The Italian approach to the safety assessment of coatings intended for

food contact application

FIP Network - EFSA ( TC) 16 february 2017

Riccardo CREBELLI, Maria Rosaria MILANA

Istituto Superiore di Sanità – Roma ( ITALY)

The italian legislation: an overview

• Plastic*

• Rubber

• Paper & Board DM 21/3/73 + ca.50

• Regenerated Cellulose* amendments

• Glass (last in 2016)

• Stainless steel

• Ceramic * DM 4/4/85

• Tin plate DM 18/2/84

• Tin free steel DM 1/6/88

• Aluminium D 18/4/2007

* Partially or totally harmonized with EU legislation

Evaluation flow for risk assessment in IT

Ministerial decree 21 /03/1973 : national guidelines

Ministerial Decree 3/06/1994 : SCF Guidelines + Note for Guidance (European Commission)

NB: the protocol has the function of a guidance. Other data can be requested whenever necessary)

RA body: ISS, Rome

National Institute

for Health)

Coatings: annual workload On demand Impossible to foreseen a flow In IT no separate positive list therefore no necessary in a number of cases a specific petition A number of requests to Competent Authority of interpretation of the IT legislation

Coatings: how ? No separate positive list for coatings ( as for plastics, paper and boards etc) In general: extension of rules for plastics to coatings ( art. 9.4 Ministerial Decree 21.3.73 and amendments) No specific national guideline for the safety assessment of coatings intended to come in contact with food

Coatings: where in IT legislation ?

Therefore in place: • Positive list of substances ( Reg. Ue 10/2011) • Positive list of polymers ( resins) : DM 21/3/73 • Migration limits: OML, SML • NIAS : (art. 10 DM 21.3.73) should be compliant to Art.3

Reg 1935/2004/EC )

RA & RM for substances/materials : the steps

Ministry of Health Receiving technical dossier

Ministry of Health

• Acceptance or rejection

• Higher council of Health ( CSS)

• Acceptability for the proposed use, conditions of acceptance

• Positive list or specific rules for decrees on new materials

• Decrees according to the Italian legislative procedures

ISS:

• Checking the quality of the submitted data or information

• Evaluation of non toxicological & toxicological data

• Risk assessment ( safe exposure?)

Toxicological data

• standard as for SCF/EFSA for plastic

Full dossier

• tiered with the exposure /migration

Reduced dossier

• Case by case request, for specific points

Specific issues

Non toxicological data

• identity , physicochemical constants etc Physicochemical data

• manufacturing, techn. function, application process,

• To know purity and byproducts, not only the starting subst and NIAS

Detailed information

on manufacturing and /or application

• which packaging, maximum amount, which foods, in which conditions

Detailed Information on

final use

• migration test, calculations for total transfer, modelling, screening etc.

Migrability

Exposure estimates

from the measured migration of all the migrateables (when technically feasible) or calculated from the use level ( total transfer)

default assumptions :

• 1 kg food/day

• 60 kg body weight

• 6 dm2/kg food

.. but ad hoc parameters would be possible for special cases

The outcome of the RA in the positive list

No more than what required

Tiered restrictions (as for plastics)

In positive lists detailed authorization conditions:

• Maximum amount of use

• Only for the requested function

• Only for the requested foods

• Processing conditions ( if necessary)

• Surface to volume ( if necessary)

• Depending on the evaluation , also SML

Evaluation of coatings: a practical example

• The parent compound XX is a crosslinker ( max use level disclosed , process conditions, intended use)

• Three main impurities/process by-products are disclosed

• NIAS: byproducts after application on substrate

• Oligomers < 1000Da : 1 peak deriving from the use of the substance, exact structure not identified

• Migration tests: in non fatty food simulants

• Extraction with solvent for fatty contact

• Methods provided and some validation performed

Migrants into food simulants:

1. the parent compound XX (sum of isomers): up to 108 µg/kg food;

2. secondary amine, impurity and degradation product: up to 678 µg/kg food;

3. Acid derivative of XX, synthesis intermediate: up to 120 µg/kg food;

4. amino ester of XX, synthesis intermediate and degradation product: up to 74 µg/kg food;

5. ethyl ester of XX, synthesis intermediate and degradation product of XX): up to 67 µg/kg food;

6. DAE (impurity): < 3 µg/kg food:

7. Oligomers of XX: up to 12 µg/kg food ( total transfer);

Approaches used for safety assessment

1. Evaluation of experimental toxicity data

2. Read-across and SAR

3. TTC

4. MoE

1 - Evaluation of experimental toxicity data

• For compounds [1] (the cross-linker XX) and [2] (the main impurity) migration in food was >50 <5000 ppb. Therefore three genotox tests and an oral 90 tox study are required for safety assesment (intermediate dossier, according to the tiered approach of the SCF for plastic FCM).

• Both [1] and [2] were evaoluated as non-genotoxic, and a wide margin of safety ( 10,000 or above) could be established from the NOAEL in the 90-day studies. Conclusion: no safety concern

2 - Read across and SAR

• [3], [4] and [5] are synthesis intermediates of XX: based on the results with XX, they are anticipated to be non-genotoxic. Concerning general toxicity, a NOAEL of 20 mg/kg can be extrapolated for [3] from the NOAEL of [1] which contained 2% of [3] as impurity; [4] and [5] are simple esters expected to be hydrolyzed to the parent compound XX and to ethanol and adipic acid, for which a high ADI is established. Conclusion: no safety concern

• for the oligomers [7], no genotoxicity is expected due to the lack o genotoxicity of the monomer (FCM Note for Guidance). No other information is considered necessary at the estimated migration level of 12 μg/kg food. Conclusion: no safety concern

3 - Threshold of toxicological concern

• For the impurity [6], for which no toxicity data were available, the TTC approach was applied. Based on the lack of structural alerts for genotoxicity, a TTC of 1.5 μg/kg bw (Cramer class III) was deemed applicable for [6], which was well above the estimated human exposure (< 0.05 μg/kg bw). Conclusion: no safety concern

4 - Calculation of Margin of Exposure

• One of the impurities is a secondary amine which can undergo

endogenous nitrosation forming a genotoxic carcinogenic nitrosamine. The margin from the highest dose of this secondary amine with no detectable carcinogenic effect when co-administered with a high dose of nitrite to rats, and human exposure from the use of the coating, was > 30,000. Conclusion: no safety concern

The multifaceted approach described is largely based on the following EU and EFSA guidance documents:

• tiered toxicity testing → SCF Guidelines on FCM (2001)

• read across and SAR → EFSA and ECHA guidance in food and non-food areas, with particular reference to the proposed EFSA revised guidance for FCM (2016)

• threshold of toxicological concern → EFSA guidance document on TTC (2012) and revised FCM guideline (2016)

• margin of exposure → relevant EFSA guidance document (2005)

Evaluation of coatings: conclusions

• IT follows the standard approach for substances that have to enter in the positive list

• For NIAS, impurities, oligomers, other approaches can be applied

• NO DEFAULT application of TTC

• Case by case approach

• When necessary possibility to set SML for any migrant in addition to the listed substance