Contains Nonbinding Recommendations 
 
Preparation of Food Contact Notifications 
for Food Contact Substances in Contact 
with Infant Formula and/or Human Milk: 
Guidance for Industry 
 
Office of Food Additive Safety 
Division of Food Contact Safety, HFS-275 
Center for Food Safety and Applied Nutrition 
Food and Drug Administration 
5001 Campus Drive 
  College Park, MD  20740   
(Tel) 240-402-1200 
   
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Food Safety and Applied Nutrition 
 
 
 
May 2019 
 
 
 
OMB Control No. 0910-0495 
Current expiration date available at https://www.reginfo.gov/public/do/PRAMain  
*See additional PRA statement in Section IV of this guidance. 
  Contains Nonbinding Recommendations  
 
Table of Contents 
I.  Introduction ......................................................................................................................... 3 
II.  Background ......................................................................................................................... 4 
III.  Recommendations ............................................................................................................... 6 
A.   Chemistry Recommendations .......................................................................................... 6 
B.   Toxicology Recommendations ......................................................................................... 9 
C.  Administrative Recommendations .................................................................................. 14 
IV.  Paperwork Reduction Act of 1995 .................................................................................... 16 
V.  References ......................................................................................................................... 17 
  Contains Nonbinding Recommendations 
 
Preparation of Food Contact Notifications 
for Food Contact Substances in Contact 
1
with Infant Formula  and/or Human 
2
Milk: Guidance for Industry  
 
 
 
This guidance represents the current thinking of the Food and Drug Administrations (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 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  
 
 
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 
 
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. 
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 409 of the Federal Food, Drug, and Cosmetic Act (the FD&C Act) (21 U.S.C. 348) establishes 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.   
3 
  Contains Nonbinding Recommendations 
 
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 0-
6 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 
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 
 
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-Implementation- 
Guide/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/advocacy-
and-policy/aap-health-initiatives/HALF-Implementation- 
Guide/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, 
(http://www.fda.gov/Food/GuidanceRegulation/GuidanceDocumentsRegulatoryInformation/ucm081825.htm),  
referred to in this guidance as the 2002 toxicology guidance. 
4 
  Contains Nonbinding Recommendations 
 
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. 
 
   
5 
  Contains Nonbinding Recommendations 
 
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 foods, in 
practice, many analytes are difficult to measure in 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 
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.  
 
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.   
  
6 
  Contains Nonbinding Recommendations 
 
 
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 paper-
aluminum 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(2,6-
diphenylphenylene 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.  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 
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 
7 
  Contains Nonbinding Recommendations 
 
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.   
 
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 
8 
  Contains Nonbinding Recommendations 
 
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 (g/kg)) by 0.14 kg/kg bw/d.  As an example, if the concentration of 
the FCS in food is 1 g/kg, then the calculation would be: 
 
EDI  =  (1 g FCS/kg formula)(0.14 kg formula/kg-bw/d) 
  =  0.14 g FCS/kg-bw/d 
B.     Toxicology Recommendations 
The toxicology recommendations in this section provide a flexible approach for addressing 
specific endpoints that may be relevant to a manufacturers or suppliers 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 (g/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 
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 (g/kg 
 
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 g/p/d are:  (1) Incremental exposure at or less than 
1.5 g/p/d; (2) cumulative exposure greater than 1.5 g/p/d but not exceeding 150 g/p/d; (3) cumulative exposure 
between 150 g/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. 
9 
  Contains Nonbinding Recommendations 
 
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  Normalized Exposure Value 
Level  (from 2002 toxicology guidance)  (g/kg bw/d) 
Tier 1   1.5 g/p/d   0.025 g/kg bw/d 
Tier 2  > 1.5 g/p/d to  150 g/p/d  > 0.025 to  2.5 g/kg bw/d 
Tier 3  > 150 g/p/d to < 3000 g/p/d  > 2.5 to < 50 g/kg bw/d 
Tier 4  > 3000 g/p/d  > 50 g/kg bw/d 
 
2.   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 
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 
 
14 See section IV.A of the 2002 toxicology guidance.  
  
10 
  Contains Nonbinding Recommendations 
 
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.17   
 
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 
account for the unique features of the early developmental period, as certain traditionally-used 
studies may not be suitable.18   
 
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.   
17 We support the principles of the 3Rs, to reduce, refine, and replace animal use in testing when feasible.  We 
encourage sponsors to consult with us if it they wish to use a non-animal testing method they believe is suitable, 
adequate, validated, and feasible. We will consider if such an alternative method could be assessed for equivalency 
to an animal test method.   
18 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 FDAs recommendations for study design in a 
particular scenario, manufacturers or suppliers should contact FDA.  
11 
  Contains Nonbinding Recommendations 
 
 
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 g/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:  
 
  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.  
 
