EFSA Journal 2010; 8(10):1837 SCIENTIFIC OPINION Scientific Opinion on the safety evaluation of the substance,, CAS No. 120-40-1, 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 ABSTRACT This scientific opinion of EFSA deals with the risk assessment of the substance N,N-bis(2- hydroxyethyl)dodecanamide, CAS No. 120-40-1, REF. No. 39150 for which the CEF Panel concluded that there is no safety concern for the consumer if the migration of the substance does not exceed 5 mg/kg food and the residual amount of diethanolamine into plastics does not result in a migration higher than 0.3 mg/kg food. KEY WORDS N,N-Bis(2-hydroxyethyl)dodecanamide; CAS number 120-40-1; Ref. No. 39150; Food contact materials; Safety assessment; Evaluation. SUMMARY Within the general task of evaluating substances intended for use in materials in contact with food according to 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 foodstuffs, the CEF Panel received a request from a competent Member State Authority for safety evaluation of a substance following a corresponding application from the industry. The request received and the outcome of the safety evaluation is summarised below: 1 On request from the Bundesamt für Verbraucherschutz und Lebensmittelsicherheit, Germany, Question No EFSA-Q-2009-00591 adopted on 30th September 2010. 2 Panel members: Arturo Anadón, Mona-Lise Binderup, Wilfried Bursch, Laurence Castle, Riccardo Crebelli, Karl-Heinz Engel, Roland Franz, Nathalie Gontard, Thomas Haertlé, Trine Husøy, Klaus-Dieter Jany, Catherine Leclercq, Jean-Claude Lhuguenot, Wim Mennes, Maria Rosaria Milana, Karla Pfaff, Kettil Svensson, Fidel Toldrá, Rosemary Waring, Detlef Wölfle. Correspondence: CEF-Unit@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, Kettil Svensson and Detlef Wölfle as well as Wim Mennes and Marco Zeilmaker for the support provided to this EFSA scientific output. Suggested citation: EFSA Panel on food contact materials, enzymes, flavourings and processing aids (CEF); Scientific Opinion on the safety evaluation of the substance,, CAS No. 120-40-1, for use in food contact materials.. [15 pp.] doi:10.2903/j.efsa.2010.1837. Available online: www.efsa.europa.eu/efsajournal.htm European Food Safety Authority, 2010 1
The Bundesamt für Verbraucherschutz und Lebensmittelsicherheit, Germany, requested the evaluation of the substance with the CAS number 120-40-1 and the European Commission reference number (REF. No.) 39150, for use as antistatic agent in polyolefines and polystyrenes at a maximum use level of 0.5% w/w in lowdensity polyethylene (LDPE), 1.0% w/w in high-density polyethylene (HDPE), 1.0% w/w in polypropylene (PP) and 1.5% w/w in polystyrene (PS). Final articles are intended to be used for storage of all types of foodstuffs at room temperature. The dossier was submitted by Emery Oleochemicals GmbH. The CEF Panel concluded that there is no safety concern for the consumer if the migration of the substance does not exceed 5 mg/kg food and the residual amount of diethanolamine into plastics does not result in a migration higher than 0.3 mg/kg food. 2
TABLE OF CONTENTS Abstract... 1 Summary... 1 Table of contents... 3 Background as provided by the legislation... 4 Terms of reference as provided by the legislation... 4 Assessment... 5 1. Introduction... 5 2. General information... 5 3. Data available in the dossier used for this evaluation... 5 4. Evaluation... 6 4.1. Non-toxicological data... 6 4.2. Toxicological data... 7 Conclusions... 8 Remarks for the Commission:... 9 Documentation provided to EFSA... 9 References... 9 Appendices... 11 Abbreviations... 15 3
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 the 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 4. According to this procedure the industry submits applications to the Member States competent Authorities which in their turn transmit the applications to the EFSA for their evaluation. The application is supported by a technical dossier submitted by the industry 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). In this case, EFSA received an application from the Bundesamt für Verbraucherschutz und Lebensmittelsicherheit, Germany, requesting the evaluation of the substance N,N-bis(2- hydroxyethyl)dodecanamide with the CAS number 120-40-1 and the European Commission reference number (REF. No.) 39150. TERMS OF REFERENCE AS PROVIDED BY THE LEGISLATION The EFSA is required by Article 10 of Regulation (EC) No. 1935/2004 of the European Parliament and of the Council on materials and articles intended to come into contact with food to carry out risk assessments on the risks originating from the migration of substances from food contact materials into food and deliver a scientific opinion on: 1. new substances intended to be used in food contact materials before their authorisation and inclusion in a positive list; 2. substances which are already authorised in the framework of Regulation (EC) No. 1935/2004 but need to be re-evaluated. 4 This Regulation replaces Directive 89/109/EEC of 21 December 1988, OJ L 40, 11.2.1989, P.38. 4
