Scientific Opinion on the safety and efficacy of cassia gum for dogs and cats based on a dossier submitted by Intercolloid (UK) Ltd 1

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1 EFSA Journal 2014;12(11):3901 SCIENTIFIC OPINION Scientific Opinion on the safety and efficacy of cassia gum for dogs and cats based on a dossier submitted by Intercolloid (UK) Ltd 1 EFSA Panel on Additives and Products or Substances used in Animal Feed (FEEDAP) 2,3 ABSTRACT European Food Safety Authority (EFSA), Parma, Italy The additive cassia gum, the ground, purified endosperm of the seeds of Cassia tora and Cassia obtusifolia, is intended to be used as a technological additive (functional groups: thickeners and gelling agents) in feedingstuffs for all dogs and cats. The Panel on Additives and Products or Substances used in Animal Feed (FEEDAP) concluded that only purified semi-refined cassia gum that meets the specifications of cassia gum as a food additive (< 0.5 mg anthraquinones/kg) can be considered safe for cats and dogs, at a maximum content of mg/kg complete feed. Cassia gum is regarded as a skin and respiratory sensitiser and as a potential irritant to skin and eyes. It would be prudent to assume that cassia gum has the potential to harm workers who might be exposed via skin, eyes or inhalation. The FEEDAP Panel could not conclude on the efficacy of cassia gum used as a gelling agent and thickener in feedingstuffs for dogs and cats. European Food Safety Authority, 2014 KEY WORDS technological additive, gelling agent, cassia gum, thickener, safety, efficacy, dogs and cats 1 On request from the European Commission, Question No EFSA-Q , adopted on 29 October Panel members: Gabriele Aquilina, Alex Bach, Vasileios Bampidis, Maria De Lourdes Bastos, Lucio Guido Costa, Gerhard Flachowsky, Mikolaj Antoni Gralak, Christer Hogstrand, Lubomir Leng, Secundino López-Puente, Giovanna Martelli, Baltasar Mayo, Fernando Ramos, 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 Technological Additives, including Georges Bories, Jurgen Gropp, Anne-Katrine Lundebye and Carlo Nebbia, for the preparatory work on this scientific opinion. Suggested citation: EFSA FEEDAP Panel (EFSA Panel on Additives and Products or Substances used in Animal Feed), Scientific Opinion on the safety and efficacy of cassia gum for dogs and cats based on a dossier submitted by Intercolloid (UK) Ltd. EFSA Journal 2014;12(11):3901, 15 pp. doi: /j.efsa Available online: European Food Safety Authority, 2014

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 cassia gum as a technological additive in feedingstuffs for dogs and cats. The FEEDAP Panel concluded that only purified semi-refined cassia gum that meets the specifications of cassia gum as a food additive (< 0.5 mg anthraquinones/kg) can be considered safe for cats and dogs, at a maximum content of mg/kg complete feed. Cassia gum is regarded as a skin and respiratory sensitiser and as a potential irritant to skin and eyes. It would be prudent to assume that cassia gum has the potential to harm workers who might be exposed via skin, eyes or inhalation. The FEEDAP Panel could not conclude on the efficacy of cassia gum used as a gelling agent in feedingstuffs for dogs and cats. The FEEDAP Panel made a recommendation to align the specifications of cassia gum as a feed additive with those of cassia gum authorised as a food additive. EFSA Journal 2014;12(11):3901 2

3 TABLE OF CONTENTS Abstract... 1 Summary... 2 Background... 4 Terms of reference... 4 Assessment Introduction Characterisation Anthraquinone content Physical properties Stability and homogeneity Conditions of use Evaluation of the analytical methods by the European Union Reference Laboratory (EURL) 8 3. Safety Absorption, distribution, metabolism and excretion Toxicology of cassia gum Reproduction and developmental studies in laboratory animals Pharmacology/toxicology of anthraquinones Safety for the target species Dogs Cats Considerations on the safety for the target species Conclusions on safety for the target species Safety for the user Conclusion on safety for the user Safety for the environment Efficacy Conclusions and recommendations Documentation provided to EFSA References Appendix EFSA Journal 2014;12(11):3901 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 Intercolloid (UK) Ltd 5 for re-evaluation of the product cassia gum, when used as a feed additive for dogs and cats (category: technological additive; functional group: gelling agent) 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 23 February The additive cassia gum is authorised as technological additive, functional groups gelling agent, thickeners emulsifying and stabilising agent for use in food for dogs and cats. The Joint FAO/WHO Expert Committee on Food Additive has assessed the safety of cassia gum (JECFA, 2010a). The EFSA Panel on Food additives, flavourings, processing aids and materials in contact with food (AFC) issued an opinion on cassia gum as food additive (EFSA, 2006). 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 animal(s), user and the environment and the efficacy of the product Cassia gum, 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. Intercolloid (UK) Ltd, 3 Warner House, Bessborough Road, HA1 3EX, Harrow, United Kingdom. EFSA Dossier reference: FAD A new mandate was received by EFSA on EFSA Journal 2014;12(11):3901 4

