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Following a request from the European Commission, EFSA was asked to deliver a scientific opinion on the assessment of the application for renewal of the authorisation of Enterococcus lactis NCIMB 11181 (Lactiferm®) as a zootechnical additive for weaned piglets, calves for fattening and calves for rearing. The product under assessment is based on a strain originally identified as Enterococcus faecium. During the current assessment, the active agent has been reclassified as Enterococcus lactis. The additive currently authorised is marketed in two formulations: Lactiferm Basic 50 (a solid formulation to be used in feed), and Lactiferm WS200 (a solid ‘water‐soluble’ formulation to be used in water for drinking). The applicant has provided evidence that the additive currently on the market complies with the existing conditions of authorisation. The Panel concludes that the use of Lactiferm® under the authorised conditions of use remains safe for the target species (calves up to 6 months and weaned piglets up to 35 kg), consumers and the environment. The Lactiferm WS200 formulation of the additive is not irritant to skin or eyes. Owing to the proteinaceous nature of the active agent, both formulations of the additive are considered respiratory sensitisers. It is not possible to conclude on the irritating potential for skin and eyes of the Lactiferm Basic 50 formulation or on the potential of both forms of the additive to cause skin sensitisation. There is no need for assessing the efficacy of the additive in the context of the renewal of the authorisation.

The EFSA ANS Panel was asked to provide a scientific opinion on the safety of green tea catechins from dietary sources including preparations such as food supplements and infusions. Green tea is produced from the leaves of Camellia sinensis (L.) Kuntze, without fermentation, which prevents the oxidation of polyphenolic components. Most of the polyphenols in green tea are catechins. The Panel considered the possible association between the consumption of (‐)‐epigallocatechin‐3‐gallate (EGCG), the most relevant catechin in green tea, and hepatotoxicity. This scientific opinion is based on published scientific literature, including interventional studies, monographs and reports by national and international authorities and data received following a public ‘Call for data’. The mean daily intake of EGCG resulting from the consumption of green tea infusions ranges from 90 to 300 mg/day while exposure by high‐level consumers is estimated to be up to 866 mg EGCG/day, in the adult population in the EU. Food supplements containing green tea catechins provide a daily dose of EGCG in the range of 5–1,000 mg/day, for adult population. The Panel concluded that catechins from green tea infusion, prepared in a traditional way, and reconstituted drinks with an equivalent composition to traditional green tea infusions, are in general considered to be safe according to the presumption of safety approach provided the intake corresponds to reported intakes in European Member States. However, rare cases of liver injury have been reported after consumption of green tea infusions, most probably due to an idiosyncratic reaction. Based on the available data on the potential adverse effects of green tea catechins on the liver, the Panel concluded that there is evidence from interventional clinical trials that intake of doses equal or above 800 mg EGCG/day taken as a food supplement has been shown to induce a statistically significant increase of serum transaminases in treated subjects compared to control.

The prompt identification of chemical molecules with potential effects on liver may help in drug discovery and in raising the levels of protection for human health. Besides approaches, computational methods in toxicology are drawing attention. We built a structure-activity relationship (SAR) model for evaluating hepatotoxicity. After compiling a data set of 950 compounds using data from the literature, we randomly split it into training (80%) and test sets (20%). We also compiled an external validation set (101 compounds) for evaluating the performance of the model. To extract structural alerts (SAs) related to hepatotoxicity and non-hepatotoxicity we used SARpy, a statistical application that automatically identifies and extracts chemical fragments related to a specific activity. We also applied the chemical grouping approach for manually identifying other SAs. We calculated accuracy, specificity, sensitivity and Matthews correlation coefficient (MCC) on the training, test and external validation sets. Considering the complexity of the endpoint, the model performed well. In the training, test and external validation sets the accuracy was respectively 81, 63, and 68%, specificity 89, 33, and 33%, sensitivity 93, 88, and 80% and MCC 0.63, 0.27, and 0.13. Since it is preferable to overestimate hepatotoxicity rather than not to recognize unsafe compounds, the model's architecture followed a conservative approach. As it was built using human data, it might be applied without any need for extrapolation from other species. This model will be freely available in the VEGA platform.

