Fernando Ramos

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

Draft Endorsed by the FEEDAP Panel * 18 May 2017 Submitted for public consultation 15 June 2017 End of public consultation 15 September 2017 Adopted by the FEEDAP Panel 21 February 2018 Implementation date 1 September 2018 * Sections 3.1 and 3.2 were also endorsed by the EFSA Panel on Genetically Modified Organisms (GMO), EFSA Panel on Food Contact Materials, Enzymes, Flavourings and Processing Aids (CEF) and EFSA Panel on Food Additives and Nutrient Sources Added to Food (ANS) on 18 May (GMO) and 7 June (CEF and ANS) 2017. 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.

Guidance on the assessment of the safety of feed additives for the consumer

Draft Endorsed by the FEEDAP Panel 17 May 2017 Submitted for public consultation 24 May 2017 End of public consultation 21 July 2017 Adoption by the FEEDAP Panel 27 September 2017 Entry into force 1 May 2018 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 assessment of the safety for the consumer.

Safety and efficacy of Sacox® microGranulate (salinomycin sodium) for chickens for fattening and chickens reared for laying

Abstract Salinomycin sodium (SAL‐Na) is active against certain Gram‐positive bacteria, while Gram‐negative species are resistant. SAL‐Na at the proposed concentration is unlikely to increase shedding of Salmonella, Escherichia coli and Campylobacter and or induce resistance and cross‐resistance to antimicrobials important in human and animal therapy. SAL‐Na is safe for chickens for fattening at 70 mg/kg complete feed, for chickens reared for laying at 50 mg/kg complete feed in the first 12 weeks of life. The simultaneous use of SAL‐Na and certain antibiotic drugs (e.g. tiamulin) is contraindicated. SAL‐Na is absorbed and extensively metabolised. Metabolites have reduced ionophoric activity. SAL is the marker residue (MR). No residues in eggs are expected. SAL‐Na is not genotoxic and not a carcinogen. A NOAEL of 0.5 mg/kg body weight (bw) per day is derived from a cardiovascular study in dogs as well as from a 12‐month dog study. Consumer exposure complies with an acceptable daily intake of 0.005 mg SAL/kg bw after 1 h withdrawal. A withdrawal time and maximum residue limits are not considered necessary. SAL‐Na from Sacox® is not an irritant to skin and eyes; it is a potential sensitiser to skin and the respiratory tract. A toxicological risk by inhalation for persons handling the additive cannot be excluded. SAL‐Na in feed for chickens will not pose a risk for the aquatic environment. A risk for the terrestrial ecosystem is considered unlikely due to metabolisation and the rapid degradation of SAL in the environment. SAL‐Na at a minimum concentration of 50 mg/kg complete feed is an effective coccidiostat for chickens for fattening. This conclusion is extended to chickens reared for laying. SAL‐Na in Sacox® 120 microGranulate and Sacox® 200 microGranulate is considered bioequivalent with respect to its anticoccidial effect.

Safety and efficacy of Bacillus subtilis PB6 (Bacillus subtilis ATCC PTA‐6737) as a feed additive for sows

Abstract Bacillus subtilis PB6 is a feed additive based on viable spores of a strain of Bacillus subtilis. EFSA has already issued several opinions on the safety and efficacy of the additive when used in the feed for a number of avian and porcine species/categories. The applicant is now seeking authorisation for use in sows in order to have benefits in piglets. In the course of previous assessments, no evidence of a toxigenic potential or resistance to relevant antibiotics was found. Consequently, the strain of B. subtilis in the additive, following the qualified presumption of safety approach to safety assessment, is presumed safe for target animals including sows and their offspring, consumers and the environment. In a previous assessment, it was also concluded that the additive is not a skin/eye irritant or a skin sensitiser and that there were no concerns on respiratory sensitisation. The use of the additive with feed for sows is considered unlikely to introduce hazards for users of the product not already considered. Five studies are described in which groups of sows given the additive for a minimum period from the last 3 weeks of pregnancy, throughout farrowing and lactation, until weaning of piglets were compared with a control group. In only two of five studies, there was a significant beneficial effect seen in terms of piglet performance. However, when data from the four similar were pooled and analysed, significant increases in weaned weight and average daily gain were indicated for piglets from sows given the additive. Consequently, the FEEDAP Panel concludes that Bacillus subtilis PB6 when added to diets of sows from 3 weeks before parturition until weaning of piglets at a dose of 1 × 108 CFU/kg complete feed has the potential to improve the growth of piglets from birth to weaning.

