tests and in long term experiments and carcinogenic effects on rat-liver that could not be reproduced in experiments with primates. According to today's standards, a NEL [no effect level] cannot be derived nor can a ADI".¹⁹⁴ Carbadox was administered by producers in the European Communities as a feed additive. The use of carbadox was governed by the Feed Additives Directive. It appeared that no MRL or safety limit had been established for this compound under the MRLs Regulation.

IV.246 Olaquindox was another antimicrobial feed additive used as a growth promoter in pigs, which had been evaluated by the JECFA in 1994. JECFA had concluded that:

"... because of the genotoxic potential of the parent compound and the absence of specific toxicity studies on the metabolites, it was still unable to allocate an ADI. However, it noted that the parent drug was absent in muscle at the proposed withdrawal time and that the toxicity of the metabolites could be partially evaluated on the basis of toxicity studies in experimental animals because the metabolites are similar to those in the target species. The Committee extended the temporary acceptance of residues resulting from the use of olaquindox in pigs in accordance with good practice in the use of veterinary drugs."¹⁹⁵

IV.247 The 1991 study commissioned by the European Communities described the public safety aspects of olaquindox as follows:

"For Olaquindox a NEL of 1 mg/kg has been determined. Without withdrawal time the residue concentration are above the ADI value. Data concerning kinetics of excretion and practical experience indicate that a withdrawal time of 4 weeks and its use only up to 4 months of age respectively are sufficient to exclude risks for human health." ¹⁹⁶

The study went on to conclude:

"Considering the residues [of the 11 antimicrobial growth promoters studied], all growth permitters approved seem to show a high level of safety, except carbadox and olaquindox. .... The quinoxalines and olaquindox deserve special attention concerning the safety aspects because they are nearly completely absorbed in the gut and are proven to be mutagenic. Carbadox is also carcinogenic. Therefore, a safety evaluation should be extended to the target animal as well as to human beings." ¹⁹⁷

IV.248 Canada observed that olaquindox was administered by EC producers as a feed additive. The use of olaquindox was governed by the Feed Additives Directive, and no MRL or safety limit had been established for this compound under the MRLs Regulation.

IV.249 Canada indicated that there was a body of scientific evidence suggesting that avoparcin presented serious risks to human health, through the development of antibiotic-resistant bacteria. The use of this type of antibiotic at sub-therapeutic levels for growth promoting purposes, could result in resistant strains of bacteria in animals. These resistant strains had the potential to enter the human food chain, causing food borne illness. Other risks included transferring antibiotic resistance to other human disease-causing organisms, thus rendering the traditional therapy of human diseases ineffective.¹⁹⁸ The European Communities had also examined this issue in detail and SCAN had recommended further research into the effects of avoparcin, even though there was evidence of a human health risk.¹⁹⁹ Avoparcin was still permitted for use in the European Communities, with the exception of those countries that had implemented a national ban. The scientific community had raised doubts about the safety of avoparcin, particularly with respect to the detrimental effects that the continued use of this drug could have for human therapy and development of pathogenic microbial-resistant strains that could appear in the food chain. Avoparcin was administered by producers as a feed additive, and could be used without veterinary supervision. It was governed by the Feed Additives Directive and, therefore, it appeared that no MRL or safety limit had been established for this compound under the MRLs Regulation.

IV.250 Canada submitted that benzylpenicillin was one of the most widely used antibiotics in both animals and humans. It was primarily used to control mastitis in dairy cows and for treating infections of the urinary tract, gastrointestinal system and respiratory tract. Benzylpenicillin was also administered as a feed additive to pigs to control streptococcal meningitis, and was included as an additive in the drinking-water of poultry.²⁰⁰ This drug had been evaluated by JECFA in 1990. The Committee had concluded that allergic reactions in humans was the determining factor in the safety evaluation of residues of benzylpenicillin:

"Among the adverse reactions which had been reported in people consuming food containing benzylpenicillin residues, hypersensitivity reactions were the most common. The overall prevalence of allergy to penicillin, taking into account various reports of allergic reactions in different populations and using a variety of test procedures, was estimated to be 3-10 per cent."²⁰¹

IV.251 Codex had adopted MRLs for meat and for milk.²⁰² The European Communities had also set MRLs for milk and meat that were the same as the Codex levels.²⁰³ To ensure that the MRLs were attained, proper dosage of the animal was essential. Exceeding the MRLs could result in severe allergic reaction in 3-10 per cent of the population. Canada noted that although proper dose-level was critical to the safety of meat or milk products, benzylpencillin was sold without prescription and administered directly by farmers in certain EC member States.

IV.252 Canada indicated that carazolol, a non-specific b-adrenoceptor-blocking agent, primarily used in pigs to prevent sudden death due to stress during transportation, had been reviewed by JECFA in 1994 at its forty-third meeting. The drug had also been used in cattle for the same reasons and was usually administered to the animals just prior to being loaded for shipment to a slaughter facility. The JECFA Report noted that:

"The Committee [JECFA] recognized that humans with chronic bronchitis or asthma are highly sensitive to the effects of carazolol. It also recognized that this subgroup forms a substantial part of the general population and that adequate allowance should be made for variations between individuals."²⁰⁴

IV.253 The JECFA had established an ADI and MRLs for certain tissues. However, the proposed standards had not yet passed through the eight step Codex process and were, therefore, subject to change, based on comments from countries. Nonetheless, concerning the use of this drug, the JECFA Report provided a cautionary note to regulators by stating:

"The Committee recommended that registration authorities should pay particular attention to the potential risk of residues of carazolol in tissue at the injection site. Considering the potential risk, the Committee concluded that the use of carazolol in pigs to reduce stress during transportation to slaughter is inconsistent with the safe use of veterinary drugs in food producing animals²⁰⁵" (emphasis added).

IV.254 In June 1995, the European Communities had revised its provisional MRLs and had set final MRLs permitting the use of this drug in pigs.²⁰⁶ In its answer to a question from Canada, the European Communities had stated that, "Carazolol is used in pigs to prevent 'mors subita' during transport". Canada noted that this practice was precisely what JECFA concluded was inconsistent with the safe use of veterinary drugs in food-producing animals.

IV.255 Canada noted that ivermectin was an antiparasitic agent. It had been evaluated by JECFA in 1990 and again in 1993. Ivermectin was a mixture of two homologous compounds. While the compound was very effective in dealing with parasites, the mode of action in parasites had remained elusive, and the mechanisms of the toxic action of ivermectin in mammalian species had not been elucidated.²⁰⁷ The typical signs of acute toxicity of ivermectin had been attributed to its effects on the central nervous system. Codex had adopted the JECFA recommended ADIs and MRLs for cattle, sheep and pigs²⁰⁸ for ivermectin as Codex standards.²⁰⁹ Ivermectin was approved for use in the European Communities, and an MRL in the target tissues of liver and fat had been set for the bovine and porcine species. It was available for use by producers without a veterinarian prescription in some EC member States.

IV.256 Canada submitted that in veterinary medicine, a pesticide was a compound which was active against parasites that live on the skin of animals or which spend part of their lives in the animal's body (e.g., warble fly larvae). In their larval stage, these parasitic organisms known as ectoparasites, might migrate through the tissue of the host, or burrow into and live in the superficial skin layers. To counter ectoparasites, therefore, it was important to have a compound that could destroy the parasites at every stage of their life cycle, including the larval stage. A range of application modes for the pesticides were available to treat the animals, such as dips, sprays, dusts, feed additives, or subcutaneous injections. Due to environmental concerns, the organophosphourous compounds had replaced most of the organochloride compounds for use as pesticides. Unfortunately, the organophosphourous compounds were more toxic to man than the organochlorides, although they were rapidly metabolized and excreted. Compounds such as diazionon were used in the European Communities.²¹⁰

