Document ID: FDA-2016-F-1253-0440
Agency: fda
Document Type: Proposed Rule
Title: Natural Resources Defense Council, et al.; Denial of Food Additive Petition; Denial Without Prejudice of Food Additive Petition
Posted Date: 2022-05-20T04:00Z

[Federal Register Volume 87, Number 98 (Friday, May 20, 2022)]
[Proposed Rules]
[Pages 31066-31079]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2022-10530]

[[Page 31065]]

Vol. 87

Friday,

No. 98

May 20, 2022

Part II

Department of Health and Human Services

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Food and Drug Administration

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21 CFR Parts 175, 176, 177, et al.

Natural Resources Defense Council, et al.; Denial of Food Additive 
Petition; Denial Without Prejudice of Food Additive Petition; Proposed 
Rule

  Federal Register / Vol. 87 , No. 98 / Friday, May 20, 2022 / Proposed 
Rules  

[[Page 31066]]

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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Parts 175, 176, 177, and 178

[Docket No. FDA-2016-F-1253]

Natural Resources Defense Council, et al.; Denial of Food 
Additive Petition; Denial Without Prejudice of Food Additive Petition

AGENCY: Food and Drug Administration, HHS.

ACTION: Notification; denial of petition.

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SUMMARY: The Food and Drug Administration (FDA or we) is denying a food 
additive petition (FAP 6B4815) submitted by Natural Resources Defense 
Council, et al., requesting that we amend or revoke specified 
regulations to no longer provide for the food contact use of 28 ortho-
phthalates. (We use the terms ``phthalates'' and ``ortho-phthalates'' 
interchangeably in this notification to refer to the subset of 
phthalates substituted in the ``ortho'' position).

DATES: This notification is applicable May 20, 2022, except as to any 
provisions that may be stayed by the filing of proper objections. 
Submit either electronic or written objections and requests for a 
hearing on the document June 21, 2022. See Section V for further 
information on the filing of objections.

ADDRESSES: You may submit objections and requests for a hearing as 
follows. Please note that late, untimely filed objections will not be 
considered. Electronic objections must be submitted on or before June 
21, 2022. The https://www.regulations.gov electronic filing system will 
accept objections until 11:59 p.m. Eastern Time at the end of June 21, 
2022. Objections received by mail/hand delivery/courier (for written/
paper submissions) will be considered timely if they are postmarked or 
the delivery service acceptance receipt is on or before that date.

Electronic Submissions

    Submit electronic objections in the following way:
     Federal eRulemaking Portal: https://www.regulations.gov. 
Follow the instructions for submitting comments. Objections submitted 
electronically, including attachments, to https://www.regulations.gov 
will be posted to the docket unchanged. Because your objection will be 
made public, you are solely responsible for ensuring that your 
objection does not include any confidential information that you or a 
third party may not wish to be posted, such as medical information, 
your or anyone else's Social Security number, or confidential business 
information, such as a manufacturing process. Please note that if you 
include your name, contact information, or other information that 
identifies you in the body of your objection, that information will be 
posted on https://www.regulations.gov.
     If you want to submit an objection with confidential 
information that you do not wish to be made available to the public, 
submit the objection as a written/paper submission and in the manner 
detailed (see ``Written/Paper Submissions'' and ``Instructions'').

Written/Paper Submissions

    Submit written/paper submissions as follows:
     Mail/Hand Delivery/Courier (for written/paper 
submissions): Dockets Management Staff (HFA-305), Food and Drug 
Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852.
     For written/paper objections submitted to the Dockets 
Management Staff, FDA will post your objection, as well as any 
attachments, except for information submitted, marked and identified, 
as confidential, if submitted as detailed in ``Instructions.''
    Instructions: All submissions received must include the Docket No. 
FDA-2016-F-1253 for ``Natural Resources Defense Council, et al.; Denial 
of Food Additive Petition; Denial Without Prejudice of Food Additive 
Petition.'' Received objections, those filed in a timely manner (see 
ADDRESSES), will be placed in the docket and, except for those 
submitted as ``Confidential Submissions,'' publicly viewable at https://www.regulations.gov or at the Dockets Management Staff between 9 a.m. 
and 4 p.m., Monday through Friday, 240-402-7500.
     Confidential Submissions--To submit an objection with 
confidential information that you do not wish to be made publicly 
available, submit your objections only as a written/paper submission. 
You should submit two copies total. One copy will include the 
information you claim to be confidential with a heading or cover note 
that states ``THIS DOCUMENT CONTAINS CONFIDENTIAL INFORMATION.'' We 
will review this copy, including the claimed confidential information, 
in our consideration of comments. The second copy, which will have the 
claimed confidential information redacted/blacked out, will be 
available for public viewing and posted on https://www.regulations.gov. 
Submit both copies to the Dockets Management Staff. If you do not wish 
your name and contact information to be made publicly available, you 
can provide this information on the cover sheet and not in the body of 
your comments and you must identify this information as 
``confidential.'' Any information marked as ``confidential'' will not 
be disclosed except in accordance with 21 CFR 10.20 and other 
applicable disclosure law. For more information about FDA's posting of 
comments to public dockets, see 80 FR 56469, September 18, 2015, or 
access the information at: https://www.govinfo.gov/content/pkg/FR-2015-09-18/pdf/2015-23389.pdf.
    Docket: For access to the docket to read background documents or 
the electronic and written/paper comments received, go to https://www.regulations.gov and insert the docket number, found in brackets in 
the heading of this document, into the ``Search'' box and follow the 
prompts and/or go to the Dockets Management Staff, 5630 Fishers Lane, 
Rm. 1061, Rockville, MD 20852, 240-402-7500.

FOR FURTHER INFORMATION CONTACT: Jessica Urbelis, Center for Food 
Safety and Applied Nutrition (HFS-275), Food and Drug Administration, 
5001 Campus Dr., College Park, MD 20740, 240-402-5187; or Meadow Platt, 
Office of Regulations and Policy (HFS-024), Center for Food Safety and 
Applied Nutrition, Food and Drug Administration, 5001 Campus Dr., 
College Park, MD 20740, 240-402-2378.

SUPPLEMENTARY INFORMATION:

I. Introduction

    In a notice published in the Federal Register on May 20, 2016 (81 
FR 31877), we announced that we filed a food additive petition (FAP 
6B4815) (petition) submitted by Breast Cancer Fund (now Breast Cancer 
Prevention Partners), Center for Environmental Health, Center for Food 
Safety, Center for Science in the Public Interest, Clean Water Action, 
Consumer Federation of America, Earthjustice, Environmental Defense 
Fund, Improving Kids' Environment, Learning Disabilities Association of 
America, and Natural Resources Defense Council, c/o Mr. Thomas Neltner, 
1875 Connecticut Ave. NW, Suite 600, Washington, DC 20009. In the May 
2016 notice, FDA requested comments on the petition.
    The petitioners initially requested that we amend or revoke 
specified food additive regulations under 21 CFR parts 175, 176, 177, 
and 178, to no longer provide for the food contact uses of 30 
substances that the petition identified as ortho-phthalates. We filed 
this portion of the submission as a food additive

[[Page 31067]]

