Scientific Opinion on the safety and efficacy of fumaric acid as a feed additive for all animal species 1

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1 EFSA Journal 2013;11(2):3102 SCIENTIFIC OPINION Scientific Opinion on the safety and efficacy of fumaric acid as a feed additive for all animal species 1 EFSA Panel on Additives and Products or Substances used in Animal Feed (FEEDAP) 2,3 ABSTRACT European Food Safety Authority (EFSA), Parma, Italy Fumaric acid is currently authorised as a preservative in feedingstuffs for all animal species. Fumaric acid is considered safe for pigs and poultry provided that an expected use level of mg/kg in complete diets for pigs and poultry is not exceeded. The margin of safety for pigs and poultry is approximately two. The tolerated fumaric acid concentration in complete diets for ruminants is higher. The margin of safety for pigs, poultry and ruminants is sufficiently high that setting a maximum content is not necessary. In contrast, the maximum safe level in milk replacer for veal calves (and probably other young mammals) is provisionally estimated to be mg/kg milk replacer, with no margin of safety. Fumaric acid is rapidly metabolised by well-recognised pathways, and neither fumarate nor its metabolites are expected to accumulate in animal tissues. Consequently, human exposure is not expected to be increased by the use of fumaric acid in animal nutrition. Fumaric acid is a severe irritant to eyes. Given the potential for eye irritation, the particle size and the dusting potential, exposure to other mucous membranes such as the respiratory tract may also be a concern and it is advisable to minimise exposure by inhalation. The use of fumaric acid in animal nutrition will not pose a risk to the environment. Fumaric acid has value as a food preservative only in the presence of significant moisture. Comparable situations in feed are limited to some feedingstuffs, feed processing and feeding techniques. In such situations, its function in feed is essentially the same as that in food and no further demonstration of efficacy is considered necessary. However, the FEEDAP Panel has reservations about the effectiveness of any preservative, including fumaric acid, in raw materials and compound feedingstuffs with a typical moisture content of 12 %. European Food Safety Authority, 2013 KEY WORDS Technological additive, preservative, fumaric acid, safety, efficacy 1 On request from the European Commission, Question No EFSA-Q , adopted on 29 January Panel members: Gabriele Aquilina, Alex Bach, Vasileios Bampidis, Maria De Lourdes Bastos, Gerhard Flachowsky, Josep Gasa-Gasó, Mikolaj Gralak, Christer Hogstrand, Lubomir Leng, Secundino López-Puente, Giovanna Martelli, Baltasar Mayo, Derek Renshaw, Guido Rychen, Maria Saarela, Kristen Sejrsen, Patrick Van Beelen, Robert John Wallace and Johannes Westendorf. Correspondence: FEEDAP@efsa.europa.eu 3 Acknowledgement: The Panel wishes to thank the members of the Working Group on Organic acids, including Andrew Chesson, Jurgen Gropp, Noel Dierick and Piet Wester, for the preparatory work on this scientific opinion. Suggested citation: EFSA Panel on Additives and Products or Substances used in Animal Feed (FEEDAP); Scientific Opinion on the safety and efficacy of fumaric acid as a feed additive for all animal species. EFSA Journal 2013;11(2):3102. [14 pp.] doi: /j.efsa Available online: European Food Safety Authority, 2013

2 SUMMARY 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 fumaric acid when used as a preservative in feedingstuffs for all animal species. Fumaric acid is considered safe for pigs and poultry provided that an expected use level of mg/kg in complete diets for pigs and poultry is not exceeded. The margin of safety for pigs and poultry is approximately two. The tolerated fumaric acid concentration in complete diets for ruminants is higher. The margin of safety for pigs, poultry and ruminants is sufficiently high that setting a maximum content is not necessary. In contrast, the maximum safe level in milk replacer for veal calves (and probably other young mammals) is provisionally estimated to be mg/kg milk replacer, with no margin of safety. Fumaric acid is rapidly metabolised by well-recognised pathways, and neither fumarate nor its metabolites would be expected to accumulate in animal tissues. Consequently, human exposure is not expected to be measurably increased by the use of fumaric acid in animal nutrition. Fumaric acid is a severe irritant to eyes. Given the potential for eye irritation, the particle size and the dusting potential, exposure to other mucous membranes such as the respiratory tract may also be a concern and it is advisable to minimise exposure by inhalation. The use of fumaric acid in animal nutrition will not pose a risk to the environment. Fumaric acid has value as a food preservative only in the presence of significant moisture. Comparable situations in feed are limited to some feedingstuffs, feed processing and feeding techniques. In such situations, its function in feed is essentially the same as that in food and no further demonstration of efficacy is considered necessary. However, the FEEDAP Panel has reservations about the effectiveness of any preservative, including fumaric acid, in raw materials and compound feedingstuffs with a typical moisture content of 12 %. EFSA Journal 2013;11(2):3102 2