5 Table 1: Description and conditions of use of the additive as proposed by the applicant Additive Cassia Gum (E 499) Registration number/ec No/No (if appropriate) Category(ies) of additive Functional group(s) of additive 70/524/EEC Technological Gelling agent Description Composition, description Chemical formula Cassia Gum - Purity criteria (if appropriate) - Method of analysis (if appropriate) - Trade name (if appropriate) Name of the holder of authorisation (if appropriate) Cassia Flour (with suffixes) Species or category of animal Cats and dogs Maximum Age Conditions of use Minimum content Maximum content Withdrawal mg or Units of activity or CFU kg -1 of complete feedingstuffs (select what applicable) period (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) Marker residue Other provisions and additional requirements for the labelling Maximum Residue Limit (MRL) (if appropriate) Species or category of animal Target tissue(s) or food products Maximum content in tissues EFSA Journal 2014;12(11):3901 5

6 ASSESSMENT This opinion is based in part on data provided by a single company involved in the production/distribution of cassia gum. It should be recognised that these data cover only a fraction of the existing additives containing cassia gum. The FEEDAP Panel has used the data provided, together with data from other sources, to deliver an opinion. 1. Introduction Cassia gum is currently authorised 8 in feed with a moisture content higher than 20 % as an emulsifying and stabilising agent, thickener and gelling agent, with a maximum content of mg/kg complete feed (with moisture 12 %). Cassia gum is also authorised 9 for similar technological purposes in some foodstuffs (edible ice, dairybased desserts, fermented milk products, processed cheese, dressings, dehydrated soups and broths all with a maximum content of mg/kg and heat-treated meat products with a maximum content of mg/kg). Cassia gum has previously been assessed by the EFSA Scientific Panel on Food Additives, Flavourings, Processing Aids and Materials in Contact with Food (AFC) (EFSA, 2006) and by the Joint FAO/WHO Expert Committee on Food Additives (JECFA, 2010a). The current application is for the re-evaluation of cassia gum as a feed additive (technological additive; functional group: gelling agents) for use in feed for cats and dogs, with a maximum content of mg/kg complete feedingstuffs. The applicant reported that, in practice, cassia gum is used in combination with other gelling agents such as kappa-carrageenan or xanthan gum. 2. Characterisation Cassia gum is described in Regulation (EC) No 231/2012, which lays down the specification for food additives. 10 It is the ground, purified endosperm of the seeds of Cassia tora and Cassia obtusifolia (Leguminosae) containing less than 0.05 % Cassia occidentalis. It consists mainly of high-molecularweight polysaccharides composed primarily of a linear chain of 1,4-β-D-mannopyranose units with 1,6-linked α-d-galactopyranose units. The ratio of mannose to galactose is given as about 5:1; the concentration of galactomannans is > 75 %, of acid-insoluble matter is < 2 %, of protein is < 7 %, of total ash is < 1.2 % and of lead is < 1 mg/kg; and the viscosity is < 500 mpa s. The manufacturing of cassia gum, in principle, follows conventional milling techniques. The husks are removed and the endosperm is washed with water, resulting in the semi-refined product (feed additive). The production of the food additive (purified semi-refined product) includes a further purification step with isopropanol extraction. The ratio of mannose to galactose ( ) was analysed in five batches of the additive 11 and the viscosity ( mpa s at 25 C, two hours, 1 % solution) was analysed in 16 batches, showing compliance with the specifications set for cassia gum as a food additive. 12 Galactomannans, acidinsoluble matter, protein and total ash concentrations were not analysed. The analysis of eight batches indicated a content of lead, cadmium, mercury and arsenic of < 0.1, < 0.1, < 0.03 and < 0.03 mg/kg, respectively. 13 Two batches of the additive were analysed for microbial contamination. The total 8 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). 9 Commission Directive 2010/69/EU of 22 October 2010 amending the Annex to European Parliament and Council Directive 95/27EC on food additives other than colour and sweeteners. 10 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. 11 Supplementary Information April 2013/References Technical dossier/section II/Annex_II_Reference_8. 13 Technical dossier/section II/Annex_II_Reference_9 and Supplementary Information April 2013/References EFSA Journal 2014;12(11):3901 6

