Towards a mechanism-based approach for the prediction of nongenotoxic carcinogenic potential of agrochemicals.

Chemical substances are subjected to assessment of genotoxic and carcinogenic effects before being marketed to protect man and the environment from health risks. For agrochemicals, the long-term rodent carcinogenicity study is currently required from a regulatory perspective. Although it is the current mainstay for the detection of nongenotoxic carcinogens, carcinogenicity studies are shown to have prominent weaknesses and are subject to ethical and scientific debate. A transition toward a mechanism-based weight-of-evidence approach is considered a requirement to enhance the prediction of carcinogenic potential for environmental (agro)chemicals. The resulting approach should make optimal use of innovative (computational) tools and be less animal demanding. To identify the various mode of actions (MOAs) underlying the nongenotoxic carcinogenic potential of agrochemicals, we conducted an extensive analysis of 411 unique agrochemicals that have been evaluated for carcinogenicity by the United States Environmental Protection Agency (US EPA) and the European Chemicals Agency (ECHA). About one-third of these substances could be categorized as nongenotoxic carcinogens with an average of approximately two tumor types per substance, observed in a variety of organs. For two-third of the tumor cases, an underlying MOA (network) could be identified. This analysis demonstrates that a limited set of MOA (networks) is underlying nongenotoxic carcinogenicity of agrochemicals, illustrating that the transition toward a MOA-driven approach appears manageable. Ultimately the approach should cover relevant MOAs and its associated key events; this will also facilitate the evaluation of the human relevance. This manuscript describes the results of the analysis while identifying knowledge gaps and necessities to achieve a mechanism-based weight-of-evidence approach.

A comprehensive view on mechanistic approaches for cancer risk assessment of non-genotoxic agrochemicals.

Currently the only methods for non-genotoxic carcinogenic hazard assessment accepted by most regulatory authorities are lifetime carcinogenicity studies. However, these involve the use of large numbers of animals and the relevance of their predictive power and results has been scientifically challenged. With increased availability of innovative test methods and enhanced understanding of carcinogenic processes, it is believed that tumour formation can now be better predicted using mechanistic information. A workshop organised by the European Partnership on Alternative Approaches to Animal Testing brought together experts to discuss an alternative, mechanism-based approach for cancer risk assessment of agrochemicals. Data from a toolbox of test methods for detecting modes of action (MOAs) underlying non-genotoxic carcinogenicity are combined with information from subchronic toxicity studies in a weight-of-evidence approach to identify carcinogenic potential of a test substance. The workshop included interactive sessions to discuss the approach using case studies. These showed that fine-tuning is needed, to build confidence in the proposed approach, to ensure scientific correctness, and to address different regulatory needs. This novel approach was considered realistic, and its regulatory acceptance and implementation can be facilitated in the coming years through continued dialogue between all stakeholders and building confidence in alternative approaches.

Is current risk assessment of non-genotoxic carcinogens protective?

Non-genotoxic carcinogens (NGTXCs) do not cause direct DNA damage but induce cancer via other mechanisms. In risk assessment of chemicals and pharmaceuticals, carcinogenic risks are determined using carcinogenicity studies in rodents. With the aim to reduce animal testing, REACH legislation states that carcinogenicity studies are only allowed when specific concerns are present; risk assessment of compounds that are potentially carcinogenic by a non-genotoxic mode of action is usually based on subchronic toxicity studies. Health-based guidance values (HBGVs) of NGTXCs may therefore be based on data from carcinogenicity or subchronic toxicity studies depending on the legal framework that applies. HBGVs are usually derived from No-Observed-Adverse-Effect-Levels (NOAELs). Here, we investigate whether current risk assessment of NGTXCs based on NOAELs is protective against cancer. To answer this question, we estimated Benchmark doses (BMDs) for carcinogenicity data of 44 known NGTXCs. These BMDs were compared to the NOAELs derived from the same carcinogenicity studies, as well as to the NOAELs derived from the associated subchronic studies. The results lead to two main conclusions. First, a NOAEL derived from a subchronic study is similar to a NOAEL based on cancer effects from a carcinogenicity study, supporting the current practice in REACH. Second, both the subchronic and cancer NOAELs are, on average, associated with a cancer risk of around 1% in rodents. This implies that for those chemicals that are potentially carcinogenic in humans, current risk assessment of NGTXCs may not be completely protective against cancer. Our results call for a broader discussion within the scientific community, followed by discussions among risk assessors, policy makers, and other stakeholders as to whether or not the potential cancer risk levels that appear to be associated with currently derived HBGVs of NGXTCs are acceptable.

