Safety of the proposed amendment of the ... - Wiley Online Library

SCIENTIFIC OPINION ADOPTED: 27 April 2016 doi: 10.2903/j.efsa.2016.4490

Safety of the proposed amendment of the specifications for basic methacrylate copolymer (E 1205) as a food additive EFSA Panel on Food Additives and Nutrient Sources added to Food (ANS) Abstract Following a request from the European Commission, the Panel on Food Additives and Nutrient Sources added to Food (ANS) was asked to deliver an opinion to amend the specifications regarding the ‘definition’ and the ‘particle size’ limits of basic methacrylate copolymer (BMC – E 1205) listed in Commission Regulation (EU) No 231/2012. The request resulted from the change of the manufacturing process from a bulk polymerisation process to a solution polymerisation process and that the specifications for the particle size of < 0.1 lm are set at limits of ‘between 5.1% and 5.5%’. These limits were never met and could be interpreted as requesting a defined percentage of nanoparticles in the powder. The specifications were amended as follows: at least 95% of the particles have a size below 50 lm; at least 50% have a size below 20 lm; not more than 10% have a size below 3 lm. Particles with a diameter of 0.1 lm (100 nm) or below were never observed in the batches analysed. A detailed description of the solution polymerisation process was provided together with data on residual solvents, residual monomers, stability and reaction and fate in food. No new or additional biological and toxicological data were submitted. The ANS Panel taking into account the available information and as BMC was recently evaluated by EFSA (EFSA ANS Panel, 2010), considered this conclusion would still be valid for BMC produced by the new manufacturing procedure and that the request for amending the specification can be accepted. Therefore, the Panel concluded that there is no safety concern from the proposed amendments in the specifications resulting from the changes in the manufacturing process for the food additive BMC. © 2016 European Food Safety Authority. EFSA Journal published by John Wiley and Sons Ltd on behalf of European Food Safety Authority.

Keywords: food additive, basic methacrylate copolymer, E 1205, change in specifications, manufacturing process, particle size

Requestor: European Commission Question number: EFSA-Q-2015-00223 Correspondence: fi[email protected]

www.efsa.europa.eu/efsajournal

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Safety of changes in specification for basic methacrylate copolymer (E 1205)

Panel members: Fernando Aguilar, Riccardo Crebelli, Alessandro Di Domenico, Birgit Dusemund, , Jean-Charles Maria Jose Frutos, Pierre Galtier, David Gott, Ursula Gundert-Remy, Claude Lambre Leblanc, Oliver Lindtner, Peter Moldeus, Alicja Mortensen, Pasquale Mosesso, Dominique Parent-Massin, Agneta Oskarsson, Ivan Stankovic, Ine Waalkens-Berendsen, Rudolf Antonius Woutersen, Matthew Wright and Maged Younes Acknowledgements: The Panel wishes to thank the members of the Working Group on Applications for the preparatory work on this scientific output and EFSA staff members: Paolo Colombo and Camilla Smeraldi, for the support provided to this scientific opinion. Suggested citation: EFSA ANS Panel (EFSA Panel on Food Additives and Nutrient Sources added to Food), 2016. Scientific opinion on the safety of the proposed amendment of the specifications for basic methacrylate copolymer (E 1205) as a food additive. EFSA Journal 2016;14(5):4490, 13 pp. doi:10.2903/j.efsa.2016.4490 ISSN: 1831-4732 © 2016 European Food Safety Authority. EFSA Journal published by John Wiley and Sons Ltd on behalf of European Food Safety Authority. This is an open access article under the terms of the Creative Commons Attribution-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited and no modifications or adaptations are made. The EFSA Journal is a publication of the European Food Safety Authority, an agency of the European Union.


