Improving the regulatory environmental risk assessment of human pharmaceuticals: Required changes in the new legislation.

One of the flagship actions of the Pharmaceutical Strategy for Europe is to address environmental challenges associated with pharmaceutical use. This includes strengthening the Environmental Risk Assessment (ERA) at marketing authorisation (MA) of pharmaceuticals, and revision of the pharmaceutical legislation where needed. The overall aim of an ERA should be to enable comprehensive and effective identification and management of environmental risks of pharmaceuticals without affecting the availability of pharmaceuticals to patients. As experts in the evaluation of ERAs of human medicinal products submitted by pharmaceutical industries (Applicants), we have summarized the current status of the ERA and suggest legislative changes to improve environmental protection without affecting availability. Six regulatory goals were defined and discussed, including possible ways forward: 1) mandatory ERAs in accordance to the EMA guideline at the time of the MA, 2) enforcement of risk mitigation measures including re-evaluation of the ERA, 3) facilitated exchange of environmental data between pharmaceutical and environmental legislations, 4) substance-based assessments, 5) transparency of data, and 6) a catching-up procedure for active pharmaceutical ingredients that lack an ERA. These legislative proposals can be considered as prerequisites for a harmonised assessment and effective management of environmental risks and hazards of human pharmaceuticals.

Assessment of environmental risks to groundwater ecosystems related to use of veterinary medicinal products.

The current EU guidelines for the environmental risk assessment of veterinary pharmaceutical products (VMPs) in groundwater (GW) suggest an approach based on the comparison between the calculated concentration in GW (PECgw) and a threshold concentration of 0.1 µg/L. The latter is the upper limit of the concentration for pesticides in groundwater in the EU. If the calculated PECgw does not exceed the threshold, then the risk is considered acceptable. It is assumed that the concentration of 0.1 µg/L is by default safe for both humans and exposed GW organisms. On this basis, it is not clear whether the GW is recognized as an ecosystem or as a source of drinking water. Largely unrecognized biodiversity in GW is worthy of protection through the adoption of a more scientifically sound risk analysis, which should be based on the consideration of ecological criteria. Based on the evidence of their vulnerability, we propose that risk assessments of GW ecosystems should be a compulsory part of the overall risk assessment of VMPs (as well as pesticides, biocides and feed additives). Furthermore, we suggest the use of a risk quotient approach based on the PEC/PNEC ratio in which the PNEC is calculated including an additional safety factor of 10 to the calculated PNEC for surface water.

Bioaccumulation of Polybrominated Diphenyl Ethers by Tubifex Tubifex.

The selective uptake of polybrominated diphenyl ethers (PBDEs) by oligochaetes makes it possible to assess the bioaccumulation of individual congeners in commercial mixtures. Twenty-one congeners from three BDE commercial mixtures (TBDE-71, TBDE-79 and TBDE-83R) and as individual congeners (BDE-77, BDE-126, BDE-198 and BDE-204) were tested on Tubifex tubifex in accordance with the OECD TG 315 "Bioaccumulation in Sediment-Dwelling Benthic Oligochaetes". All the congeners that were spiked in the sediment were detected at the end of the uptake phase and at the end of the experiment. The bioaccumulation factor (BAF), the kinetic bioaccumulation factor (BAFK) and the biotasediment accumulation factor (BSAF) were calculated, and indicate a high bioaccumulation potential for tri- to hexa-BDEs and a lower bioaccumulation potential for hepta- to deca-BDEs. The penta-homologues BDE-99 and BDE-100 showed the highest BSAFs of 4.84 and 5.85 (BAFs of 7.34 and 9.01), while the nona- and deca-BDEs exhibit bioaccumulation in up to one-order-lower concentrations. The change in the bioaccumulation potential between the group of trito hexa-BDEs and hepta- to deca-BDEs correlated with the generally accepted molecular-mass threshold for the molecular transition through biological membranes (700 g/mol).

The QSPR-THESAURUS: the online platform of the CADASTER project.