3 TABLE OF CONTENTS Abstract... 1 Summary... 2 Table of contents... 3 Background... 4 Terms of reference... 4 Assessment Introduction Characterisation Characterisation of the additive Stability and homogeneity Conditions of use Evaluation of the analytical methods by the European Union Reference Laboratory (EURL) 7 3. Safety Safety for the target species Poultry Pigs Ruminants Veal calves Dogs Conclusions on the safety of fumaric acid for the target animals Safety for the consumer Safety for the user Safety for the environment Efficacy Conclusions and recommendation Documentation provided to EFSA References Appendix EFSA Journal 2013;11(2):3102 3

4 BACKGROUND Regulation (EC) No 1831/ establishes the rules governing the Community authorisation of additives for use in animal nutrition. In particular, Article 10(2) of that Regulation also specifies that for existing products within the meaning of Article 10(1), an application shall be submitted in accordance with Article 7, at the latest one year before the expiry date of the authorisation given pursuant to Directive 70/524/EEC for additives with a limited authorisation period, and within a maximum of seven years after the entry into force of this Regulation for additives authorised without a time limit or pursuant to Directive 82/471/EEC. The European Commission received a request from ACIAC EEIG (Acids Authorisation Consortium European Economic Interest Grouping) 5 for re-evaluation of the product fumaric acid, when used as a feed additive for all animal species (category: technological additive; functional group: preservative) under the conditions mentioned in Table 1. According to Article 7(1) of Regulation (EC) No 1831/2003, the Commission forwarded the application to the European Food Safety Authority (EFSA) as an application under Article 10(2) (reevaluation of an authorised feed additive). EFSA received directly from the applicant the technical dossier in support of this application. 6 According to Article 8 of that Regulation, EFSA, after verifying the particulars and documents submitted by the applicant, shall undertake an assessment in order to determine whether the feed additive complies with the conditions laid down in Article 5. The particulars and documents in support of the application were considered valid by EFSA as of 26 April Fumaric acid is authorised as technological additives for use in all animal species with no limitation of age and no maximum content. The Scientific Committee on Food issued an opinion on the safety of fumaric acid for the consumer (EC, 1990) and the Scientific Committee on Animal Nutrition issued an opinion on the safety of fumaric acid for all animal species (EC, 2003). TERMS OF REFERENCE According to Article 8 of Regulation (EC) No 1831/2003, EFSA shall determine whether the feed additive complies with the conditions laid down in Article 5. EFSA shall deliver an opinion on the safety for the target animals, consumer, user and the environment and the efficacy of the product fumaric acid, when used under the conditions described in Table Regulation (EC) No 1831/2003 of the European Parliament and of the Council of 22 September 2003 on additives for use in animal nutrition. OJ L 268, , p. 29. ACIAC EEIG (Acids Authorisation Consortium European Economic Interest Grouping), Avenue Louise 130A-Box 1, 1050 Brussels, Belgium. EFSA Dossier reference: FAD EFSA Journal 2013;11(2):3102 4

5 Table 1: Description and conditions of use of the additive as proposed by the applicant Additive Registration number/ec No/No (if appropriate) Category(ies) of additive 1 Functional group(s) of additive Fumaric Acid E 297 a Composition, description Description Chemical formula Purity criteria (if appropriate) Method of analysis (if appropriate) Fumaric Acid C 4 H 4 O 4 Min. 99.5% by wt HPLC Trade name (if appropriate) Name of the holder of authorisation (if appropriate) N/A N/A Species or category of animal Maximum Age Conditions of use Minimum content Maximum content Withdrawal period mg/kg of complete feedingstuffs (if appropriate) Specific conditions or restrictions for use (if appropriate) Specific conditions or restrictions for handling (if appropriate) Post-market monitoring (if appropriate) Specific conditions for use in complementary feedingstuffs (if appropriate) Other provisions and additional requirements for the labelling None specified None specified None specified None specified Marker residue Maximum Residue Limit (MRL) (if appropriate) Species or category of animal Target tissue(s) or food products Maximum content in tissues EFSA Journal 2013;11(2):3102 5

