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.

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.

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 Monimax® (monensin sodium and nicarbazin) for chickens for fattening and chickens reared for laying.

The coccidiostat Monimax® (monensin sodium and nicarbazin) is considered safe for chickens for fattening and chickens reared for laying at the highest use level of 50 mg monensin and 50 mg nicarbazin/kg complete feed. This conclusion is extended to chickens reared for laying. For both active substances, the metabolic pathways in the chicken are similar to those in the turkey and rat. Nicarbazin, when ingested, is rapidly split in its two components dinitrocarbanilide (DNC) and 2-hydroxy-4,6-dimethylpyrimidine (HDP) which behave independently. Monimax® does not represent a genotoxic risk. No safety concerns would arise from the nicarbazin impurities p-nitroaniline and methyl(4-nitrophenyl) carbamate. The lowest no observed effect level (NOEL) identified for monensin sodium in a developmental study in rabbits is 0.3 mg monensin sodium/kg body weight (bw) per day for maternal toxicity in rabbits. The lowest no observed adverse effect level (NOAEL) identified in a 52-week study in rat using DNC + HDP was 20 mg DNC + 8 mg HDP/kg bw per day based on the absence of microcrystals in urine and related microscopic renal observations. No significant interaction between monensin sodium and nicarbazin is expected from toxicological studies. The use of Monimax® at the highest proposed dose will not pose a risk to persons consuming animal products from treated chickens for fattening. This conclusion is extended to chickens reared for laying. No withdrawal time is required for Monimax® in chickens for fattening. Residue data comply with the established maximum residue limits (MRLs) for monensin and DNC. Based on the available data, the FEEDAP Panel cannot conclude on the safety of Monimax® for the environment. Monimax® has the potential to control coccidiosis in chickens for fattening at a minimum concentration of 40 mg monensin and 40 mg nicarbazin/kg complete feed.

Safety and efficacy of Monteban® G100 (narasin) for chickens for fattening.

The feed additive Monteban® G100, containing the active substance narasin, an ionophore anticoccidial, is intended to control coccidiosis in chickens for fattening at a dose of 60-70 mg/kg complete feed. Narasin is produced by fermentation. Limited data on the taxonomic identification of the production strain did not allow the proper identification of strain NRRL 8092 as Streptomyces aureofaciens. The FEEDAP Panel cannot conclude on the absence of genetic determinants for antimicrobial resistance in Streptomyces spp. under assessment. Based on the available data set, the FEEDAP Panel cannot conclude on the safety of Monteban® G100 for chickens for fattening. The simultaneous use of Monteban® G100 and certain antibiotic drugs (e.g. tiamulin) is contraindicated. Narasin is not genotoxic. No indication of carcinogenicity or developmental toxicity was found at the doses tested in the mouse, rat and rabbit. The lowest no observed effect level (NOEL) identified in the oral toxicity studies was 0.5 mg/kg body weight (bw) per day for the neuropathy seen in a one-year dog study. The acceptable daily intake (ADI) derived from this NOEL is 0.005 mg narasin/kg bw applying a uncertainty factor of 100. Monteban® G100 is safe for the consumer. Maximum residue limits (MRLs) of 50 µg narasin/kg for all wet tissues ensure consumer safety. Monteban® G100 is irritatant to the eyes but not to the skin. It has the potential to induce skin sensitisation. Inhalation exposure would pose a risk to persons handling the additive. Narasin, when used as a feed additive for chickens for fattening at 70 mg/kg feed, is not expected to pose a risk to the environment. The risk for sediment compartment cannot be assessed. The FEEDAP Panel cannot conclude on the efficacy of Monteban® at the minimum applied dose of 60 mg narasin/kg complete feed for chickens for fattening.

Safety and efficacy of Monteban® G100 (narasin) for ducks for fattening.