ASSESSMENT 1. Introduction The European Food Safety Authority was asked by the Bundesamt für Verbraucherschutz und Lebensmittelsicherheit, Germany, to evaluate the safety of the N,N-bis(2- hydroxyethyl)dodecanamide with a CAS number 120-40-1 and a REF. No. 39150. The request has been registered in the EFSA s register of received questions under the number EFSA-Q-2009-00591. The dossier was submitted by the applicant, Emery Oleochemicals GmbH. Since in the past the evaluation of substances used in food contact materials was undertaken by the Scientific Committee on Food (SCF), the same system of classification into a SCF list is retained for uniformity purposes. The definitions of the various SCF lists and the abbreviations used are given in the APPENDIX A. 2. General information According to the petitioner, the substance is intended to be used as antistatic agent in polyolefines and polystyrenes. Maximum percentages in formulation are 0.5% w/w in low-density polyethylene (LDPE), 1.0% w/w in high-density polyethylene (HDPE), 1.0% w/w in polypropylene (PP) and 1.5% w/w in polystyrene (PS). Final articles are intended to be used for storage of all types of foodstuffs at room temperature. The substance was evaluated in the past by the Scientific Committee on Food (EC, 1999) on the basis of 3-month oral rat and dog studies with different diethanolamides of fatty acids, three genotoxicity studies and migration data. It was classified in List 7 with the request for further information as follows: - reason for the choice of test sample (polymer and concentration of additive) for migration test, - stability of additive in food simulants under the test conditions applied, - physical-chemical data including Po/w and data on use. 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 5
Data on intended use and authorisation Data on migration of the substance and diethanolamine Data on residual content of the substance and diethanolamine Toxicity data: Bacterial gene mutation test In vitro mammalian chromosome aberration and sister chromatid exchanges test In vitro mammalian cell gene mutation test Mouse micronucleus assay with dermal application 90-day oral toxicity studies in rats and dogs Dermal chronic toxicity/carcinogenicity study in rats and mice Absorption, distribution, metabolism and excretion (ADME) study in rats and mice Experimental data and modelling on the in vivo formation of N-nitrosodiethanolamine from orally administered diethanolamine 4. Evaluation 4.1. Non-toxicological data Molecular and structural formula: (C 2 H 4 OH) 2 NCO(C 11 H 23 ) The substance is manufactured by reaction of methyllaurate (= methyldodecanoate) and diethanolamine (DELA). The residual content of DELA(CAS No. 111-42-2) as an impurity of the substance is typically 0.1% w/w. The substance is stable to hydrolysis in gastric juice simulant and in 3% acetic acid. Thermal treatment during polymer processing resulted in the formation of diethanolamine and of the monododecanoic ester of the substance which is estimated to be about 4% loss of the parent substance. 6
The migration of the substance from LDPE into 3% acetic acid, 10% ethanol, 50% ethanol and olive oil for 10 days at 40 C was 10.7, 11.7, 14.8 and 16.2 mg/kg respectively. The migration from PP into 10 % ethanol, 50% ethanol and olive oil for 10 days at 40 C, was 1.2, 1.6 and 2.1 mg/kg respectively. The migration of DELA from LDPE into 3% acetic acid for 10 days at 40 C was determined to be 0.1 mg/kg food. 4.2. Toxicological data was negative in gene mutation tests in bacteria and in cultured mammalian cells (L5178Y mouse lymphoma cells), and in chromosomal aberration assays in vitro in human lymphocytes and in Chinese hamster ovary (CHO) cells. A weak positive response