BackgroundThe potential for a compound to cause hepatotoxicity and nephrotoxicity is a matter of extreme interest for human health risk assessment. To assess liver and kidney toxicity, repeated-dose toxicity (RDT) studies are conducted mainly on rodents. However, these tests are expensive, time-consuming and require large numbers of animals. For early toxicity screening, in silico models can be applied, reducing the costs, time and animals used. Among in silico approaches, structure–activity relationship (SAR) methods, based on the identification of chemical substructures (structural alerts, SAs) related to a particular activity (toxicity), are widely employed.ResultsWe identified and evaluated some SAs related to liver and kidney toxicity, using RDT data on rats taken from the hazard evaluation support system (HESS) database. We considered only SAs that gave the best percentages of true positives (TP).ConclusionsIt was not possible to assign an unambiguous mode of action for all the SAs, but a mechanistic explanation is provided for some of them. Such achievements may help in the early identification of liver and renal toxicity of substances.

The Panel on Food Additives and Nutrient Sources added to Food (ANS) was asked to deliver a scientific opinion on the safety of monacolins in red yeast rice (RYR) and to provide advice on a dietary intake of monacolins that does not give rise to concerns about harmful effects to health. The Panel reviewed the scientific evidences available as well as the information provided by interested parties in response of a public ‘Call for data’ launched by EFSA. The Panel considered that monacolin K in lactone form is identical to lovastatin, the active ingredient of several medicinal products authorised for the treatment of hypercholesterolaemia in the EU. On the basis of the information available, the Panel concluded that intake of monacolins from RYR via food supplements, could lead to estimated exposure to monacolin K within the range of the therapeutic doses of lovastatin. The Panel considered that the available information on the adverse effects reported in humans were judged to be sufficient to conclude that monacolins from RYR when used as food supplements were of significant safety concern at the use level of 10 mg/day. The Panel further considered that individual cases of severe adverse reactions have been reported for monacolins from RYR at intake levels as low as 3 mg/day. The Panel concluded that exposure to monacolin K from RYR could lead to severe adverse effects on musculoskeletal system, including rhabdomyolysis, and on the liver. In the reported cases, the product contained other ingredients in addition to RYR. However, these reported effects in particular musculoskeletal effects, have both occurred after ingestion of monacolin K and lovastatin independently. On the basis of the information available and several uncertainties highlighted in this opinion, the Panel was unable to identify a dietary intake of monacolins from RYR that does not give rise to concerns about harmful effects to health, for the general population, and as appropriate, for vulnerable subgroups of the population.

The Panel on Food Additives and Nutrient Sources added to Food (ANS) provided a scientific opinion re‐evaluating the safety of sodium nitrate (E 251) and potassium nitrate (E 252) when used as food additives. The current acceptable daily intakes (ADIs) for nitrate of 3.7 mg/kg body weight (bw) per day were established by the SCF (1997) and JECFA (2002). The available data did not indicate genotoxic potential for sodium and potassium nitrate. The carcinogenicity studies in mice and rats were negative. The Panel considered the derivation of an ADI for nitrate based on the formation of methaemoglobin, following the conversion of nitrate, excreted in the saliva, to nitrite. However, there were large variations in the data on the nitrate‐to‐nitrite conversion in the saliva in humans. Therefore, the Panel considered that it was not possible to derive a single value of the ADI from the available data. The Panel noticed that even using the highest nitrate‐to‐nitrite conversion factor the methaemoglobin levels produced due to nitrite obtained from this conversion would not be clinically significant and would result to a theoretically estimated endogenous N‐nitroso compounds (ENOC) production at levels which would be of low concern. Hence, and despite the uncertainty associated with the ADI established by the SCF, the Panel concluded that currently there was insufficient evidence to withdraw this ADI. The exposure to nitrate solely from its use as a food additive was estimated to be less than 5% of the overall exposure to nitrate in food based on a refined estimated exposure scenario. This exposure did not exceed the current ADI (SCF, 1997). However, if all sources of exposure to dietary nitrate are considered (food additive, natural presence and contamination), the ADI would be exceeded for all age groups at the mean and the highest exposure.