3.   Age Dependent Cancer Risk Analysis of Carcinogenic Constituents  
An FCN should include risk assessments for carcinogenic constituents of FCSs, as appropriate.19 
If the results of epidemiology studies or rodent carcinogenicity studies on the constituent are 
either positive or equivocal, the manufacturer or supplier ordinarily should calculate an extreme-
case, 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 
 
19 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 
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. 
12 
  Contains Nonbinding Recommendations 
 
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.  EPAs guidance addresses the 0-2 year age 
range based on exposure.  We have modified EPAs 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:  
R  = Unit Cancer Risk (UCR) x 10 x infant exposure x (0.5yr/78yr) 
0-6 mos
Risk for 6 months through 2 years:  
R  = UCR x 10 x general population exposure x (1.5yr/78yr) 
6 mos-2 yrs
Risk for 2 years to 78 years: 
R  = UCR x general population exposure x (76yr/78yr) 
2-78 yrs
LCR = R  + R  + R   
0-6 mos 6 mos-2 yrs 2-78 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 EPAs 2005 
supplemental guidance (U.S. EPA 2005b) to incorporate early life susceptibility into cancer risk 
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.     
13 
  Contains Nonbinding Recommendations 
 
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).   
 
 
   
14 
  Contains Nonbinding Recommendations 
 
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 
manufacturers or suppliers 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.20  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 
 
 
20 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.  
15 
  Contains Nonbinding Recommendations 
 
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 
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 obtain recommendations 
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.  Paperwork Reduction Act of 1995 
This guidance contains information collection provisions that are subject to review by the Office 
of Management and Budget (OMB) under the Paperwork Reduction Act of 1995 (44 U.S.C. 
3501-3520).   
The time required to complete this information collection is estimated to average 5 hours per 
response, including the time to review instructions, search existing data sources, gather the data 
needed, and complete and review the information collection.  Send comments regarding this 
burden estimate or suggestions for reducing this burden to: 
 
Office of Food Additive Safety, HFS-265 
Center for Food Safety and Applied Nutrition 
Food and Drug Administration 
5001 Campus Drive 
College Park, MD 20740 
 
An agency may not conduct or sponsor, and a person is not required to respond to, a collection of 
information unless it displays a currently valid OMB control number.  The OMB control number 
for this information collection is 0910-0495 (To find the current expiration date, search for this 
OMB control no. available at https://www.reginfo.gov/public/do/PRAMain).     
 
   
16 
  Contains Nonbinding Recommendations 
 
V.  References  
 
The following references marked with an asterisk (*) are on display at the Dockets Management 
Staff, Food and Drug Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852.  You 
may see them in person at this location between 9 a.m. and 4 p.m., Monday through Friday; they 
are also available electronically at https://www.regulations.gov.  References without asterisks are 
not on public display at https://www.regulations.gov because they have copyright restriction.  
Some may be available at the website address, if listed.  References without asterisks are 
available for viewing only at the Dockets Management Staff.  FDA has verified the website 
addresses, as of the date this document publishes in the Federal Register, but websites are 
subject to change over time. 
 
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 86:463-
  469. 
 
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. 
 
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 40:230-
  236. 
 
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. * 
17 
  Contains Nonbinding Recommendations 
 
 
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, Minino 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. 
 
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), 7581. 
 
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 lifestage-
  specific 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. 
 
18 
  Contains Nonbinding Recommendations 
 
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/determination-
  appropriate-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.* 
 
27.  U.S. EPA (2005b). Supplemental Guidance for Assessing Susceptibility from Early-Life 
  Exposure to Carcinogens. Risk Assessment Forum, Washington, DC; EPA/630/R-
  03/003F.  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. 
19