0495 GFI infant formula and milk FCN

Contains Nonbinding Recommendations
Draft-Not for Implementation

Preparation of Food Contact Notifications
for Food Contact Substances in Contact
with Infant Formula1 and/or Human
Milk: Guidance for Industry

DRAFT GUIDANCE
This guidance document is being distributed for comment purposes only.
Although you can comment on any guidance at any time (see 21 CFR 10.115(g)(5)), to ensure
that FDA considers your comment on this draft guidance before we begin work on the final
version of the guidance, submit either electronic or written comments on the draft guidance
within 60 days of publication in the Federal Register of the notice announcing the availability of
the draft guidance. Submit electronic comments to http://www.regulations.gov. Submit written
comments to the Division of Dockets Management (HFA-305), Food and Drug Administration,
5630 Fishers Lane, rm. 1061, Rockville, MD 20852. All comments should be identified with
the docket number [FDA-2016-D-1814] listed in the notice of availability that publishes in the
Federal Register.
For questions regarding this draft document contact the Center for Food Safety and Applied
Nutrition (CFSAN) at 240-402-1200.

U.S. Department of Health and Human Services
Food and Drug Administration
Center for Food Safety and Applied Nutrition
December 2016

1

Under 21 CFR 106.3, infant formula means a food which purports to be or is represented for special dietary use
solely as a food for infants by reason of its simulation of human milk or its suitability as a complete or partial
substitute for human milk.

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Table of Contents
I.

Introduction ................................................................................... 1

II.

Background .................................................................................... 2

III. Recommendations ......................................................................... 4
A. Chemistry Recommendations ................................................................4
B. Toxicology Recommendations ...............................................................7
C. Administrative Recommendations ......................................................12

IV. References .................................................................................... 14

Contains Nonbinding Recommendations
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Preparation of Food Contact Notifications
for Food Contact Substances in Contact
with Infant Formula and/or Human Milk:
Guidance for Industry2
This draft guidance, when finalized, will represent the current thinking of the Food and Drug
Administration’s (FDA or we) on this topic. It does not establish any rights for any person and is not
binding on FDA or the public. You can use an alternative approach if it satisfies the requirements of the
applicable statutes and regulations. To discuss an alternative approach, contact the FDA staff responsible
for this guidance as listed on the title page.

I.

Introduction

We are providing this guidance to represent our current thinking on recommendations for
preparation of food contact notification (FCN) submissions for food contact substances (FCSs) 3
used in contact with infant formula and/or human (breast) milk.
This document is intended to provide specific guidance to help manufacturers or suppliers
submitting an FCN in the safety assessment of FCNs for substances that are intended for use in
contact with infant formula and/or human milk. FCSs that would be affected by this guidance
document may include infant formula packaging for both liquid (concentrate and ready to feed)
and powdered formula, baby bottles, bottle inserts, nipples, and any other materials that are in
contact with infant food. 4

2

This guidance has been prepared by Office of Food Additive Safety, Division of Food Contact Notifications in the
Center for Food Safety and Applied Nutrition at the Food and Drug Administration.

3

Section 309 of the Food and Drug Administration Modernization Act of 1997 (FDAMA) amended section 409 of
the Federal Food, Drug, and Cosmetic Act (the FD&C Act) (21 U.S.C. 348) to establish an FCN process as the
primary method by which FDA regulates food additives that are FCSs. An FCS is any substance that is intended for
use as a component of materials used in manufacturing, packing, packaging, transporting, or holding food if such
use of the substance is not intended to have any technical effect in such food.

4

For purposes of this guidance our use of the phrase "infant food" is limited to infant formula and human milk.

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There has been increased scientific interest in the role of human lifestages in the evaluation of
chemical safety (Makris et al., 2008). This interest has largely been spurred by scientific
advances in the fields of developmental biology and toxicology that suggest that different
lifestages, particularly pediatric lifestages, involve fundamental biological differences that may
influence responses to chemical exposures (Bruckner, 2000; Scheuplein et al., 2002; Ginsberg et
al., 2004a,b; Felter et al., 2015). These scientific advances have caused us to reevaluate our
approach to the safety assessment of FCSs that contact infant food. Not only does exposure to
such FCSs occur during a period of important developmental processes (Neal-Kluever et al.,
2014), but infants also frequently consume infant formula and/or human milk exclusively for the
first 6 months of life. 5 Because infants consume greater amounts of food relative to their body
weight than do adults (Lawrie, 1998), 6 this developmental period is the period of highest intake
of food contact migrants relative to body weight (Neal-Kluever et al., 2014).
This guidance describes our thinking as to how manufacturers or suppliers of FCSs intended for
infant food use should consider these dynamics. Notifications for FCSs must contain sufficient
scientific information to demonstrate that the substance that is the subject of the notification is
safe for the intended use (section 409(h) of the FD&C Act). This guidance contains
recommendations regarding how the scientific information in FCNs for infant food uses should
demonstrate that the FCS is safe for the specific intended use.
While the period of infancy extends beyond the first 6 months after birth, we recognize that the
period during which infants exclusively consume human milk and/or infant formula may largely
be restricted to the first 6 months. 7 Therefore, this guidance focuses only on the 0-6 month age
range. For the purpose of this guidance document, the term “infant” refers to individuals aged 06 months.
FDA's guidance documents, including this guidance, do not establish legally enforceable
responsibilities. Instead, guidances describe our current thinking on a topic and should be
viewed only as recommendations, unless specific regulatory or statutory requirements are cited.
The use of the word should in FDA guidances means that something is suggested or
recommended, but not required.

II.

