Safety assessment of the substance diethyl[[3 ... - Wiley Online Library

SCIENTIFIC OPINION ADOPTED: 23 June 2016 doi: 10.2903/j.efsa.2016.4536

Safety assessment of the substance diethyl[[3,5-bis (1,1-dimethylethyl)-4-hydroxyphenyl]methyl] phosphonate, for use in food contact materials EFSA Panel on Food Contact Materials, Enzymes, Flavourings and Processing Aids (CEF) Abstract This scientific opinion of the EFSA Panel on Food Contact Materials, Enzymes, Flavourings and Processing Aids (CEF) deals with the safety evaluation of the substance diethyl[[3,5-bis(1,1dimethylethyl)-4-hydroxyphenyl]methyl]phosphonate. The substance with the CAS no 976-56-7 and the food contact materials (FCM) substance no 1007 is intended to be used in the polymerisation reaction to make poly(ethyleneterephthalate) (PET) plastic. The substance is intended to become a component of the backbone of the polymer and function as an antioxidant, providing thermal stability to the polyester during heat processing. The applications intended are contact with all types of food under any condition of time and temperature. A PET sample made with 0.2% w/w of the substance (i.e. twice the maximum intended) was subjected to a comprehensive set of migration tests. Migration of the substance was not detectable, with detection limits in the range of 3–6 lg/kg for the different simulants used. Using the results provided from a range of extraction and migration tests conducted on the PET sample, the Panel concluded that the potential migration into food of any impurities and possible reaction products coming from the substance was well below 2 lg/kg. Based on negative results from four in vitro genotoxicity tests, the Panel concluded that there is no evidence of genotoxicity of the substance. The substance is an organophosphorus compound but due to its low migration, there is no concern for neurotoxicity. Considering the structures and the low migration of the impurities and reaction products, the Panel concluded that they do not give rise to safety concern. The CEF Panel concluded therefore that the substance diethyl[[3,5-bis(1,1-dimethylethyl)-4hydroxyphenyl]methyl]phosphonate does not raise a safety concern for the consumer if used up to 0.2% w/w (based on the weight of the polymer) in the polymerisation to make PET intended for contact with all types of foods under any contact conditions. © 2016 European Food Safety Authority. EFSA Journal published by John Wiley and Sons Ltd on behalf of European Food Safety Authority.

Keywords: diethyl[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]methyl]phosphonate, CAS no 976-56-7, FCM substance no 1007, food contact materials, safety assessment

Requestor: Ministero della Salute, Italy Question number: EFSA-Q-2012-00908 Correspondence: fi[email protected]

www.efsa.europa.eu/efsajournal

EFSA Journal 2016;14(7):4536

Diethyl[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]methyl]phosphonate

Panel members: Claudia Bolognesi, Laurence Castle, Jean-Pierre Cravedi, Karl-Heinz Engel, Paul €renlampi, Wim Mennes, Maria €rtler, Trine Husøy, Sirpa Ka Fowler, Roland Franz, Konrad Grob, Rainer Gu Penninks, Vittorio Silano, Andrew Smith, Maria de Fa tima Tavares Pocßas, Rosaria Milana, Andre €lfle, Holger Zorn and Corina-Aurelia Zugravu Christina Tlustos, Detlef Wo Acknowledgements: The Panel wishes to thank the members of the Working Group on Food Contact Materials: Claudia Bolognesi, Laurence Castle, Jean-Pierre Cravedi, Roland Franz, Konrad Grob, tima Pocßas, Kettil Svensson and Martine Kolf-Clauw, Eugenia Lampi, Maria Rosaria Milana, Maria de Fa € Detlef Wolfle for the preparatory work on this scientific opinion and EFSA staff member: Cristina Croera for the support provided to this scientific opinion. Suggested citation: EFSA CEF Panel (EFSA Panel on Food Contact Materials, Enzymes, Flavourings and Processing Aids), 2016. Scientific opinion on the safety assessment of the substance diethyl[[3,5bis(1,1-dimethylethyl)-4-hydroxyphenyl]methyl]phosphonate, for use in food contact materials. EFSA Journal 2016;14(7):4536, 7 pp. doi:10.2903/j.efsa.2015.4536 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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Table of contents Abstract.................................................................................................................................................... 1. Introduction...................................................................................................................................... 1.1 Background and Terms of Reference as provided by the requestor........................................................ 2. Data and methodologies .................................................................................................................... 2.1. Data................................................................................................................................................. 2.2. Methodologies................................................................................................................................... 3. Assessment....................................................................................................................................... 3.1. Non-toxicological data ....................................................................................................................... 3.2. Toxicological data .............................................................................................................................. 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

Before a substance is authorised to be used in food contact materials (FCMs) and is included in a positive list, EFSA0 s opinion on its safety is required. This procedure has been established in Articles 8, 9 and 10 of Regulation (EC) No 1935/20041 of the European Parliament and of the Council of 27 October 2004 on materials and articles intended to come into contact with food. According to this procedure, the industry submits applications to the Member States competent authorities which transmit the applications to the European Food Safety Authority (EFSA) for evaluation. In this case, EFSA received an application from the Ministero della Salute, Italy, requesting the evaluation of the substance diethyl[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]methyl]phosphonate, with the CAS no 976-56-7 and the FCM substance no 1007. 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.