IV.257 Canada indicated that because the use of agricultural production aids, such as veterinary drugs, presented a risk, albeit minuscule, to the consumer, the United States Department of Agriculture (USDA) had developed a method to determine the relative risk of various agricultural production aids such as veterinary drugs, naturally occurring toxins, and pesticides. The USDA's Compound Evaluations System ("CES"), developed in 1983, had guided a number of countries in the development of their residue monitoring programmes. This allowed for testing to be targeted at those compounds that were more likely to present a health risk to the consumer.

IV.258 The likelihood of a health hazard of compounds which left residues in food was rated A to D or Z. The highest health hazard compounds were scored A and the lowest received a D. Those compounds for which insufficient information was available to conduct a toxicologic or pharmacologic evaluation, received a rating of Z. Each compound was also assigned a rating to evaluate the probability of exposure to the consumer. The categories ranged from 1, meaning a high probability of exposure, to 4, which was negligible probability of exposure. Category Z designated a substance with insufficient information available to estimate the probability of exposure to humans.²¹¹ The CES could thus be used to rank compounds based on their relative risk. The compounds presenting the highest risk to human health would score A1, and the compounds with the lowest risk to human health would be those compounds with a score of D4. Compounds of unknown hazard or exposure risk would receive a Z rating.

TO CONTINUE WITH EC MEASURES CONCERNING MEAT AND MEAT PRODUCTS (HORMONES) COMPLAINT BY CANADA

¹⁶¹ Codex Alimentarius,Vol. 3: "Residues of Veterinary Drugs in Foods", 2nd ed. (Rome: FAO, 1996) pp.77.

¹⁶² Canada explained that feed additives are incorporated into feedingstuffs for oral animal feeding. Substances used in accordance with the Feed Additives Directives are available, in the European Communities, without a veterinary prescription.

¹⁶³ Regulated under Directives 81/851/EEC and 81/852/EEC and their amendments ("Veterinary Medicines Directives", including: Directive 81/851/EEC; Directive 81/852/EEC and Directive 93/40/EEC.

¹⁶⁴ Regulated under Directive 70/524/EEC and its amendments, "Feed Additives Directives", including Directive 70/524/EEC; Directive 84/587/EEC; Directive 93/113/EC; Directive 93/114/EC and Directive 96/51/EC. Directive 91/248/EC appears to contain the most recent consolidation of the annexes to the Feed Additives Directives.

¹⁶⁵ Set out in Regulation 2377/90/EEC and its amendments.

¹⁶⁶ Set out in Directives 86/469/EEC and 96/23/EC ("Residues Directives").

¹⁶⁷ Established by Directive 81/851/EEC.

¹⁶⁸ A.R.M. Kidd, Distribution of Veterinary Medicines Within the European Community: Final Report prepared for DG III of the Commission of the European Communities (September 1992) p.25 (hereinafter Distribution of Veterinary Medicines Within the European Community: Final Report). See also A.R.M. Kidd, "Distribution of veterinary drugs within the European Union" (1994) 8:2 Vet. Drug Reg. Newsletter 35, pp.35-38.

¹⁶⁹ Distribution of Veterinary Medecines Within the European Community: Final Report, note 33, Table 6, p.47.

¹⁷⁰ Distribution of Veterinary Medicines in the Single Market.

¹⁷¹ Canada indicated that this was the case in Germany, for example.

¹⁷² EC Veterinary Medecine Directorate, "Regulation 2377/90: Consolidated Annexes".

¹⁷³ Directive 86/469/EEC.

¹⁷⁴ Directive 85/358/EEC.

¹⁷⁵ Council Directive 96/23/EC, preamble.

¹⁷⁶ Van Der Wal, P. & Berende, P.L.M. "Effects of anabolic agents on food producing animals" in, "Anabolics in Animal Production: Public health aspects, analytical methods and regulation", OIE Symposium (Paris, 15-17 February 1983), p.72.

