SCIENTIFIC OPINION. EFSA Panel on Food Contact Materials, Enzymes, Flavourings and Processing Aids (CEF) 2, 3

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1 SCIENTIFIC OPINION Scientific Opinion on the safety evaluation of the substance, methacrylic acid, 2-hydroxypropyl ester, 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 opinion, published on 5 th July, replaces the earlier version published on 5 th June ABSTRACT This scientific opinion of EFSA deals with the safety evaluation of the monomer methacrylic acid, 2- hydroxypropyl ester (synonym: 2-hydroxypropyl methacrylate - HPMA), FCM Substance No 995, to be used as monomer in acrylic resin coatings for food cans at use levels up to 20%. No HPMA monomer was determined in the acetonitrile extract of coated cans at a detection limit corresponding to a maximum migration of 3 µg/6 dm². In the acetonitrile extract the oligomeric fraction with MW < 1000 Da containing the HPMA moiety can be estimated to be up to 1.25 mg/kg food assuming total transfer to the food. The toxicity of HPMA was tested in three in vitro genotoxicity tests with and without metabolic activation and in combined in vivo micronucleus and Comet assays in rats and it was considered as non-genotoxic in vivo. In addition, read-across from a 90-day oral study in rat, with a NOAEL of 150 mg/kg b.w./day, for an oligomer with similar structure was considered feasible. The CEF Panel concluded that there is no safety concern for the consumer if the substance is used as monomer in acrylic resin coatings for food cans, cured at a temperature of at least 200 C. European Food Safety Authority, 2012 KEY WORDS methacrylic acid, 2-hydroxypropyl ester ; 2-hydroxypropyl methacrylate; methacrylic acid, 2-hydroxy-1- methylethyl ester; 2-hydroxy-1-methylethyl methacrylate; CAS No ; CAS No FCM Substance No 995; Food contact materials; Safety assessment; Evaluation. 1 On request from the The Ministry of Health, Welfare and Sport, The Netherlands, Question No EFSA-Q Panel members: Ulla Beckman Sundh, Mona-Lise Binderup, Leon Brimer, Laurence Castle, Karl-Heinz Engel, Roland Franz, Nathalie Gontard, Rainer Gürtler, Trine Husøy, Klaus-Dieter Jany, Catherine Leclercq, Jean-Claude Lhuguenot, Wim Mennes, Maria Rosaria Milana, Maria de Fátima Poças, Iona Pratt, Kettil Svensson, Fidel Toldrá, Detlef Wölfle. One member of the Panel did not participate in the discussion because of potential conflicts of interest identified in accordance with the EFSA policy on declarations of interests. Correspondence: cef@efsa.europa.eu 3 Acknowledgement: The Panel wishes to thank the members of the Working Group on Food Contact Materials for the preparation of this opinion: Mona-Lise Binderup, Laurence Castle, Riccardo Crebelli, Roland Franz, Nathalie Gontard, Eugenia Lampi, Jean-Claude Lhuguenot, Maria Rosaria Milana, Karla Pfaff, Fatima Poças, Philippe Saillard, Kettil Svensson and Detlef Wölfle for the support provided to this EFSA scientific output. 4 Editorial changes have been made on page 1. The changes do not affect the overall conclusions of the opinion. Suggested citation: EFSA Panel on food contact materials, enzymes, flavourings and processing aids (CEF); scientific Opinion on the safety evaluation of the substance, methacrylic acid, 2-hydroxypropyl ester, CAS No , for use in food contact materials.. [9 pp.] doi: /j.efsa Available online: European Food Safety Authority, 2012