2.

Data and methodologies

2.1.

Data

The applicant has submitted a dossier in support of their application for the authorisation of diethyl [[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]methyl]phosphonate to be used in FCMs. Data submitted and used for the evaluation are: Non-toxicological data and information

• • • • • • • •

Chemical identity Description of manufacturing process of substance/FCM Physical and chemical properties Intended use Existing authorisation(s) Migration of the substance Residual content of the substance Identification, quantification and migration of reaction products and impurities

Toxicological data

• • • • 2.2.

Bacterial gene mutation test Two in vitro mammalian cell gene mutation tests In vitro mammalian chromosome aberration test In vitro micronucleus test

Methodologies

The assessment was conducted in line with the principles laid down in Regulation (EC) No 1935/2004 on materials and articles intended to come into contact with food. This Regulation underlines that applicants may consult 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 FCMs prior to its authorisation (European Commission, 2001), including the corresponding data requirements. The dossier that the applicant submitted for evaluation was in line with the SCF guidelines (European Commission, 2001). The methodology is based on the characterisation of the substance that is the subject of the request for safety assessment prior to authorisation, its impurities and reaction and degradation products, the evaluation of the exposure to those substances through migration, and the definition of minimum sets of toxicity data required for safety assessment. To establish the safety from ingestion of migrating substances, the toxicological data indicating the potential hazard and the likely human exposure data need to be combined. Exposure is estimated from

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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, 13.11.2004, p. 4–17.


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studies on migration into food or food simulants and considering that a person may consume daily up to 1 kg of food in contact with the relevant FCM. As a general rule, the greater the exposure through migration, the more toxicological data is required for the safety assessment of a substance. Currently, there are three tiers with different thresholds triggering the need for more toxicological information as follows:

• • •

In case of high migration (i.e. 5–60 mg/kg food), an extensive data set is needed. In case of migration between 0.05 and 5 mg/kg food, a reduced data set may suffice. In case of low migration (i.e. < 0.05 mg/kg food), only a limited data set is needed.

More detailed information on the required data is available in the SCF guidelines (European Commission, 2001). 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 considering the relevant guidance from the EFSA Scientific Committee.

3.

Assessment

According to the applicant, the substance diethyl[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl] methyl]phosphonate is intended to be used up to 0.2% w/w in the polymerisation reaction to make poly(ethyleneterephthalate) (PET) plastic. The substance is intended to be incorporated as a component of the backbone of the polymer and its function is to act as an antioxidant providing thermal stability to the polyester during processing and moulding of end-use articles, such as bottles and films. PET is intended for contact with all types of food under any condition of time and temperature. The substance has not been evaluated by the SCF or EFSA in the past.

3.1.

Non-toxicological data

Chemical formula: C19H33O4P Chemical structure:

The molecular weight of the substance is 356 Da. The log Po/w of the substance was estimated to be 4.9. The substance has high chemical purity and the impurities identified were typical for such an antioxidant considering the information on the production process that was supplied as confidential. It is virtually insoluble in water and is freely soluble in organic solvents, such as methanol, acetone, chloroform and benzene. According to differential scanning calorimetry, the substance decomposes above 350°C which is well above the maximum intended polymer processing temperature (approx. 280°C) and therefore no thermal degradation products are to be expected. Tests were conducted on a sample of PET that was made using nearly twice the maximum intended level of the substance (i.e. 0.2% vs 0.11% w/w). The food simulants used were 20% ethanol and 3% acetic acid at two contact conditions (10 days at 40°C and 10 days at 60°C), 50% ethanol (10 days at 40°C) and olive oil (10 days at 60°C). No migration of the substance was detectable, with detection limits in the range of 3–6 lg/kg depending on the simulant used. One reason for these low migration results is that during the polymerisation process the substance is intentionally chemically incorporated (‘bound’) into the polyester chain. This was evidenced by the fact that the solventextractable amount of the substance from PET was only 8 mg/kg which is far lower than the formulation level of 0.2% (2,000 mg/kg). Concerning the impurities detected and identified in the substance itself, migration tests used 10% ethanol and 50% ethanol for 2 h at 66°C followed by 10 days at 40°C. Migration was not detectable at the detection limit of 3 lg/kg.


