Table 1.

Comparison of regulatory frameworks and regulatory requirements for FCM chemical safety assessment in the United States and European Union.

Regulatory framework	United States of America (U.S.)	European Union (E.U.)
Regulations	Food Additive Amendment, 1958 (21CFR170)	FCM Framework Regulation (EC 1935/2004)
Risk management	Acceptable Daily Intake (ADI) based on Cumulative Estimated Daily Intake (CEDI)	Specific Migration Limit (SML) based on Tolerable Daily Intake (TDI)
Toxicity requirements	Tiered toxicity testing, based on estimated daily intake (EDI)	Plastics FCM: Tiered toxicity testing, based on estimated migration
Toxicity data (Muncke 2009)	Tiered, based on estimated daily intake:	For plastic FCMs only; tiered, based on estimated migration into food:
	1. $>3000\mathrm{\mu }\mathrm{g}/\text{person}/\text{day}$: includes in vivo tests (two generation, chronica) plus all tests below	1. $>5000\mathrm{\mu }\mathrm{g}/\mathrm{kg}$ food: includes in vivo tests (2 generation, chronicd) plus all tests below
	2. $>150\mathrm{\mu }\mathrm{g}/\text{person}/\text{day}$: includes in vivo tests (subchronicb) plus all tests below	2. $>50\mathrm{\mu }\mathrm{g}/\mathrm{kg}$ food: includes in vivo tests (subchronice) plus all tests below
	3. $>1.5\mathrm{\mu }\mathrm{g}/\text{person}/\text{day}$: includes in vitro tests (genotoxicityc)	3. $\le 50\mathrm{\mu }\mathrm{g}/\mathrm{kg}$ food: in vitro tests (genotoxicityf) required for all substances that are expected to migrate (no threshold for exemption)
	4. $\le 1.5\mathrm{\mu }\mathrm{g}/\text{person}/\text{day}$: no testing, but substance must not have structural alerts for genotoxicity
Exemptions	Substances used before 1958 and those below 0.5 ppb in food (with no structural alerts for genotoxicity) are exempted from testing requirements	No exemptions specified (all migrating substances require minimum testing for authorization); unauthorized substances may be used in plastic FCMs behind a functional barrier, if migration is below 10 ppb and substances are not in nano form or substances known to be carcinogenic, mutagenic, or toxic to reproduction (CMR).
Model assumption: surface area to food ratio	$1\mathrm{kg}\text{food}/6{.45\text{dm}}^2$ ($10{\mathrm{g}/\text{in}}^2$)	${1\mathrm{kg}\text{food}/6\text{dm}}^2$
Model assumption: food consumption	$3\mathrm{kg}$ foodstuff (solids, liquids)	$1\mathrm{kg}$ of any foodstuff (solids, liquids)
Permissions for use of a substance	— Indirect Food Additive: once authorized, anyone can use according to limitations, intended use	— Monomers, additives in plastics: European Commission authorizes substance for general use, sets limitations of use and SML (Directorate General for Health and Food Safety (DG Santé))
	— Food Contact Substance Notification: only for applying industry’s use according to intended use, limitations
	— Threshold of Regulation: anyone can use according to limitations, intended use
	— Generally recognized as Safe (GRAS): general use of GRAS substances under notified uses
Publicly available information	Applicant, chemical identity, limitations of use (FDA 2017); additional information available upon request	European Food Safety Authority (EFSA) scientific opinions; limitations of use and SML in Annex I (EC 2017a)
Enforcement	FDA enforces compliance if violations are found. Notifications to manufacturers are Warning Letters for significant violations, or Untitled Letters for lesser violations (FDA 2016). Industry can report serious violations to the Reportable Food Registry (FDA 2016)	Member States’ national authorities, European Reference Laboratory (EURL) for FCMs. Noncompliance is documented on the Rapid Alert System for Food and Feed (RASFF) portal (EC 2017b)

^aChronic toxicity and carcinogenicity in two rodent species (2 years), one study incl. in utero phase; two-generation reproductive toxicity study (in rats).

^bChromosomal damage in rodent hematopoietic cells in vivo; two subchronic oral toxicity tests in vivo (rodent and non-rodent species) (90 days); further testing (chronic exposure) with further endpoints can be recommended (e.g., metabolism studies, teratogenicity, reproductive toxicity, neurotoxicity, immunotoxicity studies).

^cMammalian in vitro cytogenicity assay or $\text{tk}+$ assay; gene mutations (bacteria, e.g., Ames).

^dReproduction study (one species), developmental toxicity (in two species); chronic toxicity and carcinogenicity in two species (2 y); ADME study (absorption, distribution, metabolism and excretion) in vivo.

^eTwo subchronic oral toxicity tests in vivo (rodent and nonrodent species) (90 d) plus study on ADME (adsorption, distribution, metabolism and excretion) if log ${\mathrm{P}}_{\text{OW}}>3$.

^fChromosomal aberrations in mammalian cells in vitro; gene mutations in mammalian cells in vitro ($\text{tk}+$ assay); gene mutations (bacteria).