petition (81 FR 31877 at 31878). In addition, the petitioners requested 
that FDA amend regulations in 21 CFR part 181 related to prior-
sanctioned uses of five ortho-phthalates and issue a new regulation in 
21 CFR part 189 prohibiting the use of eight specific ortho-phthalates 
in food contact articles. We declined to file these portions of the 
submission as a food additive petition because those requests were not 
within the scope of a food additive petition (81 FR 31877 at 31878). 
Consequently, those portions of the petition are not the subject of 
this notice.
    Following our May 20, 2016, announcement that we had filed the food 
additive petition, the petitioners provided supplementary information 
on October 8, 2016, and August 24, 2017 (Supp., October 8, 2016, and 
Supp., August 24, 2017, respectively). Included in the October 8, 2016, 
response, the petitioners also requested that FDA remove two substances 
(diphenylguanidine phthalate (CAS Reg No. 17573-13-6) and di(2-
ethylhexyl) hexahydrophthalate (CAS Reg No. 84-71-9)) from the 
petitioners' original list of 30 substances, stating that they are not 
ortho-phthalates (Supp., October 8, 2016). Consequently, the subject of 
the petition is limited to food additive regulations for 28 ortho-
phthalates.
    The 28 subject ortho-phthalates are regulated as food additives 
under the Federal Food, Drug, and Cosmetic Act (FD&C Act). The FD&C Act 
authorizes us to regulate ``food additives'' (see section 409(a) of the 
FD&C Act (21 U.S.C. 348(a))). The FD&C Act defines ``food additive,'' 
in relevant part, as any substance the intended use of which results or 
may reasonably be expected to result, directly or indirectly, in its 
becoming a component of food or otherwise affecting the characteristics 
of any food (see section 201(s) of the FD&C Act (21 U.S.C. 321(s))). 
Food additives can include both substances added directly to food and 
indirectly and can also include ``food contact substances.'' ``Food 
contact substances'' are substances intended for use in materials that 
come into contact with food, for instance in food packaging or 
manufacturing, but which are not intended to have any technical effect 
in the food (see Sec.  170.3(e)(3) (21 CFR 170.3(e)(3))). Food 
additives are deemed unsafe and prohibited except to the extent that we 
permit their use (see, e.g., sections 301(a), 301(k), and 409(a) of the 
FD&C Act (21 U.S.C. 331(a), 331(k), and 348(a))). The FD&C Act provides 
a process through which persons who wish to use a food additive may 
submit a petition proposing the issuance of a regulation prescribing 
the conditions under which the additive may be safely used (see section 
409(b)(1) of the FD&C Act). Such a petition is referred to as a ``food 
additive petition.''
    Under section 409(c)(3) of the FD&C Act, we will not establish a 
regulation for the use of a food additive if a fair evaluation of the 
data fails to establish that the proposed use of the food additive, 
under the conditions of use to be specified in the regulation, will be 
safe. Any food additive regulation that we issue authorizes a specific 
use of the substance. Our regulations, at Sec.  170.3(i), define safety 
as a reasonable certainty in the minds of competent scientists that the 
substance is not harmful under the intended conditions of use.
    The FD&C Act provides that we must, by regulation, prescribe the 
procedure by which a food additive regulation may be amended or 
repealed (see section 409(i) of the FD&C Act). Our regulation specific 
to the administrative actions for food additives provides that the 
Commissioner of Food and Drugs, on his own initiative or on the 
petition of any interested person, may propose the issuance of a 
regulation amending or repealing a regulation pertaining to a food 
additive (see Sec.  171.130(a) (21 CFR 171.130(a))). ``When a food 
additive petition seeks to amend an existing regulation, the petitioner 
must include `full information on each proposed change' '' (In re 
Natural Resources Defense Council, 645 F.3d 400, 403 (D.C. Cir. 2011) 
(quoting Sec.  171.1 (21 CFR 171.1))). Our regulation, at Sec.  
171.130(b), further provides that any such petition must include an 
assertion of facts, supported by data, showing that new information 
exists with respect to the food additive or that new uses have been 
developed or old uses abandoned, that new data are available as to 
toxicity of the chemical, or that experience with the existing 
regulation or exemption may justify its amendment or repeal. Under 
Sec.  171.1(c), a petition must include full reports of investigations 
made with respect to the safety of the food additive. With respect to 
the showing that is required, a petition that seeks to amend or repeal 
existing regulations based on safety must contain sufficient data to 
establish the existence of safety questions significant enough to 
support a finding that there is no longer a reasonable certainty of no 
harm from the currently approved uses (see generally section 409(c) of 
the FD&C Act) (describing the data requirements) and Sec. Sec.  171.1 
through 171.130 (food additive petition regulations)). Should FDA 
determine that there is sufficient data to raise safety concerns, FDA 
ensures that these concerns are addressed or that substances are no 
longer used as food additives. The FD&C Act makes clear that food 
additives introduced into commerce must be shown to be safe (see 
generally sections 402 (21 U.S.C. 342) and 409 of the FD&C Act). If FDA 
determines that a food additive is no longer safe, FDA will revoke the 
approval or otherwise ensure that the food additive is no longer in 
use.
    The petitioners requested that FDA amend parts 175, 176, 177, and 
178 to no longer provide for the food contact use of 28 specified 
ortho-phthalates. The ortho-phthalates and corresponding regulations in 
parts 175, 176, 177, and 178 are as follows:

21 CFR 175.105 Adhesives

    Butyl benzyl phthalate (Chemical Abstract Service (CAS) No. 85-68-
7), Butyl decyl phthalate (CAS No. 89-19-0), Butyl octyl phthalate (CAS 
No. 84-78-6), Butyl phthalyl butyl glycolate (CAS No. 85-70-1), 
Di(butoxyethyl) phthalate (CAS No. 117-83-9), Dibutyl phthalate (CAS 
No. 84-74-2), Dicyclohexyl phthalate (CAS No. 84-61-7), Di(2-
ethylhexyl) phthalate (CAS No. 117-81-7), Diethyl phthalate (CAS No. 
84-66-2), Dihexyl phthalate (CAS No. 84-75-3), Dihydroabietyl phthalate 
(CAS No. 26760-71-4), Diisobutyl phthalate (CAS No. 84-69-5), 
Diisodecyl phthalate (CAS No. 26761-40-0), Diisooctyl phthalate (CAS 
No. 27554-26-3), Dimethyl phthalate (CAS No. 131-11-3), Dioctyl 
phthalate (CAS No. 117-84-0), Diphenyl phthalate (CAS No. 84-62-8), 
Ethyl phthalyl ethyl glycolate (CAS No. 84-72-0), Methyl phthalyl ethyl 
glycolate (CAS No. 85-71-2), Octyl decyl phthalate (CAS No. 119-07-3), 
and Diallyl phthalate (CAS No. 131-17-9).

21 CFR 175.300 Resinous and Polymeric Coatings

    Dibutyl phthalate (CAS No. 84-74-2), Diethyl phthalate (CAS No. 84-
66-2), Diisooctyl phthalate (CAS No. 27554-26-3), Di(2-ethylhexyl) 
phthalate (CAS No. 117-81-7), Diisodecyl phthalate (CAS No. 26761-40-
0), Butyl phthalyl butyl glycolate (CAS No. 85-70-1), and Ethyl 
phthalyl ethyl glycolate (CAS No. 84-72-0).

21 CFR 175.320 Resinous and Polymeric Coatings for Polyolefin Films

    Butyl phthalyl butyl glycolate (CAS No. 85-70-1), Diethyl phthalate 
(CAS No. 84-66-2), and Ethyl phthalyl ethyl glycolate (CAS No. 84-72-
0).

[[Page 31068]]

21 CFR 176.170 Components of Paper and Paperboard in Contact With 
Aqueous and Fatty Foods

    Butyl benzyl phthalate (CAS No. 85-68-7), Dibutyl phthalate (CAS 
No. 84-74-2), Dicyclohexyl phthalate (CAS No. 84-61-7), and Diallyl 
phthalate (CAS No. 131-17-9).

21 CFR 176.180 Components of Paper and Paperboard in Contact With Dry 
Food

    Butyl benzyl phthalate (CAS No. 85-68-7) and Diallyl phthalate (CAS 
No. 131-17-9).

21 CFR 176.210 Defoaming Agents Used in the Manufacture of Paper and 
Paperboard

    Di(2-ethylhexyl) phthalate (CAS No. 117-81-7).

21 CFR 176.300 Slimicides

    Dibutyl phthalate (CAS No. 84-74-2), Didecyl phthalate (CAS No. 84-
77-5), and Dodecyl phthalate (CAS No. 21577-80-0).

21 CFR 177.1010 Acrylic and Modified Acrylic Plastics, Semirigid and 
Rigid

    Di(2-ethylhexyl) phthalate (CAS No. 117-81-7) and Dimethyl 
phthalate (CAS No. 131-11-3).

21 CFR 177.1200 Cellophane

    Castor oil phthalate with adipic acid and fumaric acid diethylene 
glycol polyester (CAS No. 68650-73-7), Castor oil phthalate, 
hydrogenated (FDA No. 977037-59-4), Dibutyl phthalate (CAS No. 84-74-
2), Dicyclohexyl phthalate (CAS No. 84-61-7), Di(2-ethylhexyl) 
phthalate (CAS No. 117-81-7), Diisobutyl phthalate (CAS No. 84-69-5), 
and Dimethylcyclohexyl phthalate (CAS No. 1322-94-7).

21 CFR 177.1210 Closures With Sealing Gaskets for Food Containers

    Diisodecyl phthalate (CAS No. 26761-40-0).

21 CFR 177.1460 Melamine-Formaldehyde Resins In Molded Articles

    Dioctyl phthalate (CAS No. 117-84-0).

21 CFR 177.1590 Polyester Elastomers

    Dimethyl phthalate (CAS No. 131-11-3).

21 CFR 177.2420 Polyester Resins, Cross-Linked

    Butyl benzyl phthalate (CAS No. 85-68-7), Dibutyl phthalate (CAS 
No. 84-74-2), and Dimethyl phthalate (CAS No. 131-11-3).