7 aerobic microbial count was < colony-forming units (CFU)/g and the coliforms count was < 100 CFU/g; Escherichia coli, Salmonella, Staphylococcus aureus and Clostridium perfringens were absent. 14 Aflatoxin B1 was in the range µg/kg and aflatoxins B2, G1 and G2, deoxynivalenol, fumonisin, zearalenone and ochratoxin A were below their limits of quantification (0.5, 1.0, 1.0, 18.5, 25.0, 50.0 and 2.5 µg/kg, respectively). 15 The concentrations of pesticides 16 analysed in three batches did not give rise to concern. 17 No information was provided regarding the concentration of dioxins and dioxins-like polychlorinated biphenyls (PCBs) Anthraquinone content Cassia gum is a well-recognised source of anthraquinones, a group of functional diverse aromatic chemicals, structurally related to anthracene, with the parent structure 9,10-dioxoanthracene. They are potent pharmacologically active substances. They naturally occur in Cassia species in free (aglycone) and glycosylated forms. The most prominent representatives of this group are chrysophanic acid (up to 50 % of total anthraquinones in seed samples (Crawford and Friedman, 1990, Crawford et al., 1990)), emodin, aloe-emodin, rhein, physcion and danthrone. Colorimetric methods identified 0.01 to 0.04 % free, 1.01 to 1.29 % bound and 1.04 to 1.31 % total anthraquinones in Cassia seeds (Koshioka and Takino, 1978). The introduction of purification steps in the production of cassia gum resulted in a considerable reduction in the anthraquinone concentration. The use of more specific analytical methods (high-performance liquid chromatography (HPLC)) enabled the separation of individual anthraquinones (Dekant, 2003). The analytical method published by JECFA (2010b) refers to emodin, aloe-emodin (not present in C. obtusifolia and C. tora), physcion, rhein and chrysophanic acid. Specifications of cassia gum as a food additive give a maximum content of total anthraquinones of 0.5 mg/kg (detection limit). No information on the concentrations of anthraquinones in the additive was provided by the applicant Physical properties The results of sieve analysis of 378 batches of cassia gum showed that % of particles had a diameter < 75 µm (w/w). 18 No information was provided regarding particles of smaller diameter or on dusting potential Stability and homogeneity Since cassia gum is used as a feed additive, together with carrageenan or other gums, to obtain optimal gelling and the demonstration of stability is based on the maintenance of the gelling effect, the stability data refer to the combined effect of cassia gum and carrageenan. The shelf life of five batches of the additive was studied, analysing the moisture content, the viscosity and the brittle fraction index (BFI: the ratio of the average gel strength of test samples to the gel strength of a standard sample) of a solution containing 0.5 % cassia gum mixed with 0.2 % carrageenan. After one year s storage in glass flasks closed with a rubber stopper at 25 C and at 40 C, no significant differences in the moisture content of the additive, the viscosity or the BFI were recorded. The gel strength values of one commercial canned complete feed for dogs (one batch, two subsamples) labelled as containing only cassia gum (as a gelling agent) at a concentration of about 0.2 % were measured after purchase and after three months storage. No significant losses of gel strength were observed (see also section 4). 14 Supplementary Information April 2013/References Supplementary Information April 2013/References Organochlorines, organophosphates and pyrethroids. 17 Supplementary Information April 2013/References Technical dossier/section II/Annex_II_Reference_10. EFSA Journal 2014;12(11):3901 7