Background

FDA has previously provided guidance for the safety assessment of FCSs. 8 Our previous
guidance, however, does not specifically address dietary exposure and safety assessment

5

The American Academy of Pediatricians recommends consumption of only formula and/or human milk to the age
of 6 months (http://www.aap.org/en-us/advocacy-and-policy/aap-health-initiatives/HALF-ImplementationGuide/Age-Specific-Content/Pages/Infant-Food-and-Feeding.aspx#none).
6
See National Health and Nutrition Examination Survey (NHANES) data at http://www.cdc.gov/nchs/nhanes.htm.
7
See recommendation of the American Academy of Pediatricians, available at http://www.aap.org/en-us/advocacyand-policy/aap-health-initiatives/HALF-ImplementationGuide/Age-Specific-Content/Pages/Infant-Food-and-Feeding.aspx#none.
8
See U.S. Food and Drug Administration, Guidance for Industry: Preparation of Food Contact Notifications for
Food Contact Substances: Toxicology Recommendations, Final Guidance, Revised April 2002,

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considerations related to the migration of chemical substances from packaging and other food
contact articles as it pertains to infants. This guidance helps fill this gap, and is based on the
scientific advances described in section I of this guidance. Consumer exposure to any one food
chemical is expected to be relatively low in adults and children, as adults and children eat a
variety of foods packaged in a variety of materials. However, infants aged 0-6 months typically
consume human milk and/or infant formula exclusively and consume higher amounts of food in
relation to their body weight than an adult. These factors contribute to a higher, albeit
temporally limited, exposure to potential migrants from the FCSs.
There are clear differences between adults and infants when comparing pharmacokinetic
parameters (e.g., metabolism). Differences in metabolic capacity result in different metabolic
profiles between adults and infants (Alcorn and McNamara, 2003; Ginsberg et al., 2004a,b;
Ginsberg et al., 2002). The metabolic profile of infants can result in either increased or
decreased susceptibility to the toxicity of chemicals, depending on, for example, whether
metabolism results in biological activation or inactivation of the chemical (U.S. EPA 2002b,
2005a; Ginsberg et al., 2004a,b; Ginsberg et al., 2002). Compared to adults, other factors that
can influence the biological responses of infants to chemicals include body water to lipid ratios,
altered levels of plasma proteins, altered organ perfusion rates, maturation of cellular
transporters, and differences in water and food intake (relative to body weight) (Alcorn and
McNamara, 2003; Ginsberg et al., 2004a,b; Landrigan and Goldman, 2011).
In addition to differences in pharmacokinetic processes, infants undergo distinctive periods of
rapid growth and development. The rapid growth, extensive tissue reorganization, and cellular
changes associated with structural maturation and functional differentiation during the
developmental period of 0-6 months may result in enhanced susceptibility to toxicants that may
initiate chronic disease. The brain, reproductive organs, endocrine system, immune system,
kidney, liver, and skeleton in infants are immature at birth and may be susceptible to toxic insult
during maturational processes (Zoetis et al., 2003; Zoetis and Hurtt, 2003; Watson et al., 2006;
Cappon et al., 2009; Schwenk et al., 2003). For example, neurodevelopmental effects from
exposure to chemicals, such as lead, methyl mercury, and some pesticides, during brain
development are well established (Grandjean and Landrigan, 2006). Links between early life
exposure to certain chemicals and other outcomes, such as developmental immunotoxicity and
inflammatory diseases (e.g., atherosclerosis, coronary heart disease), also have been suggested
(DeWitt et al., 2012a; Leifer and Dietert, 2011).
The importance of this developmental period and the potential for elevated exposures on a body
weight basis suggests that these parameters be considered when assessing the safety of
components of FCSs in contact with infant food. FCN submissions for substances that will
contact human milk and/or infant formula should therefore consider the myriad of biological
changes and growth during the developmental period and whether infants are more or less
sensitive than the general population when exposed to equivalent levels of migrants from FCSs.

(http://www.fda.gov/Food/GuidanceRegulation/GuidanceDocumentsRegulatoryInformation/ucm081825.htm),
referred to in this guidance as the “2002 toxicology guidance”.

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III. Recommendations
A. Chemistry Recommendations
1.

Migration Testing

Our general recommendations pertaining to chemistry information that should be submitted in a
FCN are outlined in our 2007 chemistry guidance for FCSs. 9 As described in our 2007
chemistry guidance, the concentration of an FCS in the daily diet may be determined from
measured levels in food or in food simulants. It may also be estimated using information on
formulation or residual levels of the FCS in the food-contact article and the assumption of 100%
migration of the FCS to food. Although we always accept reliable analyses of FCSs in real
foods, in practice, many analytes are difficult to measure in real foods. As an alternative,
manufacturers or suppliers may submit migration data obtained with food simulants that
reproduce the nature and amount of migration of the FCS into food. The submitted migration
data should reflect the most severe temperature/time conditions to which the food-contact article
containing the FCS will be exposed. The recommendations outlined below are specific to those
FCSs intended for use in infant food contact applications.
a.

Food Simulant

Test protocols (including those in our 2007 chemistry guidance) recommend the use of 10%
ethanol as a food simulant for aqueous and acidic foods (i.e., Food Types I, II, IV-B, VI-B, and
VII-B, including milk products identified as oil-in-water emulsions (Food Type IV-B)). 10
Recently, studies conducted in conjunction with the “Food Migrosure” migration modeling
project suggest that 50% ethanol might be a more appropriate general simulant for liquid dairy
products because it more closely tracks the actual migration levels of many dairy products. 11 As
such, we consider 50% ethanol as a generally appropriate simulant for infant formula (liquid or
otherwise reconstituted) and human milk. We also consider 50% ethanol as a generally accepted
simulant for non-dairy based infant formulas, such as soy-based infant formulas, since the fat
content of such formulas is similar to the fat content of milk-based infant formulas. This
simulant will cover the range of formula compositions and account for the varying fat content of
individual products. The use of 95% ethanol also has been found to be an effective fatty-food

9

U.S. Food and Drug Administration, Guidance for Industry: Preparation of Premarket Submissions for Food
Contact Substances: Chemistry Recommendations, Revised December 2007,
(http://www.fda.gov/Food/GuidanceRegulation/GuidanceDocumentsRegulatoryInformation/ucm081818.htm),
referred to in this guidance as the “2007 chemistry guidance”.
10
For further information on food types, see Appendix V of 2007 chemistry guidance or
http://www.fda.gov/Food/IngredientsPackagingLabeling/PackagingFCS/FoodTypesConditionsofUse/default.htm.
11
The aim of the “Food Migrosure” project was to extend existing migration models that are currently applied to
food simulants to food itself. The foods applicable to this guidance include condensed milk (10% fat) and whipping
cream (30% fat), representing fatty foods, and milk powder, representing dry foods (www.foodmigrosure.org).
Commission Regulation (EU) No 10/2011 of 14 January 2011 on plastic materials and articles intended to come into
contact with food. Official Journal of the European Union, Volume L12, pp. 1-89.