21 CFR 177.2600 Rubber Articles Intended for Repeated Use

    Amyl decyl phthalate (CAS No. 7493-81-4), Dibutyl phthalate (CAS 
No. 84-74-2), Didecyl phthalate (CAS No. 84-77-5), Diisodecyl phthalate 
(CAS No. 26761-40-0), Dioctyl phthalate (CAS No. 117-84-0), and Octyl 
decyl phthalate (CAS No. 119-07-3).

21 CFR 178.3740 Plasticizers in Polymeric Substances

    Butyl benzyl phthalate (CAS No. 85-68-7), Dicyclohexyl phthalate 
(CAS No. 84-61-7), Diisononyl phthalate (CAS No. 28553-12-0), Dihexyl 
phthalate (CAS No. 84-75-3), and Diphenyl phthalate (CAS No. 84-62-8).

21 CFR 178.3910 Surface Lubricants Used in the Manufacture of Metallic 
Articles

    Diisodecyl phthalate (CAS No. 26761-40-0), Di(2-ethylhexyl) 
phthalate (CAS No. 117-81-7), and Diethyl phthalate (CAS No. 84-66-2).

II. Evaluation of the Information Contained in the Petition

    The petition concludes that the authorized food contact uses for 
the 28 specified ortho-phthalates no longer meet the safety standard of 
``reasonable certainty of no harm'' and, therefore, the ortho-
phthalates should no longer be authorized under the existing 
regulations.
    The petition is premised on three distinct assertions (which for 
ease of reference we refer to as Assertions A, B, and C). Assertion A 
claims that the 28 subject ortho-phthalates are chemically and 
pharmacologically related and should therefore be treated as a class 
for purposes of evaluating their safety. Under Assertion B, the 
petition proposes applying a purported acceptable daily intake (ADI) 
for di(2-ethylhexyl) phthalate (DEHP) to all 28 ortho-phthalates that 
are the subject of the petition (i.e., the petition proposes applying 
the proposed ADI to the entire purported class). Assertion C states 
that the estimated daily intake (EDI) for the asserted class of ortho-
phthalates significantly exceeds the proposed ADI, thus rendering the 
purported class unsafe for their use as food contact substances.
    We address each assertion in turn.

A. Assertion A: Ortho-Phthalates Are a Class of Chemically and 
Pharmacologically Related Substances for Purposes of Determining Safety 
Pursuant to Section 409 of the FD&C Act and Sec.  170.18 (21 CFR 
170.18)

    The petition asserts that all 28 phthalates have similar chemical 
structures and similar or related pharmacological effects sufficient to 
be treated as one class of compounds for the purposes of evaluating the 
safety of these compounds. The petition states that such an approach 
would be consistent with section 409(c)(5)(B) of the FD&C Act, which 
directs FDA to consider, among other factors, the cumulative effect of 
an additive in the diet of man or animals, taking into account any 
chemically or pharmacologically related substance or substances in such 
diet, and Sec.  170.18(a), which states that food additives that cause 
similar or related pharmacological effects will be regarded as a class, 
and in the absence of evidence to the contrary, as having additive 
toxic effects and will be considered as related food additives.
1. Information Provided in the Petition To Support the 28 Ortho-
Phthalates as Chemically Related Substances
    The primary document the petition relies on to support the proposed 
grouping of the 28 ortho-phthalates as chemically related substances is 
the Organization for Economic Co-operation and Development (OECD) 
guidance on Grouping Chemicals (Ref. 1). The petition states that the 
OECD guidance lists five underpinning rationales in the category 
approach and asserts that the 28 ortho-phthalates ``meet'' two of the 
five rationales: (i) The common functional group rationale, and (iv) 
the likelihood of common precursors and/or breakdown products via 
physical or biological processes that result in structurally similar 
chemicals rationale.
    While we note that the OECD guidance does not establish criteria 
for chemical grouping (rather, it provides guidance on how to ensure 
that any chemical categories selected are sufficiently robust), in the 
discussion that follows we nevertheless address each of the OECD 
rationales adopted by the petition.
2. FDA's Evaluation of the Information Provided To Support the 28 
Ortho-Phthalates as Chemically Related Substances
    In support of the assertion that the 28 ortho-phthalates ``meet'' 
rationale (i) of the OECD guidance (i.e., share a common functional 
group), the petition states that all 28 phthalates share a general 1,2-
benzene diester chemical structural framework comprised of a benzene 
ring with two ester functional groups attached at adjacent carbons 
(referred to as ortho positions). A functional group is a part of an 
organic molecule that gives the molecule its characteristic physical 
and chemical

[[Page 31069]]

properties. The physical-chemical properties are one of many factors 
that may determine the toxicity of a substance for one or more given 
endpoints. Contrary to the petition's assertion that there is a similar 
structural framework shared by all 28 ortho-phthalates, we reviewed the 
chemical structures of the phthalates provided by the petitioner and 
determined that four of the 28 phthalates do not contain the framework 
described by the petition (i.e., do not contain the framework of 
sharing a general 1,2-benzene diester chemical structural framework 
comprised of a benzene ring with two ester functional groups attached 
at adjacent carbons). Specifically, two compounds, dimethylcyclohexyl 
phthalate and dodecyl phthalate, contain only one ester side chain and 
are, therefore, considered mono- (not di-) esters of 1,2-
benzenedicarboxylic acid and cannot be classified as ortho-phthalates. 
Two other phthalates (castor oil phthalate, hydrogenated and castor oil 
phthalate with adipic acid and fumaric acid-diethylene glycol) are 
polymeric in nature and, therefore, have many possible chemical 
structures (Ref. 3). Thus, the shared structural framework described in 
the petition is not, in fact, shared by these four ortho-phthalates.
    In addition, the petition does not address the structural 
differences in the ester side chains across the 28 phthalates. 
Structural differences across substances may impact whether they share 
characteristic physical and chemical properties (i.e., whether they 
possess a ``common functional group'' for the purposes of risk 
assessment). It is not appropriate to group substances into a class for 
the purposes of risk assessment based merely on the assertion that they 
have a common functional group. Rather, the common functional group 
rationale should be supported with a discussion of any structural 
variations within that common functional group definition and an 
explanation of why the chemical-structural differences between members 
would not impact the suitability of the category for risk assessment. 
Notably, OECD guidelines state that when structural variations across a 
category impact functionality, inclusion of such variances in a 
category should be limited (Ref. 1). Across the 28 phthalates, the 
number of carbon atoms in the ester side chains vary from one carbon 
atom (e.g., dimethyl phthalate (DMP)) to as many as 10 carbon atoms 
(e.g., diisodecyl phthalate (DIDP)). The ester side chains also differ 
by consisting of either branched or linear carbon chains, and varying 
degrees of saturation and oxidation (Ref. 3). Indeed, the chemical-
structural differences of the side chains among the ortho-phthalates 
are associated with differences in physical-chemical properties (e.g., 
volatility). For example, phthalates with ester side chains with more 
than eight carbon atoms are generally less volatile than phthalates 
with ester side chains with eight or fewer carbon atoms. Also, 
phthalates that contain straight ester side chains are generally less 
volatile than their branched-chain counterparts. The petition does not 
discuss these structural differences nor does the petition discuss 
whether structural variances across substances would still allow for 
those substances to be grouped with a ``common functional group'' for 
the purposes of a risk assessment. The petition, therefore, does not 
provide adequate evidence to demonstrate that the asserted shared 
structural similarity (i.e., a benzene ring attached to two ester 
functional groups) is sufficient to group the 28 substances into a 
single class.
    The petition also cites FDA's previous evaluation of long-chain 
perfluorinated compounds (PFCs) in support of utilizing the rationale 
of a common functional group to constitute the 28 phthalates as a class 
of chemically related substances. FDA's evaluation of long-chain PFCs 
was limited to a set of compounds with very specific structural 
similarities in their designated common functional group. Due to the 
structural similarity, and in the absence of contrary data, FDA 
determined that data demonstrating reproductive developmental toxicity 
for some long-chain PFCs was applicable to the three long-chain PFCs 
under evaluation (81 FR 5 at 7, January 4, 2016). Across the three 
compounds at issue in FDA's action on long-chain PFCs, the only 
variance in the common functional group was the number of carbons in 
the linear perfluorinated alkyl chain. This contrasts with the 28 
ortho-phthalates that are the subject of the current petition, where 
there are significant structural differences, and these differences 
result in large differences in chemical-structural properties (Refs. 3 
and 4). The classification of the subject ortho-phthalates as 
chemically related would not be akin to FDA's previous evaluation of 
long-chain PFCs.
    With respect to the petition's assertion that the ortho-phthalates 
subject to the petition ``meet'' rationale (iv) of the OECD guidance 
(i.e., share common precursors and/or breakdown products via physical 
or biological processes that result in structurally similar chemicals), 
the petition asserts that the ortho-phthalates share common metabolites 
and a common metabolic pathway (petition at 4).
    We address the assertion of common metabolites first. The petition 
provides a list of 10 ortho-phthalates and their metabolites to support 
the claim that there are common metabolites (Supp., August 24, 2017, at 
3-4). However, the data provided in the petition only demonstrate one 
common metabolite shared by only two parent phthalates (Ref. 4). As the 
petitioners were only able to provide metabolic data pertaining to 10 
of the 28 phthalates, and that data does not support that these 10 
ortho-phthalates share common metabolites, this information does not 
support common metabolites for the other 18 phthalates or the group of 
28 phthalates as a whole.
    In addition, the petition discusses a common metabolic pathway as 
support for the assertion that the subject 28 ortho-phthalates ``meet'' 
rationale (iv) of the OECD guidance. We note that rationale (iv) is not 
based on identification of shared steps in a metabolic pathway as 
described in the petition. Rather, the OECD guidance explains that this 
rationale is based on the applicability of data from a parent chemical 
to identify the hazards of its metabolites (or vice versa). The data 
between parent chemical and metabolite may be related because the 
toxicity induced by treatment with the parent chemical is likely due to 
the exposure to the metabolite(s). Likewise, under OECD rationale (iv), 
several different parent chemicals and their metabolite(s) could be 
considered as one class if a common metabolite is formed from these 
parent chemicals. Therefore, the assertion of a common metabolic 
pathway, without supporting information indicating that this pathway 
results in common metabolites, is not consistent with the approach to 
grouping in rationale (iv) of the OECD guidance.
    Furthermore, FDA does not agree that the petition has demonstrated 
that the subject ortho-phthalates share a common metabolic pathway. 
While the petition purports to identify three common steps associated 
with the metabolism of all 28 phthalates, it also acknowledges that not 
all 28 phthalates follow the purported metabolic pathway (see Supp., 
August 24, 2017). The petition notes that phthalates that lack longer 
alkyl side chains either do not or might not follow steps two 
(oxidation) or three (glucuronidation) of the purported common 
metabolic pathway (id. at 2). The data cited to support the list of 10 
ortho-phthalates and their metabolites provided in the petition also