Integrating in vitro data and physiologically based kinetic (PBK) modelling to assess the in vivo potential developmental toxicity of a series of phenols.

Toxicity outcomes derived in vitro do not always reflect in vivo toxicity values, which was previously observed for a series of phenols tested in the embryonic stem cell test (EST). Translation of in vitro data to the in vivo situation is therefore an important, but still limiting step for the use of in vitro toxicity outcomes in the safety assessment of chemicals. The aim of the present study was to translate in vitro embryotoxicity data for a series of phenols to in vivo developmental toxic potency values for the rat by physiologically based kinetic (PBK) modelling-based reverse dosimetry. To this purpose, PBK models were developed for each of the phenols. The models were parameterised with in vitro-derived values defining metabolism and transport of the compounds across the intestinal and placental barrier and with in silico predictions and data from the literature. Using PBK-based reverse dosimetry, in vitro concentration-response curves from the EST were translated into in vivo dose-response curves from which points of departure (PoDs) were derived. The predicted PoDs differed less than 3.6-fold from PoDs derived from in vivo toxicity data for the phenols available in the literature. Moreover, the in vitro PBK-based reverse dosimetry approach could overcome the large disparity that was observed previously between the in vitro and the in vivo relative potency of the series of phenols. In conclusion, this study shows another proof-of-principle that the in vitro PBK approach is a promising strategy for non-animal-based safety assessment of chemicals.

The Isolated Chicken Eye test to replace the Draize test in rabbits.

In 1944, Draize et al., published a paper entitled "Methods for the study of irritation and toxicity of substances applied topically to the skin and mucous membranes". The Organization for Economic Co-operation and Development published their first guideline on eye irritation in 1981, using rabbits. In the early eighties the development of alternative non-animal tests to replace the Draize eye test started. The first attempts to validate alternative tests for eye irritation were considered to be relatively simple by comparing in vitro and in vivo irritation index scores. In the early nineteen-eighties, we introduced the use of isolated eyes as an alternative test for the Draize eye irritation test. What was expected to be a process of several years, however, turned out to be a decades spanning process still not fully completed. For a large part, this can be attributed to the nature of the in vivo test in rabbits, which is more complicated and compromised than originally believed. This paper describes, most chronologically, the development, performance, validation and application of the Isolated Eye Test and, in broader perspective, the international validation and acceptance of this alternative test by regulatory authorities and agencies.

An integrative test strategy for cancer hazard identification.

Assessment of genotoxic and carcinogenic potential is considered one of the basic requirements when evaluating possible human health risks associated with exposure to chemicals. Test strategies currently in place focus primarily on identifying genotoxic potential due to the strong association between the accumulation of genetic damage and cancer. Using genotoxicity assays to predict carcinogenic potential has the significant drawback that risks from non-genotoxic carcinogens remain largely undetected unless carcinogenicity studies are performed. Furthermore, test systems already developed to reduce animal use are not easily accepted and implemented by either industries or regulators. This manuscript reviews the test methods for cancer hazard identification that have been adopted by the regulatory authorities, and discusses the most promising alternative methods that have been developed to date. Based on these findings, a generally applicable tiered test strategy is proposed that can be considered capable of detecting both genotoxic as well as non-genotoxic carcinogens and will improve understanding of the underlying mode of action. Finally, strengths and weaknesses of this new integrative test strategy for cancer hazard identification are presented.

Prediction of carcinogenic potential of chemicals using repeated-dose (13-week) toxicity data.

Sub-chronic toxicity studies of 163 non-genotoxic chemicals were evaluated in order to predict the tumour outcome of 24-month rat carcinogenicity studies obtained from the EFSA and ToxRef databases. Hundred eleven of the 148 chemicals that did not induce putative preneoplastic lesions in the sub-chronic study also did not induce tumours in the carcinogenicity study (True Negatives). Cellular hypertrophy appeared to be an unreliable predictor of carcinogenicity. The negative predictivity, the measure of the compounds evaluated that did not show any putative preneoplastic lesion in de sub-chronic studies and were negative in the carcinogenicity studies, was 75%, whereas the sensitivity, a measure of the sub-chronic study to predict a positive carcinogenicity outcome was only 5%. The specificity, the accuracy of the sub-chronic study to correctly identify non-carcinogens was 90%. When the chemicals which induced tumours generally considered not relevant for humans (33 out of 37 False Negatives) are classified as True Negatives, the negative predictivity amounts to 97%. Overall, the results of this retrospective study support the concept that chemicals showing no histopathological risk factors for neoplasia in a sub-chronic study in rats may be considered non-carcinogenic and do not require further testing in a carcinogenicity study.