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simulant; however, it may exaggerate migration. We provide our current thinking for simulants
for powdered infant formula immediately following in section III.A.1.b.i of this guidance.
b.

Migration Protocols
i.

Articles in Contact with Packaged Formula

Liquid formula (both concentrate and ready-to-feed) lawfully marketed in the United States is
primarily packaged in plastic containers or polymer-coated metal cans and is frequently intended
to be thermally treated by the manufacturer in the container. Our recommended migration
testing protocols for this type of thermal treatment are the same as those described for single use
articles in Appendix II, section 1, “General Protocols (Single-Use Applications) Corresponding
to Condition of Use” of our 2007 chemistry guidance, and are intended to model thermal
treatment and extended storage conditions. For polymer-coated metal cans, where the contents
are retorted in the can, Condition of Use A is recommended. As provided in our 2007 chemistry
guidance, Condition of Use A includes the food contact article being heat-sterilized or retorted
under transient temperatures (ca. 121 ºC (250 ºF)). For plastic articles where sterilization occurs
outside the container, other conditions of use may be appropriate. As discussed in our 2007
chemistry guidance, a food mass-to-surface area ratio of 10 grams per square inch (10 g/in2)
should be used to convert migration values to a concentration in infant food.
Powdered formula lawfully marketed in the United States is primarily packaged in paperaluminum foil composite cans or plastic tubs and is not intended to be thermally processed or
retorted in the container. To determine migration into powdered formula, we recommend that
testing be conducted with 50% ethanol, or a dry food simulant such as Tenax (Poly(2,6diphenylphenylene oxide)), or other appropriate medium. The use of a liquid food simulant for
powdered formula would result in a worst-case migration estimate. Our recommended migration
testing protocol for this application is the same as that recommended under Condition of Use E
(Room temperature filled and stored (no thermal treatment in the container)) in Appendix II,
section 1 of our 2007 chemistry guidance. That is, we recommend that the manufacturer or
supplier conduct migration studies for 240 hours at 40 °C (104 °F). We also recommend that the
test solutions be analyzed after 24, 48, 120, and 240 hours, and that any calculations use a food
mass-to-surface area ratio of 10 g/in2 and account for the powder concentration in reconstituted
formula (on average about 13%).
ii.

Articles in Contact with Infant Food for Feeding (e.g., baby bottles)

Baby bottles are generally intended for repeated use by infants and are typically made of glass or
polymers, such as polypropylene.
When human milk and infant formula are consumed through baby bottles, some thermal
treatment of the human milk or formula in the bottle may occur (e.g., from conditions as mild as
warming of formula before feeding to simultaneous sterilization of water and bottles). We
recommend testing according to either Condition of Use B (Boiling water sterilized) in Appendix
II, section 1 of our 2007 chemistry guidance, or Appendix II, section 4 (Articles Intended for
Repeated Use). As set forth in our 2007 chemistry guidance, Condition of Use B involves the

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same protocol as for Condition of Use A, except that the highest test temperature in Condition of
Use B is 100 °C (212 °F). Including this highest test temperature should adequately represent
the time-temperature-use conditions encountered in the preparation, holding, storage, and/or
feeding of infant food in articles such as nursing bottles. An alternative approach for conducting
migration studies that we also recommend is following the recommendations in Appendix II,
section 4, of our 2007 chemistry guidance. As set forth in section 4 of our 2007 chemistry
guidance, migration studies may be conducted with 50% ethanol for 240 hours at the highest
intended temperature of use.
As further discussed in Appendix II, section 4, of our 2007 chemistry guidance, estimates of the
weight of food contacting a known surface area over the service lifetime of the repeat-use
articles are also used to estimate exposure. Together with the migration data, this will allow
calculation of migration to all the food processed over the service life of the article. We
recommend that the estimate for the mass of food contacting a known surface area should take
into account the fact that baby bottles may be used multiple times a day and over a period of
several months. Based on these factors, we have determined that a food mass-to-surface area
ratio of 1400 g/in2 is adequate to represent the mass of food that would contact a feeding bottle
over its service lifetime. We recommend that the food mass-to-surface area ratio of 1400 g/in2
be used to convert migration values to a concentration in infant food for this repeat use scenario.
iii.

Other Articles

For notifications involving other food contact articles intended to contact human milk and/or
infant formula, we recommend that manufacturers or suppliers consult with us through a
Premarket Notification Consultation (PNC) before submitting an FCN. (See section III.C.5 of
this guidance for further information on the PNC process.)
iv.

Alternatives to Testing on Food Contact Articles

In the absence of validated migration studies, migration levels to food may also be assessed by
the assumption of 100% migration of the FCS to food. Alternatively, migration modeling could
also be used if the applicable parameters are known. For further guidance regarding migration
modeling, consult our 2007 chemistry guidance.
2.

Exposure Estimation

As discussed in section II.E of our 2007 chemistry guidance, exposure estimates for FCSs are
generally based on “Consumption Factors” and “Food-Type Distribution Factors.” These factors
are average values for all foods expected to contact specific types of packaging materials. They
are not based on consumption patterns typical of the infant period because infants aged 0-6
months frequently consume human milk and/or infant formula exclusively and infants often rely
on one or just a few brands of infant formula or baby bottles. Accordingly, we do not
recommend use of Consumption Factors or Food-Type Distribution Factors for calculating
exposure to infant food.