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Summary The subject of the present evaluation by the Panel on Food Additives and Nutrient Sources added to Food (ANS) is a request by the applicant to amend the specifications regarding the ‘definition’ and the ‘particle size’ of basic methacrylate copolymer (BMC – E 1205), as presently listed in Commission Regulation (EU) No 231/2012, and whether this could give rise to a safety concern. The request for this amendment derives from a change in the manufacturing process for BMC from a bulk polymerisation process to a solution polymerisation process in 2013. A detailed description of the solution polymerisation process was provided by the applicant. Data on the residual solvents and on the residual monomers were also provided. This was accompanied by data on the stability, and the reaction and fate in food of basic methacrylate produced via the new process were provided. The Panel noted that substantial analytical data were provided by the applicant which confirmed that with the exception of the changes proposed, the product from the solution polymerisation process met most of the existing specifications for BMC. No significant differences were found between products from the solution polymerisation process as compared to products from the bulk polymerisation process. No new or additional biological and toxicological data were submitted by the applicant. BMC was previously evaluated by the EFSA ANS Panel (2010). Based on the available database at that time, the Panel considered that ‘in the light of the high molecular weight of the substance, its lack of absorption and its low toxicity profile, the Panel considers these margins of safety adequate. In conclusion, the use of BMC as a glazing agent/coating agent in solid food supplements is not of safety concern at the proposed use levels’. The present Panel considered that this conclusion would still be valid for BMC produced by the new manufacturing procedure. The Panel requested further clarifications from the applicant concerning the description of proposed particle size distribution in order to better reflect the available data and especially avoid misinterpretation regarding the possible presence of a nanoscale fraction within the material. The clarification of the particle size information provided by the applicant gave reassurance that BMC did not contain detectable nanoscale material. The specifications were amended as follows: at least 95% of the particles have a size below 50 lm; at least 50% have a size below 20 lm; not more than 10% have a size below 3 lm. The Panel concluded that there is no safety concern from the proposed amendments in the specifications resulting from the changes in the manufacturing process for the food additive BMC.


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Table of contents Abstract................................................................................................................................................. Summary............................................................................................................................................... 1. Introduction.............................................................................................................................. 1.1. Background and Terms of Reference as provided by the requestor................................................ 1.1.1. Terms of Reference ................................................................................................................... 1.2. Interpretation of the Terms of Reference..................................................................................... 1.3. Additional information................................................................................................................ 1.3.1. Authorisations and evaluations in the European Union.................................................................. 2. Data and methodologies ............................................................................................................ 2.1. Data......................................................................................................................................... 2.2. Methodologies........................................................................................................................... 3. Assessment............................................................................................................................... 3.1. Technical data........................................................................................................................... 3.1.1. Identity of the substance ........................................................................................................... 3.1.1.1. Synonyms................................................................................................................................. 3.1.2. Specifications ............................................................................................................................ 3.1.3. Manufacturing process ............................................................................................................... 3.1.3.1. Residual monomers and processing aids ..................................................................................... 3.1.4. Methods of analysis in food........................................................................................................ 3.1.5. Reaction and fate in food........................................................................................................... 3.1.6. Current uses and use levels ....................................................................................................... 3.1.7. Biological and toxicological data ................................................................................................. 3.2. Discussion ................................................................................................................................ 4. Conclusions............................................................................................................................... Documentation provided to EFSA ............................................................................................................ References............................................................................................................................................. Abbreviations .........................................................................................................................................


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1.

Introduction

1.1.

Background and Terms of Reference as provided by the requestor

The use of food additives is regulated under the European Parliament and Council Regulation (EC) No 1333/20081 on food additives. Only food additives that are included in the Union list, in particular in Annex II to that regulation, may be placed on the market and used in foods under the conditions of use specified therein. Moreover, food additives shall comply with the specifications as referred to in Article 14 of that Regulation and laid down in Commission Regulation (EU) No 231/20122. The European Food Safety Authority (EFSA) evaluated the safety of basic methacrylate copolymer (BMC – E 1205) as a food additive and expressed its opinion in 20103 and consequently BMC was authorised as a food additive in the European Union for use in food supplements supplied in a solid form and specifications were defined. The manufacturer has requested an amendment to the present specifications of BMC in terms of the following:

• •

A change of the definition, with regard to the short description of the manufacturing process; due to a modernisation of this process. A change of the definition, with regard to the particle size of the powder, based on the clarification of the particle size that was originally submitted.

The applicant confirms that all other data in the specifications and data on characteristics, stability and functionality remain unchanged compared to the first submission of 2008.

1.1.1.

Terms of Reference

The European Commission requests EFSA to provide a scientific opinion on the safety of the proposed amendment of the specifications of the food additive BMC, in accordance with Regulation (EC) No 1331/20084 establishing a common authorisation procedure for food additives, food enzymes and food flavourings.

1.2.

Interpretation of the Terms of Reference

In order to address the safety of this proposed change in specifications, the Panel decided that an evaluation of the possible impact of these proposed changes on the characteristic of the product and on its safety profile would be adequate. As the scientific assessment of BMC by the ANS Panel is recent (EFSA ANS Panel, 2010), a full re-evaluation was not considered necessary.

1.3.