Safety and efficacy of Kelforce® (l‐glutamic acid, N,N‐diacetic acid, tetrasodium salt (GLDA‐Na4)) as a feed additive for chickens for fattening

Abstract l‐Glutamic acid, N,N‐diacetic acid, tetrasodium salt (GLDA‐Na4) (Kelforce®) is sought to be used as a zootechnical feed additive in chickens for fattening to improve the absorption of zinc from feed, reducing zinc emissions through manure and thus, affecting favourably the environment. The product has not been authorised in the European Union as a feed additive. Kelforce® is intended to be marketed as a liquid and solid formulation, containing ≥ 47% and ≥ 30% of GLDA‐Na4, respectively. Kelforce® is safe for chickens for fattening at the maximum level of 1,000 mg GLDA‐Na4/kg complete feed. Based on the toxicological profile of GLDA‐Na4 and the consumer exposure to GLDA‐Na4 and to nitrilotriacetic acid trisodium salt (NTA‐Na3; an impurity of the additive), the use of Kelforce® at the maximum proposed level in feed of chickens for fattening is of no concern for consumer safety. Due to its low inhalation toxicity, the exposure to GLDA‐Na4 is unlikely to pose a risk by inhalation. However, owing to the high‐dusting potential of the solid formulation, a risk from such high level of dust, even if toxicologically inert, cannot be excluded. Kelforce® is not a skin/eye irritant or skin sensitiser. No risks for the terrestrial compartment were identified at the maximum use level of the additive. Risks for the aquatic compartment cannot be excluded based on the secondary effect of the additive on green algae. In the absence of data, the Panel cannot conclude on the safety for the sediment compartment or the possible ground water contamination. The risk of bioaccumulation and secondary poisoning caused by the additive is considered very low. Owing to the inconsistent and conflicting results from the studies assessed, the Panel on Additives and Products or Substances used in Animal Feed (FEEDAP) cannot conclude on the efficacy of the additive. The Panel made a recommendation regarding the levels of formaldehyde and cyanide in the active substance.

Safety and efficacy of l‐arginine produced by fermentation using Corynebacterium glutamicum KCCM 10741P for all animal species

Abstract l‐Arginine is considered to be a non‐essential amino acid for most adult mammalian species, but it is classified as essential for birds, fish, possibly reptiles and also for strict carnivores. The product subject of this assessment is l‐arginine produced by fermentation using a non‐genetically modified strain of Corynebacterium glutamicum (KCCM 10741P). It is intended to be used in feed and water for drinking for all animal species and categories. Species identity of the production organism was confirmed and the strain was sensitive to antibiotics at concentrations at or below thresholds specified by EFSA; thus, C. glutamicum KCCM 10741P may be considered safe by the qualified presumption of safety (QPS) approach. No viable cells of C. glutamicum were detected in the final product. The amount of identified material exceeded 99.8%, and no impurities of concern were detected. The use of l‐arginine produced by C. glutamicum KCCM 10741P is safe for target species when supplemented to diets in appropriate amounts, for the consumer and the environment. l‐Arginine produced by C. glutamicum KCCM 10741P is considered corrosive to skin and eyes and therefore poses a risk by inhalation. The additive is an effective source of arginine for all species. For the supplemental l‐arginine to be as efficacious in ruminants as in non‐ruminant species, it requires protection against microbial degradation in the rumen.