6 ASSESSMENT This opinion is based in part on data provided by a single company involved in the production/distribution of fumaric acid. It should be recognised that these data cover only a fraction of existing additives consisting of the active substance. The FEEDAP Panel has used the data provided together with data from other sources to deliver an opinion. 1. Introduction Fumaric acid (E297) is included in the European Union Register of Feed Additives pursuant to Regulation (EC) No 1831/2003. It is currently authorised in application of Article 9t (b) of Council Directive 70/524/EEC 7 concerning additives in feedingstuffs (2004/C 50/01) for use in all animal species as a technological additive and foreseen for re-evaluation. No maximum content for fumaric acid in feed is set in the EU. The applicant has asked for the re-evaluation of the use of fumaric acid as preservative in feed for all animal species and categories. Fumaric acid is authorised for use in food (Directive 95/2/EC) 8 up to a maximum level of 4 g/kg. The Joint FAO/WHO Expert Committee on Food Additives (JECFA) in 1967 set an acceptable daily intake (ADI) of 6 mg/kg body weight (JECFA, 1967). The Scientific Committee on Food (SCF) in 1990 adopted the ADI of 6 mg/kg body weight (EC, 1990) originally set by JECFA in In 1990, the FAO/WHO Expert Committee reviewed its previous opinion and proposed an ADI of not specified for fumaric acid and its salts (JECFA, 1990). This position was retained by the Committee in 1999 (JECFA, 2000). 2. Characterisation 2.1. Characterisation of the additive The additive is a powder containing by specification at least 99.5% of fumaric acid (Chemical Abstracts Service (CAS) number , chemical formula C 4 H 4 O 4, molecular weight ). The additive is produced by isomerisation of maleic acid followed by a series of purification steps. The analysis of 10 batches showed concentrations of fumaric acid > 99.8 %. 9 The impurities analysed (maleic acid, lead, mercury and arsenic) 10 were in compliance with the specifications set by Commission Regulation (EU) No 231/ for food additives. Cadmium was also measured in five batches and found to be below 2 mg/kg. The absence of any microbiological contamination was confirmed by the analysis of five batches of the additive. 12 The analysis of four batches of the product by sieving showed a maximum of 27 % (w/w) of particles smaller than 75 µm. 13 Laser diffraction analysis of one batch identified that 24 % of the particles had a 7 Commission List of the authorised additives in feedingstuffs published in application of Article 9t (b) of Council Directive 70/524/EEC concerning additives in feedingstuffs (2004/C 50/01). OJ C 50, , p European Parliament and Council Directive No 95/2/EC of 20 February 1995 on food additives other than colours and sweeteners. OJ No L 61, , p Supplementary Information October 2012/Annex_Qi_Fumaric acid_product composition and impurities_1 and Annex_Qi_Fumaric acid_product composition and impurities_2. 10 Supplementary Information October 2012/Annex_Qi_Fumaric acid_product composition and impurities_1 and Annex_Qi_Fumaric acid_product composition and impurities_2. 11 Commission Regulation (EU) No 231/2012 of 9 March 2012 laying down specifications for food additives listed in Annexes II and III to Regulation (EC) No 1333/2008 of the European Parliament and of the Council. OJ L 83, , p Supplementary Information/Annex_Qi_Fumaric acid_product composition and impurities_1. 13 Technical dossier/section II/Annex_II_2. EFSA Journal 2013;11(2):3102 6

7 diameter of 50 µm and about 1 % of the particles a diameter of 10 µm. 14 The dusting potential of one batch was 0.76 g/m Stability and homogeneity Four batches of fumaric acid were stored in commercial polyethylene bags for 24 months in ambient conditions (temperature C, protected from direct sunlight). 16 Analysis of the samples showed full recovery of the acid after two years. Fumaric acid from one batch was incorporated into three different vitamin/mineral premixtures at concentrations of 20 %, 20 % and 16.7 % (for laying hens, piglets and ruminants, respectively). 17 The three samples of premixtures including the additive were stored for six months in polyethylene bottles at room temperature. The analysis showed essentially full recovery of fumaric acid after six months storage. Fumaric acid was added at 1 % concentration to chickens for fattening and piglet feeds (mash and pelleted form) and to a ruminant feed (pelleted only). The samples were stored at room temperature for three months. Pelleting resulted in a small loss of fumaric acid (approximately 4 %). After three months storage, the active substance was essentially fully recovered. 18 From each of the five feed samples used for the stability studies, 10 subsamples were taken to study the homogeneous distribution of the active substance. The coefficient of variation for the five feeds varied between 2.8 and 5 % Conditions of use Fumaric acid is intended to be used as a preservative in feedingstuffs for all animal species and categories. The applicant proposes a maximum content of mg fumaric acid/kg complete feed. However, the applicant suggests that typical inclusion levels in feed would range between and mg/kg feed Evaluation of the analytical methods by the European Union Reference Laboratory (EURL) EFSA has verified the EURL report as it relates to the methods used for the control of the fumaric acid in animal feed. The Executive Summary of the EURL report can be found in the Appendix. 