Additional information

The applicant has provided information on identity and characterisation of the substance, on specifications and on the modernised polymerisation manufacturing process with particular emphasis on effects on the particle size, including a statement on the absence of nanoscale material.

1.3.1.

Authorisations and evaluations in the European Union

In 2010, the EFSA Panel on Food Additives and Nutrient Sources added to Food (ANS) evaluated the use of BMC as a glazing agent in solid food supplements and in solid foods for special medical purposes (EFSA ANS Panel, 2010). BMC did not raise concern with respect to genotoxicity but the Panel noted that no data on reproductive toxicity were provided and that the database on developmental toxicity was limited. The Panel therefore considered that an acceptable daily intake (ADI) for BMC should not be derived. The NOAELs (no observed adverse effect levels) derived from the available studies were: 1,000 mg/kg body weight (bw) per day from a developmental study in the rat (the only dose level tested) and 2,000 mg/kg bw per day from a 26-week feeding study in the rat 1

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Regulation (EC) No 1333/2008 of the European Parliament and of the Council of 16 December 2008 on food additives. OJ L 354, 31.12.2008, p. 16–33. Regulation (EC) 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, 22.3.2012, p. 1–4. EFSA Journal 2010;8(2):1513. Regulation (EU) No 1131/2011 of 11 November 2011 amending Annex II to Regulation (EC) No 1333/2008 of the European Parliament and of the Council with regard to steviol glycosides. OJ L 295, 12.11.2011, p. 205–211.


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(highest dose tested). The estimated combined exposure for heavy users to BMC from both its use in food supplements and in pharmaceuticals, given a coating level of 100 mg/tablet, was calculated to be equal to 23.4 mg/kg bw per day for a 60-kg adult and 16 mg/kg bw per day for children (4–18 years). The margin of safety (MoS) values for the exposure only from food supplements were calculated to be in the range of 85–171 for adults and 125–250 for children. In the light of the high molecular weight of the substance, its lack of absorption and its low toxicity profile, the Panel considered these MoS were adequate. Overall, the ANS Panel concluded that the use of BMC as a glazing agent/coating agent in solid food supplements was not of safety concern at the proposed use levels. As regards the monomers used in the manufacturing process, the Scientific Committee on Food (SCF) evaluated methyl methacrylate (MMA; Ref. No 21130) and butyl methacrylate (BMA; Ref. No 2010) and allocated a group TDI (tolerable daily intake) of 0.1 mg/kg bw per day (expressed as methacrylic acid) (SCF, 1999). The third monomer, dimethylaminoethyl methacrylate (DMAEMA; Ref. No 20530), was evaluated by the SCF (1998) for use in food contact materials but no TDI was established as residues could not be detected. The SCF stated that the substance hydrolyses readily at neutral pH and above, and so it will be unstable in many foods. On the basis of these data, the Panel in 2010 calculated the worst-case exposure to the monomers (MMA, BMA, and DMAEMA) was < 50 lg/kg bw per day for adults and < 32 lg/kg bw per day for children, both being significantly below the group TDI of 0.1 mg/kg bw per day.

2.

Data and methodologies

2.1.

Data

The applicant has submitted a new dossier to supplement its previous application with a request to amend the specifications for the use of BMC as a protective coating (e.g. for purely mechanical stabilisation, moisture protection, taste or odour masking) for solid dosage forms such as tablets and fine particles.

2.2.

Methodologies

The current ‘Guidance for submission for food additive evaluations’ (EFSA ANS Panel, 2012) has been followed by the ANS Panel for evaluating the proposed change in manufacturing process and changes in the definition, with regard to the particle size of the powder. The assessment was conducted in line with the principles described in the EFSA Guidance on transparency in the scientific aspects of risk assessment (EFSA, 2009) and following the relevant existing Guidances from the EFSA Scientific Committee.

3.

Assessment

3.1.

Technical data

3.1.1.