2 SUMMARY The CEF Panel received a request from the Ministry for Health, Welfare and Sports, the Netherlands, for safety evaluation of a substance following a corresponding application from the company The Valspar Corporation, UK. The safety evaluation of the substance methacrylic acid, 2-hydroxypropyl ester (synonym: 2- hydroxypropyl methacrylate HPMA ) which is an isomeric mixture of methacrylic acid, 2-hydroxyn-propyl ester (CAS No ) and methyacrylic acid, 2-hydroxy-1-methylethylester (CAS No ) and the FCM substance No 995, is requested for use as monomer up to 20% in acrylic coatings for food cans, for contact with all types of food at conditions of sterilisation (for 1 h at 130 C), followed by storage at room temperature for a long period of time. The dossier was submitted on behalf of the applicant, The Valspar Corporation, UK. Cans coated with an acrylic resin based on HPMA, 2,3-epoxypropyl methacrylate, butylmethacrylate and styrene were extracted with acetonitrile for 24 h at room temperature. No HPMA monomer was determined in the dry acetonitrile extract at a detection limit corresponding to a maximum migration of 3 µg/6 dm². It was estimated that the low molecular weight oligomers containing the HPMA moiety may migrate up to 1.25 mg/kg food. The toxicity of HPMA was tested in three in vitro genotoxicity tests with and without metabolic activation and in combined in vivo micronucleus and Comet assays in rats. HPMA was clastogenic and induced polyploidy in cultured mammalian cells, both in presence and absence of an exogenous metabolic activation; evidence for a clastogenic potential was also obtained in the mouse lymphoma tk+/- assay. Gene mutation assays in bacteria provided negative results. The genotoxic activity of HPMA observed in vitro is not expressed in vivo, in a combined in vivo micronucleus and Comet assays in rats, so HPMA was considered non-genotoxic in vivo. No toxicological data were provided for the low molecular weight oligomers. However, these oligomers are derived from a non-genotoxic monomer and they are expected to be less reactive than the composing monomer. Therefore they do not raise a genotoxicity concern. Moreover, read-across from a 90-day oral rat study for the oligomeric fraction with molecular weight below 1000 Da of the polymeric additive 2,3-epoxypropyl methacrylate-ethyl methacrylate copolymer, with a NOAEL of 150 mg/kg b.w./day, is feasible due to the structural similarity of the oligomers. Based on these considerations, the estimated migration of HPMA oligomers does not raise a safety concern. The CEF Panel concluded that there is no safety concern for the consumer if the substance is used as monomer in acrylic resin coatings for food cans cured at a temperature of at least 200 C. 2

3 TABLE OF CONTENTS Abstract 1 Summary... 2 Table of contents... 3 Background... 4 Terms of reference... 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 Glossary and abbreviations

4 BACKGROUND The company The Valspar Corporation, UK, has submitted a technical dossier to the Ministry for Health, Welfare and Sport, the Netherlands, with the request to evaluate the safety of the substance methacrylic acid, 2-hydroxypropyl ester (synonym: 2-hydroxypropyl methacrylate) for use as a co-monomer for the manufacture of acrylic resins which can be in direct contact with food. The dossier was compiled following 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). The substance methacrylic acid, 2-hydroxypropyl ester is intended to be used as a co-monomer in modified acrylic resins. The coated cans are intended to be used for contact with all types of food. For substances used in the manufacture of coatings there is no specific Community measure. Therefore no authorisation is foreseen at EU level for substances used in coatings. The Ministry for Health, Welfare and Sport, the Netherlands, transmitted this request for the safety evaluation of the substance to the EFSA. TERMS OF REFERENCE The EFSA was requested by the Ministry for Health, Welfare and Sport, the Netherlands, to evaluate the safety of the substance methacrylic acid, 2-hydroxypropyl ester, CAS number and FCM Substance No 995, for use in acrylic resins which can be in direct contact with food. 4

