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Following a request from the European Commission, the EFSA Panel on Additives and Products or Substances used in Animal Feed (FEEDAP Panel) was asked to deliver a scientific opinion on the safety and efficacy of a copper(II)-betaine complex as nutritional feed additive for all animal species. Based on the results of a tolerance study carried out in chicken, the FEEDAP Panel concluded that the additive is safe for chickens for fattening when used up to the current maximum authorised levels of copper in feed; this conclusion was extrapolated to all animal species and categories at the respective maximum copper levels in complete feed authorised in the European Union. The FEEDAP Panel concluded that the use of the copper(II)-betaine complex in animal nutrition at the maximum copper levels authorised for the animal species poses no concern to the safety of consumers. Regarding the safety for the environment, the use of the additive in feed for terrestrial animals and land-based aquaculture is considered safe under proposed conditions of use. The data available do not allow the conclusion to be made on the safety of the additive for marine sediment when it is used in sea cages. The additive is not a skin irritant, but it is an irritant to the eyes. Due to the traces of nickel, the additive is considered to be a respiratory and skin sensitiser. The Panel could not conclude on the efficacy of the product.

Following a request from the European Commission, EFSA was asked to deliver a new scientific opinion on the coccidiostat halofuginone hydrobromide (STENOROL®) when used as a feed additive for chickens for fattening and turkeys for fattening/reared for breeding. The Panel on Additives and Products or Substances used in Animal Feed (FEEDAP) concludes that the safety for turkeys for fattening established in its previous opinion can be extended to turkeys for breeding up to 12 weeks of age. Based on the new data provided on the safety for consumer, environment and efficacy, the Panel updates its previous conclusions as follows: halofuginone hydrobromide is not genotoxic. Applying an uncertainty factor of 100 to the lowest no observed adverse effect level (NOAEL) of 0.03 mg/kg body weight (bw) per day, an acceptable daily intake (ADI) of 0.3 μg halofuginone/kg bw is established. The chronic exposure of consumers to residues of halofuginone would amount to 6–19% of the ADI after 3 days of withdrawal. Therefore, the Panel considers that the additive is safe for the consumer of tissues obtained from chickens for fattening and turkeys for fattening fed the additive at a maximum level of 3 mg/kg complete feed at a 3-day withdrawal time. For control purposes, the Panel recommends the setting of the following maximum residue limits (MRLs): liver, 50 μg/kg; kidney, 40 μg/kg; muscle, 3 μg/kg; skin/fat, 10 μg/kg wet tissue. Based on an updated environmental risk assessment, no concern for groundwater is expected. Halofuginone is unlikely to bioaccumulate and the risk of secondary poisoning is not likely to occur. No safety concerns are expected for terrestrial and aquatic environments. The additive has the potential to control coccidiosis in chickens for fattening and turkeys for fattening/reared for breeding up to 12 weeks of age at a minimum level of 2 mg/kg complete feed.

Following a request from the European Commission, EFSA was asked to deliver a scientific opinion on the safety and efficacy of a zinc(II)–betaine complex as nutritional additive for all animal species. The EFSA Panel on Additives and Products or Substances used in Animal Feed (FEEDAP) concluded that the additive is safe for chickens for fattening. This conclusion could be extrapolated to all animal species and categories provided that the maximum authorised levels in the EU for total zinc in feed are not exceeded. The FEEDAP Panel concluded that the use of the zinc(II)–betaine complex in animal nutrition is of no concern for consumer safety provided that the maximum authorised total zinc levels in feed are respected. The additive is considered to be a skin and respiratory sensitiser due to the presence of nickel; it is irritant to the eyes, but not to the skin. The use of the additive in animal nutrition for terrestrial animals and land-based aquaculture at the proposed use levels is considered safe for terrestrial and aquatic ecosystems. The available data do not allow the conclusion to be made on the safety of the additive for the marine sediment when it is used in sea cages. Based on the deposition of zinc in edible tissues/organs in chickens for fattening, the FEEDAP Panel concluded that the additive is a source of bioavailable zinc, comparable to the standard inorganic zinc source, and therefore, the additive is efficacious in meeting the birds zinc requirements. This conclusion can be extrapolated to all animal species and categories.

Following a request from the European Commission, EFSA was asked to deliver a scientific opinion on the safety and efficacy of ROVABIO® ADVANCE (liquid and solid) which contains endo-1,4-beta-xylanase and endo-1,3(4)-beta-glucanase. The enzymes present in the additive are produced by two strains of Talaromyces versatilis, one of them genetically modified. The additive is intended to be used as a feed additive for weaned piglets and pigs for fattening. Viable cells of the production strains and DNA of the genetically modified strain were not detected in the fermentation product used to formulate the additive. Based on the results of a tolerance trial in weaned piglets, the FEEDAP Panel concluded that ROVABIO® ADVANCE is safe for weaned piglets under the recommended conditions of use. This conclusion was extended to pigs for fattening. Based on the outcome of the toxicological studies performed, the Panel concluded that the additive is of no concern regarding consumer safety. ROVABIO® ADVANCE is not irritant to the skin or eyes but it is a skin and respiratory sensitiser. No risks to the environment are expected from the use of the additive in animal nutrition. Owing to the lack of sufficient data, the FEEDAP Panel could not conclude on the efficacy of ROVABIO® ADVANCE.

