Risk Mitigation Measures: An Important Aspect of the Environmental Risk Assessment of Pharmaceuticals
2. Sources of RMMs
2.1. Compilation of Existing RMM from Authorized VMP and Scientific Literature
- The product should not enter surface waters;
- Treated animals should not have access to watercourses;
- The long-term effect of the product on the population dynamics of dung organisms is unknown; therefore, it is advisable not to treat animals on the same pasture every season.
- Short-term measures; e.g., improved disposal and sewage treatment techniques, refusal of the spreading of contaminated manure;
- Mid-term measures; e.g., modified risk perception and risk communication of producers and consumers of medicinal products;
- Long-term measures; e.g., decisions that foster the concept of sustainable pharmacy.
2.2. Derivation of RMM Based on Exposure Models
|PECsoil initial||Predicted environmental concentration in soil||-||(µg kg−1)|
|D||Daily dose of the active ingredient||From SmPC||(mg kgbw−1 d−1)|
|Ad||Number of days of treatment||From SmPC||(d)|
|BW||Animal body weight||Default ||(kgbw)|
|SD||Stocking density||Default ||(animal ha−1)|
|Fh||Fraction of herd treated||Between zero and one; default ||(--)|
|1500||Bulk density of dry soil||||(kg m−3)|
|10,000||Area of one hectare||||(m2 ha−1)|
|0.05||Depth of penetration into soil||||(m)|
|1000||Conversion factor||||(μg mg−1)|
- Reduction of the fraction of herd treated;
- Reduction of the maximum applicable amount of nitrogen per hectare and year;
- Reduction of the fraction of dip entering dirty water;
- Reduction of the spreading rate for dirty water;
- Reduction of the animal turnover rate per place per year in intensively reared animals;
- Reduction of the stocking density per hectare and year in pasture animals;
- Increase of the housing factor per year from 0.5 to one for intensively reared cattle and horses;
- Increase of the depth of penetration of dung into soil (>5 cm).
- Reduction of the highest fraction of the dose excreted in dung in one day;
- Increase of the length of time that manure is stored;
- Increase of the number of spreading events of dung;
- Avoidance of the removal of topically applied ectoparasiticides;
- Avoidance of the release to soil with a low adsorption capacity.
3. Selection of Appropriate RMMs
3.1. Evaluation Criteria for RMM
- Exposure of the drug to the environment is effectively reduced (effectiveness);
- The measure has a long-lasting effect (sustainability);
- The effectiveness of the measure is verifiable (verifiability), e.g., by means of re-assessment of the exposure, taking the measure into account;
- The measure is explicitly directed to the appropriate addressee (addressing);
- Action is in accordance with good agricultural practices (practicality, for VMP);
- The measure is proportionate (proportionality principle);
- The measure is consistent with the relevant law(s) (legitimacy).
3.2. Legal Boundaries for the Application of RMMs
- The problem of the addressee: The addressee of the authorization to market pharmaceuticals is the pharmaceutical industry (marketing authorization holder). If an unacceptable environmental risk was identified within the marketing authorization procedure (i.e., RQ ≥ 1), which could be reduced due to THE RMM (RQ < 1), the marketing authorization holder receives the permission with the condition of THE RMM. However, the addressee of the RMM in practice is, in most cases, not the marketing authorization holder itself, but the user of the VMP. Thus, the RMM restricts the user in its freedom of exercise of profession, e.g., this would be the case for the RMM. “U-22: Animals [animal group] from free-range husbandry must be kept indoors during treatment and x days following treatment.” In Germany, a restriction of the freedom of exercise of profession by the government must be based on an authorization. This is not provided in the European Directive 2001/82/EC  and not in the AMG . Thus, in such a case, the RMM is only applicable if another European (German) regulation authorizes the state for such restrictions;
- Principle of proportionality: The restriction of the freedom of exercise of profession by the state due to RMM needs to be proportional, i.e.: (1) the measure needs to be suitable for reaching the goal; (2) a milder measurement to reach the goal is not available; and (3) the measure is reasonable. The principle of proportionality was originally required in the case of restrictions of German fundamental rights by the state. In the meantime, it is also implemented in other regulations and in European legislation ;
- Periods when fertilization is prohibited;
- Minimum storage capacity for livestock manure (at least six months; use only when the crop needs nutrients) according to national administrative regulations  and local ordinances;
- Rules to control the spread of nutrients near water or on slopes, to reduce the risk of contamination, e.g., by immediate incorporation of the applied slurry into the soil and under consideration of nitrogen (N) balance between nitrogen added to the soil (e.g., mineral fertilizer, livestock manure, etc.) and nitrogen removed from the soil in crops. The prevention of excessive levels of nutrients on farmland is a binding principle of the Good Agricultural Practices as laid down in the DüV . A breach of this requirement would be considered as an administrative offence;
- A limit of 170 kg nitrogen per hectare per year (in justified exceptional cases, higher amounts are possible upon application).