¹⁷⁷ Crosby, N.T., "Determination of Veterinary Residues in Food", Ellis Horwood Series in Food Science and Technology, pp.33-36, p.34 (hereinafter "Determination of Veterinary Residues in Food").

¹⁷⁸ Brander, G.C. et al., eds., "Veterinary Applied Pharmacology & Therapeutics", 5th ed. (London: Bailliere Tindall, 1991), p.279 (hereinafter Veterinary Applied Pharmacology & Therapeutics).

¹⁷⁹ P. Schmidely & M. Hadjipanayiotou, "Growth Promoters for Fattening Kids," in P. Morand-Fehr, ed., "Goat Nutrition" (Pudoc Wageningen, 1991) p.184.

¹⁸⁰ "Determination of Veterinary Residues in Food", supra, note 146.

¹⁸¹ Ibid.

¹⁸² "K.N. Woodward & G. Shearer, (Arlington, VA: AOAC International, 1995) "Antibiotic Use in Animal Production in the European Union - Regulation and Current Methods for Residue Detection" in H. Oka et al., eds., Chemical Analysis for Antibiotics Used in Agriculture, note 42, p.55.

¹⁸³ Canada indicated that SCAN was an EC independent advisory body which comments on the safety of feed additives and has seen certain benefits in following the MRL route in assuring consumer safety.

¹⁸⁴ "Maximum Residue Limits - The Impact of UK and EC Legislation," pp.169-170.

¹⁸⁵ EC Official Journal L 270, 14 December 1970, p.1.

¹⁸⁶ EC Official Journal L 64, 7 March 1987, p.19. The European Communities added that Directive 95/63/EC of 25.10.95 (EC Official Journal. L 265, 8 November 1995, p.17) laid down the principles relating to official controls of feedingstuffs, and Directive 95/69/EC, of 22 December 19.95 (EC Official Journal L 332, 30 December 1995, p.15) laid down the conditions for the control of establishments producing certain sensitive additives, such as antibiotics and growth promoters.

¹⁸⁷ The European Communities noted that this principle applied also to imports of meat from third countries.

¹⁸⁸ EC Official Journal L 224, 18 August 1990, p.1.

¹⁸⁹ Canada explained that an ionophore was "an organic substance which binds a polar compound and acts as an ion transfer agent to facilitate movement of monovalent (i.e., sodium and potassium) and divalent ions (i.e., calcium) through cell membranes. The change in electrical charge in membranes influences transport of nutrients and metabolites across the cell membrane, but the exact mechanism by which ionophores improve growth performance in growing ruminants is not known" (D.H. Beermann, "Existing and Emergerging Strategies for Enhancing Efficiency and Composition of Meat Animal Growth", 1995 EC Scientific Conference Proceedings, p.45).

¹⁹⁰ J. Weissinger, "Miscellaneous Growth Promotants," in L.M. Crawford & D.A. Franco, eds., "Animal Drugs and Human Health" (Lancaster: Technomic Publishing Co., 1994) c. 8, p.117.

¹⁹¹ K.N. Woodward & G. Shearer, "Antibiotic Use in Animal Production in the European Union - Regulation and Current Methods for Residue Detection" in H. Oka et al., eds., "Chemical Analysis for Antibiotics Used in Agriculture" (Arlington, VA: AOAC International, 1995) c. 3, p.54.

¹⁹² "Evaluation of certain veterinary drug residues in food: Thirty-sixth Report of the Joint FAO/WHO Expert Committee on Food Additives", Technical Report Series 799 (Geneva: WHO, 1990), pp 45-50 (hereinafter "Thirty-Sixth Report").

¹⁹³ "Residues of Veterinary Drugs in Foods", supra, note 146.