was obtained in a limited indicator assay (in vitro sister chromatid exchange) in CHO cells. No increase of micronuclei in blood cells was observed in mice after 14 weeks dermal application. Based on these results is considered non genotoxic. In oral subchronic toxicity studies in rats and dogs, administration of the compound produced mild alterations of biochemical parameters and increased liver and kidney weights, with no histological changes. The lowest NOAEL derived from these studies was based on the effects on clinical chemistry and organ observed in a 90-day oral toxicity study in rat and established to be 50 mg/kg bw. Ancillary information is provided by a dermal chronic toxicity/oncogenicity NTP study in rats and mice. In this study there was no evidence of carcinogenicity of N,N-bis(2- hydroxyethyl)dodecanamide in rats (both genders) and in male mice. In female mice, there was some evidence of carcinogenicity based on a not dose-related increased incidence of hepatocellular adenomas and carcinomas. This was attributed to the presence of 5% of DELA in the sample tested. DELA is a known hepatocarcinogen even in the absence of formation of nitrosamine (Stott and al., 2000). In any case, in view of the lack of genotoxicity of both the substance and of DELA, a nongenotoxic thresholded mechanism is expected to be implicated in the oncogenic effect observed, which is thus considered of no relevance for low-dose oral exposure. Oral doses of are readily absorbed, converted into polar metabolites and mainly excreted in urine. Only a small fraction (< 5%) of the administered dose is retained in the body after 72 hrs. Overall, data indicate a scarce potential for accumulation in man. The thermal reaction product, monododecanoic ester of the substance, is expected to hydrolyse in vivo in the parent substance and in dodecanoic acid. Dodecanoic acid is an authorised substance without any restriction under the REF. No. 19470 and 63280 (EC, 2002). Therefore the monododecanoic ester of the substance is also not expected to raise a safety concern. DELA is an impurity and a thermal degradation product of the substance. Based on the negative results obtained in a package of in vitro tests (gene mutation in bacteria and mammalian cells, 7
structural chromosomal aberrations and sister chromatid exchanges), and in an in vivo micronucleus test in mice with subacute dermal administration, DELA is considered non-genotoxic (NTP, 1999a). In oral toxicity studies in rats DELA showed moderate toxicity, with NOAEL for subchronic and maternal/developmental toxicity of 20 and 50 mg/kg bw per day, respectively (Clayton & Clayton 1981-82; NTP, 1999b). In a dermal chronic toxicity/carcinogenicity study in F/344 rats and B6C3F1 mice, there was no evidence of carcinogenicity of DELA in rats (both genders),while there was clear evidence of carcinogenicity in mice, with increased incidence of renal tubule hyperplasia and neoplasms in males and increased incidence of hepatocellular adenomas and carcinomas in both males and females (NTP, 1999a). These findings are also relevant for the interpretation of the results of the NTP dermal carcinogenicity study on. The same considerations, expressed there, for the implication of a thresholded mechanism in the oncogenic effect can be made. As a secondary amine, DELA may undergo nitrosation to form the genotoxic and carcinogenic N- nitrosodiethanolamine (NDELA). Experiments in mice indicate that detectable amounts of NDELA in gastric fluids are only formed following co-administration of relatively large, bolus dosages of DELA and sodium nitrite. Based on nitrosation kinetics it is calculated under conservative assumptions (assuming that 0.3 mg DELA/kg food, which is 3 times higher than the migration measuered from a typical LDPE sample, taken all in one meal and remaining for two hours in the stomach under optimum ph and nitrate conditions for nitrosation) that, only trace amounts of NDELA are formed in human stomach from DELA migrating in food from the material under evaluation (Zeilmaker M. and Mennes W.; 2010). The huge margin of exposure (10 9 or greater) from endogenously formed NDELA and the benchmark dose associated with rodent liver tumours indicates a negligible human risk (EFSA, 2005). The Panel proposes, however, that the presence of DELA, as an impurity and decomposition product of the substance, should be controlled and kept at