3. Safety 3.1. Safety for the target species Regulation (EC) No 429/2008 indicates that, in the case of feed additives already authorised for use in food, tolerance studies may not be required. Given the few foodstuffs for which the addition of fumaric acid is permitted, the FEEDAP Panel considers that an extrapolation from the food concentrations to safe concentrations for all animal species would not be applicable. Although specific tolerance studies were not provided, the applicant made reference to a number of published studies carried out in different animal species and with varying dietary concentrations of fumaric acid. 14 Supplementary Information October 2012/Annex_Qii_Fumaric acid_stauber-heubach. 15 Supplementary Information October 2012/Annex_Qii_Fumaric acid_stauber-heubach. 16 Technical dossier/section II/Annex_II_4. 17 Technical dossier/section II/Annex_II_4. 18 Technical dossier/section II/Annex_II_4. 19 Technical dossier/section II/Annex_II_4. EFSA Journal 2013;11(2):3102 7

8 Poultry Fumaric acid for all animal species Islam et al. (2008) fed isonitrogenous and isocaloric diets, consisting mainly of wheat and soybean meal and containing 0, 1.25, 2.50, 3.75, 5.00 and 7.50 % fumaric acid, to one-day-old chickens for fattening (Lohmann) for 26 days. Twelve replicates with eight chicks per replicate were used for each treatment. Final body weight and gain to feed ratio were approximately the same in the control group and the group receiving 3.75 % fumaric acid (1 506 vs g body weight and vs , respectively). Fumaric acid at 1.25 and 2.50 % resulted in an improved body weight gain, whereas 5.00 and 7.50 % fumaric acid significantly reduced body weight (1 342 and g, respectively). Higher gain was associated with higher feed intake. The relative weight of heart, liver and spleen was not affected by the treatment. The group receiving 7.50 % fumaric acid showed the highest incidence of kidney alterations (discoloration). The authors concluded that the most effective dose, 1.25 % fumaric acid, has a margin of safety of about three since 3.75 % fumaric acid appeared to be well tolerated. Adil et al. (2010) carried out a 35-day study of the effect of different organic acids, among them 2.0 and 3.0 % fumaric acid, on performance and organ morphology in seven-day-old chickens for fattening (Cobb). There were three replicates of 15 chicks per treatment. Clinical chemistry parameters, carcass characteristics and intestinal histomorphology were investigated in six birds in each treatment group. Feed consisted mainly of maize, soybean meal and fishmeal. Fumaric acid at both levels significantly improved body weight gain (1 525 vs vs g/day) and feed to gain ratio (2.02 vs vs. 1.83). Villus height in the jejunum was significantly increased at both levels of fumaric acid supplementation. No effects in the other parameters were observed. Ghazala et al. (2011), also in chickens for fattening, studied the effect of different organic acids, among them 0.5, 1.0 and 1.5 % fumaric acid, on performance, nutrient digestibility, intestinal ph and organ morphology. Three replicates with nine chicks per replicate were used for each treatment. The duration of the study was 42 days. Feed consisted mainly of maize, soybean meal and corn gluten. Two birds in the control group and one in the group receiving 1.0 % fumaric acid died. Fumaric acid significantly increased body weight gain at all levels (1 457 vs vs vs g/day); feed to gain ratio was also numerically improved. All levels of fumaric acid significantly increased the apparent digestibility of crude protein and fat. Fumaric acid significantly reduced the ph of intestinal contents, particularly in the crop, the gizzard and the ileum. Villus height in the duodenum was significantly increased at all levels of fumaric acid supplementation. The weight of lymphoid organs (bursa, thymus and spleen) was also increased by fumaric acid, but the effect was not dose dependent. In three experiments, one-day-old male chickens for fattening (Cobb 500) were fed for 42 days diets containing 0, 0.5, 1.0 or 2.0 % fumaric acid (Waldroup et al., 1995). Two replicates with 60 birds per replicate were used for each treatment. The aim of the study was to examine the effect of various organic acids on the colonisation of Salmonella in the hindgut (no effect found). The publication did not consistently include all data on the performance endpoints measured (body weight gain, feed intake, feed conversion). In the case of fumaric acid there is only the statement of the authors that there were no effects on performance due to feeding fumaric acid (data not shown). Biggs and Parsons (2008) conducted four experiments to evaluate the effects of different organic acids on growth and nutrient digestibility in male New Hampshire Columbian chicks from hatch to day 21. Five replicates with five chicks per replicate were used for each treatment. For average daily gain and feed conversion, maize soybean-type diets containing 1.5, 3.0 or 4.5 % fumaric acid had no significant effect on growth. Cumulative weight gain was 446, 452, 452 and 436 g in the groups receiving 0, 1.5, 3.0 and 4.5 % fumaric acid, respectively; gain to feed ratio was 0.658, 0.657, and 0.649, respectively Pigs The Scientific Committee on Animal Nutrition (EC, 2003) concluded, based on studies in piglets fed for four weeks with diets containing fumaric acid concentrations up to 4 %, that fumaric acid EFSA Journal 2013;11(2):3102 8