¹⁹⁴ CEAS Consultants (Wye) Ltd. et al., "The Impact on Animal Husbandry in the European Community of the Use of Growth Promoters: Final Report,Vol. 1: Growth Promoters in Animal Feed" (February 1991), p.138 (hereinafter "The Impact on Animal Husbandry in the European Community of the Use of Growth Promoters").

¹⁹⁵ "Evaluation of certain veterinary drug residues in food: Forty-second Report of the Joint FAO/WHO Expert Committee on Food Additives", Technical Report Series 851 (Geneva: WHO, 1995) p.19.

¹⁹⁶ The Impact of Animal Husbandry in the European Community of the Use of Growth Promoters", supra, note 160.

¹⁹⁷ Ibid.., pp.140-141.

¹⁹⁸ J. Davies, "Bacteria on the rampage", Nature, Vol. 383 (19 September 1996) p.219):

Avoparcin is chemically related to vancomycin (although its name disguises the fact.). In Denmark in 1993, 22 kg of vancomycin were employed in human therapy, while animal use consumed 19,000 kg of avoparcin - inadvertently breaking European Community rules, which state that no agents used in humans and none that cause cross-resistance can be used in animal feed additives. Not surprisingly, resistance to vancomycin sharing the same biochemical mechanisms as that found in humans isolates is now common in farm animals.

Avoparcin was also used in Germany, where vancomycin-resistant enterococci are now widespread and can be detected on supermarket meat products (W.Witte, Robert Goch Inst.). Use of avoparcin is now prohibited in Germany and Denmark, but a powerful lobby is trying to dissuade the European Community from taking general preventative action.

Other difficulties associated with the increase in antibiotic resistant bacteria is an inability to treat human infectious diseases. As reported by S. Kingman ("Resistance a European Problem, Too," Science, Vol. 264 (15 April 1994) pp.363-365, the rising level of antibiotic resistance is a real cause for concern, and reports from around Europe show that severe problems already exist in some countries:

The emergence of vancomycin-resistant Enterococci is worrisome because these bacteria are themselves a significant cause of hospital infections. But even more alarming is the possibility that Enterococci will spread vancomycin resistance to other genera of bacteria. Researchers think this will eventually happen because bacteria are very adept at exchanging their antibiotic resistance genes

¹⁹⁹ Canada noted that Agra-Europe had reported that "...evidence had been presented to SCAN by Denmark and Germany that the use of avoparcin in animal feed could cause a resistance to antibiotics in humans but SCAN found that the two countries' evidence was insufficient proof of a link between the additive and increased antibiotic resistance." ("Opposition to avoparcin in EU growing," (25 October 1996), Agra Europe, p. E/4.)

²⁰⁰ Thirty-Sixth Report, supra, note 158.

²⁰¹ Ibid., pp.37-38.

²⁰² "Residues of Veterinary Drugs in Foods", supra, note 147.

²⁰³ R.J. Heitzman, ed., "Agriculture - Veterinary Drug Residues - Residues in food-producing animals and their products: Reference materials and methods" (Luxembourg: Office for Official Publications of the European Communities, 1992), pp.1-7, p.4.

²⁰⁴ "Evaluation of Certain Veterinary Drug Residues in Food: Forty-third report of the Joint FAO/WHO Expert Committee on Food Additives" (Geneva: WHO) Section 3, "Comments on residues of specific veterinary drugs," 3.1 "b-Adrenoceptor-blocking agent." p.6.

²⁰⁵ Ibid., p.8.

²⁰⁶ Regulation 1442/95/EC.

²⁰⁷ Thirty-sixth Report, supra, note 158.

²⁰⁸ Ibid., p.30.

²⁰⁹ "Residues of Veterinary Drugs in Foods", supra, note 147.

²¹⁰ Regulation 1442/95/EC establishes a MRL for diazinon.

²¹¹ "Compound Evaluation and Analytical Capability: National Residue Program Plan 1993" (Washington: U.S. Department of Agriculture, Food Safety and Inspection Service), pp.1.3-1.7.