8 No information on the homogeneous distribution of the additive in premixture and feedingstuffs was provided by the applicant. However, the FEEDAP Panel notes that cassia gum is water soluble and is expected to follow the water fraction in feed with a higher moisture content Conditions of use Cassia gum is intended to be used as a gelling agent in complete feed for cats and dogs with a moisture content higher than 20 %. The applicant proposes a maximum content of mg cassia gum/kg complete feed (moisture 12%) 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 cassia gum in animal feed. The Executive Summary of the EURL report can be found in the Appendix. 3. Safety 3.1. Absorption, distribution, metabolism and excretion In its opinion on cassia gum as a food additive, the AFC Panel (EFSA, 2006) summarised the absorption, bioavailability and metabolism of cassia gum as follows: Galactomannans were shown to be stable in artificial gastric juice (Nurnberg and Bleimuller, 1981). No information is available on the bioavailability of galactomannans from cassia gum: other galactomannans appear to undergo no or only minimal hydrolysis by the digestive juices. Fermentation of the galactomannans from cassia gum by gut microflora may occur to a small extent (Nyman and Asp, 1982). Any hydrolysed material would be absorbed and metabolised in normal biochemical pathways (Mathews and van Holde, 1990). The bioavailability of the anthraquinones contained in cassia gum is poorly understood. In general, anthraquinones are considered to be poorly bioavailable, although a fraction of such compounds is thought to be absorbed and to undergo liver oxidative and conjugative biotransformation followed by biliary excretion and partial re-absorption via the enterohepatic circulation (JECFA, 2010a). The reported side-effects of certain anthraquinone derivatives (e.g. nausea, vomiting) suggest that it is likely that a fraction of anthraquinones may cross the hepatic filter and enter the systemic circulation (Bombardelli and Pifferi, 1988). Recent studies demonstrate that emodin bioavailability is greatly affected by the extent of presystemic metabolism, particularly by the rate of glucuronidation. The emodin glucuronidation rate differs considerably between species (up to five-fold between monkeys, dogs, rats and mice) and sexes (up to 10-fold higher plasma levels in female than in male rats), mainly related to differences in uridine-diphosphoglucuronosyltransferase (UGT) expression (Liu et al., 2010, 2011). As regards the target animals, the lack of UGT1A6 and UGT1A9 displayed by cats results in a poor capacity for efficient glucuronidation of several compounds, especially those of an aromatic nature (Court, 2013), such as anthraquinones; therefore, the bioavailability of emodin and possibly of other anthraquinones is expected to be higher in cats than in dogs Toxicology of cassia gum The AFC Panel (EFSA, 2006) assessed the available data on the toxicology of cassia gum prepared following the old production method (semi-refined cassia gum; about 70 mg anthraquinones/kg) or following a new one (purified semi-refined cassia gum with anthraquinones below the limit of detection (< 0.5 mg anthraquinones/kg)). The main findings are summarised below: Cassia gum of the old specifications (about 70 mg anthraquinones/kg) was not mutagenic or clastogenic in mammalian cells (chromosome aberration test in human lymphocytes and gene EFSA Journal 2014;12(11):3901 8

9 Cassia gum for dogs and cats mutation assay in L5178Y mouse lymphoma). However, a positive response was obtained in a bacterial reversion assay with Salmonella strain TA100. The response was elicited both in the presence and in the absence of metabolic activation. Based on the results of recent genotoxicity studies, cassia gum, prepared by the newly defined production method, did not increase the number of revertants in any of the four Ames tester strains (S. Typhimurium TA1535, TA1537, TA98 and TA100), or in the E. coli WP2uvrA test strain either in the presence or in the absence of S9-metabolic activation (Organisation for Economic Cooperation and Development (OECD) No 471: bacteria reverse mutation test). It was concluded that cassia gum complying with the newly defined specifications does not give rise to safety concern with respect to genotoxicity. Cassia gum of the old specifications was tested in acute, sub-chronic, reproductive and developmental toxicity studies and it does not have significant toxicological properties. The no observed adverse effect level (NOAEL) in the 28-day rat study (OECD No 407: repeated dose 28-day oral toxicity study in rodents) was 230 mg/kg body weight (bw) per day. The slight biochemical and haematological effects occurring at the higher dose levels were generally not dose related and were of limited toxicological significance. Furthermore, in 90- day studies in dogs and cats, there were no effects at doses up to and mg/kg bw per day, respectively. Long-term carcinogenicity studies on cassia gum were not