9 stimulates feed intake and that an improvement in ileal digestibility of gross energy, crude protein and amino acids is plausible. No adverse effects were observed. The recommended effective concentration is between 1.5 and 2 %. Eight studies of fumaric acid ( % in feed) in weanling pigs, summarised in a review on dietary acidifiers in pig nutrition (Kil et al., 2011), found no significant influence on growth rate, feed consumption and gain to feed ratio. Giesting and Easter (1985) performed a series of experiments with fumaric acid on weanling piglets. In one of the studies, a total of 100 piglets (initial body weight 8.6 kg) were fed maize soybean diets (19 % crude protein) containing 0, 1, 2, 3 or 4 % fumaric acid, added at the expense of maize starch, for four weeks (final body weight 16.4 kg). Four replicates with five piglets per replicate were used for each treatment (with a constant sex ratio). Average daily weight gain was in the range of g and gain to feed ratio in the range of Addition of graded levels of fumaric acid resulted in linear increases in daily weight gain and gain to feed ratio. Radecki et al. (1988) administered a maize soybean diet containing three dietary levels of fumaric acid (0, 1.5 and 3.0 %) to a total of 96 crossbred, four-week-old weanling piglets (initial body weight 7.1 kg). The three diets were fed to two replicates of six pens with eight pigs each for four weeks (average final body weight 13.7 kg). Average daily gain was significantly improved by fumaric acid during the first week, and gain to feed ratio during the first two weeks. Over the whole experimental period, no significant effect was seen in the fumaric acid groups compared with the unsupplemented group in terms of weight gain and gain to feed ratio. Lawlor at al. (2005) studied the effects on piglets (10 per treatment, individually housed) of fumaric acid up to 3 % in diets containing different levels of dairy products, which were administered for four weeks after weaning. No adverse effects on body weight gain and gain to feed ratio were seen Ruminants Remling et al. (2011) performed a trial in growing bulls fed grass or maize silage to study the influence of various amounts of fumaric acid on performance and parameters of acid base balance. A total of 62 fattening bulls (German Holstein breed, initial body weight 266 kg), randomly assigned to eight feeding groups, received one of four levels of fumaric acid (0, 100, 200 or 300 g/day) with both silage types. The actual fumaric acid concentrations in feed dry matter (DM) corresponding to 100, 200 and 300 g/day were 1.2, 2.3 and 3.4 % for the maize silage groups and 1.1, 2.3 and 3.5 % for the grass silage groups. The daily feed and water intake and the live weight were measured over the entire testing period of 280 days. Total feed intake (8.81 kg DM/day) and daily weight gain (1 277 g/day) were not significantly influenced by treatments. Fumaric acid supplementation did not affect blood chemistry or other haematological parameters. No signs of any intolerance to fumaric acid were observed in the animals over the entire experimental period. The ability of fumaric acid and encapsulated fumaric acid (EFA, about % fumaric acid) to decrease methane formation was studied in lambs (Wallace at al., 2006; Wood et al., 2009). For this purpose, 120 Welsh Mule cross lambs (5 6 months old; average weight 26 kg) were randomly allocated to 12 subgroups and placed into pens of 10 animals. The basal diet (a concentrate consisting of wheat, barley, wheat feed, rapeseed meal, palm kernel, sugar beet pulp and molasses) was either unsupplemented or supplemented with 100 g/kg fumaric acid from either fumaric acid or EFA. The 12 subgroups were then randomly allocated to one of the three treatments. Lambs were fed ad libitum and presented with unlimited amounts of straw and fresh water. The growth trial lasted for 56 days, during which lamb weight and feed intake were recorded. Weight gain over 43 days was 184, 165 and 206 g/day (P = 0.267) in the control, fumaric acid and EFA groups, respectively, while gain to feed ratio was 0.135, and 0.159, respectively (concentrate only) (P = 0.605). Both treatments significantly reduced methane formation, with EFA (75 % decrease in methane) being significantly (P < 0.05) more effective than fumaric acid (50 % decrease in methane). The trial indicates that lambs tolerate very EFSA Journal 2013;11(2):3102 9

