Scientific Opinion on the safety assessment of the substance adipic acid dihydrazide, CAS No , for use in food contact materials 1

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1 EFSA Journal 2015;13(1):3961 SCIENTIFIC OPINION Scientific Opinion on the safety assessment of the substance adipic acid dihydrazide, CAS No , for use in food contact materials 1 EFSA Panel on Food Contact Materials, Enzymes, Flavourings and Processing Aids (CEF) 2, 3 European Food Safety Authority (EFSA), Parma, Italy This scientific output, published on 7 October 2015, replaces the earlier version published on 13 January ABSTRACT This scientific opinion of EFSA s Panel on Food Contact Materials, Enzymes, Flavourings and Processing Aids (CEF) deals with the risk assessment of adipic acid dihydrazide, CAS No , FCM substance No 987 for use as a crosslinker for acrylic polymer with keto side groups coated on polyolefins and adhesives in laminates made from plastics. The coating is not for direct food contact but used in inner layers of plastics laminates which are intended to be used for all types of foodstuffs at all time-temperature conditions applicable according to the laminate s properties. Specific migration of the substance was measured from a coated low-density polyethylene (LDPE) film, the substance was not detectable (limit of detection (LOD) mg/kg) with the food simulants 3 % acetic acid, 10 % ethanol for 10 days at 40 C and isooctane for 2 days at 20 C. According the in vitro and in vivo studies available the substance is not considered genotoxic. Based on an in vivo micronucleus test, the substance is not considered to be clastogenic/aneugenic under the tested conditions. The CEF Panel concluded that there is no safety concern for the consumer if the substance is used as a crosslinker for non-self-supporting coatings on plastics and not in direct contact with food. The migration of the substance should not exceed mg/kg food. European Food Safety Authority, 2015 KEY WORDS adipic acid dihydrazide, 1,6-dihydrazide hexanedioic acid, CAS No , FCM substance No 987, food contact materials, safety assessment, evaluation 1 On request from the Bundesamt für Verbraucherschultz und Lebensmittelsicherheit, Germany, Question No EFSA-Q , adopted on 11 December Panel members: Claudia Bolognesi, Laurence Castle, Jean-Pierre Cravedi, Karl-Heinz Engel, Paul Fowler, Roland Franz, Konrad Grob, Rainer Gürtler, Trine Husøy, Wim Mennes, Maria Rosaria Milana, André Penninks, Vittorio Silano, Andrew Smith, Maria de Fátima Tavares Poças, Christina Tlustos, Fidel Toldrá, Detlef Wölfle and Holger Zorn. One member of the Panel did not participate in the discussion on the subject referred to above because of potential conflicts of interest identified in accordance with the EFSA policy on declarations of interests. Correspondence: fip@efsa.europa.eu 3 Acknowledgement: The Panel wishes to thank the members of the Working Group on Food Contact Materials: Mona-Lise Binderup, Claudia Bolognesi, Laurence Castle, Jean-Pierre Cravedi, Riccardo Crebelli, Roland Franz, Nathalie Gontard, Konrad Grob, Ragna Bogen Hetland, Martine Kolf-Clauw, Eugenia Lampi, Maria Rosaria Milana, Maria de Fátima Tavares Poças, Philippe Saillard, Kettil Svensson and Detlef Wölfle for the preparatory work on this scientific opinion. 4 The word additive has been deleted before the name of the substance on pages 1 and 4. The word polyolefines has been replaced by plastics in the Abstract. Suggested citation: EFSA CEF Panel (EFSA Panel Food Contact Materials, Enzymes, Flavourings and Processing Aids), Scientific Opinion on the safety assessment of the substance adipic acid dihydrazide, CAS No , for use in food contact materials. EFSA Journal 2015;13(1):3961, 8 pp. doi: /j.efsa Available online: European Food Safety Authority, 2015