5 ASSESSMENT 1. Introduction The European Food Safety Authority was asked by the Ministry of Health, Welfare and Sport, The Netherlands, to evaluate the safety of methacrylic acid, 2-hydroxypropyl ester (synonym: 2-hydroxypropyl methacrylate - HPMA), with a CAS number and the FCM substance No 995. The request has been registered in the EFSA s register of received questions under the number EFSA-Q The dossier was submitted on behalf of the applicant, The Valspar Corporation, UK. 2. General information According to the applicant, the substance methacrylic acid, 2-hydroxypropyl ester (synonym: 2- hydroxypropyl methacrylate) is intended to be used as co-monomer in acrylic resin coatings for food cans up to 20%. Application of the coating by spraying is followed by baking at a temperature above 200 C. The coated cans are intended to be used for contact with all types of food at conditions of sterilisation (for 1 h at 130 C), followed by storage at room temperature for a long period of time. 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 residual content of the substance Data on quantification and migration of oligomers Toxicity data: Gene mutation test in bacteria In vitro mammalian cell gene mutation test In vitro mammalian chromosome aberration test Combined in vivo micronucleus and Comet assays 4. Evaluation 5

6 4.1. Non-toxicological data Chemical formula: C 7 H 12 O 3 Chemical structures: O O CH 3 H 2 C O CH 3 H 2 C O OH CH 3 OH Methacrylic acid, 2-hydroxy-n-propyl ester CH 3 Methacrylic acid, 2-hydroxy-1-methylethyl ester Molecular weight: 144 g/mol The substance methacrylic acid, 2-hydroxypropyl ester (synonym: 2-hydroxypropyl methacrylate - HPMA), is a mixture of the two isomers: methacrylic acid, 2-hydroxy-n-propyl ester, CAS No , and methacrylic acid, 2-hydroxy-1-methylethyl ester, CAS No in the ratio 2.72:1, respectively. HMPA is well soluble in water. Log P O/W is 0.97 (20 C). Cans coated with an acrylic resin, based on 2,3-epoxypropyl methacrylate, butylmethacrylate, styrene and containing HPMA at around the maximum intended use level, were extracted with acetonitrile for 24h at room temperature. The extractable amount was 1.6 mg/dm². In the acetonitrile extract the fraction with MW < 1000 Da was determined by GPC to be 28%. When assuming a suface to volume ratio of 6 dm² per kg food from these data a maximum migration of the low molecular weight (LMW) fraction would be up 2.7 mg/kg food. The composition of the acetonitrile extract was further analysed by LC-ToF-MS in positive and negative ionisation modes to identify those LMW oligomers containing the HPMA moiety. Overall 29 peaks with molecular weight < 1000 Da were identified. Out of the 29 compounds, 12 oligomers were found which contain or possibly contain HPMA. Under the assumption of total migration of these 12 oligomers, the maximum amount of HPMA-containing oligomers <1000 Da can be estimated to be 1.25 mg/kg food. In addition, the content of HPMA monomer was also determined in the acetonitrile extract by LC-MS/MS. HPMA was not detected at a detection limit corresponding to a maximum migration of 3 µg/6 dm² Toxicological data HPMA was tested in the three requested in vitro genotoxicity tests with and without metabolic activation and in combined in vivo micronucleus and Comet assays in rats. In the bacterial reversion mutation assays using the Salmonella typhimurium strains TA98, TA100, TA1535, TA1537, and the Escherichia coli strain WPuvrA the test substance did not induce gene mutations.. Evidence for a clastogenic potential was obtained in the in vitro mouse lymphoma tk+/- assay, where HPMA significantly increased the frequency of small mutant colonies without metabolic activation. HPMA was also clastogenic and induced polyploidy in the chromosomal aberration test in cultured Chinese hamster lung cells, both in presence and absence of an exogenous metabolic activation. When administered to male Sprague-Dawley rats by the oral route at the maximum tolerated dose (2000 mg/kg bw, gavage), in the combined in vivo micronucleus and Comet tests, HPMA did not induce biologically relevant increases in number of micronucleated polychromatic erythrocytes in bone marrow, where the bioavailability of the substance was demonstrated by a reduced ratio 6