The aim of the CADASTER project (CAse Studies on the Development and Application of in Silico Techniques for Environmental Hazard and Risk Assessment) was to exemplify REACH-related hazard assessments for four classes of chemical compound, namely, polybrominated diphenylethers, per and polyfluorinated compounds, (benzo)triazoles, and musks and fragrances. The QSPR-THESAURUS website (http: / /qspr-thesaurus.eu) was established as the project's online platform to upload, store, apply, and also create, models within the project. We overview the main features of the website, such as model upload, experimental design and hazard assessment to support risk assessment, and integration with other web tools, all of which are essential parts of the QSPR-THESAURUS.

Experimental assessment of the environmental fate and effects of triazoles and benzotriazole.

The environmental fate and effects of triazoles and benzotriazoles are of concern within the context of chemical regulation. As part of an intelligent testing strategy, experimental tests were performed on endpoints that are relevant for risk assessment. The experimental tests included the assessment of ecotoxicity to an alga, a daphnid and zebrafish embryos, and the assessment of ready biodegradability. Triazole and benzotriazole compounds were selected for testing, based on existing toxicity data for vertebrate and invertebrate species, as well as on the principal component analysis of molecular descriptors aimed at selecting the minimum number of test compounds in order to maximise the chemical domain spanned for both compound classes. The experimental results show that variation in the toxicities of triazoles and benzotriazole across species was relatively minor; in general, the largest factor was approximately 20. The study conducted indicated that triazoles are not readily biodegradable.

Evaluation of CADASTER QSAR models for the aquatic toxicity of (benzo)triazoles and prioritisation by consensus prediction.

QSAR regression models of the toxicity of triazoles and benzotriazoles ([B]TAZs) to an alga (Pseudokirchneriella subcapitata), Daphnia magna and a fish (Onchorhynchus mykiss), were developed by five partners in the FP7-EU Project, CADASTER. The models were developed by different methods - Ordinary Least Squares (OLS), Partial Least Squares (PLS), Bayesian regularised regression and Associative Neural Network (ASNN) - by using various molecular descriptors (DRAGON, PaDEL-Descriptor and QSPR-THESAURUS web). In addition, different procedures were used for variable selection, validation and applicability domain inspection. The predictions of the models developed, as well as those obtained in a consensus approach by averaging the data predicted from each model, were compared with the results of experimental tests that were performed by two CADASTER partners. The individual and consensus models were able to correctly predict the toxicity classes of the chemicals tested in the CADASTER project, confirming the utility of the QSAR approach. The models were also used for the prediction of aquatic toxicity of over 300 (B)TAZs, many of which are included in the REACH pre-registration list, and were without experimental data. This highlights the importance of QSAR models for the screening and prioritisation of untested chemicals, in order to reduce and focus experimental testing.

Guidance on the assessment of the safety of feed additives for the environment.

This guidance document is intended to assist the applicant in the preparation and the presentation of an application, as foreseen in Article 7.6 of Regulation (EC) No 1831/2003, for the authorisation of additives used in animal nutrition. It specifically covers the assessment of the safety for the environment. [Table: see text].

Safety and efficacy of an essential oil from Elettaria cardamomum (L.) Maton when used as a sensory additive in feed for all animal species.

Following a request from the European Commission, the EFSA Panel on Additives and Products or Substances used in Animal Feed (FEEDAP) was asked to deliver a scientific opinion on the safety and efficacy of an essential oil from the seeds of Elettaria cardamomum (L.) Maton when used as a sensory additive for all animal species. Characterisation of the essential oil identified 37 components accounting for > 99% of its composition, with terpineol acetate (> 35%) and 1,8-cineole (> 20%) being the most prevalent compounds. In the absence of toxicological data of the feed additive itself, a component-based approach was applied to assess the safety of the essential oil as a mixture. Based on structural and metabolic similarity, the components of cardamom oil were allocated to seven assessment groups. Assuming the absence of toxicologically relevant interactions among components, dose addition was applied within each assessment group by calculating the combined margin of exposure as a basis for risk characterisation. The FEEDAP Panel concluded that the additive under assessment is safe at the proposed use level of 5 mg/kg in feed for all animal species. A concentration of 5 mg/L water for drinking is considered safe for all animal species. The use of cardamom essential oil in animal feed is considered safe for the consumer. In the absence of studies, the Panel cannot conclude on the safety for the users when handling the additive. The use of the essential oil under assessment in animal production is not expected to pose a risk for the environment. Since the seeds of E. cardamomum and their preparations are recognised to flavour food and their function in feed would be essentially the same, no further demonstration of efficacy is considered necessary. The Panel made a recommendation to limit the content of methyleugenol in the oil.