10 high doses of fumaric acid. Since straw intake was not measured, the fumaric acid concentration in the total diet cannot be calculated. However, it is probable that straw did not amount to more than 15 % of the total daily ration. The tolerated fumaric acid concentration would then be about 8.4 % in a complete diet Veal calves A total of 32 veal calves (Pie Rouge) with an initial body weight of 43 kg were fed, in two consecutive runs (first run: six males and two female calves per treatment; second run: four males and four females per treatment), milk replacer without and with 2 % fumaric acid for 14 weeks (De Vuyst et al., 1974). The milk replacer of the first run contained 23 % crude protein (CP) and 20 % ether extract (EE) and that of the second run contained 24 % CP and 19 % EE. The calves were weighed at start and at the end of the trial and feed intake was recorded weekly. One calf died in the control group (second run) and one in the fumaric acid group (first run). In the first run, total gain in the control group was kg/calf and in the fumaric acid group 99.6 kg (about 6 % less). Although feed intake was similar in the two groups, the calves receiving fumaric acid consumed about 7 % more feed per unit gain (ratio 1.56) than the control calves (ratio 1.46). In the second run, total gain was kg/calf in the control group and kg (about 4 % less) in the fumaric acid group. Although feed intake was similar in the two groups, the calves receiving fumaric acid consumed about 4 % more feed per gain (ratio: 1.59) than the control calves (ratio 1.53). Fumaric acid (2 % in a milk replacer) consistently reduced the performance of veal calves Dogs JECFA reviewed a study in which fumaric acid was fed to four groups of six young dogs (0, 1, 3 and 5 % of the diet) for two years without adverse effect on body weight gain, development, haematological parameters, blood sugar and urea levels, haemoglobin and urine. Organ weights and gross and histopathological examination of all principal organs and tissues revealed no effects attributable to the treatment (Harrison and Abbott, 1962, cited in JECFA, 1975) Conclusions on the safety of fumaric acid for the target animals The few data available in literature indicate that about 4 % fumaric acid in complete diets is likely to be tolerated without adverse effects in poultry, pigs and dogs. This concentration is about twice the expected maximum use concentration. The tolerance of ruminants is considerably higher, reaching values of about 8 %. Based on the limited available data, the preruminant calf was the most sensitive animal category. An upper safe level is provisionally estimated to be 1 % in milk replacer Safety for the consumer Fumaric acid is an organic dicarboxylic acid naturally present in all organisms. It predominantly originates from the oxidation of succinate and is further converted to malic acid in the tricarboxylic acid cycle. Exogenous fumaric acid will be rapidly metabolised by well-recognised pathways, and neither fumarate nor its metabolites would be expected to accumulate in animal tissues. Consequently, human exposure is not expected to be measurably increased by the use of fumaric acid in animal nutrition Safety for the user Fumaric acid is a bulk industrial chemical and the hazards for those handling this substance are well known and documented in the literature. No specific studies were provided by the applicant. Two reviews of the hazards for those handling fumaric acid have been published by International Programme on Chemical Safety and the Commission of the European Communities (IPCS-ICSC) for fumaric acid under ICSC: 1173 (IPCS-ICSC, 2001) and by the Cosmetic Ingredient Review Expert Panel (CIR, 2009). Both concluded that fumaric acid is a severe irritant to eyes and a minimal irritant to skin. Fumaric acid caused no skin sensitisation in mouse local lymph node and guinea pig EFSA Journal 2013;11(2):

11 maximisation tests (Kreiling et al., 2008). Given the potential for eye irritation, exposure to other mucous membranes may cause similar effects in the respiratory tract. Based on the relatively high proportion of particles with diameter < 50 µm, coupled with a moderate dusting potential, it is advisable to reduce exposure by inhalation Safety for the environment Fumaric acid is a natural constituent of plants and animals. Its use in animal nutrition would not measurably increase its concentration in the environment. No further assessment is considered necessary. 