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 Monteban® G100 for ducks. Monteban® G100, containing narasin, is intended for the prevention of coccidiosis in ducks for fattening at a dose range of 60-70 mg/kg of complete feed. Narasin from Monteban® G100 is safe for ducks for fattening at a level of 70 mg/kg complete feed with a margin of safety of about 4. The FEEDAP Panel assumes that the residues in duck tissues would be of the same magnitude as those measured in the physiologically similar major species, chickens for fattening. The use of Monteban® G100 at a maximum concentration of 70 mg/kg complete feed for ducks for fattening is safe for the consumer without applying a withdrawal period, provided the maximum residue limit (MRL) of 50 µg narasin/kg for all wet tissues would not be exceeded. Monteban® G100 is irritant to the eyes but not to the skin. It has the potential to induce skin sensitisation. The acute systemic toxicity following dermal application is low. Inhalation exposure would pose a risk to persons handling the additive. Narasin, when used as feed additive for ducks for fattening at 70 mg/kg feed, is not expected to pose a risk to the environment. The risk for sediment compartment cannot be assessed. Narasin is not considered to have a bioaccumulation potential. Insufficient data were provided to allow a conclusion on the efficacy of Monteban® G100 in ducks.

Safety and efficacy of Coxiril® (diclazuril) for chickens reared for laying.

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 Coxiril® (diclazuril) for chickens reared for laying. Coxiril®, containing 0.5% diclazuril, is intended for the prevention of coccidiosis in chickens reared for laying at a dose range of 0.8-1.2 mg diclazuril/kg of complete feed up to a maximum age of 12 weeks. Derived from data already assessed for chickens and turkeys for fattening, diclazuril from Coxiril® is safe for chickens reared for laying up to 1.2 mg/kg complete feed when applied until 12 weeks of age. The FEEDAP Panel extended its previous assessment of consumer safety for the use of diclazuril from Coxiril® in chickens for fattening to chickens reared for laying. No measurable diclazuril residues were found in the first eggs laid from chickens reared for laying fed diclazuril from Coxiril® at 1.2 mg/kg complete feed until 12 weeks of age. Coxiril® was considered as a non-irritant to eyes and skin. It is not a potential skin sensitiser. User inhalation exposure to Coxiril®, as a result of normal handling, is unlikely to cause respiratory or systemic toxicity. The use of diclazuril from Coxiril® in chickens reared for laying at the highest proposed feed concentration would not pose a risk to the environment for neutral/alkaline soils (pH ≥ 7). A final conclusion on the risk resulting from the use of diclazuril in acid soil from Coxiril® cannot be done due to the high uncertainties related to potential accumulation of diclazuril over time. Derived from data already assessed for chickens for fattening, diclazuril from Coxiril® has the potential to control coccidiosis in chickens reared for laying at a minimum concentration of 0.8 mg/kg complete feed.

Safety and efficacy of Coxiril® (diclazuril) for pheasants.

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 Coxiril® for pheasants. Coxiril®, containing 0.5% diclazuril, is intended for the prevention of coccidiosis in pheasants at a dose range of 1.0-1.2 mg/kg of complete feed. Diclazuril from Coxiril® is considered safe for pheasants at a level of 1.2 mg/kg complete feed. The conclusion was made by extrapolating the results of a tolerance study with turkeys for fattening. The FEEDAP Panel considered that the residues in pheasant tissues and eggs would be of the same magnitude as those measured in the physiologically similar major species chickens and turkeys for fattening. The use of diclazuril at a maximum concentration of 1.2 mg/kg complete fed for pheasants would be safe for the consumer, provided that the maximum residue limits (MRLs) established for poultry would not be exceeded. The conclusions on the safety of the additive for the target species and the consumer are made under the provision that Coxiril® is not fed to laying birds. Coxiril® is considered as a non-irritant to eyes and skin. It is not a potential skin sensitiser. User inhalation exposure to Coxiril®, as a result of normal handling, is unlikely to cause respiratory or systemic toxicity. The use of diclazuril from Coxiril® in pheasants does not pose a risk to the environment for neutral/alkaline soils (pH ≥ 7). A final conclusion on the risk resulting from the use of the additive in acid soil cannot be done due to the high uncertainties related to potential accumulation of diclazuril over time. The FEEDAP Panel concluded that diclazuril from Coxiril® at a minimum dose of 1 mg/kg complete feed has the potential to control coccidiosis in pheasants.

Safety and efficacy of Zinc-l-Selenomethionine as feed additive for all animal species.