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The exposure of certain sub-populations of interest to an FCS can be estimated by examining
foods specific to the population group of interest, and then assessing the food-contact articles
that may contain the FCS. This is frequently done using information on the consumption of a
specific food(s) derived from food consumption survey data. We recommend considering the
intakes of the identified foods and the concentration of the substance in each of those foods. 12
To apply this approach to FCSs that are intended to contact infant food, we have developed
default values for both infant body weight (6.3 kg-bw/infant) and infant food consumption (900
g formula/infant/day) that were determined based on the 2-day 2005-2010 National Health and
Nutrition Examination Survey (NHANES) food consumption survey. These values resulted in a
consumption-to-mass ratio of 140 grams per kilogram body weight per day (140 g/kg bw/d), or
0.14 kg/kg bw/d. We recommend calculating the estimated daily intake (EDI) of the FCS for
infants by multiplying the migration of the substance to infant food (in parts per billion (ppb) or
micrograms per kilogram (µg/kg)) by 0.14 kg/kg bw/d. As an example, if the concentration of
the FCS in food is 1 µg/kg, then the calculation would be:
EDI

B.

= (1 µg FCS/kg formula)(0.14 kg formula/kg-bw/d)
= 0.14 µg FCS/kg-bw/d

Toxicology Recommendations

The toxicology recommendations in this section provide a flexible approach for addressing
specific endpoints that may be relevant to a manufacturer’s or supplier’s determination that the
intended use of the FCS in contact with infant formula and/or human milk is safe. In general, we
recommend that manufacturers or suppliers develop their safety assessment based on the
estimation of exposure, and that other available scientific information on the FCS also inform the
manufacturer or supplier as to the type of testing and safety analysis needed to demonstrate that
the FCS is safe for the intended use under section 409(h) of the FD&C Act. As described in
section III.B.2 of this guidance, it may be appropriate to conduct additional safety testing,
beyond the safety testing recommended in our 2002 toxicology guidance to assess the safety of
an FCS for infants 0-6 months of age.
1.

Exposure Based Testing Tiers

Our 2002 toxicology guidance makes testing recommendations based on four tiers. For each tier,
we make recommendations for studies and other information to assess the safety of an FCS (and
each constituent as appropriate). Each tier in our 2002 toxicology guidance is based on exposure
calculated in micrograms per person per day (µg/p/d), and includes the assumption of 60 kg of
body weight per person as well as consumption amounts that are not specific to the infant
period. 13 To account for differences between general and infant populations with respect to body
12

See discussion of sub-populations in U.S. Food and Drug Administration, Guidance for Industry: Estimating
Dietary Intake of Substances in Food, August 2006.
(http://www.fda.gov/Food/GuidanceRegulation/GuidanceDocumentsRegulatoryInformation/ucm074725.htm)
13
The four tiers in the 2002 toxicology guidance, expressed in µg/p/d are: (1) Incremental exposure at or less than
1.5 µg/p/d; (2) cumulative exposure greater than 1.5 µg/p/d but not exceeding 150 µg/p/d; (3) cumulative exposure

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weight and food intake, we have normalized the exposure values for each of the four tiers in our
2002 toxicology guidance. The normalized tiers, which are set forth in Table 1, are based on
estimated daily intakes expressed as micrograms per kilograms of body weight per day (µg/kg
bw/d). To determine the recommended tier for the infant food contact toxicological evaluation,
manufacturers or suppliers should calculate the estimated daily intake for infants considering the
intended use of the substance that is the subject of the notification. The estimated daily intake
should also include any other uses specifically authorized for infant food-contact use. The
method for calculating the estimated daily intake should be applied to the FCS and each
constituent as appropriate. Manufacturers or suppliers should then use the estimated daily intake
values to determine the applicable tier, using Table 1.
Table 1: Tier Values:
Tier
Exposure Value
Level
(from 2002 toxicology guidance)
Tier 1 < 1.5 μg/p/d
Tier 2 >1.5 μg/p/d to < 150 μg/p/d
Tier 3
>150 μg/p/d to < 3000 μg/p/d
Tier 4 > 3000 μg/p/d
2.

Normalized Exposure Value
(μg/kg bw/d)
≤ 0.025 μg/kg bw/d
>0.025 to < 2.5 μg/kg bw/d
>2.5 to < 50 μg/kg bw/d
> 50 μg/kg bw/d

Minimum Testing Recommendations

We recommend that FCNs for substances intended for use in contact with infant food refer to our
2002 toxicology guidance for testing recommendations based on tier level. 14 That is, for FCSs
that fall within Tier 1, we recommend that FCNs follow the corresponding recommendations for
safety testing in section IV.A.1 in our 2002 toxicology guidance. For FCSs that fall within Tier
2, we recommend that FCNs follow the corresponding recommendations for safety testing in
section IV.A.2 in that guidance. For FCSs that fall within Tiers 3 and 4, we recommend that
FCNs follow the corresponding recommendations for safety testing in sections IV.A.3 and
IV.A.4 in that guidance, respectively. As with the recommendations in our 2002 toxicology
guidance, the recommendations in this guidance are consistent with the general principle that the
potential risk of a substance is likely to increase as exposure increases.
Although the tiered recommendations provide our general thinking regarding the type of testing
and information that may be appropriate for assessing safety, there may be circumstances where
we would recommend additional information and/or data in order to determine the safety of an
FCS for use in contact with infant formula and/or human milk. Such circumstances are likely to
arise if there is inadequate information to assess safety for use in contact with infant formula
and/or human milk, or where there is information suggesting potential toxicity or other safety
concerns. As noted in section II. Background of this guidance, the infant developmental period
is characterized by continuous changes in physiological processes, such as pharmacokinetic
parameters and organ and system development, which suggests that the minimum testing
between 150 µg/p/d and 3 mg/p/d; and (4) cumulative exposure at or greater than 3 mg/p/d. See section IV.A. of the
2002 toxicology guidance.
14
See section IV.A of the 2002 toxicology guidance.