available. Given that cassia gum is not genotoxic and that many other related galactomannan gums are not carcinogenic, the AFC Panel did not consider long-term carcinogenicity studies essential for the safety assessment of cassia gum. The AFC Panel concluded that the toxicological data on cassia gum are insufficient to establish an acceptable daily intake (ADI). On the other hand, the existing data do not give reason for concern. The FEEDAP Panel agrees with the conclusions reached by the AFC Panel (EFSA, 2006) Reproduction and developmental studies in laboratory animals JECFA (2010a) described a two-generation reproduction study in rats and two developmental toxicity studies, one in rats and one in rabbits. In the two-generation reproductive toxicity study in rats (OECD No 416: two-generation reproduction study), the only effects observed were a slightly reduced pregnancy rate (which was not observed in a subsequent second mating resulting in an F1b generation) and a slight, but not significant, decrease in pup weights of the F1a and F2 generations at the highest dose level. Therefore, mg semi-refined cassia gum/kg feed (equal to mg/kg bw per day), the highest dose tested, was taken to be the NOAEL. In the developmental study on rats (OECD No 414: prenatal developmental toxicity study), feed intake was statistically significantly reduced at mg semi-refined cassia gum/kg bw per day (the highest dose tested), accompanied by a statistically significant reduction in mean body weight gain. In the rabbit study, a reduction in mean daily feed intake was reported, as well as a slight reduction in mean fetal weights at mg semi-refined cassia gum/kg bw per day (the highest dose tested), but these reductions were not statistically significant. These effects are probably related to the viscous nature of cassia gum and were not considered to be of toxicological relevance. No embryotoxicity, fetotoxicity or teratogenicity was observed in either species. The NOAEL was mg semi-refined cassia gum/kg bw per day, the highest dose tested, in both rats and rabbits Pharmacology/toxicology of anthraquinones Anthraquinones are naturally occurring compounds found in several plants, including the Cassia genus, which have a very long history of use in traditional medicine. Aside from the well-known cathartic properties, plant extracts containing different anthraquinones and other compounds have been reported to display antimicrobial and antioxidant activities, as well as antimutagenic and EFSA Journal 2014;12(11):3901 9

10 anticarcinogenic properties, which have been linked to the induction of apoptosis and the inhibition of cell proliferation (Yadav et al., 2010). On the other hand, clinical signs and lesions involving skeletal muscles, the heart, the liver, the kidneys and the nervous system have been reported in different animal species as a result of exposure to anthraquinone-containing plants (Vashishtha et al., 2009). Emodin and chrysophanol may undergo cytochrome P450-mediated bioactivation to genotoxic metabolites (Mueller et al., 1998). Finally, experiments using an in vivo mouse model disclosed that consumption of water for drinking containing μm emodin led to decreased oocyte maturation and in vitro fertilisation, as well as early embryonic developmental injury (Chang et al., 2012) Safety for the target species One study in dogs and two studies in cats, although not classical tolerance studies, were used to assess the safety of cassia gum for the target species. These studies have been assessed by JECFA (2010a) Dogs In a 90-day study (OECD No 409: repeated dose 90-day oral toxicity study in non-rodents) (Schuh, 1990), three groups of four beagle dogs of either sex received a diet of canned food supplemented with 0.75 or 2.5 % semi-refined cassia gum or with 0.23 % carob (crushed locust bean), which was considered the control group. The concentration of the additive in the experimental diets was analytically confirmed; however, the test item was not specified. No mortality occurred. JECFA (2010a) concluded that: the only treatment-related effect was a dose-dependent increase in water consumption. However, as this was most likely associated with water retention in the gastrointestinal tract by colloidally dissolved cassia gum, it is not considered to be of toxicological relevance. In line with the view of JECFA (2010a), the Panel concludes that the highest dose tested was tolerated by dogs Cats In a one-generation reproduction toxicity study (OECD No 409: repeated dose 90-day oral toxicity study in non-rodents; and No 415: one-generation reproduction toxicity study) (Virat, 1989), three groups of 10 male and 20 female cats were exposed for 83 weeks to