Predicting individual responses to pravastatin using a physiologically based kinetic model for plasma cholesterol concentrations.

We used a previously developed physiologically based kinetic (PBK) model to analyze the effect of individual variations in metabolism and transport of cholesterol on pravastatin response. The PBK model is based on kinetic expressions for 21 reactions that interconnect eight different body cholesterol pools including plasma HDL and non-HDL cholesterol. A pravastatin pharmacokinetic model was constructed and the simulated hepatic pravastatin concentration was used to modulate the reaction rate constant of hepatic free cholesterol synthesis in the PBK model. The integrated model was then used to predict plasma cholesterol concentrations as a function of pravastatin dose. Predicted versus observed values at 40 mg/d pravastatin were 15 versus 22 % reduction of total plasma cholesterol, and 10 versus 5.6 % increase of HDL cholesterol. A population of 7,609 virtual subjects was generated using a Monte Carlo approach, and the response to a 40 mg/d pravastatin dose was simulated for each subject. Linear regression analysis of the pravastatin response in this virtual population showed that hepatic and peripheral cholesterol synthesis had the largest regression coefficients for the non-HDL-C response. However, the modeling also showed that these processes alone did not suffice to predict non-HDL-C response to pravastatin, contradicting the hypothesis that people with high cholesterol synthesis rates are good statin responders. In conclusion, we have developed a PBK model that is able to accurately describe the effect of pravastatin treatment on plasma cholesterol concentrations and can be used to provide insight in the mechanisms behind individual variation in statin response.

Risk assessment of feed components of botanical origin - Approaches taken in the European Union.

In view of a continuous trend in replacing synthetic feed additives and especially flavouring compounds by botanical preparations, different aspects of the safety evaluations of plants and plant-derived preparations and components in feed are discussed. This includes risk assessment approaches developed by the European Food Safety Authority (EFSA) for phytotoxins regarding unintentional exposure of target animals and of consumers to animal derived food via carry-over from feed. Relevant regulatory frameworks for feed additives and feed contaminants in the European Union are summarised and the essentials of existing guidelines used in the safety evaluation of botanicals and their preparations and components in feed are outlined. The examples presented illustrate how the safety of the botanicals, their preparations and components present in feed is assessed. An outlook on possible future developments in risk assessment by applying new in vitro and in silico methodologies is given.

Assessment of the feed additive consisting of Saccharomyces cerevisiaeMUCL 39885 (Biosprint®) for cattle for fattening for the renewal of its authorisation (Prosol SPA).

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 Saccharomyces cerevisiae MUCL 39885 (Biosprint®) as a feed additive for cattle for fattening (category: zootechnical; functional group: gut flora stabiliser). The applicant provided evidence that the additive currently in the market complies with the conditions of authorisation. The EFSA Panel on Additives and Products or Substances used in Animal Feed (FEEDAP) confirmed that the use of Biosprint® under the current authorised conditions of use remains safe for the target species, the consumers and the environment. Taking into account the nature of the additive, the FEEDAP Panel concludes that the additive should be considered as a potential skin and respiratory sensitiser, and any exposure through skin and respiratory tract is considered a risk. The additive is not a skin/eye irritant. There is no need to assess the efficacy of Biosprint® in the context of the renewal of the authorisation.

Safety and efficacy of a feed additive consisting of lanthanum carbonate octahydrate for dogs (Porus GmbH).

Following a request from the European Commission, EFSA was asked to deliver a scientific opinion on the safety and efficacy of lanthanum carbonate octahydrate as a zootechnical feed additive for dogs. The additive is already authorised for use in feed for cats. The FEEDAP Panel concluded that the additive lanthanum carbonate octahydrate is safe for adult dogs at the maximum recommended level of 7500 mg/kg complete feed. The additive is not irritant to skin or eyes, is not a skin sensitiser and exposure by inhalation is considered to be unlikely. The Panel also concluded that lanthanum carbonate octahydrate is efficacious in the reduction of phosphorus bioavailability in adult dogs at the minimum inclusion level of 1500 mg/kg complete feed.

Safety and efficacy of a feed additive consisting of l-threonine (produced with Escherichia coliCGMCC 7.455) for all animal species (Kempex Holland B.V.).