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 expressed lemon oil and distilled lemon oil from Citrus limon (L.) Osbeck and lime oil from Citrus aurantiifolia (Christm.) Swingle, when used as sensory additives in feed for all animal species. The use of the expressed lemon oil and its residual fraction and the use of lime oil in feed is not expected to increase the exposure to furocoumarins and methoxycoumarins and perillaldehyde of those target species that are already fed citrus by‐products a relevant extent (< 10%). For companion animals and ornamental fish not normally exposed to citrus by‐products, no conclusion can be drawn. For the other species and for the distilled fraction of expressed lemon oil, the FEEDAP Panel concludes that the additives under assessment are safe at the maximum proposed or at reduced use levels in complete feed. The Panel considers that the use in water for drinking is safe provided that the total daily intake of the additive does not exceed the daily amount that is considered safe when consumed via feed. No concerns for consumer safety were identified following the use of the additives at the maximum proposed use level in feed. The additives under assessment should be considered as irritants to skin and eyes and the respiratory tract and as skin sensitisers. Since expressed lemon oil and its fractions contain furocoumarins, they may cause phototoxicity. The use of the additives under the proposed conditions of use in animal feed is not expected to pose a risk for the environment. Since C. limon and C. aurantiifolia and their preparations are recognised to flavour food and its function in feed would be essentially the same as that in food, no further demonstration of efficacy is considered necessary.

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 leaves of Laurus nobilis L. (laurel leaf oil), when used as a sensory additive for all animal species. The additive contains up to 4% methyleugenol. The use of the additive at 2 mg/kg complete feed in dogs and cats was considered of low concern. For other long‐living and reproductive animals, the use of the additive at 10 mg/kg was considered of concern. For short‐living animals, the Panel had no safety concern when the additive is used at 10 mg/kg complete feed for turkeys for fattening, piglets and other growing Suidae, pigs for fattening, veal calves (milk replacer), cattle for fattening and other growing ruminants, horses and rabbits for meat production, salmonids and other fin fish; and at 8.5 mg/kg for chickens for fattening, other growing poultry and other minor species for fattening. The use of laurel leaf oil up to the highest level in feed which was considered of no concern for target animals was also expected to be of no concern for consumers. The additive should be considered as irritant to skin and eyes and the respiratory tract. Due to the high concentration of methyleugenol (≥ 1%), the additive was classified by the applicant as suspected of causing genetic defects and of causing cancer and should be handled accordingly. The use of the additive under the proposed conditions of use was not expected to pose a risk for the environment. Since the leaves of L. nobilis and their preparations were recognised to flavour food and their function in feed would be the same, no further demonstration of efficacy was considered necessary.

The present scientific opinion deals with the evaluation of the safety of nisin (E 234) in the light of new toxicological data and with the proposed extension of use in unripened cheese and heat‐treated meat products. Nisin (E 234) is currently an authorised food additive in the EU under Annex II of Regulation (EC) 1333/2008 for use in several food categories. The safety of nisin (E 234) as a food additive has been evaluated in 2006 by the EFSA Panel on Food Additives, Flavourings, Processing Aids and Materials in Contact with Food, where an acceptable daily intake (ADI) of 0.13 mg/kg body weight (bw) was confirmed as previously established by Scientific Committee on Food (SCF). In addition to the studies previously evaluated by EFSA in 2006, the Panel considered in the present opinion, data from a new subchronic toxicity study. No adverse effects were observed in a repeated dose oral toxicity study in which rats were administered nisin A for 90 days. A no observed adverse effect level (NOAEL) of 225 mg nisin A/kg bw per day, the highest dose tested, was identified for this study. Using this NOAEL, an ADI of 1 mg nisin A/kg bw per day for nisin (E 234) was calculated applying a default uncertainty factor of 200 for extrapolation of subchronic to chronic exposure and inter‐ and intra‐species variability. The Panel calculated exposure estimates for both the current and the proposed uses based on the data available in the EFSA Comprehensive Database. The Panel considered that the overall exposure estimate was below the new ADI for nisin A for all population groups. The Panel concluded that the proposed extension of use of nisin (E 234) as a food additive in unripened cheese (at maximum level of 12 mg/kg) and in heat‐treated meat products (at maximum level of 25 mg/kg) would not be of safety concern.

Following a request from the European Commission, EFSA was asked to deliver a scientific opinion on the assessment of the application for renewal of authorisation of betaine anhydrous (3a920) as a feed additive for all animal species. In the context of the renewal application, the applicant requested a change of the authorised specifications for purity of the liquid form of betaine anhydrous from 47% to 38%. The applicant has provided data demonstrating that the additive currently in the market complies with the conditions of authorisation or with the newly proposed specifications. No new evidence that would lead the EFSA Panel on Additives and Products or Substances used in Animal Feed (FEEDAP) to reconsider its previous conclusions is available. Thus, the FEEDAP Panel concludes that the additive remains safe for the target species, consumers and the environment. Due to the lack of data, the FEEDAP Panel cannot conclude on the safety for the user of the additive. There is no need to assess the efficacy of the additive in the context of the renewal of the authorisation.