4. Efficacy Fumaric acid has value as a food preservative only in the presence of significant moisture. Comparable situations in feed are limited to some feedingstuffs, feed processing and feeding techniques. In such situations, its function in feed is essentially the same as that in food and no further demonstration of efficacy is considered necessary. The FEEDAP Panel has reservations about the effectiveness of any preservative, including fumaric acid, in raw materials and compound feedingstuffs with a typical moisture content of 12 %. However, it is recognised that, under practical conditions of storage, the moisture content of all or part of the feed may rise above this level. Under these circumstances, the additive could be effective in preventing or reducing deterioration. CONCLUSIONS AND RECOMMENDATION CONCLUSIONS Fumaric acid is considered safe for pigs and poultry provided that the proposed use level of mg/kg complete diets for pigs and poultry is not exceeded. The margin of safety for pigs and poultry is approximately 2. The tolerated fumaric acid concentration in complete diets for ruminants is higher. The margin of safety for pigs, poultry and ruminants is sufficiently high that setting a maximum content is not necessary. In contrast, the maximum safe level in milk replacer for veal calves (and probably other young mammals) is provisionally estimated to be mg/kg milk replacer, with no margin of safety. Human exposure is not expected to be measurably increased by the use of fumaric acid in animal nutrition. Fumaric acid is a severe irritant to eyes. Given the potential for eye irritation, the particle size and the dusting potential, exposure to other mucous membranes such as the respiratory tract may also be a concern and it is advisable to minimise exposure by inhalation. The use of fumaric acid in animal nutrition will not pose a risk to the environment. Fumaric acid has value as a food preservative only in the presence of significant moisture. Comparable situations in feed are limited to some feedingstuffs, feed processing and feeding techniques. In such situations, its function in feed is essentially the same as that in food and no further demonstration of efficacy is considered necessary. However, the FEEDAP Panel has reservations about the effectiveness of any preservative, including fumaric acid, in raw materials and compound feedingstuffs with a typical moisture content of 12 %. RECOMMENDATION The FEEDAP Panel recommends that a maximum content of mg fumaric acid/kg milk replacer be established. EFSA Journal 2013;11(2):

12 DOCUMENTATION PROVIDED TO EFSA Fumaric acid for all animal species 1. Fumaric acid for all animal species. September Submitted by ACIAC EEIG (Acids Authorisation Consortium European Economic Interest Grouping). 2. Fumaric acid for all animal species. Supplementary information. October ACIAC EEIG (Acids Authorisation Consortium European Economic Interest Grouping). 3. Evaluation report of the European Union Reference Laboratory for Feed Additives on the Methods(s) of Analysis for fumaric acid. 4. Comments from Member States received through the ScienceNet. REFERENCES Adil S, Banday T, Bhat GA, Mir MS and Rehman M, Effect of dietary supplementation of organic acids on performance, intestinal histomorphology, and serum biochemistry of broiler chicken. Veterinary Medicine International, 2010, 1 7. Biggs P and Parsons CM, The effects of several organic acids on growth performance, nutrient digestibilities, and cecal microbial populations in young chicks. Poultry Science, 87, Cosmetic Ingredient Review Expert Panel (CIR), Final Report of the Cosmetic Ingredient Review Expert Panel: Safety Assessment of Fumaric Acid and Related Salts and Esters as Used in Cosmetics. Available from: De Vuyst A, Moreels A, Arnould R, SKA P and Romedenne JJ, L action de l acide fumarique dans l alimentation du veau à l engrais. Revue de l Agriculture, 1, EC (European Commission), 1991, online. Reports of the Scientific Committee for food: First Series of Food Additives of Various Technological Functions. Available from EC (European Commission), 2003, online. Report of the Scientific Committee on Animal Nutrition on the Safety of Fumaric Acid. Available from Ghazalah AA, Atta AM, Elkloub K, Moustfa MEL and Shata RFH, Effect of dietary supplementation of organic acids on performance, nutrients digestibility and health of broiler chicks. International Journal of Poultry Science, 10, Giesting DW and Easter RA, Response of starter pigs to supplementation of corn soybean meal diets with organic acids. Journal of Animal Science, 60, Harrison JWE, Abbott DD, Unpublished report of LaWall and Harrisson Research Laboratories, submitted to WHO, cited in JECFA, International Programme on Chemical Safety and the Commission of the European Communities (IPCS-ICSC), 2001, online. International Chemical Safety Cards (ICSCs). (ICSC: 1173). Available from Islam KMS, Schuhmacher A, Aupperle H and Gropp JM, Fumaric acid in broiler nutrition. A dose titration study and safety aspects. International Journal of Poultry Science, 7, Joint FAO/WHO Expert Committee On on Food Additives (JECFA), toxicological evaluation of some antimicrobials, antioxidants, emulsifiers, stabilizers, flour-treatment agents, acids and bases. Tenth Rreport of the Joint FAO/WHO Expert Committee On on Food Additives, Geneva, Available from: Joint FAO/WHO Expert Committee oon Food Additives (JECFA), 1975, online. toxicological evaluation of some food colours, enzymes, flavour enhancers, thickening agents, and certain food additives. Eighteenth Rreport of the Joint FAO/WHO Expert Committee On on Food Additives, Geneva, Available from EFSA Journal 2013;11(2):