4. Proposed RMM for Use within the Authorization of VMP
|Precautions for disposal|
|D-01||The user (e.g., veterinarian or livestock owner) has to ensure that any unused product or waste materials derived from the product, such as empty containers, do not contaminate water courses, surface waters or other parts of the environment. Veterinary pharmaceutical products must not be disposed of via sewage, but should be disposed of preferentially via local return systems for hazardous waste. If disposed with household waste, it should be taken care that no misuse of these wastes could occur.|
|D-02||The user (e.g., veterinarian or livestock owner) has to ensure that any unused product or the rest of the dip do not contaminate water courses, surface waters or other parts of the environment. Dips must not be disposed of via sewage, but should be disposed of via local return systems for hazardous waste.|
|Precautions for use in aquacultures|
|U-01||Constraint to the user (fish owner): Prior to the use of the product, a discharge certificate is required from the relevant authority for the release of this product into the aquatic environment.|
|U-02||Constraint to the user (fish owner): Use only if the flow rate of untreated waters allows for an x-fold dilution of the volume of treated water before discharge into surface waters. Where the appropriate dilution of treated water cannot be achieved, the farm must have a discharge process to limit the release of product into the environment to within the parameters described. This can be achieved by the use of holding tanks and ponds, discharge lagoons and biofilters to clean treated water. Where this applies, the user must monitor the discharge concentration to ensure that the parameters are not exceeded.|
|Precautions for use in intensively reared animals|
|U-11||Constraint to the farmer: Before spreading slurry (manure) from treated animals, it has to be stored for at least x days/months.|
|U-12||Constraint to the farmer: Slurry (manure) from treated animals must not be spread on areas where run-off could occur (slope > 10%).|
|U-13||Constraint to the farmer: Slurry (manure) from treated animals must only be spread on arable land if it is x-fold diluted with slurry (manure) from untreated animals.|
|U-14||Constraint to the farmer: When spreading slurry (manure) from treated animals onto arable land, a safety margin of x meters to the water’s edge has to be maintained.|
|U-15||Constraint to the farmer: When spreading slurry (manure) from treated animals onto arable land, the maximum nitrogen spreading limit must not exceed x kg N ha−1 yr−1.|
|U-16||Constraint to the farmer: Slurry (manure) from treated animals must only be spread on arable land in x portions of the maximum nitrogen spreading limit with minimum time intervals of y days.|
|U-17||Constraint to the farmer: Slurry (manure) from treated animals must not be spread on soils with an organic C content < x%.|
|U-18||Constraint to the farmer: After spreading of slurry (manure) from treated animals, soil must be ploughed to a depth of at least x cm (>5 cm).|
|Precautions for use in pasture animals|
|U-21||Constraint to the veterinarian/animal holder: Strategic treatment of stock is only allowed after the fly or dung beetle season in autumn or in early spring.|
|U-22||Constraint to the animal holder: Animals [animal group] from free-range husbandry must be kept indoor during treatment and x days following treatment.|
|U-23||Constraint to the animal holder: During treatment and x hours/days following treatment animals [animal group] must be kept away from watercourses.|
|U-24||Constraint to the animal holder: [Product] is toxic to dung organism (flies, beetles). Therefore, animals [animal group] must not be kept on the same pasture every season.|
|Precautions for use in intensively reared and pasture animals|
|U-31||Constraint to the veterinarian/animal holder: Only treat affected animals [animal group] when required. For correct diagnosis and development of an appropriate treatment schedule, a veterinarian should be consulted. Fecal worm (worm egg) counts can be used as an indicator of whether treatment is needed or not.|
|U-32||Constraint to the user of the product: During the use of the teat dipping or spraying, dripping residues must be collected and disposed of separately (cf. special precautions for disposal, SmPC, Section 6.6).|
|U-33||Constraint to the farmer: Dirty water must only be spread with a maximum spreading rate of x L (<50,000) ha−1 onto arable land or pastures.|
5. Evaluation of RMMs for HMPs
6. Discussion and Conclusions
number of days of treatment
Arzneimittelgesetz (German Pharmaceuticals Act)
Bundesamt für Verbraucherschutz und Lebensmittelsicherheit (German Federal Office of Consumer Protection and Food Safety)
animal body weight
daily dose of the active ingredient
Düngeverordnung (German Fertilization Ordinance; implementation of the Nitrate Council Directive in German law)
European Economic Community
European Medicines Agency
European public assessment report
environmental risk assessment
environmental risk-benefit assessment
fraction of herd treated
human medicinal product
predicted environmental concentration
predicted no effect concentration
risk mitigation measure
summary of product characteristics
International Cooperation on Harmonization of Technical Requirements for Registration of Veterinary Medicinal Products
veterinary medicinal product
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Liebig, M.; Floeter, C.; Hahn, T.; Koch, W.; Wenzel, A.; Römbke, J. Risk Mitigation Measures: An Important Aspect of the Environmental Risk Assessment of Pharmaceuticals. Toxics 2014, 2, 35-49. https://doi.org/10.3390/toxics2010035
Liebig M, Floeter C, Hahn T, Koch W, Wenzel A, Römbke J. Risk Mitigation Measures: An Important Aspect of the Environmental Risk Assessment of Pharmaceuticals. Toxics. 2014; 2(1):35-49. https://doi.org/10.3390/toxics2010035Chicago/Turabian Style
Liebig, Markus, Carolin Floeter, Thorsten Hahn, Wolfgang Koch, Andrea Wenzel, and Jörg Römbke. 2014. "Risk Mitigation Measures: An Important Aspect of the Environmental Risk Assessment of Pharmaceuticals" Toxics 2, no. 1: 35-49. https://doi.org/10.3390/toxics2010035