Identity of the substance

The applicant has provided evidence that BMC is a fully polymerised copolymer derived from acrylic and methacrylic acid esters. The substance is described as a cationic copolymer based on DMAEMA and neutral methacrylic esters (BMA and MMA). According to the International Union of Pure and Applied Chemistry (IUPAC), the designation is as follows: Poly[(dimethylaminoethyl methacrylate)-co-(methyl methacrylate)-co-(butyl methacrylate)]. The molar ratio is 0.24:0.34:0.25 and the weight ratio % is 49:25:26. The CAS Registry Number is 24938-16-7. The applicant provided evidence that in the substance under consideration in this opinion the molar ratio of the monomers is in accordance with the IUPAC designation. The applicant provided comparative data on the weight average molecular weight (Mw) of BMC of four validated batches from solution polymerisation and four batches from bulk polymerisation tested by gel permeation chromatography (GPC). As shown in Table 1, the weight average Mw, and accordingly the mean Mw, of solution polymerisation products and bulk polymerisation products are almost identical and are in the range of approximately 45,000–48,000 g/mol. As these batches appear to be consistently manufactured with very similar characteristics within the proposed specifications, the Panel considered that in these circumstances, data from a fifth batch were not necessary. www.efsa.europa.eu/efsajournal

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Table 1:

Comparative data of the weight average molecular weight (Mw) of batches of basic methacrylate copolymer obtained via solution polymerisation and bulk polymerisation processes

Bulk polymerisation batches

Weight average Mw (g/mol)

Solution polymerisation batches

Weight average Mw (g/mol)

E111101211

45,900

B130401503

47,200

E120501112 E120901204

45,800 45,900

B130401504 B130401505

47,500 46,300

E110201045

45,500

B130401506

46,900

Mean weight average Mw (rounded)

45,800

Mean weight average Mw (rounded)

47,000

The applicant further indicated that the number average molecular weight (Mn) is approximately 22,000 g/mol. The applicant also stated that during the production a constant molecular weight range was controlled by constant production parameters and by control of the viscosity number (cm3/g) or by the apparent viscosity (mPa.s). The representative structural formula of BMC is shown in Figure 1. CH3

CH3 x

O

O O

O

O N

y

y

O

H3C

CH3

C4H9

CH3

CH3

n

Figure 1: Representative structural formula of basic methacrylate copolymer According to the applicant, cross linking in the polymer cannot occur. A copolymer of the monomers DMAEMA, BMA and MMA after radical polymerisation will only form chains because the monomers only carry one double bond that can be involved in free radical polymerisation and because the monomers do not carry a second double bond necessary for cross linking. Solubility: One gram of BMC dissolves in 7 g of methanol, ethanol, 2-propanol, acetone, ethyl acetate, methylene chloride or 1 N hydrochloric acid to give clear to slightly cloudy solutions. An organic solution of 12% BMC can be mixed with these solvents and with petroleum ether in a ratio of 1:1. The solid substance is practically insoluble in petroleum ether and in water. The polymer is precipitated from a 12.5% solution when mixed with water in a ratio of 1:1. BMC films are soluble in gastric juice and weakly acidic solutions, up to approximately pH 5, due to the formation of polymeric salts of the 2-dimethylaminoethyl groups. 3.1.1.1. Synonyms Basic butylated methacrylate copolymer; amino methacrylate copolymer; aminoalkyl methacrylate copolymer E; butyl methacrylate, dimethylaminoethyl methacrylate, methyl methacrylate polymer; butyl methacrylate, methyl methacrylate, dimethylaminoethyl methacrylate polymer.

3.1.2.

Specifications

The applicant stated that, overall, the specifications for BMC remain unchanged when compared with the specification published in Commission Regulation (EU) No 231/2012 but requested amendment of the ‘Definition’ and the limits for the ‘particle size’ of the powder in the EU specifications. The request for amending the term ‘definition’ in the current EU specification is based on modification of the manufacturing process from a bulk polymerisation process to a solution polymerisation process (see section on manufacturing).


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The applicant stressed that the chemical synthesis in the manufacturing process remains unchanged and that it is still based on radical polymerisation. According to the applicant, the product from the solution polymerisation process meets the existing specifications for E 1205 and provides equivalent functionality. The applicant provided analytical data from validation lots confirming this statement. As regards the particle size of BMC (powder), the Panel noted that the specification for E 1205 in Commission Regulation (EU) No 231/2012 set a limit for the particle size of < 0.1 lm between 5.1% and 5.5%. According to the applicant, this limit appeared to be based on a misunderstanding of some data provided by the applicant in 2009. The applicant indicated that this specification has never been met by the commercial product. The Panel noted that the current EU specification for E 1205 could be interpreted as requiring a defined percentage of nanoparticles in the powder. The applicant provided data on the particle size distribution for BMC manufactured via solution polymerisation. Particle size analysis was performed using the laser diffraction method. The Panel noted that with the type of instrument used by the applicant, particle sizes down to 0.01 lm (10 nm) can be measured. From the data provided by the applicant, particles with a diameter of 0.1 lm (100 nm) or less were not observed. The applicant stated that BMC was never intended or expected to be a nanomaterial. The amendments for the present EU specifications as proposed by the applicant are given in Table 2. Table 2:

Comparison of the specifications according to Commission Regulation (EU) No 231/2012 and the proposals for amending these specifications by the applicant Specifications according to Commission Regulation (EU) No 231/2012

Specification proposed by applicant

Requested amendment by the applicant

Synonyms

Basic butylated methacrylate copolymer; amino methacrylate copolymer; aminoalkyl methacrylate copolymer E; butyl methacrylate, dimethylaminoethyl methacrylate, methyl methacrylate polymer; butyl methacrylate, methyl methacrylate, dimethylaminoethyl methacrylate polymer

Basic butylated methacrylate copolymer; amino methacrylate copolymer; aminoalkylmethacrylate copolymer E; butyl methacrylate, dimethylaminoethyl methacrylate, methyl methacrylate polymer; butyl methacrylate, methyl methacrylate, dimethylaminoethyl methacrylate polymer

None

Definition

Basic methacrylate copolymer is manufactured by thermic controlled polymerisation of the monomers methyl methacrylate, butyl methacrylate and dimethylaminoethyl methacrylate, dissolved in propan-2-ol) by using a free radical donor initiator system. An alkyl mercaptan is used as the chain modifying agent. The solid polymer is milled (first milling step) and extruded and granulated under vacuum to remove residual volatile components. The resultant granules are commercialised as such or undergo a second milling step (micronisation)

Delete: solid Insert: solution Delete: milled (first milling step), second

Chemical name

Poly(butyl methacrylate-co(2-dimethylaminoethyl)methacrylateco-methylmethacrylate) 1:2:1

Basic methacrylate copolymer is manufactured by thermic controlled polymerisation of the monomers methyl methacrylate, butyl methacrylate and dimethylaminoethyl methacrylate (dissolved in propan-2ol) by using a free radical donor initiator system. An alkyl mercaptan is used as the chain modifying agent. The polymer solution is extruded and granulated under vacuum to remove residual volatile components. The resultant granules are commercialised as such or undergo a milling step (micronisation) Poly(butyl methacrylate-co(2-dimethylaminoethyl)methacrylateco-methylmethacrylate) 1:2:1

Chemical formula

Poly[(CH2:C(CH3)CO2(CH2)2 N(CH3)2)Poly[(CH2:C(CH3)CO2(CH2)2 co-(CH2:C(CH3)CO2CH3)-co-(CH2:C(CH3) N(CH3)2)-co-(CH2:C(CH3)CO2CH3)CO2(CH2)3CH3)] co-(CH2:C(CH3)CO2(CH2)3CH3)]


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None

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Specifications according to Commission Regulation (EU) No 231/2012

Specification proposed by applicant

Weight average molecular weight estimated by gel permeation chromatography

Approximately 47,000 g/mol

Approximately 47,000 g/mol

Particle size of powder (when used forms a film)

< 50 lm more than 50% < 0.1 lm 5.1–5.5%

< 50 lm at least 95% < 20 lm at least 50% < 3 lm not more than 10%

Assay

20.8–25.5% dimethylaminoethyl (DMAE) groups on dry substance

20.8–25.5% dimethylaminoethyl (DMAE) groups on dry substance

Description

Granules are colourless to yellow tinged; the powder is white

Granules are colourless to yellow tinged; the powder is white

Requested amendment by the applicant

Delete: < 50 lm more than 50% < 0.1 lm 5.1–5.5% Insert: < 50 lm at least 95% < 20 lm at least 50% < 3 lm not more than 10% None None

Identification Infrared absorption To be identified spectroscopy 3–6 mPa.s Viscosity of a 12.5% solution in 60:40 (w/w/) propan-2-ol to acetone

To be identified 3–6 mPa.s None

Refractive index

[n] D20 1,380–1,385

[n] D20 1,380–1,385

Solubility

1 g dissolves in 7 g methanol, ethanol, propan-2-ol, dichloromethane, aqueous hydrochloric acid 1 N Not soluble in petroleum ether

1 g dissolves in 7 g methanol, ethanol, propan-2-ol, dichloromethane, aqueous hydrochloric acid 1 N Not soluble in petroleum ether

Text in italics indicates specifications to be modified.

The Panel noted that the particle size distribution proposed by the applicant could also be more clearly described as: at least 5% > 50 lm, at least 50% > 20 lm, at least 90% > 3 lm.