[[Page 31070]]

demonstrate that for four phthalates (dimethyl phthalate (DMP), diethyl 
phthalate (DEP), butyl benzyl phthalate (BBP), and dicyclohexyl 
phthalate (DCHP)), only primary (hydrolytic) metabolites and no 
secondary (oxidized) metabolites were identified (see Supp., August 24, 
2017, at 3-4). These four phthalates therefore differ from other 
phthalates in both the metabolic pathway (only undergoing step one of 
three) and the resulting metabolites from that pathway. Similar trends 
between chain length and metabolism were also observed in the three 
biomonitoring articles cited in the petition, which identified excreted 
metabolites that may result from phthalate exposure. The phthalates 
with shorter side chain length (e.g., DMP, DEP, and BBP) exhibit 
hydrolytic monoesters as the major urinary metabolites; however, for 
phthalates with longer side chain length (e.g., DEHP, di-isononyl 
phthalate (DINP), and DIDP)), the hydrolytic monoesters are 
predominantly further metabolized before excretion in urine (Ref. 4). 
The existence of different metabolic pathways among phthalates is also 
demonstrated by a 2008 National Academy of Science (NAS) report (Ref. 
5). The NAS report notes that monoesters are the main detected 
metabolites of the low molecular weight phthalates, such as DEP and 
dibutyl phthalate (DBP). However, phthalate monoesters with five or 
more carbons in the ester side chain (i.e., not low molecular weight 
phthalates) are efficiently transformed further to oxidized metabolites 
arising mainly from oxidation at the terminal or penultimate carbon of 
the alkyl ester side chain. All of these examples demonstrate how the 
differences in chemical structure among phthalates studied give rise to 
differences in metabolism and resulting metabolites.
    In addition to side chain length and molecular weight, the other 
structural differences among the 28 ortho-phthalates described earlier 
in this subsection suggest that it is unlikely common metabolites and/
or breakdown products exist for the purported class. Phthalates with 
ester side chains containing different structural elements (e.g., 
double bonds, bulky side chain, and extra ester linkage) can be 
expected to metabolize differently than phthalates with saturated ester 
side chains. For example, available information suggests steric 
hindrance of the bulky side chain of dihydroabietyl phthalate may 
prevent hydrolysis (which is usually the first step in the metabolic 
pathway for phthalates with straight/branched side chains). The bulky 
side chain may prevent hydrolysis by blocking the access of the 
esterases (which are the enzymes that perform this reaction) to the 
ester linkage, therefore reducing the likelihood of this reaction 
occurring (Ref. 1). Alternatively, methyl phthalyl ethyl glycolate 
(MPEG), ethyl phthalyl ethyl glycolate (EPEG), and butyl phthalyl butyl 
glycolate (BPBG) have extra ester linkages in their side chains that 
could subject them to an additional hydrolysis step and produce 
glycolyl phthalate (GP) that is not expected to generate from ortho-
phthalates without the extra ester bond (e.g., DEHP) (Ref. 4). These 
examples further demonstrate how the chemical structure differences 
across these phthalates impact their metabolic pathway, and therefore 
result in different metabolites and/or breakdown products.
    As discussed earlier in this section, the petition does not support 
the assertion of a common metabolic pathway for the subject ortho-
phthalates. Furthermore, data cited in the petition as well as other 
available information contradict the claim of a common metabolite or 
group of metabolites for all 28 ortho-phthalates. The petition 
therefore does not justify the applicability of rationale (iv) of 
OECD's guidance for grouping chemicals to all 28 ortho-phthalates.
3. Information Provided in the Petition To Support the 28 Ortho-
Phthalates as Pharmacologically Related Substances
    In support of the proposed grouping of the 28 ortho-phthalates as 
pharmacologically related substances, the petition discusses the 2014 
report from the Chronic Hazard Advisory Panel on Phthalates and 
Phthalate Alternatives (the CHAP report) (Ref. 6) and the results of a 
literature search for toxicological information that yielded 
information on health effects for 12 of the 28 phthalates. The petition 
asserts that these data demonstrate that ``[w]hen ortho-phthalates have 
been studied, similar or related pharmacological effects have been 
identified affecting children's health'' (petition at 5). The petition 
also states that ``[r]eproductive, developmental, and endocrine 
toxicity effects were among the health endpoints identified for 
multiple compounds'' (petition at 5). The petition asserts that ``while 
the specific effects associated with ortho-phthalate exposure may vary 
among some studies, these effects nonetheless are pharmacologically 
related because they result from the effects of ortho-phthalates on the 
endocrine system'' (Supp., August 24, 2017, at 6). The petition also 
asserts that the 12 phthalates with available data have ``at least some 
evidence of endocrine disruption'' (id.) and that this information 
supports the conclusion that the 28 phthalates are therefore 
``pharmacologically related by endocrine disrupting effects'' (id. at 
13).
4. FDA's Evaluation of the Information Provided To Support the 28 
Ortho-Phthalates as Pharmacologically Related Substances
    In asserting that the 28 ortho-phthalates constitute a class of 
pharmacologically related substances for purposes of determining 
safety, the petition states that ``eleven ortho-phthalate have 
reproductive, developmental and endocrine health effects.'' The 
petition further points to ``adverse effects on endpoints relevant to 
children's health,'' as summarized in table 1, that the petition 
characterizes as showing ``similar toxic effects.'' However, 
reproductive, developmental, and endocrine effects are broad 
categorizations that cover a wide range of toxicological effects that 
are not necessarily similar and can be caused by a variety of different 
mechanisms. The petition's generalized assertion that all of the cited 
effects are pharmacologically related because they ``result from the 
effects of ortho-phthalates on the endocrine system'' (Supp., August 
24, 2017, at 6) does not acknowledge that the endocrine system is a 
generic term that encompasses multiple organs and multiple hormonal 
pathways. A substance that exhibits activity in one hormonal pathway 
may not have any effect on a different hormonal pathway, and disruption 
of different hormonal pathways may not result in common health outcomes 
(Ref. 4).
    The petition's assertion that all studied ortho-phthalates 
demonstrate similar effects on the endocrine system is also directly 
contradicted by data cited in the petition (see Supp., August 24, 
2017). One of the most commonly studied pharmacological effects for 
phthalates is antiandrogenicity; antiandrogens affect the endocrine 
system by modulating the production of testicular testosterone 
pertaining to the development of the male reproductive system. The data 
cited in the petitioners' literature search indicates that, among the 
12 phthalates with available toxicological information, 7 phthalates 
exhibit antiandrogenic effects (i.e., butyl benzyl phthalate (BBP), 
diisobutyl phthalate (DiBP), DBP, dicyclohexyl phthalate (DCHP), 
dihexyl phthalate (DHP), DEHP, and diisononyl phthalate (DINP)) (see 
Supp., August 24, 2017, Appendix B). Importantly, four of