Following a request from the European Commission, EFSA was asked to deliver a scientific opinion on the safety and efficacy of the feed additive consisting of l-threonine produced by fermentation with Escherichia coli CGMCC 7.455 when used as a nutritional additive in feed and water for drinking for all animal species and categories. The production strain is genetically modified. None of the introduced genetic modifications raised a safety concern. Viable cells of the production strain and its DNA were not detected in the final additive. Therefore, the final product does not give raise to any safety concern regarding the genetic modification of the production strain. The use of l-threonine (≥ 98.5%) produced with E. coli CGMCC 7.455 to supplement feed is safe for the target species. The Panel on Additives and Products or Substances used in Animal Feed (FEEDAP) has concerns on the safety of the simultaneous oral administration of l-threonine via water for drinking and feed due to possible amino acid imbalances and hygienic reasons. The use of l-threonine produced with E. coli CGMCC 7.455 in animal nutrition raises no safety concerns to consumers of animal products and to the environment. In the absence of data, the FEEDAP Panel cannot conclude on the potential of the additive to be irritant to skin or eyes, or on its potential to be a dermal sensitiser. The endotoxin activity in the additive does not pose a risk for the user via inhalation. The additive l-threonine is regarded as an effective source of the amino acid l-threonine for all non-ruminant species. In order to be as efficacious in ruminants as in non-ruminants, it should be protected from ruminal degradation.

Safety and efficacy of a feed additive consisting of l-tryptophan (produced with Escherichia coliCGMCC 7.460) for all animal species (Kempex Holland B.V.).

Following a request from the European Commission, EFSA was asked to deliver a scientific opinion on the safety and efficacy of the feed additive consisting of l-tryptophan produced by fermentation with Escherichia coli CGMCC 7.460 when used as a nutritional additive in feed and water for drinking for all animal species and categories. The production strain is not genetically modified. Viable cells of the production strain were not detected in the final additive. The additive does not give rise to any safety concern regarding the production strain. The use of l-tryptophan (≥ 98%) produced with E. coli CGMCC 7.460 to supplement feed is safe for non-ruminant species. There may be a risk for an increased production of toxic metabolites when unprotected tryptophan is used in ruminants. The EFSA Panel on Additives and Products or Substances used in Animal Feed (FEEDAP) has concerns on the safety of the simultaneous oral administration of l-tryptophan via water for drinking and feed due to possible amino acid imbalances and hygienic reasons. The use of l-tryptophan produced with E. coli CGMCC 7.460 in animal nutrition raises no safety concerns to consumers of animal products and to the environment. In the absence of data, the FEEDAP Panel cannot conclude on the potential of the additive to be irritant to skin or eyes, or on its potential to be a dermal sensitiser. The endotoxin activity of the additive in combination with the high dusting potential may represent a risk of exposure by inhalation to endotoxins for users. The additive l-tryptophan is regarded as an effective source of the amino acid l-tryptophan for all non-ruminant species. To be as efficacious in ruminants as in non-ruminants, it should be protected from ruminal degradation.

Safety and efficacy of a feed additive consisting of a tincture derived from the dried fruit of Schisandra chinensis (Turcz.) Baill. (omicha tincture) for poultry, horses, dogs and cats (FEFANA asbl).

Following a request from the European Commission, EFSA was asked to deliver a scientific opinion on the safety and efficacy of a tincture from the dried fruit of Schisandra chinensis (Turcz.) Baill. (omicha tincture), when used as a sensory additive in feed for horses, cats, dogs, and in feed and in water for drinking for poultry. The product is a water/ethanol (55:45 v/v) solution, with a dry matter content of not more than 4% (w/w) and a content of 0.01%-0.15% (w/w) for the sum of schisandrin and deoxyschisandrin. The Panel on Additives and Products or Substances used in Animal Feed (FEEDAP) concluded that omicha tincture is safe at the following concentrations in complete feed: 16 mg/kg for turkeys for fattening, 12 mg/kg for chickens for fattening and other poultry for fattening or reared for laying/reproduction, 18 mg/kg for laying hens and other laying/reproductive birds, 56 mg/kg for dogs and 47 mg/kg for horses and cats. The additive is considered safe for consumers when used up to the highest safe level in feed for poultry species and horses. Omicha tincture should be considered as irritants to skin and eyes, and as dermal and respiratory sensitisers. The use of omicha tincture as a flavour in feed for poultry species and horses was not considered to be a risk to the environment. Since it was recognised that the fruit of S. chinensis can influence sensory properties of feedingstuffs, no further demonstration of efficacy was considered necessary for the tincture under assessment.