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recommendations for the four tiers identified in our 2002 toxicology guidance may not always be
adequate to assess the safety of an FCS that contacts human milk and/or infant formula
consumed during this period of early development (Neal-Kluever et al., 2014).
Additional testing or safety information beyond the recommendations for each of the four tiers in
our 2002 toxicology guidance may be necessary to determine whether an FCS is safe for its
intended use in contact with human milk and/or infant formula. Manufacturers or suppliers
should consider, among other things, the potential for a toxic response in the apical endpoints
with known developmental differences. Such potential may be identified as a result of available
toxicity data, chemical structure(s), structure activity methods, or other resources, 15 and may
indicate a potential for developmental toxicity (such as neurotoxicity, immunotoxicity,
reproductive toxicity, or other endpoints). 16 Additionally, effects may be identified in juvenile or
adult animal toxicity studies that may predict a different effect or change in magnitude or
sensitivity in an infant. Information on absorption, distribution, metabolism, and excretion
(ADME), mode of action (MOA), toxicokinetic (TK), toxicodynamic (TD), and/or
pharmacokinetic (PK) profile may be useful in evaluating safety.
When designing studies and evaluating data to reduce uncertainty in the safety assessment for
infant exposures, we recommend considering that PK, ADME, TK/TD, and/or other relevant
data can be incorporated to more accurately describe interspecies differences or differences
between juvenile and adult animals. We also recommend considering that the type of study and
any specialized endpoints or modifications added to reproductive/developmental studies may be
informed by the results of subchronic studies and additional available information. In addition,
manufacturers or suppliers should understand any gaps relevant to infant exposure in the safety
studies on which they rely and identify ways to address them. For example, a subchronic study,
as described in our 2002 toxicology guidance, does not include dosing during the postnatal
development period. Additionally, the protocols for most reproductive/developmental toxicity
studies do not include estimation of exposure of a substance from human milk. Moreover, they
typically do not include direct dosing of neonatal or juvenile animals during the postnatal period.
These potential gaps in study design might be addressed by modifying subchronic or other
studies (for example, see Delclos et al., 2014), by use of PK/ADME data, and/or by use of other
information related to the structure of the chemical to determine if exposure would be expected
through lactation and whether the expected exposure can be quantified. Given the variety of
different potential study design gaps and areas of uncertainty, manufacturers or suppliers should,
as a general matter, consider whether it is necessary to modify traditional toxicity studies to

15

Examples of possible resources include: Structure-activity relationship (SAR; e.g., EFSA, 2011), Cramer classes
(Cramer et al., 1978), or the National Center for Toxicological Research Endocrine Disruptor Knowledgebase
(EDKB) http://www.fda.gov/ScienceResearch/BioinformaticsTools/EndocrineDisruptorKnowledgebase/default.htm.
These are examples only and not an exhaustive list.
16
This information may be identified during preparation of the comprehensive toxicological profile (CTP), which,
as described in the 2002 toxicology guidance, serves to identify all unpublished and published safety studies and
related information relevant to the safety assessment of the FCS and to address all safety studies that identify
adverse effects of the substance.

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account for the unique features of the early developmental period, as certain traditionally-used
studies may not be suitable. 17
The following are examples of scenarios in which additional or modified studies may be
recommended to demonstrate the safety of FCSs for infant food uses. These examples are not
inclusive or representative of all scenarios of when additional studies or study modifications may
be recommended to demonstrate safety. For our examples, we assumed that the estimated
exposure to a chemical ranges from 2.5 to < 50 μg/kg bw/d (Tier 3), such that, at minimum, the
standard data package for Tier 3 as outlined in section IV.A.3 of our 2002 toxicology guidance
would ordinarily be recommended. The examples describe how relevant information could be
considered in the interpretation of the standard data package (in this case Tier 3) and whether
possible modifications or additions to the standard data package may be warranted.
•

Alerting information (hazard identification) for toxicity relevant to the infant
developmental time period (e.g., renal toxicity) was observed in an in vivo study in adult
or juvenile animals. For example, a modified 90-day subchronic toxicity study initiated
in the early postnatal time period in rodents (Postnatal Day 1-5) with direct dosing of
neonatal and juvenile rodents (pups) may address the safety concern in this scenario.

•

Alerting information (hazard identification) relevant to ongoing, long term, or latent
effects (e.g., reproductive, endocrine, or neurological effects; or immunotoxicity) was
observed in an in vivo study in adult or juvenile animals. In the absence of other safety
information, a study (e.g., a two-generation or extended one-generation assay with
possible modifications such as direct dosing of pups) may address the safety concern in
this scenario.

Conversely, there may be situations in which we would not recommend additional studies. For
example:
•

3.

Available information or studies indicate that there is no elevated risk or differential
susceptibility for toxicity in pre-weaned animals. A 90-day study in juvenile/adult
animals may be sufficient to support the safety of a chemical in this scenario, and no
additional studies would be needed.
Age Dependent Cancer Risk Analysis of Carcinogenic Constituents

An FCN should include risk assessments for carcinogenic constituents of FCSs, as appropriate. 18
If the results of epidemiology studies or rodent carcinogenicity studies on the constituent are
17

To the extent that manufacturers or suppliers may seek additional information about the possible considerations in
study design specific to the early postnatal period, we note that several recent studies have addressed this issue.
Examples include: Neal-Kluever et al., 2014; Delclos et al., 2014; Churchwell et al., 2014; Moser et al., 2005; and
note 17 in ICH S5(R2), (2005). For specific information about FDA’s recommendations for study design in a
particular scenario, manufacturers or suppliers should contact FDA.
18

Section 409(c)(3)(A) of the FD&C Act prohibits the approval of food additives, including FCSs, found to induce
cancer when ingested by man or animal, or if it is found, after tests which are appropriate for the evaluation of the