[[Page 31071]]

the phthalates (i.e., dimethyl phthalate (DMP), diethyl phthalate 
(DEP), di-n-octyl phthalate (DnOP), and DiDP) have been shown to not 
exhibit antiandrogenic effects. As the petitioners provide data for 
only 12 of the 28 ortho-phthalates, and those data do not support the 
12 ortho-phthalates as having similar pharmacological-effects on the 
endocrine system, this information does not support that the remaining 
16 ortho-phthalates also exhibit similar pharmacological effects (see 
Supp., August 24, 2017). Similarly, the data do not support the notion 
that the group of 28 ortho-phthalates as a whole consists of phthalates 
with similar pharmacological effects (see Ref. 4).
    Furthermore, the petition's approach to class grouping is not 
consistent with the approach taken by other regulatory and scientific 
bodies. Other regulatory and scientific bodies have not grouped 
phthalates based on broad criteria such as non-specific effects on the 
endocrine system. Instead, other regulatory and scientific bodies have 
focused on common health outcomes that result from a discrete mechanism 
of action. Specifically, reports from regulatory or scientific bodies 
cited in the petition (i.e., the 2014 CHAP report and the NAS report) 
as well as other reviews conducted by OECD (Ref. 7), the European Food 
Safety Authority (EFSA) (Ref. 8), and the Government of Canada (Ref. 
9), grouped small subsets of ortho-phthalates for cumulative risk 
assessment based on specific related health (i.e., pharmacological) 
effects. These assessments relied on defined toxicological endpoints 
with a common mechanism of action to conduct grouping, and also relied 
on specific and well-defined similarities in chemical structure. For 
example, the CHAP report concluded that phthalates with three to eight 
carbon atoms in the backbone of the alkyl side chain have the same 
endpoint of antiandrogenicity, while phthalates with alkyl side chains 
having carbon atoms outside of this range are not antiandrogenic and 
therefore should not be considered in the same class for a safety 
assessment (Ref. 6). The CHAP report did not group together these 
different categories of phthalates. Similarly, the NAS report noted 
that phthalates with ester chains of four to six carbon atoms are most 
potent in causing effects on the development of the male reproductive 
system (i.e., antiandrogenicity), but phthalates with shorter or longer 
chains typically exhibit less severe or no effects (see Ref. 5). While 
the petition states that the NAS report ``recommends that effects of 
ortho-phthalates should be considered additive'' (petition at 6), the 
relevant point in the NAS report only pertains to those ortho-
phthalates that cause common adverse outcomes of antiandrogenicity 
(Ref. 5). The NAS report similarly did not group together the different 
categories of phthalates.
    Additionally, a 2004 OECD report grouped phthalates for the purpose 
of assessing human health and ecotoxicity endpoints but only did so 
with respect to seven high molecular weight phthalates consisting of 
esters with an alkyl carbon backbone with seven carbon atoms or 
greater. OECD noted that the seven phthalates in the group produce 
little (if any) effects of developmental or reproductive toxicity, and 
only phthalates with alkyl carbon backbones of four to six carbon atoms 
cause adverse effects in development and reproduction (Ref. 4).
    Since the petition was filed, EFSA and the Government of Canada 
also conducted their own assessments of phthalates. Both regulatory 
bodies grouped phthalates using defined toxicological endpoints. EFSA 
considered five ortho-phthalates commonly used in food contact 
materials, but only grouped four based on the common mechanism of fetal 
testosterone reduction and excluded the fifth (i.e., DIDP) due to not 
sharing this effect (Ref. 8 at 1). The Government of Canada conducted a 
``screening assessment'' of 28 ortho-phthalates but only grouped those 
with ester side-chains of three to seven carbons for the purposes of 
cumulative risk assessment based on the observation of antiandrogenic 
effects for this group (Ref. 9 at 7). Thus, the approach proposed in 
the petition (i.e., grouping a large number of phthalates together 
despite data showing that those phthalates do not share the same toxic 
endpoints), is not consistent with the approach taken in the scientific 
literature, including reports cited in the petition. The petition also 
cites FDA's previous decision on PFCs as support for grouping the 28 
ortho-phthalates as pharmacologically related substances. As discussed 
previously in section II.A.2, our grouping of long-chain PFCs was 
limited to a strict subset of structurally similar compounds, 
distinguishable from the wide structural differences in the 28 ortho-
phthalates that are the subject of the current petition.
    The petition also specifically invokes Sec.  170.18 as support for 
its proposed class grouping approach. In accordance with Sec.  
170.18(a), food additives that cause similar or related pharmacological 
effects will be regarded as a class, and in the absence of evidence to 
the contrary, as having additive toxic effects and will be considered 
as related food additives. Our regulation, at Sec.  170.18(b), states 
that tolerances established for such related food additives may limit 
the amount of a common component that may be present or may limit the 
amount of biological activity that may be present, or may limit the 
total amount of related food additives that may be present. Section 
170.18(c) provides that where food additives from two or more chemicals 
in the same class are present in or on a food, the tolerance for the 
total of such additives shall be the same as that for the additive 
having the lowest numerical tolerance in this class, unless there are 
available methods that permit quantitative determination of the amount 
of each food additive present or unless it is shown that a higher 
tolerance is reasonably required for the combined additives to 
accomplish the physical or technical effect for which such combined 
additives are intended and that the higher tolerance will be safe 
(Sec.  170.18(c)).
    The petition asserts that Sec.  170.18 is applicable to the 
evaluation of the 28 ortho-phthalates subject to the petition. 
Specifically, the petition asserts that the toxicokinetic and 
toxicodynamic properties of the ortho-phthalates ``may be comparable'' 
and ``similar or related pharmacological effects have been identified 
affecting children's health.'' The petition further states that 
``[r]eproductive, developmental and endocrine toxicity effects were 
among the health endpoints identified for multiple compounds and at low 
exposure.'' Based on what the petition describes as ``similar toxicity 
effects'' from 13 ortho-phthalates, the petition states that ortho-
phthalates are ``pharmacologically related food additives for purposes 
of 21 CFR 170.18.'' (Note that the August 2017 supplement refers to 
data only for 12 ortho-phthalates). Further, the petition states that 
``we found several publications reporting on additive mixtures of four 
and five ortho-phthalates on developmental and reproductive endpoints'' 
and that the NAS report ``recommends that effects of ortho-phthalates 
should be considered additive'' (petition at 6).
    The petition has not demonstrated that Sec.  170.18 is applicable 
because the petition has not shown that the 28 ortho-phthalates cause 
similar or related pharmacological effects. By its terms, Sec.  170.18 
only provides that food additives are to be regarded as a class if it 
has been shown that the food additives cause similar or related

[[Page 31072]]