Safety and efficacy of Deccox® (decoquinate) for chickens for fattening.

Deccox®, containing decoquinate as the active substance, is a feed additive intended to be used for the prevention of coccidiosis in chickens for fattening at a dose range of 20-40 mg/kg complete feed. Decoquinate from Deccox® is safe for chickens for fattening at the highest applied concentration in complete feed of 40 mg/kg. No practically relevant interactions with other additives or veterinary drugs exist except with bentonite. Decoquinate does not have antibacterial action. Decoquinate is not genotoxic and not carcinogenic. Deccox® is safe for the consumer under the proposed conditions of use. No withdrawal period is required to ensure consumer safety. No maximum residue limits are considered necessary. The inhalation risk for users is considered negligible since inhalation toxicity and exposure are very low. Deccox® is not an irritant to skin and eyes and has no sensitisation potential. The ratios predicted environmental concentration/predicted no effect concentration (PEC/PNEC) for terrestrial, aquatic compartment and sediment are below 1, indicating that decoquinate used in chickens for fattening up to the highest proposed dose, does not pose a risk for these compartments; as well, no risk is expected neither for secondary poisoning nor for groundwater contamination. Due to insufficient evidence, the potential of decoquinate to prevent coccidiosis in chickens for fattening cannot be established.

Safety and efficacy of Robenz® 66G (robenidine hydrochloride) for chickens for fattening and turkeys for fattening.

Following a request from European Commission, the Panel on Additives and Products or Substances used in Animal Feed (FEEDAP) was asked to deliver a scientific opinion on the safety and efficacy of Robenz® 66G (robenidine hydrochloride (HCl)) when used as a feed additive for chickens for fattening and turkeys for fattening. The coccidiostat Robenz® 66G is considered safe for chickens for fattening at the highest proposed level of 36 mg robenidine HCl/kg complete feed with a margin of safety of approximately 2.5. This conclusion is extrapolated to turkeys for fattening. Robenidine HCl is active against Gram-positive but not against Gram-negative bacteria. It is not expected that the use of robenidine HCl as a feed additive would induce resistance or cross-resistance to antimicrobials used in human and animal therapy. The use of robenidine HCl from Robenz® 66G at the highest proposed level of 36 mg/kg complete feed in chickens and turkeys for fattening is considered safe for the consumer. The existing maximum residues limits for both avian species are confirmed. Robenidine HCl is not a skin or eye irritant and not a skin sensitiser. The risk via inhalation is considered negligible. The use of robenidine HCl from Robenz® in feed for chickens for fattening and turkeys for fattening up to 36 mg/kg complete feed does not pose a risk to either the terrestrial or the aquatic compartment. A risk for bioaccumulation cannot be excluded. The risk for secondary poisoning is not likely to occur. The FEEDAP Panel concludes that 36 mg robenidine HCl/kg complete feed from Robenz® 66G has the potential to effectively control coccidiosis of chickens for fattening under field conditions but cannot conclude on the efficacy of robenidine HCl in turkeys for fattening. The existing 5-day withdrawal period to avoid off-flavours in edible tissues should be maintained.

Efficacy of Cylactin® (Enterococcus faecium NCIMB 10415) as a feed additive for pigs for fattening.

Cylactin® is the trade name for a feed additive based on dehydrated cells of Enterococcus faecium. It is marketed in three forms: Cylactin® LBC ME10 and Cylactin® LBC ME20 Plus - which contain the microencapsulated bacterium in concentrations of 1 × 1010 CFU/g and 2 × 1010 CFU/g, respectively - and Cylactin® LBC G35, a granulated form with a guaranteed content of 3.5 × 1010 CFU/g. In 2012, EFSA was requested by the European Commission to re-evaluate the product when used as a zootechnical additive in feed for weaned piglets, sows and pigs for fattening. In the opinion delivered in 2015, the safety of the additive for consumers, users, the environment and target animals and its efficacy for piglets and sows were established. However, since only two efficacy studies with pigs for fattening could be considered and showed positive results, the Panel could not conclude on the efficacy for this target species due to insufficient data. The applicant has produced three additional feeding trials in pigs for fattening receiving the additive at the proposed inclusion level of 3.5 × 108 CFU/kg feedingstuffs, which are the subject of this assessment. None of these studies showed a significant effect on the performance of pigs for fattening. The data on average daily gain and feed to gain ratio of the three new studies and of the two from the previous opinion were pooled. Based on the results of this pooled analysis of five studies, but not supported by four out of the five individual studies, the EFSA Panel on Additives and Products or Substances used in Animal Feed concludes that Cylactin® has some potential to improve performance of pigs for fattening at 3.5 × 108 CFU/kg feed.