The additive, 'Zinc-l-selenomethionine' (Zn-l-SeMet) is intended to be used as a source of selenium for all animal species. The applicant intends to market the active compound blended with inert carriers (Availa®Se). Zn-l-SeMet is a safe source of selenium for chickens for fattening; the conclusion is extended to all animal species. Selenium from Zn-l-SeMet does not elicit any adverse effects not expected for a selenium compound. The use of Zn-l-SeMet in animal nutrition is expected to result in a similar increase in selenium deposition in animal tissues/products as that resulting from other sources of SeMet. The use of the additive up to the maximum selenium supplementation level established for other sources of organic selenium (0.2 mg/kg complete feed) and complying with the maximum authorised total selenium content is safe for consumers. The additive is hazardous upon inhalation; owing to the high dusting potential, persons handling Availa®Se are at risk by inhalation. Availa®Se is not an irritant to the skin. In the absence of data, no conclusion on the eye irritation and skin sensitisation can be drawn. The use of Zn-l-SeMet in feed does not pose an additional risk to the environment, compared with other sources of selenium for which it will substitute, as long as the maximum authorised content in complete feed is not exceeded. Zn-l-SeMet is an effective source of selenium in chickens for fattening and laying hens; this conclusion is extended to all animal species. The maximum contribution of zinc in total feed deriving from the use of the additive (< 0.2 mg Zn/kg feed) is considered low and does not need any safety assessment except for users.

Safety and efficacy of hydroxy analogue of methionine and its calcium salt (ADRY+®) for all animal species.

The European Commission asked EFSA Panel on Additives and Products or Substances used in Animal Feed (FEEDAP) to deliver a scientific opinion on the safety and efficacy of ADRY+®. ADRY+® consists of hydroxy analogue of methionine (HMTBa) and its calcium salt (HMTBa-Ca), both precursors of l-methionine. HMTBa and HMTBa-Ca are currently authorised for use as a nutritional additives, under the functional group 'amino acids, their salts and analogues'. ADRY+® is produced by chemical synthesis and it is intended to be used in feed for all animal species and categories. The FEEDAP Panel concluded that ADRY+® is safe for the target animals. The use of the additive in animal nutrition is not expected to result in an accumulation of HMTBa or its metabolites in edible tissues and animal products. Therefore, its use does not raise safety concerns for the consumer. ADRY+® is irritant to eyes and not irritant to the skin. The FEEDAP Panel cannot conclude on the skin sensitisation potential of this additive. The exposure of the users to the additive by inhalation is expected to be low. The use of this product as a feed additive does not represent a risk to the environment. ADRY+® is an effective source of methionine for protein synthesis in non-ruminant animals and fish, although HMTBa may show a lower bioefficacy than dl-methionine. In ruminants, HMTBa is more slowly degraded in the rumen than dl-methionine.

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 3-phytase FLF1000 as a feed additive for chickens reared for laying and minor poultry species.

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 3-phytase FLF1000 as a feed additive for chickens reared for laying and minor poultry species. Safety aspects regarding the use of this additive in feed including the safety for the consumer, for the users and for the environment have been previously evaluated by EFSA. The FEEDAP Panel considered that the new use requested by the applicant would not modify those conclusions. In the previous assessment, the Panel evaluated the safety and efficacy for chickens for fattening and laying hens. In the current evaluation, no new studies were submitted to support the safety and the efficacy in new species/categories. Therefore, the data on the tolerance and efficacy in major species previously evaluated was taken into consideration for this assessment. The results of the tolerance trial in chickens for fattening previously evaluated showed that chickens tolerated well 10-fold the maximum recommended dose. The Panel extended the conclusion reached in chickens for fattening to chickens reared for laying and extrapolated it to minor poultry species for fattening purposes or reared for laying/breeding. In the previous assessment, the FEEDAP Panel concluded that the additive has a potential to be efficacious in chickens for fattening at 500 FTU/kg feed. The Panel extended the conclusion on the efficacy in chickens for fattening to chickens reared for laying and extrapolated it to minor poultry species for fattening purposes or reared for laying/breeding.

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 natural mixtures of talc (steatite) and chlorite (E 560) as a feed additive for all animal species.