13 Joint FAO/WHO Expert Committee On on Food Additives (JECFA), 1990, online. Evaluation of certain food additives and contaminants. Thirty-Fifth Report of Joint FAO/WHO Expert Committee On on Food Additives, GeneveGeneva, Available from Joint FAO/WHO Expert Committee On on Food Additives (JECFA), 2000, online. Evaluation of certain food additives and contaminants. Fifty-Third Report of Joint FAO/WHO Expert Committee On on Food Additives, GeneveGeneva, Available from Kil DY, Kwon WB and Kim BG, 2011, Dietary acidifiers in weanling pig diets: a review., Revista Colombiana de Ciencias Pecuarias, 24, Kreiling R, Hollnagel HM, Hareng L, Eigler D, Lee MS, Griem P, Dreessen B, Kleber M, Albrecht A, Garcia C and Wendel A, 2008, Comparison of the skin sensitizing potential of unsaturated compounds as assessed by the murine local lymph node assay (LLNA) and the guinea pig maximization test (GPMT). Food and Chemical Toxicology, 46, Lawlor PG, Lynch PB and Caffrey PJ, Effect of creep feeding, dietary fumaric acid and level of dairy product in the diet on post-weaning pig performance. Irish Journal of Agricultural and Food Research, 44, Radecki SV, Juhl MR and Miller ER, Fumaric and citric acids as feed additives in starter pig diets: Effect on performance and nutrient balance. Journal of Animal Science, 66, Remling N, Hachenberg S, Meyer U, Höltershinken M, Flachowsky G and Dänicke S, Influence of various amounts of fumaric acid on performance and parameters of the acid -base balance of growing bulls fed with grass or maize silage. Archives of Animal Nutrition, 65, Waldroup A, Kaniawati S and Mauromoustakos A, Performance characteristics and microbiological aspects of broilers fed diets supplemented with organic acids. Journal of Food Protection, 58, Wallace RJ, Wood TA, Rowe A, Price J, Yáñez-Ruiz DR, Williams SP and Newbold CJ, Encapsulated fumaric acid as a means of decreasing ruminal methane emissions. International Congress Series 1293, Wood TA, Wallace RJ, Rowe A, Price J, Yáñez-Ruiz DR, Murray P and Newbold CJ, Encapsulated fumaric acid as a feed ingredient to decrease ruminal methane emissions. Animal Feed Science and Technology, 152, EFSA Journal 2013;11(2):

14 APPENDIX Executive Summary of the Evaluation Report of the European Union Reference Laboratory for Feed Additives on the Method(s) of Analysis for Fumaric acid 20 In the current application authorisation is sought for fumaric acid (E297), under article 10, category/functional group 1(a) technological additives/preservatives, according to the classification system of Annex I of Regulation (EC) No 1831/2003. Fumaric acid is already authorised as feed additive under Commission Directive 70/524/EEC. According to the Applicant, the feed additive is an odourless white crystalline powder with a minimum purity of 99.5 % fumaric acid. Specifically, authorisation is sought for the use of fumaric acid as preservative for all animal species and categories. The feed additive is intended to be mixed into premixtures or feedingstuffs with a proposed maximum level of 20 g/kg in complete feedingstuff. For the determination of fumaric acid in the feed additive, the Applicant submitted the Food Chemical Codex 7 (FCC) methods, based on infrared absorption spectrophotometry and acid/base titration. Even though no performance characteristics of these methods are provided, the EURL recommends for official control the internationally recognised FCC methods based on infrared absorption spectrophotometry and titrimetry to determine fumaric acid in the feed additive. For the determination of fumaric acid in premixtures and feedingstuff the Applicant proposed a multianalyte method based on High Performance Liquid Chromatography with UltraViolet detection (HPLC-UV). This method does not distinguish between fumaric acid and its salts. In addition the Applicant stated that the method is also applicable to pure acid and acid blends. The following performance characteristics for the quantification of total fumaric acid, were derived from the singlelaboratory validation study: a relative standard deviation for repeatability (RSD r ) ranging from 2.8 % to 11.7%, for concentrations ranging from 0.01 to 1000 g/kg; a recovery rate (R rec ) ranging from 90.9 to 107.5%; and a limit of quantification (LOQ) of 6.5 mg/kg in feedingstuffs. Furthermore, the method was ring trial validated with four laboratories and a relative standard deviation for reproducibility (RSD R ) ranging from 1.6 % to 8.1 % was determined for premixtures and feedingstuffs containing 8.8 to 66 g fumaric acid/kg, respectively. Based on the performance characteristics presented, the EURL recommends for official control the ring trial validated method based on ion-exclusion HPLC-UV to determine fumaric acid (expressed as total fumaric acid) in premixtures and feedingstuffs. Further testing or validation of the methods to be performed through the consortium of National Reference Laboratories as specified by Article 10 (Commission Regulation (EC) No 378/2005) is not considered necessary. 20 The full report is available on the EURL website: pdf EFSA Journal 2013;11(2):