Safety and efficacy of a feed additive consisting of an essential oil derived from fresh leaves of Melaleuca cajuputi Maton & Sm. ex R. Powell and Melaleuca leucadendra (L.) L. (cajuput oil) for use in all animal species (FEFANA asbl).

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 cajuput oil obtained from fresh leaves of Melaleuca cajuputi Maton & Sm. ex R. Powell and Melaleuca leucadendra (L.) L., when used as a sensory additive for all animal species. The FEEDAP Panel concluded that cajuput oil is safe up to the maximum proposed use levels in complete feed of 30 mg/kg for sows and dogs, 50 mg/kg for horses and ornamental fish, 40 mg/kg for salmon and 5 mg/kg for cats. For the other species, the calculated safe concentrations were 18 mg/kg for chickens for fattening, 26 mg/kg for laying hens, 23 mg/kg for turkeys for fattening, 37 mg/kg for pigs for fattening, 31 mg/kg for piglets, 78 mg/kg for veal calves (milk replacer), 69 mg/kg for cattle for fattening and sheep/goats, 45 mg/kg for dairy cows and 28 mg/kg for rabbits. These conclusions were extrapolated to other physiologically related species. For any other species, the additive is safe at 5 mg/kg complete feed. The use of cajuput oil in water for drinking was considered safe provided that the total daily intake does not exceed the daily amount considered safe when consumed via feed. No concerns for consumers and the environment were identified following the use of the additive up to the highest safe use level in feed. The essential oil under assessment should be considered as an irritant to skin and eyes, and as a dermal and respiratory sensitiser. Since cajuput oil was recognised to flavour food and their function in feed would be essentially the same as that in food, no further demonstration of efficacy was considered necessary.

Safety and efficacy of a feed additive consisting of a dry extract obtained from the leaves of Ginkgo biloba L. (ginkgo extract) for horses, dogs, cats, rabbits and guinea pigs (FEFANA asbl).

Following a request from the European Commission, EFSA was asked to deliver a scientific opinion on the safety and efficacy of a feed additive obtained from the dried leaves of Ginkgo biloba L. (ginkgo extract) when used as a sensory additive in feed for horses, dogs, cats, rabbits and guinea pigs. Ginkgo extract contains ≥ 24% total flavonoids, ≥ 6% total terpene lactones and ≤ 1 mg/kg ginkgolic acids. The EFSA Panel on Additives and Products or Substances used in Animal Feed (FEEDAP) concluded that ginkgo extract is safe for the target species at the following concentrations in complete feed: 2.8 mg/kg for horses and cats, 1.1 mg/kg for rabbits and guinea pigs, and 3.3 mg/kg for dogs. No safety concern would arise for the consumers from the use of ginkgo extract up to the highest level in feed which is considered safe for food-producing species (horses and rabbits). The additive should be considered as irritant to skin and eyes, and as a dermal and respiratory sensitiser. The use of the additive at the proposed level in feed for the target species is not considered to be a risk to the environment. While the available data indicate that Ginkgo preparations have a distinctive flavour profile, there is no evidence that the ginkgo extract would impart flavour to a food or feed matrix. Therefore, the FEEDAP Panel cannot conclude on the efficacy of the additive.

Assessment of the feed additive consisting of l-cystine for all animal species for the renewal of its authorisation (Bretagne Chimie Fine [BCF Life Sciences]).

Following a request from the European Commission, EFSA was asked to deliver a scientific opinion on the assessment of the application for the renewal of the authorisation of l-cystine as nutritional feed additive. The additive is authorised for use in all animal species (3c391). The applicant has provided evidence that the additive currently in the market complies with the existing conditions of authorisation. The EFSA Panel on Additives and Products or Substances used in Animal Feed concluded that the use of the feed additive in animal nutrition remains safe for the target species, the consumers and the environment. As regards the safety for the user, l-cystine is not an irritant to skin or eyes and is not a skin sensitiser. Exposure by inhalation of persons handling the additive cannot be excluded. The present application for the renewal of the authorisation does not include any modification proposal that would have an impact on the efficacy of the additive and therefore there is no need for reassessing the efficacy.

Safety and efficacy of a feed additive consisting of a tincture derived from the flowers of Syzygium aromaticum (L.) Merr. & L.M. Perry (clove tincture) for all animal species (FEFANA asbl).