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either positive or equivocal, the manufacturer or supplier ordinarily should calculate an extremecase, upper-bound, lifetime risk to humans from exposure to the constituent. A manufacturer or
supplier may use another approach to estimate the risk presented by a carcinogenic constituent
and should present scientific evidence justifying their alternative approach. Our 2002 toxicology
guidance contains guidance for calculating the lifetime risk, but does not contain guidance
regarding the role of infant exposure in contributing to the lifetime risk. However, the U.S.
Environmental Protection Agency (EPA) has published guidance for assessing cancer risk from
early-life exposure (U.S. EPA 2005a, 2005b, 2011), and it is our view that the EPA guidance
provides a helpful framework for evaluating lifetime cancer risk (LCR) from infant exposure to
FCSs that contact infant formula and/or human milk. EPA’s guidance addresses the 0-2 year age
range based on exposure. We have modified EPA’s cancer risk equations to include the specific
0-6 month exposure scenario in the 0-2 year age as set forth below. We recommend that
manufacturers or suppliers apply the equations below if the results of epidemiology studies or
rodent carcinogenicity studies on the constituent are either positive or equivocal in order to
assess LCR. A manufacturer or supplier may use another approach to estimate the LCR
presented by a carcinogenic constituent, and should present scientific evidence justifying their
alternative approach. The equations that we recommend for assessing LCR are as follows:
Risk for birth through 6 months:
R0-6 mos = Unit Cancer Risk (UCR) x 10 x infant exposure x (0.5yr/78yr)
Risk for 6 months through 2 years:
R6 mos-2 yrs = UCR x 10 x general population exposure x (1.5yr/78yr)
Risk for 2 years to 78 years:
R2-78 yrs = UCR x general population exposure x (76yr/78yr)
LCR = R0-6 mos + R6 mos-2 yrs + R2-78 yrs
As the equations make clear, we recommend that manufacturers or suppliers calculate the
extreme-case, upper-bound, lifetime risk by first conducting three separate calculations that
involve: (1) the unit cancer risk or UCR; (2) the estimated exposure for each specific population
exposure; (3) the age-dependent adjustment factor (ADAF) based on age; and (4) percent of
lifespan for each age group. The three different calculations represent risk from exposure during
the 0-6 month age period; risk from exposure during the 6 month through 2-year age period; and
risk from exposure during the 2-year through 78-year age period. LCR represents the sum of the
risk from all three age periods. The average lifespan age of 78 years is used in the equations and
reflects the current average U.S. lifespan (Kochanek et al., 2011).
As described above, these equations for assessing LCR includes an age-dependent adjustment
factor (ADAF). As a general matter, we recommend an ADAF of 10 to account for the potential
variability (increased susceptibility) during the developmental periods of 0-6 months and 6
months-2 years. This ADAF was recommended in certain scenarios in EPA’s 2005
supplemental guidance (U.S. EPA 2005b) to incorporate early life susceptibility into cancer risk
safety of food additives, to induce cancer in man or animal. Importantly, section 409(c)(3)(A) applies to the additive
itself and not to constituents of the additive. If a food additive that is an FCS has not been shown to cause cancer in
man or animal, but contains a carcinogenic constituent, FDA will evaluate the safety of the constituent under the
general safety standard (section 409(c)(3)(A) of the FD&C Act) using quantitative risk assessment procedures.

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assessment, and it reflects the possibility that different age groups may be less or more
responsive to effects of carcinogens from FCSs. However, a manufacturer or supplier may use
another ADAF or no ADAF to estimate LCR if it is scientifically justified. Such scientific
evidence may exist if, for example, TK/TD or MOA data suggest lesser or greater susceptibility
in the infant population.
Although we generally recommend the use of the above equations for assessing LCR, there may
be circumstances when modification of the formula is appropriate. We suggest manufacturers or
suppliers consult us if they believe such circumstances exist.

C. Administrative Recommendations
1.

Acknowledgement of an FCN

We intend to continue acknowledging receipt of an FCN in writing within 30 days of receipt.
This acknowledgment informs the manufacturer or supplier of the date when we received the
complete FCN, and thereby the effective date of the notification if we do not object to the
marketing of the substance. The acknowledgment also identifies the substance and use that is the
subject of the notification.
In cases where the FCN does not designate an infant FCS use, the acknowledgment letter will
include language in the “Limitation/Specifications” section indicating that, because the use of the
FCS does not explicitly include a use for contact with infant formula and/or human milk, we are
restricting our review to exclude these uses and are instead including in our review the general
exposure from other food contact uses.
For further information on “Intended Use” and “Limitations/Specifications” language, see
http://www.accessdata.fda.gov/scripts/fdcc/?set=fcn.
On the other hand, if the FCN specifies infant food use, we recommend that the manufacturer or
supplier demonstrate the safety of the infant food use in accordance with this guidance. In such
cases, the acknowledgement letter will state that the intended use of the FCS includes uses for
contact with human milk and/or infant formula, as specified in the notification. Specifically, the
“Intended Use” and “Limitations/Specifications” sections of acknowledgement letters will
indicate that the intended use includes contact with infant food.
Manufacturers or suppliers should review carefully the description of the intended conditions of
use and applicable limitations/specifications in the acknowledgment letter, as this will determine
the uses for which the notification will become effective within the meaning of section 409(h) of
the FD&C Act (21 U.S.C. 348(h)). The description also will affect the language that we include
in the “Intended Use” and “Limitations/Specifications” sections in our Inventory of Effective
Notifications (see section III.C.4 of this guidance for more information about our Inventory).

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2.