Safety and efficacy of l‐arginine produced by fermentation with Escherichia coli NITE BP‐02186 for all animal species

Abstract l‐Arginine is considered as a non‐essential amino acid for most adult mammalian species, but it is classified as essential for birds, fish, possibly reptiles and also for strict carnivores. l‐Arginine produced by fermentation with Escherichia coli NITE BP‐02186, genetically modified to enhance the production of l‐arginine, is intended to be used in feed and water for drinking for all animal species and categories. The product under assessment does not give rise to any safety concern with regard to the genetic modification of the production strain. Its use as a nutritional additive is safe for target species when supplemented to diets in appropriate amounts. The use of l‐arginine as a feed flavouring agent is unlikely to pose any concern. No risks are expected for the consumer from the use of the product under assessment as a feed additive. It is not irritant to skin or eyes, nor a skin sensitiser. Although the presence of endotoxin activity is of no concern, the available exposure and toxicological data indicate that the additive may pose a risk to users by inhalation. The use of this additive in animal nutrition does not pose a risk to the environment. The additive is an effective source of arginine for all species. l‐Arginine is considered efficacious when used as a flavouring compound in animal nutrition.

Safety of zinc chelate of methionine sulfate for the target species

Abstract Zinc chelate of methionine sulfate is intended to be used as a nutritional additive (functional group: compounds of trace elements). The additive is zinc chelated with methionine in a molar ratio 1:1. It is intended to supply zinc as a nutritional additive to all animal species/categories. In 2017, the EFSA Panel on Additives and Products or Substances used in Animal Feed (FEEDAP) adopted an opinion on the safety and efficacy of zinc chelate of methionine sulfate for all animal species. In that opinion, the Panel could not conclude on the safety of the additive for the target species. The Commission gave the applicant the possibility of submitting additional information to allow the FEEDAP Panel to complete its assessment. For this reason, additional data have been provided related to the safety of the additive for the target species and this new information is the subject of this opinion. The new tolerance study on chickens for fattening has been assessed; the results of this study indicate that the additive does not promote adverse effects in the birds as compared to an inorganic source of zinc (zinc oxide). The FEEDAP Panel concluded that the additive under assessment ‘zinc chelate of methionine sulfate’ is safe for chickens for fattening when used up to the maximum content of zinc in complete feed authorised in the EU; this conclusion is extended to all animal species.

Guidance on the assessment of the efficacy of feed additives

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 assessment of the efficacy of feed additives. Draft Endorsed by the FEEDAP Panel 28 November 2018 Submitted for public consultation 4 December 2017 End of public consultation 28 January 2018 Adoption by the FEEDAP Panel 17 April 2018 Implementation date 1 September 2018

Scientific Opinion on the safety and efficacy of Aviax 5% (semduramicin sodium) for chickens for fattening

Abstract The feed additive Aviax 5%, containing the active substance semduramicin sodium, an ionophore anticoccidial, is intended to control coccidiosis in chickens for fattening at a dose of 20−25 mg/kg complete feed. Semduramicin sodium is present in Aviax 5% in its mycelial form and is produced by fermentation of Actinomadura spp. (ATCC 53664). Semduramicin sodium is active against certain Gram‐positive bacteria, while Gram‐negative bacteria are resistant; its use as a feed additive is unlikely to increase shedding of Salmonella, Escherichia coli and Campylobacter and to induce resistance and cross‐resistance to antimicrobials used of human and animal relevance. In the absence of a tolerance study in chickens for fattening performed according to the current EU standards, the FEEDAP Panel cannot conclude on the safety of Aviax 5%, containing semduramicin mycelium. Semduramicin sodium in the feed is not compatible with the concurrent use of tiamulin. Mycelial semduramicin sodium is not genotoxic. There is no evidence that the mycelial semduramicin is more toxic than the crystalline by oral administration. The acceptable daily intake (ADI) of 0.00125 mg/kg set for the crystalline semduramicin is applicable to mycelial semduramicin. The use of semduramicin sodium is safe for the consumer provided a withdrawal time of 24 h is respected. No conclusions can be made on the irritancy of Aviax 5% to skin and eye and on the potential for dermal and respiratory sensitisation. Model calculations on inhalation exposure of persons handling the additive indicate a serious risk. Aviax 5% used in feed for chickens for fattening up to 25 mg/kg complete feed does not pose a risk for the terrestrial compartment. A risk for the aquatic compartment and for groundwater pollution cannot be excluded. Aviax 5% at a minimum dose of 20 mg/kg feed has the potential to effectively control coccidiosis in chickens for fattening.