Safety and efficacy of Pediococcus pentosaceus DSM 32291 as a silage additive for all animal species.

Following a request from the European Commission, the Panel on Additives and Products or Substances used in Animal Feed was asked to deliver a scientific opinion on the safety and efficacy of a strain of Pediococcus pentosaceus when used as a technological additive intended to improve ensiling at a proposed application rate of 5 × 107 CFU kg/fresh matter. The species P. pentosaceus is considered by EFSA to be suitable for the qualified presumption of safety approach to safety assessment and not to require specific demonstration of safety other than the absence of resistance to antibiotics of human and veterinary significance. As the identity of the strain was clearly established and as no antibiotic resistance was detected, the use of the strain in the production of silage is presumed safe for livestock species, consumers of products from animals fed treated silage and the environment. In the absence of data, no conclusion can be drawn on the skin and eye irritancy of the additive. The additive should be considered a potential respiratory sensitiser. Pediococcus pentosaceus DSM 32291 at a minimum dose of 5 × 107 CFU/kg has the potential to improve the production of silage from easy and moderately difficult to ensile materials by decreasing dry matter loss and protein degradation during ensiling.

Safety and efficacy of Alterion NE® (Bacillus subtilis DSM 29784) as a feed additive for minor poultry species for fattening and reared for laying.

Following a request from the European Commission, the EFSA Panel on Additives and Products or Substances used in Animal Feed was asked to deliver a scientific opinion on the safety and efficacy of Alterion NE ® when used in feed for chickens for fattening and chickens reared for laying. Alterion NE ® is a preparation containing viable spores of Bacillus subtilis DSM 29784 intended for use in feed for the target species at the recommended dose of 1 × 108 CFU/kg complete feedingstuffs. B. subtilis is a species considered by EFSA to be suitable for the qualified presumption of safety (QPS) approach to safety assessment, which requires the identity of the strain to be conclusively established, evidence that the strain is not toxigenic and that it does not show resistance to antibiotics of human and veterinary importance. The strain was found to meet the criteria for the QPS approach in the context of a previous opinion and since concerns are not expected from other components of the additive, the additive is presumed safe for all target species, consumers and the environment. In the same opinion, the FEEDAP Panel concluded that Alterion NE ® is not a dermal irritant but is irritant to eyes and should be considered a potential respiratory sensitiser. In the absence of data, no conclusion could be drawn on the dermal sensitisation of the additive. Alterion NE ® at the recommended dose 1 × 108 CFU/kg feed has the potential to be efficacious in minor poultry species for fattening and reared for laying. B. subtilis DSM 29784 is compatible with the coccidiostats monensin sodium, narasin/nicarbazin, salinomycin sodium, lasalocid sodium, diclazuril, narasin, maduramicin ammonium, robenidine hydrochloride and decoquinate at the respective authorised levels.

Safety and efficacy of Lactococcus lactis NCIMB 30160 as a feed additive for all animal species.

Following a request from European Commission, the Panel on Additives and Products or Substances used in Animal Feed (FEEDAP) was asked to deliver a scientific opinion on the proposed modification of the terms of the authorisation regarding the formulation of the product Lactococcus lactis NCIMB 30160. The applicant has proposed to modify the manufacturing process by replacing one ingredient in the freeze-drying step with polyethylene glycol (PEG 4000), a product authorised in the EU as a food additive. The use of PEG 4000 as an excipient in formulations with Lactococcus lactis NCIMB 30160 would not change the previous conclusions regarding the safety for the target animals, consumers and users. The FEEDAP Panel concludes that the additive is safe for target species and for consumers of products from animals fed the treated silage. The additive is not a skin irritant but is a potential skin/respiratory sensitiser. In the absence of data, the Panel is unable to conclude on the safety for the environment of the proposed use of PEG 4000 as excipient in formulations of the additive. The FEEDAP Panel sees no reason to reconsider the conclusions on efficacy previously drawn that the additive containing L. lactis NCIMB 30160 has the potential to improve the production of silage from all forages by increasing lactic acid content and the preservation of dry matter, by reducing the pH and moderately the loss of protein, as determined by ammonia-N.