Following a request from the European Commission, EFSA was asked to deliver a scientific opinion on the safety and efficacy of a tincture from the dried flower bud of Syzygium aromaticum (L.) Merr. & L.M. Perry (clove tincture) when used as a sensory additive in feed and water for drinking for all animal species. The product is a ■■■■■) solution, with a dry matter content of ~ 1.66%. The product contains on average 0.511% phenolic acids (of which 0.0344% were flavonoids), 0.039% eugenol, 0.00019% methyleugenol and 0.00008% estragole. The Panel on Additives and Products or Substances used in Animal Feed (FEEDAP) concluded that the use of clove tincture is very unlikely to be of safety concern for the target species up to the maximum proposed use level of 50 mg clove tincture/kg complete feed for all animal species, except for horses, for which the proposed use level is 200 mg/kg complete feed. The FEEDAP Panel considers that the use in water for drinking alone or in combination with use in feed should not exceed the daily amount that is considered very unlikely to be of safety concern when consumed via feed alone. No safety concern would arise for the consumer and the environment from the use of clove tincture up to the maximum proposed use levels in feed. The additive under assessment should be considered as irritant to skin and eyes, and as a dermal and respiratory sensitiser. When handling the additive, exposure of unprotected users to methyleugenol and estragole may occur. Therefore, to reduce the risk, the exposure of the users should be minimised. Since the flower buds of S. aromaticum and their preparations were recognised to flavour food and their function in feed would be essentially the same, no demonstration of efficacy was considered necessary.

Safety and efficacy of a feed additive consisting of an essential oil obtained from the wood of Juniperus deppeana Steud. (cedarwood Texas oil) for use in all animal species (FEFANA asbl).

Following a request from the European Commission, EFSA was asked to deliver a scientific opinion on the safety and efficacy of an essential oil obtained from the wood of Juniperus deppeana Steud. (cedarwood Texas oil), when used as a sensory additive for all animal species. The EFSA Panel on Additives and Products or Substances used in Animal Feed (FEEDAP) concluded that the essential oil under assessment is safe up to the maximum proposed use levels in complete feed of 15 mg/kg for veal calves (milk replacer), cattle for fattening, sheep, goats, horses, dogs, salmonids and ornamental fish. For the other species, the calculated safe concentrations in complete feed were 5 mg/kg for chickens for fattening, 8 mg/kg for laying hens, 7 mg/kg for turkeys for fattening, 10 mg/kg for piglets, 12 mg/kg for pigs for fattening, 14 mg/kg for sows and dairy cows, 8.5 mg/kg for rabbits and 4 mg/kg for cats. These conclusions were extrapolated to other physiologically related species. For any other species, the additive was considered safe at 4 mg/kg complete feed. The use of cedarwood Texas oil in water for drinking was considered 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 consumers and the environment were identified following the use of the additive up to the maximum proposed use level in feed. The additive under assessment should be considered as irritant to skin and eyes, and as a skin and respiratory sensitiser. Since the individual components of cedarwood Texas oil are recognised to flavour food and their function in feed would be essentially the same as that in food, no further demonstration of efficacy was considered necessary.

Efficacy of a feed additive consisting of Saccharomyces cerevisiae DBVPG 48 SF (BioCell®) for ruminants (Mazzoleni S.p.A.).

Following a request from the European Commission, EFSA was asked to deliver a scientific opinion on the safety and efficacy of Saccharomyces cerevisiae DBVPG 48 SF (BioCell®) as a zootechnical feed additive for horses, pigs and ruminants. In a previous opinion, the Panel on Additives and Products or Substances used in Animal Feed (FEEDAP) concluded that the additive has the potential to be efficacious at the proposed conditions of use for horses, dairy ruminants and all pigs. However, the Panel was not in the position to conclude on the efficacy of BioCell® for calves, and, consequently, for other ruminants for fattening or rearing. The applicant provided three additional efficacy trials in veal calves to support the efficacy of BioCell® for ruminants for fattening or rearing. The three studies showed positive effects of the supplementation with the additive at 1.7 × 109 colony forming unit (CFU)/kg complete feed on the performance of veal calves. Considering the previously submitted studies in dairy cows and the new submitted trials, the FEEDAP Panel concluded that the additive has the potential to be efficacious for all ruminants at the proposed condition of use: 4.0 × 108 CFU/kg complete feed for dairy ruminants and 4.0 × 109 CFU/kg complete feed for ruminants for fattening and rearing.