7 of polychromatic to normochromatic erythrocytes, and did not induce DNA damage measured by Comet assay in liver and at the site of first contact (stomach). It is concluded that the genotoxic activity of HPMA observed in vitro is not expressed in vivo, and that HPMA does not raise concern for genotoxicity. The genotoxicity results with HPMA are in line with observations on other substances with methacrylate structures; it was frequently reported that positive results obtained with in vitro genotoxicity tests are not confirmed by in vivo assays (Johannsen et al., 2008). No toxicological data were provided for the LMW oligomers which may migrate up to 2.7 mg/kg food for all oligomers and up to 1.25 mg/kg food for those containing the HPMA moiety. Since the genotoxicity in vitro is likely to be associated with the double bond in the methacrylic acid moiety of HPMA, which is lost in the polymerization process, genotoxicity is not anticipated for the oligomers. In addition, no genotoxicity in vivo for the parent substance was observed. In addition, a 90-day oral rat study for the oligomeric fraction with molecular weight below 1000 Da of the polymeric additive methacrylic acid, 2,3-epoxypropyl ester, copolymer with methacrylic acid, ethyl ester (2,3-epoxypropyl methacrylate-ethyl methacrylate copolymer), has been evaluated by the CEF Panel (FCM Substance No 958) (EFSA, 2012). In this study, doses of 30, 150 and 750 mg/kg b.w./day were administrated to Wistar rats; increased liver weights and changes in clinical chemistry (increased alkaline phosphate and gamma-glutamyl transferase activities, decreased alanine aminotransferase activity and increased cho lesterol concentrations) at the high dose level, indicating a hepatotoxic adverse effect of the test substance, were reported. Based on these findings a NOAEL of 150 mg/kg b.w./day was derived for the test substance. Considering the structures of 2,3-epoxypropyl methacrylate-ethyl methacrylate copolymer and HPMA, 2,3- epoxypropyl methacrylate, butylmethacrylate, styrene oligomers a read across from the former to the latter would be feasible. Therefore the estimated migration of HPMA oligomers from its intended use does not raise a safety concern. CONCLUSIONS The CEF Panel considers that the substance methacrylic acid, 2-hydroxypropyl ester is not a safety concern for the consumer if the substance is used as monomer in acrylic resin coatings up to 20%, for food cans cured at a temperature of at least 200 C. DOCUMENTATION PROVIDED TO EFSA Dossier referenced: AR /SIT. Dated: 12 November Submitted on behalf of The Valspar Corporation, UK. 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; EC (European Commission), Opinion of the Scientific Committee on Food on an additional list of monomers and additives for food contact materials; expressed on 17/6/1999; EFSA (European Food Safety Authority) Scientific Opinion on the safety evaluation of the substance, Methacrylic acid, 2,3-epoxypropyl ester, copolymer with acrylic and/ or methacrylic acid alkyl (C1-C4) 7

8 esters, for use in food contact materials ; EFSA Journal 2012; 10(5):2744; F.R. Johannsen, B. Vogt, M. Waite, R. Deskin, Mutagenicity assessment of acrylate and methacrylate compounds and implications for regulatory toxicology requirements, Regulatory Toxicology and Pharmacology 50 (2008)

9 GLOSSARY AND ABBREVIATIONS Overall migration: The sum of the amounts of volatile and non volatile substances, except water, released from a food contact material or article into food or food simulant Specific migration: The amount of a specific substance released from a food contact material or article into food or food stimulant ADI bw CAS CEF Da EC EFSA FCM LC-MS NOAEL PET REF No SCF w/w Acceptable Daily Intake Body weight Chemical Abstracts Service Scientific Panel on food contact materials, enzymes, flavourings and processing aids Dalton European Commission European Food Safety Authority Food Contact Material(s) Liquid chromatography with mass detection No-Observed Effect Level Poly(ethylene terephthalate) European Commission Reference Number Scientific Committee on Food Weight by weight 9