cassia gum in the diet at levels of 0, 0.75 and 2.5 %. The quality of the study was impaired by an unusually high post-partum litter loss in the control group within 13 weeks (more than 50 %). The study is not considered further. In a 90-day study (OECD No 409: repeated dose 90-day oral toxicity study in non-rodents) (Virat, 1984), groups of five cats of either sex were given diets of canned food containing semi-refined cassia gum at levels of 0, 0.5 or 2.5 %. No adverse or treatment-related effects in terms of mortality, behaviour, clinical signs, body weight gain, food and water consumption, haematology, clinical biochemistry, necropsy, organ weights and histology were observed. In line with the view of JECFA (2010a), the Panel concludes that the highest dose tested was tolerated Considerations on the safety for the target species The 90-day studies with dogs and cats, although not classical tolerance studies, could be used to assess safety for the target species, since a multiple of the proposed use level of cassia gum (about 0.3 %) was administered. The studies showed that 2.5 % semi-refined cassia gum in the diet was tolerated by dogs and cats. The proposed maximum concentration (0.4 % in feed with 88 % dry matter may correspond to 0.3 % in feed with 80 % dry matter) might therefore have a margin of safety of about eight, which is considered sufficient to take account of the expected higher sensitivity of cats to anthraquinones. The daily intake of cassia gum by the target animals will be determined by the dry matter content of that (i.e. canned) feed. The lower the dry matter content of feed, the higher the daily intake of feed and therefore also of cassia gum. Relating a maximum content of cassia gum to a standardised complete feed would therefore respect safety considerations but possibly not the EFSA Journal 2014;12(11):

11 technological requirement for a gelling agent, which is effective in an aqueous environment. The water content of the feedingstuffs used in the two studies in cats and dogs is not known. Assuming that the water content of the diets was between 70 and 80 %, the safe concentration (0.3 %) would then correspond to 1 to 1.5 % in dry matter. A concentration of 1.5 % cassia gum in dry matter would correspond to 1.32 % ( mg/kg) in a standardised complete feed with 12 % water content. However, a final conclusion on the safety of cassia gum for target animals requires consideration of additional aspects. Cassia gum will probably be administered to dogs and cats for their lifetimes. There were positive findings in a bacterial reverse mutation test with a semi-refined cassia gum (about 70 mg anthraquinones/kg) but not with the purified semi-refined cassia gum (following the specifications of cassia gum as a food additive: < 0.5 mg anthraquinones/kg). No adverse effects on reproduction are expected if the purified semi-refined cassia gum is used Conclusions on safety for the target species The FEEDAP Panel concludes that only purified semi-refined cassia gum that meets the specifications of cassia gum as a food additive can be considered safe for cats and dogs, at a maximum content of mg/kg complete feed Safety for the user No data were provided on the irritancy of cassia gum to skin and eyes. Steget et al. (1999) performed a cross-sectional study on the prevalence of sensitisation and the respiratory health of the employees of a plant in which natural thickener products (Cassia spp., guar and tamarind flour) were used. In total, 62 workers (36 with high and 26 with low exposure) participated in the survey. Skin prick tests and specific immunoglobulin E tests with extracts of these components revealed that 11.3 % were sensitised to Cassia spp., with a significantly higher portion of atopic subjects in the sensitised group. Overall, 55 % of the subjects reported work-related symptoms (of the upper and lower airways, eyes or skin). The authors concluded that dust exposure to flours from thickener products may not only cause allergic sensitisation, but also induce chronic changes in lung function. The FEEDAP Panel considers that it would be prudent to regard cassia gum as a potential skin and respiratory sensitiser. Information on the particle size distribution does not allow the exclusion of the possibility of inhalation exposure Conclusion on safety for the user Cassia gum is regarded as a skin and respiratory sensitiser and as a potential irritant to skin and eyes. It would be prudent to assume that cassia gum has the potential to harm workers who might be exposed via skin, eyes or inhalation Safety for the environment Following the provisions of the guidance on environmental risk assessment (EFSA, 2008), there is no requirement for the assessment of the environmental impact of the use of a feed additive when used for pets. 4. Efficacy The efficacy of cassia gum (product identity not confirmed) has been studied by analysing the gel strength values of one commercial canned complete feed for dogs (about 80 % water). The feed was labelled as containing about 0.2 % cassia gum. The gel strength of the feed (one batch, two subsamples) was measured after purchase (range g/cm 2 ) and after three months storage (range g/cm 2 ). EFSA Journal 2014;12(11):