pharmacological effects. However, as the petitioners concede, they only 
have submitted data on the effects of 12 of the 28 ortho-phthalates 
that are the subject of the petition and have not submitted data 
addressing the effects of 16 of the 28 ortho-phthalates. Furthermore, 
as discussed in the previous paragraphs, the data for the 12 phthalates 
provided by the petition do not demonstrate that all 12 phthalates have 
similar or related pharmacological effects; therefore, this data also 
does not support that all 28 ortho-phthalates have similar or related 
pharmacological effects. Thus, the petition has not put forward the 
threshold evidence that is necessary to apply Sec.  170.18.
    In arguing for grouping all 28 phthalates into one class, the 
petition also points to section 409(c)(5)(B) of the FD&C Act. The FD&C 
Act provides that a food additive cannot be approved for use unless the 
data presented to FDA establish that the food additive is safe for that 
use (section 409(c)(3)(A) of the FD&C Act). To determine whether a food 
additive is safe, section 409(c)(5) of the FD&C Act requires FDA to 
consider among other relevant factors the following: (1) Probable 
consumption of the additive; (2) the cumulative effect of such additive 
in the diet of man or animals, taking into account any chemically or 
pharmacologically related substance or substances in such diet; and (3) 
safety factors recognized by experts as appropriate for the use of 
animal experimentation data (section 409(c)(5) of the FD&C Act). As a 
preliminary matter, the petition has not presented evidence to show 
that section 409(c)(5)(B) of the FD&C Act is even applicable to the 
proposed class grouping. With respect to section 409(c)(5)(B) of the 
FD&C Act, we note as a preliminary matter that the petition has not 
presented sufficient evidence to show that all 28 ortho-phthalates are 
in fact chemically or pharmacologically related substances (see 
discussion in the previous paragraphs). As an additional matter, we 
note that section 409(c)(5)(B) of the FD&C Act does not direct FDA to 
group food additives in a class in the manner proposed in the petition. 
If it is established that substances are chemically or 
pharmacologically related to a food additive under consideration, FDA 
is directed to ``tak[e] into account'' such substances in considering 
the cumulative effect of the food additive in the diet of man or 
animals. Chemically or pharmacologically related substances can be 
taken into account for this purpose in any number of scientifically 
valid ways that are distinct from the class grouping approach proposed 
by the petition (e.g., considering chemically related substances in an 
exposure analysis or considering toxicity data from one 
pharmacologically related substance to evaluate possible toxic effects 
of another pharmacologically related substance, as appropriate). To the 
extent that the petition interprets section 409(c)(5) of the FD&C Act 
to compel FDA to adopt the petition's approach to class grouping, the 
petition is incorrect. The petition proposes grouping a chemically 
diverse group of substances together, applying a proposed ADI value for 
one substance to all the substances in the purported class, and 
comparing the exposure of all the substances against that single 
proposed ADI. The FD&C Act sets forth no requirement to analyze the 
safety of a food additive in this manner.
5. Conclusion for Assertion A: Ortho-Phthalates Are Not a Class of 
Chemically and Pharmacologically Related Substances for Purposes of 
Determining Safety Pursuant to Section 409 of the FD&C Act and Sec.  
170.18
    After our review of the relevant information, we conclude that the 
petition's arguments for treating the 28 ortho-phthalates as a class 
are not supported. The petition points to two rationales in the OECD 
guidance to support its argument but fails to demonstrate that grouping 
all 28 phthalates is in fact consistent with those rationales. The 28 
phthalates do not have a common functional group, do not have similar 
or related pharmacological effects, do not share a ``common metabolic 
pathway'' or even a common mechanism of action, and do not have effects 
on the same or similar target or system (i.e., the reproductive system 
of male rodents). To the extent the petition suggests that the proposed 
class grouping is required by section 409(c)(5)(B) of the FD&C Act and/
or Sec.  170.18, the petition is incorrect.

B. Assertion B: The ADI for DEHP Should Be Assigned to All 28 Ortho-
Phthalates

    To establish with reasonable certainty that a food additive is not 
harmful under its intended conditions of use, FDA considers the 
projected human dietary exposure to the food additive, the additive's 
toxicological data, and other available relevant information (such as 
published literature). To determine safety, one approach FDA may 
utilize is to compare the EDI of the food additive to an ADI level 
established by appropriate toxicological data. Following the argument 
contained in Assertion A that all 28 phthalates should be grouped as a 
single class, the petition asserts that a single ADI should be 
established for the class and also asserts that the ADI should be used 
to set the upper exposure limit for cumulative exposure to all 28 
phthalates.
1. Information Provided in the Petition To Support Assertion B
    To establish a proposed ADI for all 28 ortho-phthalates, the 
petition cites no observed adverse effect levels (NOAELs) for specific 
phthalates that are published in a variety of sources. The petition 
then picks a NOAEL for DEHP as the basis to derive an ADI for the 
purported class because it is the lowest of the listed NOAEL values. 
The petition then proposes safety factors to be applied to that NOAEL 
to derive the proposed ADI. In the discussion that follows, we evaluate 
the petition's approach for deriving the proposed ADI for DEHP, as well 
as the applicability of the proposed ADI to all 28 phthalates.
2. FDA's Evaluation of the Information Provided To Support Assignment 
of the ADI for DEHP to All 28 Ortho-Phthalates
    An ADI is the amount of a substance that is considered safe to 
consume each day over the course of a person's lifetime (Ref. 10). The 
ADI is typically based on an evaluation of toxicological studies to 
determine the highest appropriate experimental exposure dose level in 
animal studies that was shown to cause no adverse effect (also known as 
the no-observed-adverse-effect level, or NOAEL), multiplied by an 
appropriate safety factor (Ref. 10). Accordingly, the lower the NOAEL 
for a specific substance, the lower the resulting ADI for the 
substance. A calculated dietary exposure to the food additive (i.e., 
the estimated daily intake, or EDI) at or below the ADI is considered 
consistent with a reasonable certainty of no harm (Ref. 10). Therefore, 
a lower ADI requires a lower dietary exposure to the food additive to 
meet the burden of safety than a food additive with a higher ADI.
    To establish a proposed ADI for all 28 phthalates, the petition 
identifies NOAELs for nine phthalates that are included in the 2014 
CHAP report. The petition also identifies NOAELS for 15 phthalates that 
are included in the 1973 paper by Shibko, et al. (the 1973 paper, Ref. 
2). Together, this makes for a total of 24 NOAEL values for 17 
different phthalates. The petition does not provide NOAEL values for 
the remaining 11 phthalates that are the subject of the petition. The 
petition adopts the NOAEL provided for DEHP in the 2014 CHAP report 
because it was

[[Page 31073]]

the lowest of the cited values. To calculate the ADI, the petition 
applies a total safety factor of 1,000 to the cited NOAEL for DEHP, 
resulting in a proposed ADI of 3 micrograms per kilogram of body weight 
per day ([micro]g/kg bw/d) (petition at 11). However, the petition 
fails to provide any discussion or supplementary information to justify 
why any of these NOAEL values are appropriate for assessing risk of 
dietary exposure to ortho-phthalates.
    Our regulation, at Sec.  171.1(c), requires that a petition provide 
full reports of investigations made with respect to the safety of a 
food additive and not omit, without explanation, any reports of 
investigations that would bias an evaluation of the safety of the food 
additive. Such information is necessary so that FDA can independently 
evaluate and verify the relevant evidence. However, the petition merely 
lists values published in the CHAP report and the 1973 paper and does 
not evaluate the underlying evidence supporting the NOAEL values listed 
in those publications. Although the CHAP report is the result of 
considerable scientific analysis, it was not designed to assess the 
safety of food additive uses and does not provide a comprehensive 
discussion of evidence that would be sufficient to permit FDA to 
independently evaluate the evidence used to determine the NOAELs (Refs. 
10 and 11). Similarly, the 1973 paper provides only a truncated summary 
of literature available at the time of publication. Furthermore, the 
NOAELs in the 1973 paper were derived from either subacute or chronic 
animal studies, which only tested phthalates in weanling animals. These 
studies have limitations to assess antiandrogenicity as an endpoint 
(Refs. 4 and 6) and therefore are not appropriate to determine NOAELs 
for those phthalates that are known antiandrogens. Most importantly, 
the petition does not provide additional information that would allow 
FDA to fill the gaps.
    Typically, to determine appropriate NOAEL values, FDA considers a 
wide array of information, including the results of a comprehensive 
literature search, so that we can evaluate the most relevant studies 
and their methods, determine the most appropriate endpoint(s), and 
consider the appropriateness of the animal species selected for study 
(Refs. 10 and 11). However, the petition provides no such wide array of 
information with respect to the NOAEL. Rather, the petition merely 
lists the NOAEL value that is included in the CHAP report. The petition 
does not explain why this NOAEL for DEHP is appropriate for human risk 
assessment of dietary exposure. FDA is aware of the existence of 
studies on DEHP in non-human primates that identify NOAELs based on 
testicular effects that are at least two orders of magnitude higher 
than the level derived from studies conducted in rats cited by the 
petitioners (Refs. 12 to 15). Results in primates are generally 
considered more applicable to human risk assessment than results in 
rats, and these non-human primate studies were not included in the 
assessment in the CHAP report. As the petition does not address these 
studies or others that may impact the appropriateness of the cited 
NOAEL for human risk assessment of exposure to DEHP itself, the 
petition has not provided an adequate scientific rationale to justify 
the selected NOAEL for DEHP. Thus, the information submitted in the 
petition does not amount to a full report of investigations made with 
respect to safety, as required by Sec.  171.1(c), and the petition has 
not provided adequate scientific justification for the proposed NOAEL 
for DEHP.
    In addition to lacking sufficient support for the appropriateness 
of the selected NOAEL for evaluation of DEHP itself, the petition also 
lacks scientific support to justify applying the cited NOAEL for DEHP 
to all 28 ortho-phthalates. Although the petition cites the 1973 paper 
in support of applying a single substance's ADI to a group of 
phthalates, that paper discussed this approach based on the assumption 
that the toxicity for an ortho-phthalate may be related to the toxicity 
of the alcohol moiety (which is not antiandrogenic). The paper 
describes the alcohol moiety as a common metabolite for these 
substances, when in fact more current scientific information does not 
support that all 28 phthalates share a common metabolite. Accordingly, 
the recommendation in the 1973 paper is based on a scientific 
assumption that has since been contradicted. The 1973 paper therefore 
does not support the petition's requested action.
    Furthermore, the petition's proposed NOAEL for DEHP is based on an 
antiandrogenic endpoint. Recent scientific data, including information 
contained in the petition, demonstrate that not all phthalates are 
antiandrogenic. Recent data also demonstrate that antiandrogenicity may 
not be the most sensitive endpoint for all 28 ortho-phthalates, 
including some which also demonstrate antiandrogenicity (Ref. 4). 
NOAELs serve to identify the highest dosages of a particular substance 
in which toxic effects were not observed, but a NOAEL is not useful for 
determining safe exposure levels if it is not in fact based on toxic 
effects that may result from the substance. Also, as discussed in our 
response to Assertion A, the petition has not provided sufficient 
information to demonstrate that the pharmacological effects for all 28 
ortho-phthalates are similar or related. Therefore, it is not 
appropriate to apply a NOAEL based on the effect of antiandrogenicity 
to substances that are not antiandrogenic.
    In addition, with respect to converting the NOAEL to an ADI, the 
petition has not sufficiently supported the application of additional 
safety factors to the proposed NOAEL. In general, the use of a safety 
factor is intended to provide an adequate margin of safety for 
consumers by accounting for variability, such as differences between 
animals and humans (i.e., interspecies variability) and differences in 
sensitivity among humans (i.e., intraspecies variability) (Ref. 10). In 
accordance with Sec.  170.22, a safety factor of 100 will be used as a 
general rule in applying animal test data for the purposes of safety 
assessment for human consumers.
    However, exceptions to a safety factor of 100 are permitted in 
accordance with the nature and extent of data available and the 
circumstances of use of the food additive. For reproductive and 
developmental endpoints, FDA recommends the use of a safety factor of 
1,000 if the observed effects are severe or irreversible (e.g., 
decrease in the number of pups born live) (Ref. 10). Otherwise, FDA 
recommends a safety factor of 100. Additional adjustments may be 
appropriate when considered on a case-by-case basis (Refs. 4 and 11). 
The petition proposes dividing the cited NOAEL for DEHP by a safety 
factor of 1,000 to derive the proposed ADI. In support of the 
application of an additional 10x safety factor for the severity of 
effects, the petition makes a general assertion that ``developmental, 
reproductive and endocrine toxicity effects observed after prenatal and 
postnatal exposure also represent severe findings due to their likely 
irreversibility'' (Supp., August 24, 2017, at 9). Because the petition 
does not provide critical information about the studies (e.g., study 
design, animal species, animal numbers, dosing regime, dosing duration, 
examined endpoints, and statistical methods) to support the selected 
NOAEL for DEHP, the petition fails to adequately justify an exception 
to a safety factor of 100. This absence of information means that the 
proposed ADI for DEHP lacks scientific justification.