levels which could not lead to a migration higher than 0.3 mg/kg food which is technologically feasible. CONCLUSIONS The CEF Panel concluded that the substance is not genotoxic, it does not show potential for accumulation in man and a NOAEL of 50 mg/kg bw can be established from several 90-day oral toxicity studies. The Panel took also note of the formation of the monododecanoic ester of the substance as a reaction product which however does not raise a safety concern due to its expected hydrolysis in vivo into the parent substance and dodecanoic acid. DELA is an impurity and a thermal degradation product of the substance. DELA is not genotoxic. A NOAEL of 20 mg/kg bw was established for the substance in a 90-day rat oral toxicity study. As a secondary amine DELA may undergo nitrosation to the carcinogenic NDELA. However, it is calculated that even under conservative assumptions the risk for human health related to the endogenous formation of NDELA from DELA present as impurity or degradation product is 8
negligible. Its presence, however, into plastics should be kept at low levels which is technologically feasible. Therefore, the Panel proposes that the substance be classified in the SCF_List 3, with a restriction of 5 mg/kg food. The residual amount of diethanolamine into plastics, as an impurity and decomposition product of the substance, should not result in a migration higher than 0.3 mg/kg food. This would provide a large margin of safety. REMARKS FOR THE COMMISSION: Migration from LDPE may exceed the proposed restriction. DOCUMENTATION PROVIDED TO EFSA Dossier for re-evaluation referenced: N/A. Dated: January 2010. Submitted by Emery Oleochemicals GmbH, Germany. Zeilmaker M. and Mennes W. (2010). Expert evaluation of nitrosation of diethanolamine after intake with food. Unpublished document submitted to EFSA on May 12 th, 2010 (carried out by request of EFSA). REFERENCES Clayton, G. D. and F. E. Clayton (eds.). Patty's Industrial Hygiene and Toxicology: Volume 2A, 2B, 2C: Toxicology. 3rd ed. New York: John Wiley Sons, 1981-1982., p. 3169 EC (European Commission), 2002. Commission Directive 2002/72/EC, relating to plastic materials and articles intended to come into contact with foodstuffs; http://ec.europa.eu/food/food/chemicalsafety/foodcontact/2002-72_en.pdf. 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; http://ec.europa.eu/food/fs/sc/scf/out82_en.pdf. EC (European Commission), 1999. Reports of the Scientific Committee for Food, 42th series on the compilation of the evaluation of the Scientific Committee for Food on certain monomers and additives used in the manufacture of plastics materials intended to come into contact with foodstuffs until 21 March 1997; http://ec.europa.eu/food/fs/sc/scf/reports/scf_reports_42.pdf. 9
EFSA (European Foof Safety Authority), 2005. Opinion of the Scientific Committee on a request from EFSA related to A Harmonised Approach for Risk Assessment of Substances Which are both Genotoxic and Carcinogenic Adopted on 18 October 2005. The EFSA Journal (2005) 282, 1-31. http://www.efsa.europa.eu/en/scdocs/doc/282.pdf. NTP, National Toxicology Program (1999a). Toxicology & Carcinogenesis Studies of Diethanolamine in F344/N Rats and B6C3F1 Mice p.5 Technical Report Series No. 478. NIH Publication No. 99-3968 U.S. Department of Health and Human Services, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709] NTP, National Toxicology Program (1999b). Developmental Toxicity Screen for Diethanolamine (CAS No. 111-42-2) Administered by Gavage to Sprague-Dawley (CD1) Rats on Gestational Days 6 through 19: Evaluation of Dams and Pups through Postnatal Day 21, NTP Study No. TER96001 Available from: http://ntp.niehs.nih.gov/index.cfm?objectid=0847ff31-90cc-c685-88b4d7eac975bd44 ] Stott W.T., Bartels M.J., Brzak K.A., Mar M.-H., Markham D.A., Thornton C.M., Zeisel S.H. (2000). Potential mechanisms of tumorigenic action of diethanolamine in mice. Toxicology Letters 114 (2000) 67-75. 10