3.1.3.

Manufacturing process

In 2010, EFSA evaluated the safety of BMC produced via the so-called bulk polymerisation process (EFSA ANS Panel, 2010). According to the applicant, this process was developed decades ago, mainly intended for industrial quality bulk polymers and adapted for minimal compliance with current bulk pharmaceutical excipient guidelines (IPEC GMP, International Pharmaceutical Excipient Council - Good Manufacturing Practice) and food manufacturing expectations. In 2013, the manufacturing of BMC was modernised from the bulk polymerisation, as described in the 2008 submission, to a better controlled so-called solution polymerisation process. The applicant has now submitted detailed information on the manufacturing of BMC via solution polymerisation whereby the chemical synthesis remains unchanged and is still based on radical polymerisation. This applies, accordingly, to all key product properties of the copolymer. According to this new information, the monomers (DMAEMA, BMA and MMA), solvent (propan-2-ol), the chain modifying agent (an alkyl mercaptan) and the initiator (free radical donor initiator system) are mixed and the temperature-induced radical polymerisation is started by a thermal decomposition of the initiator system. The Panel noted that in the new solution polymerisation process, the initiator system used in bulk polymerisation was exchanged for a comparable initiator system, both of them free radical donor initiator systems. By thermal decomposition the initiator is eliminated from the reaction mixture. The applicant stressed that the low initial concentration and the decomposition half-life of the new initiator during the manufacturing process would lead to a complete consumption of the initiator


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system. According to the applicant, this is supported by analytical data in that the initiator concentration in the polymer was below the detection limit and therefore well below the concentration level of max. 0.2% as set forward in the recommendations for food contact materials by the €r Risikobewertung (BfR, 2010). The applicant further stressed that, in contrast to the Bundesinstitut fu initiator system used in bulk polymerisation, the initiator system used in solution polymerisation is listed in the BfR recommendations as being a suitable initiator for polyacrylates and polymethacrylates in food contact materials. After completion of the polymerisation, the intermediate product – a viscous polymer solution – is fed directly into an extruder to avoid open processing. During the extrusion, volatile substances (e.g. propan-2-ol) are removed to a large extent by vacuum degassing. The extrusion results in the formation of solid granules of BMC. These granules can be further processed to the powder form by micronisation. The Panel noted that the safety of the decomposition of the initiator and information on side reactions of the chain modifying agent were addressed in the previous evaluation by EFSA (EFSA ANS Panel, 2010). The Panel further noted that substantial analytical data were provided by the applicant which confirmed that the product from the solution polymerisation process met most of the existing specifications for BMC (with the exception of the changes proposed) and provided equivalent functionality. No significant differences were found between products from the solution polymerisation process as compared to products from the bulk polymerisation process. Although there were quantitative changes, the Panel considered that these changes did not introduce any additional relevant toxicological hazard. 3.1.3.1. Residual monomers and processing aids The applicant provided comparative data on the concentrations of residual monomers, additives and processing aids in production lots of BMC manufactured via solution polymerisation as compared to those produced via bulk polymerisation. The data are shown in Table 3. Table 3:

Comparison of the concentrations of residual monomers and residual solvents in the solution polymerisation product to those in the bulk polymerisation product

Residual monomers

Limits as in Commission Regulation (EU) No 231/2012

Minimum and maximum values of seven lots from the bulk polymerisation

Minimum and maximum values of five lots from the solution polymerisation

(mg/kg BMC)

(mg/kg BMC)

(mg/kg BMC)

Methyl methacrylate (MMA) Butyl methacrylate (BMA)

< 1,000 < 1,000

39–79 87–205

5–14 74–101

Dimethylaminoethyl methacrylate (DMAEMA) Residual solvents

< 1,000

168–500

228–283

(%)

(%)

Isopropanol n-Butanol

< 0.5 < 0.5

0.06–0.24 < 0.01

0.01–0.03 < 0.01

Methanol

< 0.1

< 0.01

< 0.01

(%)

BMC: basic methacrylate copolymer.

Monomers: The concentrations of BMA and 2-DMAEMA in the solution polymerisation product are comparable to those of the bulk polymerisation product. The concentration of residual MMA is lower in the solution polymerisation product. The monomers are listed in Commission Regulation (EU) No 10/20115, for use in food contact materials with the following specific migration limits SML(T)6: BMA (Ref. No 20110), SML(T) = 6 mg/kg food; MMA (Ref. No 21130), SML(T) = 6 mg/kg food; DMAEMA (Ref. No. 20530), SML = not detectable at a detection limit of 0.01 mg/kg food. Propan-2-ol/Isopropanol: The concentration of propan-2-ol in the solution polymerisation product is significantly lower than in the bulk polymerisation product. 5

6

Commission Regulation (EU) No 10/2011 of 14 January 2011 on plastic materials and articles intended to come into contact with food. OJ L 12, 15.1.2011, p. 1–89. SML(T) = migration limit for the sum of all migrating monomers into the food.