[[Page 31074]]

3. Conclusion for Assertion B: The ADI Proposed in the Petition Should 
Not Be Assigned to All 28 Ortho-Phthalates
    The petition has not provided the requisite information for either 
the selected NOAEL or the proposed ADI for DEHP. Similarly, the 
petition has not justified the application of the proposed ADI for DEHP 
to all 28 phthalates. To the extent that the petition relies on Sec.  
170.18 for applying a single ADI to all 28 phthalates, there is no 
support for such an approach because, as discussed in section II.A, the 
petition has not demonstrated that the criteria in Sec.  170.18 for 
treating food additives as a class are met.

C. Assertion C: The EDI for Ortho-Phthalates Exceeds the Proposed ADI 
and, Therefore, the Intentional Use of Ortho-Phthalates as Food Contact 
Substances Are Not Safe

    The argument in Assertion C is predicated on the underlying premise 
of the petition (i.e., the establishment of a single class for all 28 
phthalates). The petition asserts that certain published dietary 
exposure estimates for several of the individual subject phthalates, as 
well as the cumulative exposure to all 28 phthalates, significantly 
exceeds the ADI proposed in the petition for the purported class. From 
this comparison between published dietary exposure estimates and the 
proposed ADI, the petition states that ``the intentional use of ortho-
phthalates as food contact substances are not safe as defined by FDA's 
regulations'' (petition at 11).
1. Information Provided in the Petition To Support Assertion C
    The petition concedes that it does not provide exposure data for 
all 28 ortho-phthalates, asserting that a cumulative exposure to all 28 
phthalates cannot be determined based on the limited information 
available (see petition at 14). Instead, the petition compares 
estimated exposures to individual phthalates for specific 
subpopulations (as reported in various published data sources) to the 
proposed ADI for the purported class. Specifically, the petition 
asserts that the following dietary exposures are all greater than the 
proposed ADI for the purported class: The average women's dietary 
exposures to DINP and DIDP, as estimated in the CHAP report; the 95th 
percentile exposure for women to DEHP, as listed in the CHAP report; 
and the infant exposure to DEHP, as listed in a 2013 publication by 
Schecter et al. (Ref. 16). Turning to biomonitoring data, the petition 
also relies on this type of data to assert that the following 
additional exposures exceed the proposed ADI: The median and 95th 
percentile exposures for pregnant women and women of reproductive age 
to DEHP; and the 95th percentile exposures for pregnant women and women 
of reproductive age to DBP and DINP. This biomonitoring data comes from 
National Health and Nutrition Examination Survey (NHANES) survey 
results covering different years.
    We have previously discussed in sections II.A and II.B that the 
petition does not demonstrate that all 28 phthalates should be 
considered as a single class, and that the petition does not 
demonstrate that the proposed ADI for DEHP should be applied to the 
purported class. Therefore, our discussion below is not focused on 
comparing published exposure estimates for members of a purported 
ortho-phthalate class to a proposed ADI for that purported class. 
Rather, our discussion below evaluates the relevance of the cited data 
for estimating U.S. dietary exposure.
2. FDA's Evaluation of the Information Provided To Support Assertion C
    Food surveys, total diet studies, and human biomonitoring studies 
can all be part of an appropriate postmarket approach to determine 
dietary exposure for a substance that is already authorized for use as 
a food contact substance. However, many factors should be addressed to 
determine the suitability of any given dataset for determining dietary 
exposure. These factors can include suitability of sample preparation 
and data analysis, relevance of the data to the current market, 
specific population or geographic region, and whether it is 
sufficiently robust in both sample breadth (number of different types 
of foods sampled) and size (number of samples within a given food type) 
to be representative. In determining sample breadth, it may be 
appropriate to consider dietary exposure from a number of sources, such 
as uses that are authorized through the food contact notification 
process or food additive regulations and uses that are determined to be 
generally recognized as safe. Rather than analyze the relevance or 
suitability of the data cited, the petition simply lists any reported 
value from any dataset that is higher than the proposed ADI for the 
purported class.
    In general, dietary exposure values for a substance can be 
calculated using the level of the substance in food (taken from food 
surveys) and the daily food consumption rate (taken from food 
categorization systems). Food categorization systems divide the daily 
diet into distinct food types. This allows for surveying consumption of 
individual foods within those food types to be representative of 
exposure from overall consumption of those types of foods by the 
consumer. Food categorization systems provide for a tiered grouping of 
foods first based on a broad category (i.e., aquatic animals, land 
animals, plants, and other) all the way down to differences in 
processing (e.g., pasteurized or not pasteurized). These subdivisions 
allow for assignment of foods to a specific category for purposes of 
determining consumption rates of individual foods or larger food 
categories (e.g., all forms of dairy). Food surveys analyze the foods 
in the average diet of the whole population in a country (i.e., Total 
Diet Study (TDS) approach), or by analyzing select foods in the diet of 
a given population within a limited geographical area (e.g., the data 
in Schecter et al. (Ref. 16)). When determining whether a particular 
food survey is relevant and suitable for estimating levels of a 
substance in the total diet of a specific population, multiple factors 
should be considered to ensure scientific validity. These include, 
among others, whether the types of food, number of samples, and 
location of where food samples were obtained represent the diet of the 
target population, the appropriateness of the sample preparation and 
analytical methods, and whether a particular food categorization system 
is suitable to calculate exposure from the levels in food obtained from 
the survey.
    As previously stated, the petition relies on dietary exposure 
estimates that are provided in the CHAP report and Schecter et al. 
study. Although the CHAP report described and supported its dietary 
exposures estimates, there are still data gaps that raise questions 
about the petition's reliance on estimated dietary exposure values that 
are derived from the CHAP report. Specifically, the CHAP report relies 
on a TDS conducted in the United Kingdom (UK). This survey may not 
reflect U.S. dietary exposures, as different supply chains in different 
continents may result in different exposures. In addition, this data 
was almost 10 years old at the time the petition was submitted to FDA 
(see Ref. 6). Further, while the data in Schecter et al. is from a 
segment of the U.S. population (i.e., food sampled in Albany, NY, in 
2011), the dataset is less robust than the UK TDS. Schecter et al. 
analyzed for 9 phthalates in 72 commonly consumed foods, compared with 
the UK TDS that analyzed for 15 phthalate diesters and 9 phthalate 
esters, as well as phthalic acid in 261