12 Considering the absence of the identification of the additive in the trial provided, the FEEDAP Panel cannot conclude on the efficacy of the cassia gum under application as a gelling agent in feedingstuffs for dogs and cats. CONCLUSIONS AND RECOMMENDATIONS CONCLUSIONS The FEEDAP Panel concludes that only purified semi-refined cassia gum that meets the specifications of cassia gum as a food additive (< 0.5 mg anthraquinones/kg) can be considered safe for cats and dogs, at a maximum content of mg/kg complete feed. Cassia gum is regarded as a skin and respiratory sensitiser and as a potential irritant to skin and eyes. It would be prudent to assume that cassia gum has the potential to harm workers who might be exposed via skin, eyes or inhalation. The FEEDAP Panel cannot conclude on the efficacy of cassia gum used as a gelling agent in feedingstuffs for dogs and cats. RECOMMENDATIONS The FEEDAP Panel recommends that the specification for cassia gum as a feed additive should follow the specifications set for cassia gum as a food additive, listed in Commission Regulation (EU) No 231/ DOCUMENTATION PROVIDED TO EFSA 1. Cassia gum. October Submitted by Intercolloid (UK) Ltd. 2. Cassia gum. Supplementary information. April Submitted by Intercolloid (UK) Ltd. 3. Cassia gum. Supplementary information. July Submitted by Intercolloid (UK) Ltd. 4. Evaluation report of the European Union Reference Laboratory for Feed Additives on the Methods(s) of Analysis for cassia gum. 5. Comments from Member States received through the ScienceNet. REFERENCES Bombardelli E and Pifferi G, Naturally occurring anthraquinone derivatives. Bollettino Chimico Farmaceutico, 127, Chang MH, Chang SC and Chan WH, Injurious effects of emodin on maturation of mouse oocytes, fertilization and fetal development via apoptosis. International Journal of Molecular Sciences, 13, Court MH, Feline drug metabolism and disposition pharmacokinetic evidence for species differences and molecular mechanisms. Veterinary Clinics of North America, Small Animal Practice, 43, Crawford L and Friedman M, The effects of low levels of dietary toxic weed seeds (jimson weed) Datura stramonium and (sicklepod) Cassia obtusifolia, on the relative size of rat liver and levels and function of cytochrome P-450. Toxicology Letters, 54, 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. EFSA Journal 2014;12(11):

13 Crawford L, McDonald GM and Friedman M, Composition of sicklepod (Cassia obtusifolia) toxic weed seeds. Journal of Agricultural and Food Chemistry, 38, Dekant W, Identification and quantitation of anthraquinones in cassia gum. Unpublished report from the Julius-Maximilians-Universität Würzburg. EFSA (European Food Safety Authority), Opinion of the Scientific Panel on food additives, flavourings, processing aids and materials in contact with food (AFC) related to an application on the use of cassia gum as a food additive. The EFSA Journal 2006, 389, EFSA (European Food Safety Authority), EFSA Panel on Additives and Products or Substances used in Animal Feed (FEEDAP), Technical Guidance for assessing the safety of feed additives for the environment. The EFSA Journal 2008, 842, JECFA (Joint FAO/WHO Expert Committee on Food Additive), 2010a. Safety evaluation of certain food additives. Seventy-first meeting of the Joint FAO/WHO. WHO Food Additives Series 62, Geneva, Available online: JECFA (Joint FAO/WHO Expert Committee on Food Additive), 2010b. Combined Compendium of Food Additive Specifications. JECFA Monographs 10. Available online: Koshioka M and Takino Y, Studies on the evaluation of crude drug I. Quantitative estimation of anthraquinones in Cassia seeds. Chemical and Pharmaceutical Bulletin, 25, Liu W, Tang L, Ye L, Cai Z, Xia B, Zhang J, Hu M and Liu Z, Species and gender differences affect the metabolism of emodin via glucuronidation. The American Association of Pharmaceutical Scientists Journal, 12, Liu W, Zheng Z, Liu X, Gao S, Ye L, Yang Z, Hu M and Liu Z, Sensitive and robust UPLC- MS/MS method to determine the gender-dependent pharmacokinetics in rats of emodin and its glucuronide. Journal of Pharmaceutical and Biomedical Analysis, 54, Mathews CK and van