Nonacceptance of an FCN

If any element of a notification required under 21 CFR 170.101(a) through (e) is missing, we will
not accept the FCN for review, and we will provide the manufacturer or supplier with a
nonacceptance letter (see 21 CFR 170.104(b)(1)). Under § 170.101(a) and (b), an FCN
submission must include a comprehensive discussion of the basis for the manufacturer's or
supplier's determination that the use of the FCS is safe. As provided in § 170.101(a)(1) and (2),
this discussion must discuss all information and data submitted in the notification and address
any information and data that may appear to be inconsistent with the determination that the
proposed use of the FCS is safe. In addition, under § 170.101(b) all data and other information
that form the basis of the determination that the FCS is safe under the intended conditions of use
must be included. In evaluating what constitutes a comprehensive discussion of the basis of the
manufacturer’s or supplier’s determination that the use of the FCS is safe, we consider each FCN
on a case-by-case basis. Depending on the intended use of an FCS for use in contact with infant
formula and human milk and the nature and extent of the safety discussion provided, we may
determine that, in order for the discussion to be comprehensive, the discussion needs to include
data and information relevant to infant exposure and safety. In such cases, we may determine on
a case-by-case basis that the failure to provide such data and information causes the FCN to be
incomplete and therefore subject to nonacceptance under § 170.104(b)(1). In most cases, we will
provide the manufacturer or supplier an opportunity to supply the missing information, modify
the use, or withdraw the FCN. 19 If a manufacturer or supplier initially submits an FCN for an
FCS that is not intended for use in contact with human milk and/or infant formula, but then later
wishes to expand the uses for which the notification is effective to include such infant food
contact uses, we may recommend submission of a new FCN. In such circumstances, we will
recommend that the manufacturer or supplier consult this guidance and consult with us during
the Premarket Notification Consultation (PNC) process. See section III.C.5 of this guidance for
further discussion of the PNC process.
3.

Final Letter

We are not required to issue a letter in response to the FCN if we do not object to the marketing
of the notified substance. However, we realize that such a letter may serve to bring the review
process to closure. Therefore, our policy is to issue a letter to the manufacturer or supplier that
includes information identifying the FCS that is the subject of the notification and the date on
which the notification became effective. The letter will include any applicable statements
regarding infant food contact use in the “Limitations/Specification” section. (See section III.C.1.
Administrative Recommendations --- Acknowledgment of an FCN.)
4.

Inventory of Effective FCNs

We maintain an inventory of effective FCNs on our internet site. This inventory is the primary
vehicle for informing the public of effective FCNs. The inventory contains information on the
19

In accordance with 21 CFR 170.103, a manufacturer or supplier may withdraw an FCN for an FCS, without
prejudice to a future submission, at any time prior to the completion of FDA's review.

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Contains Nonbinding Recommendations
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identity of the substance that is the subject of the notification, the conditions of use shown to be
safe, any limitations on the use of the substance, specifications for the substance, the
manufacturer or supplier for whom the notification is effective, the date on which the notification
became effective, and a tracking number. The inventory is publicly available on our internet site
at http://www.accessdata.fda.gov/scripts/fdcc/?set=fcn. For FCNs with explicit authorization for
use in contact with infant formula and/or human milk, we will indicate such use(s) in the
“Intended Use” section of the web listing in the FDA inventory. For those FCNs whose FCS is
not intended for use in contact with infant formula and/or human milk, the inventory will make
clear that the FCSs are not intended for such use.
5.

Premarket Notification Consultations (PNCs)

We recommend that manufacturers or suppliers use the PNC process to seek guidance on
determining infant exposure and/or appropriate testing methods for infant FCSs. A manufacturer
or supplier may request a pre-submission meeting/consultation with us regarding a notification
for an FCS. Such interactions will occur at the discretion of the manufacturer or supplier and are
intended to facilitate the submission of successful notifications because we will not accept
notifications for review without adequate scientific support.

IV. References
We have placed the following references on display in the Division of Dockets Management,
Food and Drug Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852. You may
see them at that location between 9 a.m. and 4 p.m., Monday through Friday. As of December
4, 2016, FDA had verified the Web site address for the references it makes available as
hyperlinks from the Internet copy of this guidance, but FDA is not responsible for any
subsequent changes to Non-FDA Web site references after December 4, 2016.
1.

Alcorn J, McNamara PJ (2003). Pharmacokinetics in the newborn. Adv Drug Deliv
Rev 55:667-686.

2.

Bruckner JV (2000). Differences in sensitivity of children and adults to chemical
toxicity: the NAS panel report. Regul Toxicol Pharmacol 31:280-285.

3.

Cappon GD, Bailey GP, Buschmann J, Feuston MH, Fisher JE, Hew KW, Hoberman
AM, Ooshima Y, Stump DG, Hurtt ME (2009). Juvenile animal toxicity study designs to
support pediatric drug development. Birth Defects Res B Dev Reprod Toxicol 86:463469.

4.

Churchwell MI, Camacho L, Vanlandingham MM, Twaddle NC, Sepehr E, Delclos KB,
Fisher JW, Doerge DR (2014). Comparison of Lifestage-Dependent Internal Dosimetry
for Bisphenol A, Ethinyl Estradiol, a Reference Estrogen, and Endogenous Estradiol to
Test an Estrogenic Mode of Action in Sprague-Dawley Rats. Toxicol Sci. 139(1):4-20.

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Contains Nonbinding Recommendations
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5.

Cramer GM, Ford RA, and Hall RL (1978). Estimation of Toxic Hazard – A Decision
Tree Approach. FD. Cosmet. Toxicol. 16:255-276.

6.

Delclos KB, Camacho L, Lewis SM, Vanlandingham MM, Latendresse JR, Olson GR,
Davis KJ, Patton RE, Gamboa da Costa G, Woodling KA, Bryant MS, Chidambaram M,
Trbojevich R, Juliar BE, Felton RP, Thorn BT (2014). Toxicity Evaluation of Bisphenol
A Administered by Gavage to Sprague-Dawley Rats from Gestation Day 6 through
Postnatal Day 90. Toxicol Sci. 139(1):174-97.

7.

DeWitt JC, Peden-Adams MM, Keil DE, Dietert RR (2012a). Current status of
developmental immunotoxicity: early-life patterns and testing. Toxicol Pathol 40:230236.

8.

