The CVMP has recommended the refusal of the granting of marketing authorizations and the withdrawal of the existing marketing authorizations for veterinary medicinal products containing zinc oxide. The European Commission adopted a decision on 26 June 2017 and Member States can defer the withdrawal of marketing authorizations for up to five years from this date, if they consider that an immediate measure may have adverse effects negative on their territory given the lack of available alternatives and the changes to be made in pig farming practices.
What is zinc oxide as a veterinary drug?
Zinc oxide is an inorganic compound that is relatively poorly absorbed by the body. Veterinary medicinal products containing zinc oxide are used in the treatment and/or prevention and control of post-weaning diarrhea in piglets. Different indications and dosages are currently recommended, but zinc oxide is mainly used in feed at a dosage of 100 mg per kg of body weight per day for 14 consecutive days, which is equivalent to 2,500 ppm of zinc in the fodder.
Indeed, during their weaning, the piglets frequently present digestive disorders and growth retardation due to the change in feed and the stress linked to their grouping together in batches of animals of similar age (allotment). In order to avoid these disorders and therefore to curb the losses they cause, a large proportion of farms receive systematic and preventive antibiotic treatment in the form of medicated feed (colistin or other antibiotic in combination) . As an alternative to these antibiotic treatments, some European countries already authorize the use of zinc oxide (ZnO) at high doses in piglet feed, in the form of a medicated premix, during this same weaning period.
ANSES’s work
2013 – Request from ANSES concerning veterinary medicinal products containing zinc oxide to be administered orally (request N°2012-SA-0067, February 2013):
Antibiotic resistance is recognized as a major problem in terms of human and animal health at the international level, with the appearance, selection and increasing diffusion of strains of bacteria resistant to antibiotics. The development of alternatives to antibiotics is thus part of the measures envisaged in particular by the national plan to reduce the risks of antibiotic resistance in veterinary medicine “EcoAntibio 2017”, to combat this phenomenon. In this context, ANSES received a request from the Ministry for Agriculture to carry out a risk-benefit assessment of the use of zinc oxide in piglet feed (effectiveness for the animal, risk for humans, animals, the environment) and issue an opinion on the benefits of using this treatment to reduce the risks of antibiotic resistance.
It emerges from this work that the efficacy of zinc oxide in the prevention of moderate post-weaning diarrhea in piglets has been demonstrated at a dose of 3,100 ppm and for a maximum duration of 14 days, but this dosage remains at to optimise. Zinc oxide can be considered as a means of preventing these digestive ailments. On the other hand, its effectiveness when digestive disorders are installed are not documented to date.
- The environmental risk assessment linked to the use of zinc oxide as a medicated premix (spreading of post-weaning piglet slurry) indicates a toxic risk for the different compartments of the environment (sediment, aquatic and terrestrial ). The level of impact depends on the contexts of use, in particular the type of farming and the zinc content in the feed, throughout the farming period.
- Phenomena of bacterial resistance to zinc and cross-resistance or co-selection of resistant bacteria with certain antibiotics are described in the literature but one cannot prejudge their evolution in the event of use of zinc oxide.
On the basis of this work, the Agency considers that, with regard to the environmental risk linked to the use of zinc oxide as a medicinal premix in post-weaning piglets, management measures aimed at compensating for this risk must be considered. The first consists in using zinc oxide only in farms with fattening units, and not treating the slurry before spreading. In addition, in these farms, other management measures should also be proposed, in order to reduce zinc emissions to the environment.
ANSES specifies that the possible authorization of zinc oxide as a medicinal premix for post-weaning piglets should be accompanied by the establishment of a system for monitoring zinc resistance, cross-resistance or co-selected with certain antibiotics and annual monitoring of the quantities used at national level.
European Agency work
2017 – Assessment of the benefit/risk ratio and community decision (EMA/394961/2017, June 26, 2017):
In May 2015, following a referral procedure (EMEA/V/A/108) under Article 33(4) of Directive 2001/82/EC concerning Gutal 1000 g/kg, premix for medicated feed for piglets1, the CVMP has identified a risk for the environment caused by the accumulation of zinc. The CVMP considered that there are uncertainties associated with the calculated risks for certain environmental media and recommended various measures to limit the risks, by which it would be possible to reduce the accumulation of zinc in the environment.
In February 2016, due to remaining concerns related to the risk to the environment and the potential increase in the prevalence of antibiotic resistant bacteria caused by the use of products containing zinc oxide, the Netherlands and France have initiated a referral procedure under Article 35 of Directive 2001/82/EC concerning all veterinary medicinal products for oral administration containing zinc oxide. They further requested the CVMP to review all available data and to assess the overall benefit/risk balance for the products concerned.
On 16 March 2017, the Agency completed a review of the safety and efficacy of veterinary medicinal products containing zinc oxide for oral administration to food producing species. The CVMP concluded that the overall benefit-risk balance of veterinary medicinal products containing zinc oxide for oral administration in pigs is negative, since the benefits of zinc oxide in the prevention of diarrhea in pigs do not outweigh the environmental risks. The CVMP recognized that there is a risk of resistance co-selection (the selection of multiple antimicrobial resistance genes by one antibiotic) associated with the use of zinc oxide but that, at present, this risk cannot be quantified. No effective measures to manage the accumulation of zinc in the environment have been identified; therefore, the CVMP recommended the refusal of the granting of marketing authorizations and the withdrawal of the existing marketing authorizations for medicinal products for veterinary use containing zinc oxide.
Conclusion
The European Commission adopted a decision on 26 June 2017 and Member States can defer the withdrawal of marketing authorizations for up to five years from this date, if they consider that an immediate measure may have adverse effects negative on their territory given the lack of available alternatives and the changes to be made in pig farming practices.
References
> OPINION of the National Agency for Food, Environmental and Occupational Health Safety on the use of zinc oxide in the diet of piglets at weaning to reduce the use of antibiotics. Request No. 2012-SA-0067. anses.fr/en/system/files/ALAN2012sa0067Ra.pdf
> Questions and answers relating to veterinary medicinal products containing zinc oxide for oral administration to food producing species. Results of a referral procedure under Article 35 of Directive 2001/82/EC (EMEA/V/A/118). europa.eu/en/documents/referral/zinc-oxide-article-35-referral-questions-answers-veterinary-medicinal-products-containing-zinc-oxide_fr.pdf