Holde KE, Biochemistry. The Benjamin/Cummings Publishing Company, Inc., New York. Mueller SO, Stopper H and Dekant W, Biotransformation of the anthraquinones emodin and chrysophanol by cytochrome P450 enzymes: bioactivation to genotoxic metabolites. Drug Metabolism and Disposition, 26, Nurnberg E and Bleimuller G, Development of a galactomannan product for tablets. Pharmazeutische Industrie, 43, Nyman M and Asp N, Fermentation of dietary fibre components in the rat intestinal tract. British Journal of Nutrition, 47, Schuh W, Diagum-CS Systemic tolerance study in Beagle-dogs after daily oral (dietary) administration over a period of 90 days. Unpublished report No IC 4/90 from Schering. Steget A, Pethran A, Radon K, Praml G and Nowak D, Studies on the risk to workers health during the production of thickening agents made from natural products; including ground cassia with special regard for pulmonary function and allergic diathesis. Unpublished report dated 7 July from the Institute and Clinic for Industrial and Environmental Medicine, University of Munich, Munich, Germany. Vashishtha VM, John TJ and Kumar A, Clinical & pathological features of acute toxicity due to Cassia occidentalis in vertebrates. Indian Journal of Medical Research, 130, Virat M, week toxicity study in the cat by the oral route. Unpublished report No from Institut Français de Toxicologie, Saint Germain sur l Arbresle, France. Virat M, One-generation reproductive toxicology and subchronic toxicity study in cats. Unpublished draft report No from Hazleton Institut Français de Toxicologie, Saint Germain sur l Arbresle, France. EFSA Journal 2014;12(11):

14 Yadav JP, Arya V, Yadav S, Panghal M, Kumar S and Dhankhar S, Cassia occidentalis L.: a review on its ethnobotany, phytochemical and pharmacological profile. Fitoterapia, 81, EFSA Journal 2014;12(11):

15 APPENDIX Executive Summary of the Evaluation Report of the European Union Reference Laboratory for Feed Additives on the Method(s) of Analysis for cassia gum 20 In the current grouped application authorisation is sought under article 10(2) for Cassia gum under the category/functional groups 1(c), 1(d), 1(e) and 1(f) 'technological additives' / 'emulsifiers' (21),'stabilisers' (21,22), 'thickeners' (21,23), 'gelling agents' (21,22,23,24), according to the classification system of Annex I of Regulation (EC) No 1831/2003. Specifically, authorisation is sought for the use of the feed additive for cats and dogs. Cassia gum is already approved as feed additive under Directive 93/55/EEC, amending Council Directive 70/524/EEC concerning additives in feedingstuffs. Cassia gum is a yellowish powder produced from purified endosperm of the seeds of Cassia tora and Cassia obtusifolia belonging to the family Leguminosae. The feed additive consists of a minimum of 75 % of galactomannan with a galactose/mannose ratio close to 1:5. The Applicants (23,24) proposed maximum inclusion level of 1.76 % (17600 mg/kg) of Cassia gum in the complete feedingstuffs. For the determination of Cassia gum in the feed additive Applicants (23,24) proposed the internationally recognised FAO JECFA monographs for food additives, recommended by Commission Directive 2010/67/EU, amending the Commission Directive 2008/84/EC. Identification is based on several tests including - solubility; - gel formation with borate and xanthan gum; - viscosity; - ph; while the quantification of galactomannan is based on the "gum by difference" method. Furthermore, Applicants (21,24) submitted additional methods based on high performance anion exchange chromatography with pulsed amperometric detection (HPAEC-PAD) and high performance liquid chromatography with refractive index detection (HPLC-RI) and reported galactose/mannose ratios ranging from 1:8.5 to 1:6.6, determined with a precision of ca. 6 %. Based on the experimental evidence and the performance characteristics presented the EURL recommends for official control the methods recommended by Commission Directive 2010/67/EU and described in the FAO JECFA monographs for the identification of Cassia gum. Furthermore, the EURL recommends the additional methods submitted by the Applicants (21,24), based on HPAEC-PAD or HPLC-RI - to determine the galactose/mannose ratio in the feed additive. The Applicants provided no experimental data or any analytical methods for the determination of Cassia gum in premixtures and feedingstuffs, as the accurate determination of Cassia gum in these matrices is not achievable experimentally. Therefore the EURL cannot evaluate nor recommend any method for official control to determine Cassia gum 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: 21 FAD FAD FAD FAD EFSA Journal 2014;12(11):