APPENDICES APPENDIX A DEFINITION OF THE SCF LISTS The classification into a SCF_List is a tool used for tackling authorisation dossiers and do not prejudice the management decisions that will be taken on the basis of the scientific opinions of the CEF Panel and in the framework of the applicable legislation List 0 List 1 List 2 List 3 Substances, e.g. foods, which may be used in the production of plastic materials and articles, e.g. food ingredients and certain substances known from the intermediate metabolism in man and for which an ADI need not be established for this purpose. Substances, e.g. food additives, for which an ADI (=Acceptable Daily Intake), a t-adi (=temporary ADI), a MTDI (=Maximum Tolerable Daily Intake), a PMTDI (=Provisional Maximum Tolerable Daily Intake), a PTWI (=Provisional Tolerable Weekly Intake) or the classification "acceptable" has been established by this Committee or by JECFA. Substances for which this Committee has established a TDI or a t-tdi. Substances for which an ADI or a TDI could not be established, but where the present use could be accepted. Some of these substances are self-limiting because of their organoleptic properties or are volatile and therefore unlikely to be present in the finished product. For other substances with very low migration, a TDI has not been set but the maximum level to be used in any packaging material or a specific limit of migration is stated. This is because the available toxicological data would give a TDI, which allows that a specific limit of migration or a composition limit could be fixed at levels very much higher than the maximum likely intakes arising from present uses of the additive. Depending on the available toxicological studies a restriction of migration into food of 0.05 mg/kg of food (3 mutagenicity studies only) or 5 mg/kg of food (3 mutagenicity studies plus 90-day oral toxicity study and data to demonstrate the absence of potential for bio-accumulation in man) may be allocated. 11
List 4 4A 4B List 4 (for monomers) Substances for which an ADI or TDI could not be established, but which could be used if the substance migrating into foods or in food simulants is not detectable by an agreed sensitive method. Substances for which an ADI or TDI could not be established, but which could be used if the levels of monomer residues in materials and articles intended to come into contact with foodstuffs are reduced as much as possible. (for additives) Substances for which an ADI or TDI could not be established, but which could be used if the substance migrating into foods or in food simulants is not detectable by an agreed sensitive method. List 5 List 6 Substances that should not be used. Substances for which there exist suspicions about their toxicity and for which data are lacking or are insufficient. The allocation of substances to this list is mainly based upon similarity of structure with that of chemical substances already evaluated or known to have functional groups that indicate carcinogenic or other severe toxic properties. 6A 6B List 7 List 8 List 9 Substances suspected to have carcinogenic properties. These substances should not be detectable in foods or in food simulants by an appropriate sensitive method for each substance. Substances suspected to have toxic properties (other than carcinogenic). Restrictions may be indicated. Substances for which some toxicological data exist, but for which an ADI or a TDI could not be established. The required additional information should be furnished. Substances for which no or only scanty and inadequate data were available. Substances and groups of substances which could not be evaluated due to lack of specifications (substances) or to lack of adequate description ( groups of substances ). Groups of substances should be replaced, where possible, by individual substances actually in use. Polymers for which the data on identity specified in "SCF Guidelines" are not available. 12
List W "Waiting list". Substances not yet included in the Community lists, as they should be considered "new" substances, i.e. substances never approved at national level. These substances cannot be included in the Community lists, lacking the data requested by the Committee. 13
APPENDIX B TERMS USED RELEVANT TO MIGRATION: 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 14
ABBREVIATIONS bw CAS CEF CHO DELA EC EFSA FCM HDPE LDPE NDELA NOAEL PP PS REF No SCF w/w body weight Chemical abstracts service Scientific Panel on food contact materials, enzymes, flavourings and processing aids Chinese hamster ovary Diethanolamine European Commission European food safety authority Food Contact Material(s) High density polyethylene Low density polyethylene N-nitrosodiethanolamine No observed adverse effect level Polypropylene Polystyrene Reference Number Scientific Committee on food Weight by weight 15