Safety and efficacy of Calsporin® (Bacillus subtilis DSM 15544) as a feed additive for pigs for fattening.

Following a request from the European Commission, the European Food Safety Authority (EFSA) Panel on Additives and Products or Substances used in Animal Feed was asked to deliver a scientific opinion on the safety and efficacy of Calsporin® when used in feed for pigs for fattening. The additive contains viable spores of a single strain of Bacillus subtilis. This species is considered by EFSA to be suitable for the Qualified Presumption of Safety (QPS) approach to safety assessment. This approach requires the identity of the strain to be conclusively established, evidence that the strain is not toxigenic and that it does not show resistance to antibiotics of human and veterinary importance. The strain was found to meet the criteria for the QPS approach in the context of previous opinions and since concerns are not expected from other components of the additive, Calsporin® is presumed safe for all target species, including pigs, consumers of products derived from animals treated and for the environment. In a previous opinion, the Panel also concluded that the additive is not a dermal/eye irritant or a skin sensitiser but should be considered a potential respiratory sensitiser. The use of the additive in pigs for fattening is considered unlikely to introduce hazards for users of the product not already considered as part of the first assessment. Therefore, the conclusions reached apply to the current application. Based on the results of the pooled analysis of four studies, the Panel on additives and products or substances used in animal feed (FEEDAP) concludes that Calsporin® has the potential to improve performance of pigs for fattening at 1.5 × 108 CFU/kg feed.

Safety and efficacy of Bacillus subtilis DSM 28343 as a feed additive for calves for rearing.

Following a request from the European Commission, the EFSA Panel on Additives and Products or Substances used in Animal Feed (FEEDAP) was asked to deliver a scientific opinion on the safety and efficacy of Bacillus subtilis DSM 28343 when used in feed for calves for rearing. The additive is a preparation containing viable spores of a strain of B. subtilis. This species is considered by EFSA to be suitable for the qualified presumption of safety (QPS) approach to safety assessment. The strain was found to meet the criteria for the QPS approach in the context of a previous opinion and since concerns are not expected from other components of the additive, the additive is presumed safe for the target species, consumers of products derived from animals fed the additive and the environment. In the same opinion, the FEEDAP Panel concluded that Bacillus subtilis DSM 28343 is not an eye/skin irritant but should be considered a potential respiratory sensitiser and that no conclusion could be drawn on its skin sensitisation potential. These conclusions apply also to the current application. Insufficient evidence was provided to conclude on the efficacy of the additive in calves for rearing.

Safety and efficacy of Bacillus subtilis DSM 28343 as a feed additive for piglets.

Following a request from the European Commission, the EFSA Panel on Additives and Products or Substances used in Animal Feed (FEEDAP) was asked to deliver a scientific opinion on the safety and efficacy of Bacillus subtilis DSM 28343 when used in feed for weaned piglets. The additive is a preparation containing viable spores of a strain of B. subtilis. This species is considered by EFSA to be suitable for the qualified presumption of safety (QPS) approach to safety assessment which requires the identity of the strain to be conclusively established, evidence that the strain is not toxigenic and that it does not show resistance to antibiotics of human and veterinary importance. The strain was found to meet the criteria for the QPS approach in the context of a previous opinion and since concerns are not expected from other components of the additive, the additive is presumed safe for all target species, consumers and the environment. In the same opinion, the FEEDAP Panel concluded that Bacillus subtilis DSM 28343 is not an eye/skin irritant but should be considered as a potential respiratory sensitiser and that no conclusion could be drawn on its skin sensitisation potential. These conclusions apply also to the current application. Bacillus subtilis DSM 28343 at 1 × 109 CFU/kg feedingstuffs has the potential to be efficacious in weaned piglets.

Safety and efficacy of EB15 10 (Bacillus subtilis DSM 25841) as a feed additive for weaned piglets and minor porcine species.