The additive is a natural mixture of talc and chlorite (NTMC) that contains at least 75% of talc and chlorite as main components. The additive is intended for use as a technological additive (functional groups: (i) anticaking agents) in premixtures and feedingstuffs for all animal species at use levels of 1,000-50,000 mg/kg. No safe dietary level of NMTC could be identified for piglets, chickens for fattening and dairy cows. The use of NMTC in animal nutrition is considered not to pose a risk for the consumer of animal tissues and products from animals fed the additive. Talc could cause serious lung disease if repeatedly inhaled in large quantities over a long period. Talc is not irritant to skin and eyes. In the absence of data, no conclusion can be drawn on the skin sensitisation potential of the product. The components of the additive (talc, chlorite, dolomite and magnesite) are ubiquitous in the environment, being natural components of soil. Therefore, it is not expected that its use as a feed additive would adversely affect the environment. The additive NMTC is efficacious as an anticaking agent.

Guidance on the characterisation of microorganisms used as feed additives or as production organisms.

[Table: see text]. ABSTRACT: 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 for use in animal nutrition. It specifically covers the characterisation of microorganisms used as feed additives or as production organisms.

Safety and efficacy of sodium saccharin when used as a feed flavour for piglets, pigs for fattening, calves for rearing and calves for fattening.

Sodium saccharin is intended to be used as a sweetener in feed and water for drinking for piglets, pigs for fattening and veal calves. The Panel on Additives and Products or Substances used in Animal Feed (FEEDAP) considers the proposed maximum use level of 150 mg sodium saccharin/kg feed as safe for calves and pigs for fattening. For piglets (sucking and weaned piglets), a lower level of 100 mg sodium saccharin/kg complete feed is considered safe. The corresponding maximum safe concentrations in water for drinking are 30 mg/L for piglets and 50 mg/L for pigs for fattening, respectively. The maximum safe concentrations of sodium saccharin in feed and water for drinking are derived under the premise that only one source, feed or water for drinking, contains the additive. The FEEDAP Panel concludes that no concern for the consumer would result from the use of sodium saccharin in feed and water for drinking at the dose considered safe for the target species. The precautions for handling the product proposed by the applicant are considered to be sufficient to ensure user safety. The FEEDAP Panel concludes that the use of sodium saccharin at the dose considered safe for target species is unlikely to have detrimental effects on the terrestrial and freshwater compartments. The high mobility and relative persistence of saccharin and the high persistency of its degradation product 4-hydroxysaccharin indicate that groundwater contamination above 0.1 µg/L is likely to occur. Since the function of sodium saccharin in feed for the target species is essentially the same as that in food, the FEEDAP Panel concludes that no demonstration of efficacy is necessary.

Safety and efficacy of Sacox® microGranulate (salinomycin sodium) for rabbits for fattening.

Sacox ® microGranulates, containing salinomycin sodium (SAL-Na), for chickens for fattening and chickens reared for laying have been recently re-evaluated by Panel on Additives and Products or Substances used in Animal Feed. Following an urgent request from the European Commission, the safety and efficacy of the product when fed to rabbits for fattening was assessed based on the available data submitted by the applicant at the beginning of the assessment. SAL-Na is largely absorbed and metabolised. Metabolites have a reduced ionophoric activity. SAL is the marker residue. SAL-Na is not genotoxic and not a carcinogen. A no observed adverse effect level (NOAEL) of 0.5 mg/kg body weight (bw) per day is derived from a study in dogs. Only data on feed intake and body weight were available to conclude on the safety of SAL for rabbits. Levels of 35 mg SAL/kg feed and higher were not tolerated by growing rabbits. The Panel considers the available data indicate that the additive is tolerated by rabbits for fattening up to 25 mg/kg. The safety of SAL in rabbits for fattening needs to be established by a tolerance study compliant with the current standards. Adverse effects on breeding does cannot be excluded. The simultaneous use of SAL-Na with certain medicinal substances (e.g. tiamulin and valnemulin) and bentonite is contraindicated. Consumer exposure to residues of toxicological concern complies with the acceptable daily intake (ADI) of 0.005 mg/kg bw, after 1-day withdrawal. A provisional maximum residue limit (MRL) of 0.01 mg/kg liver would ensure consumer safety. A 5-day withdrawal period as proposed by the applicant is supported. SAL-Na in feed for rabbits will not pose a risk for the aquatic environment. A risk for the terrestrial ecosystem is considered unlikely. Efficacy and effective dose of SAL-Na under present farming conditions could not be established.