2 SUMMARY Within the general task of evaluating substances intended for use in materials in contact with food according to Regulation (EC) No 1935/2004 of the European Parliament and of the Council of 27 October 2004 on materials and articles intended to come into contact with foodstuffs, the Panel on Food Contact Materials, Enzymes, Flavourings and Processing Aids (CEF) received a request from a competent Member State Authority for safety evaluation of a substance following a corresponding application from BASF. The safety assessment of adipic acid dihydrazide with CAS No and FCM substance No 987 was requested. The substance is intended to be used as a crosslinker for acrylic copolymers with keto side groups coated on polyolefins and adhesives in laminates made from plastics. The coating is not used in direct contact with food but applied in inner layers of plastics laminates. Final articles are intended to be used for all types of foodstuffs at all time-temperature conditions applicable according to the laminate s properties. The substance is highly hydrophilic and largely soluble in water and acetic acid. The substance is thermostable up to 200 C which is higher than the maximum process temperature. Specific migration of the substance was measured from a coated low-density polyethylene (LDPE) film with the non-coated LDPE side in contact with the food simulants 3 % acetic acid, 10 % ethanol, 95 % ethanol for 10 days at 40 C and isooctane for 2 days at 20 C. The specific migration values obtained in 10 % ethanol and 3 % acetic acid can be considered to represent a realistic migration value. Under these conditions the substance was not detectable in any of the food simulants at a detection limit of mg/kg food simulant. Overall migration into 95 % ethanol and isooctane was measured against a blank LDPE sample which was not coated on the non-contact side. No significant differences between the test samples and the blank were found for any of the tested simulants, which means the coating layer did not influence the overall migration value. No additional oligomers compared to the blank LDPE were detected by Liquid Chromatography-Mass Spectrometry (LC-MS) analysis of the iso-octane overall migration solution. The substance adipic acid dihydrazide (ADH) was tested in vitro and in vivo for genotoxicity. The substance was considered to be not mutagenic under the test conditions used. The substance was tested in two in vivo micronucleus tests with male mice. It is assumed that the substance was systemically available and reached the bone marrow. Therefore, the substance is considered to be not clastogenic/aneugenic under the test conditions used. Based on the evidences available the substance is not considered genotoxic. The CEF Panel having considered the above-mentioned data concluded that the substance adipic acid, dihydrazide is not a safety concern for the consumer if the substance is only to be used in acrylic copolymers with keto side groups used for non-self-supporting coatings on plastics and not in direct contact with food. The migration of the substance should not exceed mg/kg food. EFSA Journal 2015;13(1):3961 2

3 TABLE OF CONTENTS Abstract... 1 Summary... 2 Background as provided by the legislation... 4 Terms of reference as provided by the legislation... 4 Assessment Introduction General information Data available in the dossier used for this evaluation Evaluation Non-toxicological data Toxicological data... 6 Conclusions... 7 Documentation provided to EFSA... 7 References... 7 Abbreviations... 8 EFSA Journal 2015;13(1):3961 3

4 BACKGROUND AS PROVIDED BY THE LEGISLATION Before a substance is authorised to be used in food contact materials and is included in a positive list EFSA s opinion on its safety is required. This procedure has been established in Articles 8 and 9 of the Regulation (EC) No 1935/2004 of the European Parliament and of the Council of 27 October 2004 on materials and articles intended to come into contact with food 5. According to this procedure industry submits applications to the Member State Competent Authorities which transmit the applications to EFSA for their evaluation. The application is supported by a technical dossier submitted by the industry following the guidelines of the Scientific Committee on Food (SCF) for the presentation of an application for safety assessment of a substance to be used in food contact materials prior to its authorisation (EC, 2001). In this case, EFSA received an application from Bundesamt für Verbraucherschutz und Lebensmittelsicherheit, Germany, requesting the evaluation of Adipic acid, dihydrazide with the CAS No and the FCM substance No 987. TERMS OF REFERENCE AS PROVIDED BY THE LEGISLATION According to Regulation (EC) No 1935/2004 of the European Parliament and of the Council on materials and articles intended to come into contact with food EFSA is asked to carry out an assessment of the risks related to the intended use of the substance and to deliver a scientific opinion. 5 Regulation (EC) No 1935/2004 of the European parliament and of the council of 27 October 2004 on materials and articles intended to come into contact with food and repealing Directives 80/590/EEC and 89/109/EEC. OJ L 338, , p EFSA Journal 2015;13(1):3961 4

5 ASSESSMENT 1. Introduction The European Food Safety Authority was asked by the Bundesamt für Verbraucherschutz und Lebensmittelsicherheit, Germany, to evaluate the safety of adipic acid, dihydrazide with a CAS No and FCM substance No 987. The request has been registered in EFSA s register of received questions under the number EFSA-Q The dossier was on behalf of the applicant, BASF SE, Germany. 2. General information According to the applicant, the substance adipic acid dihydrazide is intended to be used as a crosslinker for acrylic polymer with keto side groups for non-self-supporting coatings on polyolefins and adhesives in laminates made from plastics. The coating is used not in direct contact with food but applied in inner layers of plastics laminates which are intended to be used for all types of foodstuffs at all time-temperature conditions applicable according to the laminate s properties. The substance has not been evaluated by the SCF or EFSA in the past. 3. Data available in the dossier used for this evaluation The studies submitted for evaluation followed the SCF guidelines for the presentation of an application for safety assessment of a substance to be used in food contact materials prior to its authorisation (EC, 2001). Non-toxicity data: Data on identity Data on physical and chemical properties Data on intended use and authorisation Data on migration of the substance Data on residual content of the substance Data on overall migration, oligomers and reaction products Toxicity data: Bacterial gene mutation tests (five studies) In vitro mammalian cell gene mutation test In vivo mouse bone marrow micronucleus tests (two studies) 4. Evaluation 4.1. Non-toxicological data Chemical formulae: C 6 H 14 N 4 O 2 (174.2 g/mol) Chemical structure: The substance adipic acid dihydrazide (ADH), CAS No is used in a purity higher than 99 %. The substance is highly hydrophilic with a log Po/w = 2.41 and soluble in water (91 g/l) and EFSA Journal 2015;13(1):3961 5