Following a request from the European Commission, the Panelon Additives and Products or Substances used in Animal Feed (FEEDAP) was asked to deliver a scientific opinion on the safety and efficacy of Bifidobacterium longum CNCM I-5642 (PP102I) when used as a feed additive for cats and dogs. The product under assessment consists of viable cells of a strain of B. longum, a species considered suitable for the qualified presumption of safety (QPS) approach to safety assessment. The strain was unambiguously identified as B. longum and was shown not to harbour antimicrobial resistance determinants for antibiotics of human and veterinary importance, thus meeting the QPS requirements. Following the QPS approach to safety assessment and since no concerns are expected from maltodextrin, the other component of the additive, PP102I was considered safe for the target species and the environment. Owing to the lack of data, no conclusions could be drawn on the skin/eye irritancy potential of PP102I. However, it should be considered a skin and respiratory sensitiser. The Panelwas not in the position to conclude on the efficacy of PP102I for the target 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 efficacy of HOSTAZYM® X as a feed additive for sows in order to have benefits in piglets. This additive consists of endo-1,4-β-xylanase produced by a non-genetically modified strain of Trichoderma citroviride. The additive is to be used in sows at 1,500 EPU/kg feed. In a previous opinion, the FEEDAP Panel could not conclude on the efficacy of the additive when added to feed for sows in order to have benefits in piglets. The applicant provided new efficacy data to complete the assessment of the efficacy of the additive. Based on the previously assessed data and the newly submitted one, the Panel could not conclude on the efficacy of the additive.

Following a request from the European Commission, the FEEDAP Panel was asked to deliver a scientific opinion on the safety and efficacy of l-methionine ≥ 98.5% or ≥ 90% produced by the combined activities of Corynebacterium glutamicum KCCM 80245 and Escherichia coli KCCM 80246) as nutritional additive for all animal species. The two production strains are genetically modified. l-Methionine is intended to be used in feed or water for drinking for all animal species. Neither viable cells nor recombinant DNA of the production strains were detected in the final products. The additive does not pose any safety concern associated with the genetic modification of the production strains. The use of both products of l-methionine produced by C. glutamicum KCCM 80245 and E. coli KCCM 80246 in supplementing feed to compensate for l-methionine deficiency in feedingstuffs is safe for the target species. The FEEDAP Panel has concerns about the use of amino acids in water for drinking for hygienic reasons, and due to the risk of imbalances when administered simultaneously via feed. The use of both products of l-methionine produced by C. glutamicum KCCM 80245 and E. coli KCCM 80246 in animal nutrition is considered safe for the consumers and for the environment. The additive, in either product, is not an irritant to skin/eyes and not a dermal sensitiser and shows no toxicity by inhalation. Considering the respiratory exposure to endotoxins, l-methionine ≥ 90% is a risk for the user. Both products of the additive produced by C. glutamicum KCCM 80245 and E. coli KCCM 80246 are considered as an efficacious source of the essential amino acid l-methionine for non-ruminant animal species. For the supplemental l-methionine to be as efficacious in ruminants as in non-ruminant species, it would require protection against degradation in the rumen.

Amaferm® is a fermentation product produced by Aspergillus oryzae NRRL 458, containing alpha-amylase and cellulase enzyme activities, authorised for use as a feed additive for dairy cows. In 2016, the applicant requested for the renewal of the authorisation and the EFSA Panel on Additives and Products or Substances used in Animal Feed (FEEDAP) issued an opinion at that regard in 2020. In that opinion, the Panel could not confirm the previously drawn conclusions (EFSA, 2006) regarding the safety of the production strain, and consequently could not confirm the safety of the additive for the target species and consumers. In the current submission, the applicant provided supplementary information that allowed the Panel to conclude on the identity of the production strain, redefine the specifications of the additive, and finally to conclude on its safety. Therefore, the new data provided permit to conclude that Amaferm® complies with the conditions of the authorisation. However, the Panel noted that there is the need to change the specification and description of the cellulase and amylase units in the authorisation act. The data provided in the previous (EFSA FEEDAP Panel, 2020) and the current assessments support that Amaferm® remains safe under the approved conditions for target species, consumers and the environment. The additive is non-irritant to skin and eyes, or a dermal sensitiser but should be considered a potential respiratory sensitiser.