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Methanol: In the solution polymerisation process, the concentration of methanol falls below the detection limit of 10 mg/kg and is therefore significantly lower than in the bulk polymerisation product. 1-Butanol: The concentration of 1-butanol is in the same range for both solution polymerisation product and bulk polymerisation product, namely below 0.01%.

3.1.4.

Methods of analysis in food

The applicant submitted detailed information on the method used for the quantitative determination of BMC in solid dosage forms. In this method, the dosage forms are extracted with tetrahydrofuran (THF). Insoluble substances are isolated by centrifugation. The remaining clear filtrate/ supernatant is boiled down and further dried by oven drying. The residue is identified by IR (infrared) spectroscopy.

3.1.5.

Reaction and fate in food

In its original application (2008), the applicant stated that due to the polyethylene carbon backbone, degradation of the polymer chains, e.g. by hydrolysis, could be excluded and had never been observed under normal storage and handling conditions. It was also stated that, as regards the stability during processing, when using the conventional methods for coating solid dosage forms (pan-coating/fluid-bed coating), the polymer showed high thermal and chemical stability. The Panel in its original evaluation agreed with those views (EFSA ANS Panel, 2010). In the original application, the applicant also indicated that, in general, different types of ionic interactions with food components/ingredients may appear between counter-charged functional groups. Thus, cationic polymers (e.g. BMC) may form ionic interactions with anionic substances (e.g. active (pharmaceutical) ingredients, excipients, food ingredients, etc.). However, the applicant highlighted that this phenomenon was well known from the pharmaceutical applications of BMC and was not specific to polymethacrylates, but in general, related to all ionic substances. The probability of complex formation depended on different factors, e.g. contact intensity, nature of the functional groups, steric hindrances, number of ionic groups and thus frequency of contact, processing (contact time and catalytic factors such as temperature and humidity). The applicant also indicated that salt/complex formation by ionic interaction may be desired and therefore utilised for specific effects, e.g. taste-masking. As in the present application dossier the applicant provided data demonstrating that the product produced via solution polymerisation has the same characteristics and quality as the product from bulk polymerisation, the Panel agreed that these considerations were still valid. In the new application the applicant provided detailed data on the stability of BMC obtained by solution polymerisation of three validation lots stored at ambient temperatures as required by US Pharmacopeia (USP 35–NF 30, 2012). The data show the product, under powder form, to be stable for at least 14 months. The applicant indicated that two further measurements will take place after 2 and 4 years of storage. It was further stated that at the same time the routine storage stability programme under standard warehouse conditions was started for all lots from solution polymerisation. Samples will be analysed at two different times during the minimum stability period and at the end of the minimum stability period.

3.1.6.

Current uses and use levels

In its original application the applicant indicated that only low use levels for coating are needed and that taste masking and moisture protection can be achieved with coating levels of 1–5 mg BMC/cm2, equivalent to approximately 6–30 mg/tablet (for a tablet weight of 1,000 mg). According to the petitioner, the highest coating level could be up to 100 mg/tablet (1,000 mg). These use levels are still valid. On the basis of this information, the Panel in 2010 calculated the estimated combined exposure for heavy users to BMC from both its use in food supplements and in pharmaceuticals to be equal to 23.4 mg/kg bw per day for a 60-kg adult and 16 mg/kg bw per day for children (4–18 years). The calculated worst-case exposure to the monomers (MMA, BMA and DMAEMA) is < 50 lg/kg bw per day for adults and < 32 lg/kg bw per day for children, being significantly below the group TDI of 0.1 mg/kg bw per day (as methacrylic acid) set by the SCF (SCF, 1999). As the uses and use levels are unchanged, this exposure assessment remains valid.


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3.1.7.

Biological and toxicological data

Given the subject of the present request, no new biological and toxicological data were submitted by the applicant as compared to the original application (2008). The Panel agreed that as no new hazards were identified from the review of changes in the manufacturing process, the toxicological evaluation made in 2010 remained valid (EFSA ANS Panel, 2010).