EFSA (2011). Applicability of QSAR analysis in the evaluation of developmental and
neurotoxicity effects for the assessment of the toxicological relevance of metabolites and
degradates of pesticide active substances for dietary risk assessment. Accessed online at
http://www.efsa.europa.eu/en/supporting/doc/169e.pdf.

9.

Felter SP, Daston GP, Euling SY, Piersma AH, Tassinari MS (2015). Assessment of
health risks resulting from early-life exposures: Are current chemical toxicity testing
protocols and risk assessment methods adequate? Crit Rev Toxicol 45:219-244.

10.

Ginsberg G., Hattis D., Miller R., Sonawane B (2004a). Pediatric pharmacokinetic data:
implications for environmental risk assessment for children. Pediatrics 113:973-983.

11.

Ginsberg G, Hattis D, Sonawane B (2004b). Incorporating pharmacokinetic differences
between children and adults in assessing children's risks to environmental toxicants.
Toxicol Appl Pharmacol 198:164-183.

12.

Ginsberg G, Hattis D, Sonawane B, Russ A, Banati P, Kozlak M, Smolenski S, Goble R
(2002). Evaluation of child/adult pharmacokinetic differences from a database derived
from the therapeutic drug literature. Toxicol Sci 66:185-200.

13.

Grandjean P, Landrigan PJ (2006). Developmental neurotoxicity of industrial chemicals.
Lancet 368:2167-2178.

14.

ICH (2005). Detection Of Toxicity To Reproduction For Medicinal Products & Toxicity
To Male Fertility S5(R2) Accessed online at
http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Safety/S5/Step
4/S5_R2__Guideline.pdf .

15.

Kochanek KD, Xu J, Murphy SL, Miniño AM, and Kung HC, (2011). Deaths:
Preliminary Data for 2009. National Vital Statistics Reports 59(4):1-51. Accessed online
at http://www.cdc.gov/nchs/data/nvsr/nvsr59/nvsr59_04.pdf.

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Contains Nonbinding Recommendations
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16.

Landrigan PJ, Goldman LR (2011). Children's vulnerability to toxic chemicals: a
challenge and opportunity to strengthen health and environmental policy. Health Aff
(Millwood ) 30:842-850.

17.

Lawrie, C.A., 1998. Different dietary patterns in relation to age and the consequences for
intake of food chemicals. Food Addit. Contam. 15 (Suppl), 75–81.

18.

Leifer CA, Dietert RR (2011). Early life environment and developmental
immunotoxicity in inflammatory dysfunction and disease. Toxicol & Eviron Chem
93:1463-1485.

19.

Makris SL, Thompson CM, Euling SY, Selevan SG, Sonawane B (2008). A lifestagespecific approach to hazard and dose-response characterization for children's health risk
assessment. Birth Defects Res B Dev Reprod Toxicol 83:530-546.

20.

Moser VC, Walls I, Zoetis T, (2005). Direct Dosing of Preweaning Rodents in Toxicity
Testing and Research: Deliberations of an ILSI RSI Expert Working Group. International
Journal of Toxicology 24:87-94.

21.

Neal-Kluever AN, Aungst J, Gu Y, Hatwell K, Muldoon-Jacobs K, Liem AD,
Ogungbesan A, and Shackelford M, (2014). Infant Toxicology: State of the science and
considerations in evaluation of safety. Food and Chem. Toxicol 70:68-83.

22.

Scheuplein R, Charnley G, Dourson M (2002). Differential Sensitivity of Children and
Adults to Chemical Toxicity: I. Biological Basis. Regulatory Toxicology and
Pharmacology 35:429-447.

23.

Schwenk M, Gundert-Remy U, Heinemeyer G, Olejniczak K, Stahlmann R, Kaufmann
W, Bolt HM, Greim H, von KE, Gelbke HP (2003). Children as a sensitive subgroup and
their role in regulatory toxicology: DGPT workshop report. Arch Toxicol 77:2-6.

24.

U.S. EPA (2002a). A Review of the Reference Dose and Reference Concentration
Processes. U.S. Environmental Protection Agency, Risk Assessment Forum,
Washington, DC, EPA/630/P-02/002F. Accessed online at
http://www2.epa.gov/sites/production/files/2014-12/documents/rfd-final.pdf.

25.

U.S. EPA (2002b). Determination of the Appropriate FQPA Safety Factor(s) in
Tolerance Assessment. Office of Pesticide Programs, Washington, DC. Accessed online
at http://www2.epa.gov/pesticide-science-and-assessing-pesticide-risks/determinationappropriate-fqpa-safety-factors.

26.

U.S. EPA (2005a). Guidelines for Carcinogen Risk Assessment. Risk Assessment
Forum, Washington, DC; EPA/630/P-03/001F. Accessed online at
http://www2.epa.gov/risk/guidelines-carcinogen-risk-assessment.

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Contains Nonbinding Recommendations
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27.

U.S. EPA (2005b). Supplemental Guidance for Assessing Susceptibility from Early-Life
Exposure to Carcinogens. Risk Assessment Forum, Washington, DC; EPA/630/R03/003F. Accessed online at www.epa.gov/ttnatw01/childrens_supplement_final.pdf.

28.

U.S. EPA (2011). Exposure Factors Handbook: 2011 Edition. EPA/600/R-090/052F.
Accessed online at http://cfpub.epa.gov/ncea/risk/recordisplay.cfm?deid=236252.

29.

Watson RE, DeSesso JM, Hurtt ME, Cappon GD (2006). Postnatal growth and
morphological development of the brain: a species comparison. Birth Defects Res B Dev
Reprod Toxicol 77:471-484.

30.

Zoetis T, Hurtt ME (2003). Species comparison of anatomical and functional renal
development. Birth Defects Res B Dev Reprod Toxicol 68:111-120.

31.

Zoetis T, Tassinari MS, Bagi C, Walthall K, Hurtt ME (2003). Species comparison of
postnatal bone growth and development. Birth Defects Res B Dev Reprod Toxicol
68:86-110.

17