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 BA-KING® Bacillus velezensis when used as a feed additive for chickens for fattening, turkeys for fattening, chickens reared for laying, turkeys reared for breeding and all avian species for fattening, or rearing to slaughter or point of lay including non-food producing species. The product under assessment is based on viable spores of a strain identified as B. velezensis, which is considered suitable for the qualified presumption of safety (QPS) approach to safety assessment. The identity of the active agent was established, and it does not harbour acquired antimicrobial resistance genes, lacks toxigenic potential and does not have the capacity to produce aminoglycosides. Following the QPS approach to safety assessment, B. velezensis NITE BP-01844 is presumed safe for the target species, consumers of products derived from animals fed the additive and the environment. Since no concerns are expected from the other components of the additive, BA-KING® is also considered safe for the target species, consumers of products derived from animals fed the additive and the environment. BA-KING® is not irritant to skin but is potentially irritant to eyes. In addition, should be considered a skin and respiratory sensitiser. The Panel is not in the position to conclude on the efficacy of BA-KING® for the target species.

Following a request from the European Commission, the FEEDAP Panel was asked to deliver a scientific opinion on the safety and efficacy of astaxanthin (ATX)-rich Phaffia rhodozyma. The additive, belonging to the category ‘sensory additives’ and the functional group ‘substances which, when fed to animals, add colours to food of animal origin’ is intended to be used in feed for salmon and trout from an age of six months onwards up to a maximum content of 100 mg ATX/kg complete feed. The product is produced by the telemorph of Phaffia rhodozyma, Xanthophyllomyces dendrorhous, and it is declared to contain 995 g dried inactivated biomass and 5 g ascorbic acid per kg additive. The main active principle of the additive is ATX; however, the FEEDAP Panel noted that some other carotenoids are also present in lower quantities. The minimum ATX concentration is specified to be 5,000 mg per kg additive. The yeast Xanthophyllomyces dendrorhous is considered by EFSA to be suitable for the qualified presumption of safety (QPS) approach to safety assessment; therefore, the use of the production strain in the production of the additive would not raise any safety concern for the target species, the consumers of products from animals fed the additive and the environment. In the absence of a tolerance study with the additive, the FEEDAP Panel cannot conclude on the safety for the target species. In the absence of residue and toxicity data of ATX, no final conclusions on the safety for the consumer can be drawn. The FEEDAP Panel concluded that the additive is irritant to skin and eyes, and a skin and respiratory sensitiser, although exposure by inhalation is likely low. The FEEDAP Panel considers that ATX from the biomass does not pose a significant additional risk to the environment compared with other natural sources of ATX. In absence of adequate evidence, no conclusion can be made on the efficacy of the additive.

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 assessment of the application for renewal of authorisation of Lentilactobacillus buchneri (formerly Lactobacillus buchneri) DSM 12856 as a technological additive for use in forage for all animal species. The additive aims at improving the production of silage and is authorised for all animal species. The applicant has provided evidence that the additive currently on the market complies with the existing conditions of authorisation. There is no evidence to lead the FEEDAP Panel to reconsider its previous conclusions. Thus, the Panel concludes that the additive remains safe for all animal species, consumers and the environment under the authorised conditions of use. Regarding user safety L. buchneri DSM 12856 is not irritant to skin and eyes but is considered a skin and respiratory sensitiser. There was no need for assessing the efficacy of the additive in the context of the renewal of the authorisation.

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 an additive consisting of Propionibacterium freudenreichii DSM 33189 and Lentilactobacillus buchneri (formerly Lactobacillus buchneri) DSM 12856 as a technological additive for all animal species. The additive is intended to improve the production of silage at a proposed application rate of 1 × 108 colony-forming units (CFU)/kg fresh material. The bacterial species P. freudenreichii and L. buchneri are considered by EFSA to be suitable for the qualified presumption of safety (QPS) approach to assessment. As the identity of the strains has been clearly established and no acquired antimicrobial resistance determinants of concern were detected, the use of the strains as a silage additive is considered safe for livestock species, for consumers and for the environment. The additive is not irritant for eyes or skin but should be considered a respiratory sensitiser. In the absence of data, the FEEDAP Panel could not conclude on the potential of the additive to be a skin sensitiser. The additive at the proposed application rate of 1 × 108 CFU/kg fresh plant material showed the potential to improve the aerobic stability silage with dry matter content ranging from 30% to 70%.