3.2.

Discussion

The subject of the present evaluation by the ANS Panel is whether a safety concern could arise from a request by the applicant to amend the specifications regarding the ‘definition’ and the ‘particle size’ of BMC, as presently listed in Commission Regulation (EU) No 231/2012. This request derives from a change in the manufacturing process for BMC from a bulk polymerisation process to a solution polymerisation process. A detailed description of the solution polymerisation process was provided by the applicant. Data on the residual solvents and on the residual monomers were also provided. This was accompanied by data on the stability, and the reaction and fate in food of basic methacrylate produced via the new process were provided. The Panel requested further clarifications from the applicant concerning the description of proposed particle size distribution in order to better reflect the available data and avoid misinterpretation regarding the possible presence of a nanoscale fraction within the material. BMC was previously evaluated by the EFSA ANS Panel (2010). Based on the available database at that time, the Panel considered that, in the light of the high molecular weight of the substance, its lack of absorption and its low toxicity profile, the MoS were adequate and concluded that the use of BMC as a glazing agent/coating agent in solid food supplements was not of safety concern at the proposed use levels. In the present evaluation, the Panel considered that this conclusion would still be valid for BMC produced by the new manufacturing procedure. The Panel considered that the clarification of the particle size information provided reassurance that BMC did not contain detectable nanoscale material.

4.

Conclusions

Following a request from the European Commission, the Panel concluded that there is no safety concern from the proposed amendments in the specifications resulting from the changes in the manufacturing process for the food additive basic methacrylate copolymer (BMC - E 1205).

Documentation provided to EFSA 1) Request for a modification of the specification of the food additive basic methacrylate copolymer, E 1205. Dossier submitted by Evonik Industries AG on 21 November 2014 and its update of 29 June 2015 (Tables). 2) Applicant response to EFSA request for additional information, letter of 18 January 2016.

References €r Risikobewertung), 2010. Empfehlungen zu Materialien fu €r den Lebensmittelkontakt: XXII. BfR (Bundesinstitut fu €ureesterpolymerisate und deren Mischpolymerisate sowie Mischungen mit Polymerisaten. Acryl- und Methacrylsa EFSA ANS Panel (EFSA Panel on Food Additives and Nutrient Sources added to Food), 2010. Scientific opinion on the use of Basic Methacrylate Copolymer as a food additive. EFSA Journal 2010;8(2):1513, 23 pp. doi:10.2903/ j.efsa.2010.1513 EFSA ANS Panel (EFSA Panel on Food Additives and Nutrient Sources added to Food), 2012. Guidance for submission for food additive evaluations. EFSA Journal 2012;10(7):2760, 60 pp. doi:10.2903/j.efsa.2012.2760 EFSA (European Food Safety Authority), 2009. Guidance of the Scientific Committee on transparency in the scientific aspects of risk assessment carried out by EFSA. Part 2: general principles. EFSA Journal 2009; 7(5):1051, 22 pp. doi:10.2903/j.efsa.2009.1051 SCF (Scientific Committee on Food), 1998. Opinion on an additional list of monomers and additives for food contact. Opinion expressed on 10 December 1998. Available online: http://ec.europa.eu/food/fs/sc/scf/out20_en.pdf SCF (Scientific Committee on Food), 1999. Reports of the Scientific Committee for Food, 42nd Series. Available online: http://ec.europa.eu/food/fs/sc/scf/reports/scf_reports_42.pdf USP 35–NF 30, 2012. General Notices and Requirements. Applying to Standards, Tests, Assays, and Other Specifications of the United States Pharmacopeia. The Pharmacopeia of the United States of America, Thirty-Fifth Revision and the National Formulary, Thirtieth Edition.


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EFSA Journal 2016;14(5):4490


Abbreviations ADI ANS Panel BfR BMA BMC bw CAS DMAEMA GPC IR IUPAC MMA MoS Mw NOAEL SCF SML SML(T) TDI THF

acceptable daily intake EFSA Panel on Food Additives and Nutrient Sources added to Food €r Risikobewertung Bundesinstitut fu butyl methacrylate basic methacrylate copolymer body weight Chemical Abstracts Service dimethylaminoethyl methacrylate gel permeation chromatography infrared International Union of Pure and Applied Chemistry methyl methacrylate margin of safety molecular weight no-observed-adverse-effect level European Commission’s Scientific Committee on Food specific migration limits specific migration limits total tolerable daily intake tetrahydrofuran


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EFSA Journal 2016;14(5):4490