Following a request from the European Commission, the EFSA Panel on Additives and Products or Substances used in Animal Feed (FEEDAP) was asked to deliver a scientific opinion on the safety and efficacy of EB15 10 for weaned piglets and minor porcine species. The additive is a preparation containing viable spores of a strain of Bacillus subtilis intended for use in feed at the proposed dose of 5 × 108 CFU/kg complete feedingstuffs and in water for drinking at 1.7 × 108 CFU/L. The additive exists in two forms, EB15 and EB15 10, which contain the bacterium in concentrations of 1.25 × 109 CFU/g additive and 1.25 × 1010 CFU/g additive, respectively. The two formulations are considered equivalent when used to deliver the same dose. B. subtilis is considered by EFSA to be suitable for the qualified presumption of safety (QPS) approach to establishing safety. The active agent fulfils the requirements of the QPS approach to the assessment of safety. Consequently, the additive can be presumed safe for the target animals, consumers of products from treated animals and the environment. Given the proteinaceous nature of the active agent, the additive should be considered a potential respiratory sensitiser. In the absence of data, the FEEDAP Panel cannot conclude on the irritancy potential of the additive to skin and eyes or its dermal sensitisation. Insufficient evidence was provided to conclude on the efficacy of the additive in weaned piglets or minor weaned porcine species.

Safety and efficacy of ZM16 10 (Bacillus amyloliquefaciens DSM 25840) as a feed additive for weaned piglets and minor porcine species.

Following a request from the European Commission, the EFSA Panel on Additives and Products or Substances used in Animal Feed (FEEDAP) was asked to deliver a scientific opinion on the safety and efficacy of ZM16 10 for weaned piglets and minor porcine species. The additive is a preparation containing viable spores of a strain of Bacillus amyloliquefaciens intended for use in feed at the proposed dose of 5 × 108 CFU/kg complete feedingstuffs and in water for drinking at 1.7 × 108 CFU/L. The additive exists in two forms, ZM16 and ZM16 10, which contain the bacterium in concentrations of 1.25 × 109 CFU/g additive and 1.25 × 1010 CFU/g additive, respectively. The two formulations are considered equivalent when used to deliver the same dose. B. amyloliquefaciens is considered by EFSA to be suitable for the qualified presumption of safety (QPS) approach to establishing safety. The active agent fulfils the requirements of the QPS approach to the assessment of safety. Consequently, the additive can be presumed safe for the target animals, consumers of products from treated animals and the environment. Given the proteinaceous nature of the active agent, the additive should be considered a potential respiratory sensitiser. In the absence of data, the FEEDAP Panel cannot conclude on the irritancy of the additive to skin and eyes or its dermal sensitisation. Insufficient evidence was provided to conclude on the efficacy of the additive in weaned piglets or minor weaned porcine species.

Safety and efficacy of Lactobacillus acidophilus D2/CSL (Lactobacillus acidophilus CECT 4529) as a feed additive for cats and dogs.

Following a request from the European Commission, the Panel on Additives and Products or Substances used in Animal Feed (FEEDAP) was asked to deliver a scientific opinion on the safety and efficacy of Lactobacillus acidophilus D2/CSL when used in feed for cats and dogs at a minimum dose of 5 × 109 colony forming units (CFU)/kg complete feedingstuffs. The additive is a preparation of viable cells of Lactobacillus acidophilus CECT 4529. This species is considered by the European Food Safety Authority to be suitable for the qualified presumption of safety (QPS) approach to establishing safety for the target species and the environment. The safety of L. acidophilus CECT 4529 was assessed by EFSA in 2014. Following the QPS approach to safety assessment, L. acidophilus CECT 4529 is assumed to be safe for the target species and the environment without the need for further studies. No concerns are expected from other excipients present in the product, so Lactobacillus acidophilus D2/CSL is also considered safe for target animals, including cats and dogs, and the environment. The safety of the additive for the user was also considered in that opinion. The FEEDAP Panel is unaware of any new data that would lead it to revise its conclusions that the additive should be considered to be an eye/skin irritant and a skin/respiratory sensitiser. Lactobacillus acidophilus D2/CSL has some potential to reduce the moisture of stools from dogs and cats receiving the additive at 5 x 109 CFU/kg feed. However, the biological relevance of the magnitude of the effect detected is questionable.