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The potential for formation and migration of possible reaction products was investigated in a twostep process. First, using solvent extraction of PET to detect and identify any solvent extractables that may have the potential to migrate. Second, by a migration test using the two food simulants, 20% ethanol and 50% ethanol, at test conditions of 1 h of reflux followed by 30 days at 40°C. The analytical methods used were gas chromatography coupled to mass spectrometry (GC/MS), liquid chromatography coupled to mass spectrometry (LC/MS) and phosphorus-31 nuclear magnetic resonance (P-NMR), and the highest migration level found was ca. 7 lg/kg for an individual reaction product (a cyclic phosphonate ester with monoethylene glycol) into the 50% ethanol simulant. The use of 50% ethanol under the test conditions employed is severe and leads to swelling of PET that would not occur from food contact. Based on the results of these tests, the potential migration of any impurities and possible reaction products into food was concluded by the Panel to be well below 2 lg/kg. This low migration is a consequence of the low formulation level (0.2% w/w) of the substance in the PET sample tested along with the low diffusion properties of PET.

3.2.

Toxicological data

The substance was tested in in vitro genotoxicity tests with and without metabolic activation. In the bacterial reversion mutation test using the Salmonella Typhimurium strains TA 98, TA 100, TA 1535 and TA 1537, and the Escherichia coli tester strain WP2uvrA (according to OECD No 471), the substance (dissolved in dimethyl sulfoxide (DMSO)) did not induce gene mutations up to 5,000 lg/plate. Negative results for gene mutation were also obtained with mammalian cells (L5178Y/TK+/ mouse lymphoma cells and Chinese Hamster V79 cells; tests performed according to OECD No 476) treated with the test substance. The results of a chromosomal aberration study using Chinese hamster V79 cells were considered equivocal due to slight increases in the number of cells with aberrations; however, the numbers were within the historical control range. To further clarify the chromosome damaging potential of the substance, an in vitro micronucleus assay in Chinese hamster V79 cells (according to OECD No 487) using cytokinesis block method was performed. The substance (dissolved in DMSO and tested up to 25 and 50 lg/mL without and with metabolic activation, respectively, while higher concentrations were cytotoxic) did not induce an increase in micronuclei frequency. In summary, based on the results of these studies, the Panel considers that there is no evidence of genotoxicity of the substance. The Panel noted that the substance is an organophosphorus compound which might have a neurotoxic potential. However, due to the low migration of the substance, if any, which was well below the human exposure threshold of toxicological concern (TTC) for organophosphates, i.e. 18 lg/person per day (EFSA, 2012) (corresponding to 18 lg/kg food), the Panel considered that the substance does not give rise to a safety concern related to neurotoxicity. Considering the structures and the low migration of the impurities and reaction products, the Panel concluded that they do not give rise to safety concern related to genotoxicity or neurotoxicity.

4.

Conclusions

The CEF Panel, after having considered the above-mentioned data, concluded that the substance diethyl[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]methyl]phosphonate is not a safety concern for the consumer if used up to 0.2% w/w (based on the final polymer weight) in the polymerisation process to make PET intended for contact with all types of foods under any contact conditions of time and temperature.

Documentation provided to EFSA 1) Dossier ‘diethyl[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]methyl]phosphonate’. October 2012. Submitted by Intertek Testing Services Srl, Italy, on behalf of Toyobo Co. Ltd. 2) Additional data for dossier ‘diethyl[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]methyl] phosphonate’. September 2015. Submitted by Intertek Testing Services Srl, Italy, on behalf of Toyobo Co. Ltd. 3) Additional data for dossier ‘diethyl[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]methyl] phosphonate’. March 2016. Submitted by Intertek Testing Services Srl, Italy, on behalf of Toyobo Co. Ltd.


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References EFSA (European Food Safety Authority), 2009. Guidance of the Scientific Committee on transparency in the scientific aspects of risk assessments carried out by EFSA. Part 2: general principles. EFSA Journal 2009; 7(5):1051, 22 pp. doi:10.2903/j.efsa.2009.1051 EFSA (European Food Safety Authority), 2012. Scientific Opinion on Exploring options for providing advice about possible human health risks based on the concept of Threshold of Toxicological Concern (TTC). EFSA Journal 2012;10(7):2750, 103 pp. doi:10.2903/j.efsa.2012.2750 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: http://ec.europa.eu/food/fs/sc/scf/out82_en.pdf

Abbreviations CEF Panel DMSO FCM GC/MS LC/MS P-NMR Po/w PET SCF TTC w/w

EFSA Panel on Food Contact Materials, Enzymes, Flavourings and Processing Aids dimethyl sulfoxide food contact materials gas chromatography coupled to mass spectrometry liquid chromatography coupled to mass spectrometry phosphorus-31 nuclear magnetic resonance octanol/water partition coefficient poly(ethyleneterephthalate) Scientific Committee on Food threshold of toxicological concern weight by weight


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