University of Technology, Sydney. Faculty of Science. NO FULL TEXT AVAILABLE. This thesis contains 3rd party copyright material. The hardcopy may be available for consultation at the UTS Library. NO FULL TEXT AVAILABLE. This thesis contains 3rd party copyright material. ----- The venom of the Australian lowlands copperhead, Austrelaps superbus, is capable of producing significant and potentially lethal neurotoxic paralysis in cases of clinical envenomation. However, little is known about the neurotoxic components within this venom. Furthermore, there are no pharmacological data available regarding the suspected neurotoxic components in the venoms of related alpine (A. ramsayi) or pygmy (A. labialis) copperheads (Austrelaps labialis). In the isolated chick biventer cervicis nerve-muscle (CBCNM) preparation, all Austrelaps venoms caused a potent and rapid inhibition of nerve-evoked twitch contractions that was accompanied by a block of contractures to nicotinic agonists. These actions are consistent with the presence of postsynaptic neurotoxicity. Subsequent separation of Austrelaps spp. venoms under non-reducing conditions using size-exclusion liquid chromatography revealed that all three venoms contained a high molecular mass fraction with only weak phospholipase A₂ activity. In all three venoms, this fraction caused a slow inhibition of nerve-evoked twitch contractions in the CBCNM preparation, without inhibiting contractures to nicotinic agonists or KCl. These actions are consistent with the presence of presynaptic neurotoxicity, in the absence of overt myotoxicity, attributed to by the presence of snake presynaptic PLA₂ neurotoxin (SPAN) complexes. This is the first report of presynaptic neurotoxicity in Austrelaps spp. venoms. Subsequently, the first isolated SPAN complex from A. superbus venom, P-elapitoxin-As1a (P-EPTX-As1a), was pharmacologically characterised in the CBCNM preparation. P-EPTX-As1a causes ‘tetanic fade’ in muscle tension under high frequency nerve stimulation and produces a triphasic alteration to neurotransmitter release. These actions have been previously noted with other multimeric SPAN complexes, such as taipoxin. Moreover, the neurotoxic α-subunit of P-EPTX-As1a shows high homology to taipoxin α-chain. Furthermore, the presence of a class PIII snake venom metalloproteinase, C-type lectin, L-amino acid oxidase, acetylcholinesterase and phospholipase B, with potential coagulopathic and myotoxic effects, were also identified in the same high molecular mass fraction as P-EPTX-As1a. This thesis also describes the pharmacological characterisation of α-elaiptoxin-Al2a (α-EPTX-Al2a), the first snake postsynaptic α-neurotoxin from A. labialis venom. α-Elapitoxin-Al2a was isolated from A. labialis venom using a series of liquid chromatography techniques. In the CBCNM preparation, α-EPTX-Al2a (8072.77 Da) caused a concentration-dependent block of nerve-evoked twitch contractions and a complete block of contractures to nicotinic agonists. α-Elapitoxin-Al2a produces a pseudo-irreversible antagonism of chick muscle nicotinic acetylcholine receptors (nAChRs), with an estimated pA₂ value of 7.902 (KB = 12.5 nM) but failed to inhibit ganglionic α3β2/ α3β4 nAChRs in a fluorescence-based FLIPR assay using SH-SY5Y cells. The toxin contains 75 amino acid residues with five disulphide bonds and shows significant homology to classical long-chain α-neurotoxins, however it is unique among long-chain α-neurotoxins as it only produces a modest block of neuronal α7 nAChR (IC₅₀ = 1.2 μM), despite containing the critical residue, Arg³³. Monovalent tiger snake antivenom (TSAV) is the recommended treatment following Austrelaps spp. envenomation. The efficacy of TSAV in preventing or reversing neurotoxicity induced by either whole venom or isolated neurotoxins was determined in the CBCNM preparation by adding TSAV 10 minutes prior to the addition of venom or toxin or at 90% neuromuscular blockade, respectively. This thesis confirms the effectiveness of TSAV in neutralising the neurotoxicity of A. superbus whole venom. In addition, this thesis provides the first in vitro study to confirm the effectiveness of TSAV to neutralise the neurotoxicity of A. labialis and A. ramsayi whole venoms as well as isolated P-EPTX-As1a and α-EPTX-Al2a. Thus, this thesis supports the current clinical recommendation for the use of TSAV in the treatment of envenomation by all Austrelaps spp. This thesis also found that TSAV was unable to effectively reverse the neurotoxicity of Austrelaps spp. venoms, prejunctional SPAN neurotoxicity caused by the SPAN complex in all three venoms, or postsynaptic neurotoxicity caused by α-EPTX-Al2a once established. In conclusion, this thesis is the first study that confirms the suspected presence of both presynaptic and postsynaptic neurotoxic components in all Austrelaps spp. venoms. Furthermore, this thesis represents the first in vitro study to assess the efficacy of TSAV in preventing and reversing neurotoxicity caused by Austrelaps spp. venoms and their isolated neurotoxic components. Given that the neurotoxic effects caused by these venoms are only partially reversible once neurotoxicity is well established, clinicians should be aware that early antivenom intervention may be necessary to prevent the onset of irreversible neurotoxicity caused by irreversible multimeric SPAN complexes and snake postsynaptic α-neurotoxins in Austrelaps spp. venoms.