6 in acetic acid. The substance is thermostable up to 200 C. Maximum process temperature is 100 C. Due to its chemical nature it reacts easily with keto groups to form hydrazones. Specific migration of the substance was measured from a coated low-density polyethylene (LDPE) film with a thickness of 0.16 mm with the non-coated LDPE side in contact with the food simulants 3 % acetic acid, 10 % ethanol, 95 % ethanol for 10 days at 40 C and isooctane for 2 days at 20 C. The substance is not stable in 95 % ethanol, under the migration test conditions due to the reaction with traces of aldehydes. However, due to the high hydrophilic character of the substance, the specific migration values obtained in 10 % ethanol and 3 % acetic acid can be considered to represent a realistic migration value. Under these conditions the substance was not detectable in any of the food simulants at a detection limit of mg/kg food simulant. The residual content of the substance was determined in the test sample used for migration testing. The substance could not be detected at a detection limit of mg/g coated LDPE film. This supports that the substance has fully reacted and it is not detected in specific migration test. Overall migration was measured under the same conditions as for specific migration. Overall migration into 95 % ethanol and isooctane was measured against a blank LDPE sample which was not coated on the non-contact side. No significant differences between the test samples and the blank were found for any of the tested simulants, which means the coating layer did not influence the overall migration value. In order to verify that no oligomers or other reaction products have penetrated the LDPE layer and migrated into food, LC-MS analysis was performed on the iso-octane overall migration solution. No additional oligomers compared to the blank LDPE were detected. These findings can be reasonably explained by the fact that the coating consists of a crosslinked acrylic polymer which is expected to contain only little or no LMWF oligomers Toxicological data The substance adipic acid dihydrazide (ADH) was tested in vitro and in vivo for genotoxicity. Five bacterial reverse mutation tests (with Salmonella typhimurium strains TA1537, TA1535, TA98, TA100 and either TA 102 or in E. coli WP2 uvra) were performed with and without metabolic activation. Despite some limitations in these tests, the substance was considered to be not mutagenic under the test conditions used. In addition, no significant induction of mutant colonies, indicative of mutagenic and clastogenic events, was observed in mammalian cells (L5178Y TK +/- mouse lymphoma assay) with or without exogenous metabolic activation. In addition, the substance was tested in two in vivo micronucleus tests with male mice. In the first test with intraperitoneal injection at a maximum recommended dose, the substance did not induce micronucleated polychromatic erythrocytes. As no signs of toxicity in bone marrow cells were observed in mice it was not proven that the substance has reached the target organ. However, due to the intraperitoneal administration it is assumed that the substance was systemically available and reached the bone marrow. In the second micronucleus test the substance was administered to male mice by oral gavage at doses of 500, 1000 and 2000 mg/kg body weight. The substance neither induced micronucleated polychromatic erythrocytes nor signs of toxicity in bone marrow cells. To clarify whether the test substance reached the bone marrow, blood samples were taken 24 h after administration. Based on the analytical results it can be concluded that adipic dihydrazide could be detected in the plasma samples of treated mice in sufficient concentrations while no test substance could be detected in the control mouse plasma samples. In conclusion, these results provide evidence that adipic acid dihydrazide reached the bone marrow but did not induce clastogenicity. Based on the evidence available from the above mentioned in vitro and in vivo tests the substance is not considered genotoxic. EFSA Journal 2015;13(1):3961 6

7 CONCLUSIONS The CEF Panel having considered the above-mentioned data concluded that the substance adipic acid, dihydrazide is not a safety concern for the consumer if the substance is only to be used as crosslinker in acrylic copolymers with keto side groups if used in non-self-supporting coatings on plastics and not in direct contact with food. The migration of the substance should not exceed mg/kg food. DOCUMENTATION PROVIDED TO EFSA 1. Dossier: ADH. 19 November Submitted by BASF SE. 2. Additional data to dossier on ADH. January Submitted by BASF SE. 3. Additional data to dossier on ADH. June Submitted by BASF SE. REFERENCES EC (European Commission), (2001). Guidelines of the Scientific Committee on Food for the presentation of an application for safety assessment of a substance to be used in food contact materials prior its authorisation. Available online: EFSA Journal 2015;13(1):3961 7

8 ABBREVIATIONS ADH Adipic Acid Dihydrazide CAS Chemical Abstract Service CEF Scientific Panel on Food Contact Materials, Enzymes, Flavourings and Processing Aids EC European Commission EFSA European Food Safety Authority FCM Food Contact Materials LC-MS Liquid Chromatography-Mass Spectrometry LDPE Low-density polyethylene LMWF Low molecular Weight Fraction LOD Limit of detection SCF Scientific Committee on Food EFSA Journal 2015;13(1):3961 8