[[Page 31075]]

retail food items in the UK. The studies also differ in the food 
categorization systems used to calculate exposure. An appropriate way 
to utilize the Schecter et al. study in the context of the CHAP report 
would be to examine if the results from these studies reinforce each 
other while accounting for the different parameters used by each. 
However, the petition provides no such examination or analysis and 
instead adopts any exposure to any phthalate from either analysis that 
is over the proposed ADI for the purported class. As such, the petition 
does not address the results from the CHAP report and the Schecter et 
al. study that are contradictory for select reported values. For 
example, the average exposure to DEHP for women in the CHAP report is 
4.8 [micro]g/kg bw/d (over the ADI of 3 [micro]g/kg bw/d proposed in 
the petition), while the average exposure to DEHP for adults (which 
should be comparable to women) in Schecter et al. is only 0.67 
[micro]g/kg bw/d (lower than the proposed ADI) (Refs. 6 and 16). 
Further analysis is needed to determine which, if either, of these 
contradictory values is suitable for the purpose of a safety 
assessment.
    We note that other available dietary survey/TDS data that are only 
briefly discussed in the petition (Canadian TDS and Australian TDS 
studies published in 2015 and 2014, respectively) could potentially 
address several of the data gaps. These data sets are more recent than 
the CHAP report and Schecter et al. study. They are also more robust 
than the Schecter et al. study. In addition, the Canadian TDS may be 
more directly relevant to the U.S. population than the UK TDS used in 
the CHAP report, in that Canadian and U.S. diet and packaging and 
processing supply chains may be more similar than UK and U.S. diet and 
packaging and processing supply chains. Although exposure estimates 
were not calculated in the Canadian and Australian TDS reports, the 
data from these studies could be applied to an appropriate food 
categorization system and used to calculate exposure estimates. The 
petition provides no such examination or analysis.
    With respect to the petition's reliance on biomonitoring data, we 
note that biomonitoring studies are used in assessing human exposure to 
a chemical by measuring the level of the biomarker (e.g., the chemical 
itself, its metabolite(s), or reaction product(s) in a biological 
matrix such as human blood or urine) from individuals and then 
analyzing the data collectively. The exposure values calculated from 
biomonitoring data include contributions not just from the ingestion of 
food (i.e., diet), but also from inhalation and dermal contact. 
However, using exposure values from biomonitoring studies without 
discussion and supporting information to determine the specific 
contribution from dietary sources is not appropriate in the context of 
a food additive petition, as the overall exposure value in a 
biomonitoring study may not be an appropriate proxy for the probable 
dietary exposure value (see section 409(c)(5)(B) of the FD&C Act 
(directing that FDA consider the cumulative effect of a food additive 
``in the diet of man or animals'') (emphasis added); 21 CFR 171.3(i)(2) 
(providing that in determining a food additive's safety ``the 
cumulative effect of the substance in the diet'' shall be considered) 
(emphasis added)).
    As to the specific biomonitoring data cited in the petition, the 
NHANES data and resultant exposure values are relevant in that they 
reflect relatively recent dietary patterns and are generated from the 
U.S. population. However, the approach of directly comparing 
biomonitoring-based exposure values to a proposed ADI for the purpose 
of assessing the safety of a food additive is not scientifically 
appropriate. As discussed in the previous paragraph, relying on 
biomonitoring data alone does not differentiate the amount of exposure 
that results from the diet compared to environmental and other sources. 
We note that NHANES and other biomonitoring data do not differentiate 
specific sources or routes of exposure, such as exposure from dietary 
sources. Because the petition does not account for these limitations by 
addressing how the biomonitoring data accounts for dietary exposure, 
the petition's direct comparison of biomonitoring-based exposure values 
to the purported ADI is scientifically flawed.
3. Conclusion for Assertion C: The EDI Approach in the Petition Is Not 
Valid
    As discussed in sections II.A and II.B, the petition does not 
support the establishment of a single class for all 28 phthalates, nor 
does it support the proposed ADI for DEHP or the application of the 
proposed ADI to the purported class. As Assertion C is predicated on 
Assertions A and B, the approach in Assertion C of comparing published 
exposure estimates to the proposed ADI for the purported class is 
therefore scientifically flawed. In addition, the petition does not 
adequately support its proposed exposure estimates. The petition does 
not justify its approach of adopting any reported single phthalate 
exposure estimate that is over the proposed ADI for the purported 
class. Specifically, the petition does not account for: (1) The 
imprecision of relying on exposures estimates derived from 
biomonitoring studies to assess dietary exposure; (2) the diverse 
parameters used in the cited dietary exposure analyses to determine 
which analysis, if any, most accurately reflects true U.S. dietary 
exposure; and (3) the contradiction in reported dietary exposure values 
between those analyses.

D. Summary Conclusion of FDA's Review of the Petition

    As discussed in section II.A, the petition does not support the 
establishment of a proposed class for all 28 phthalates. In light of 
the differences in the chemical structures and toxicity profiles among 
the 28 phthalates, the petition does not provide adequate scientific 
support for grouping chemicals for the purpose of assessing safety. 
Section II.B explains that the petition's approach of applying the 
proposed ADI to the purported class is also flawed, in that the 
proposed ADI is not adequately supported, and it is not scientifically 
appropriate to apply the proposed ADI to the purported class of 28 
ortho-phthalates. Section II.C explains that, as it is not valid to 
group all 28 ortho-phthalates as a class of chemically or 
pharmacologically related substances for the purpose of assessing 
safety, it is also not valid to compare exposures for these ortho-
phthalates to a proposed ADI for the purported class. In addition, the 
petition's approach for estimating exposure to ortho-phthalates is not 
adequately supported. For all these reasons, the petition does not 
contain sufficient data to support a finding that there is no longer a 
reasonable certainty of no harm from the currently approved uses.
    As an additional matter, based on the information currently 
available to FDA, we do not have a basis to conclude that dietary 
exposure levels from approved ortho-phthalates exceed a safe level. As 
new information becomes available to us, we will continue to examine 
such data as appropriate to assess whether there remains a reasonable 
certainty of no harm.

III. Comments on the Filing Notice

    Overall, we received multiple comments in support of the 
petitioners' request that we amend or revoke the specified regulations 
to no longer provide for the food contact use of the 28 ortho-
phthalates. Other comments, such as those from a coalition composed of 
trade organizations, materials suppliers, compounders, formulators, 
molders, and fabricators, oppose the

[[Page 31076]]

petition. Additionally, some comments addressed matters that are 
outside the scope of the petition, and some comments were duplicate 
submissions.
    In this section, we discuss the issues raised in the comments. We 
preface each comment discussion with a numbered ``Comment'' and each 
response by ``Response'' to make it easier to identify comments and our 
responses. We have numbered each comment to help distinguish among 
different topics. The number assigned is for organizational purposes 
only and does not signify the comment's value, importance, or the order 
in which it was received.
    (Comment 1) Many comments, primarily form letters, stated that 
phthalates are hormone disrupting chemicals linked to a wide variety of 
adverse health outcomes such as: Reduced anogenital distance in male 
infants; reduced sperm quality; infertility; genital birth defects in 
boys; impaired mental and/or psychomotor development; attention deficit 
disorder and behavioral symptoms; obesity and insulin resistance; 
rhinitis; eczema; asthma; endometriosis; and renal, hepatic, thyroid, 
and hormone-dependent cancers. The comments stated that, given the 
available research, FDA should take quick action to reduce exposure to 
these chemicals in our food supply.
    (Response 1) FDA is aware of the research that has been conducted 
with respect to phthalates. While FDA considered the research in its 
evaluation of the petition, including the research identified in the 
comments, most of the research considered individual phthalates or 
mixtures of phthalates. The petition is based on the idea that the 28 
subject phthalates should be considered as a class and deemed unsafe as 
a class. For the reasons described previously, the petition does not 
provide adequate support for grouping the 28 phthalates as a single 
class, and therefore, the research pertaining to individual phthalates 
or specific mixtures of phthalates cannot be applied to all 28 
phthalates that are the subject of the petition.
    (Comment 2) Many comments cited the CHAP report and pointed to the 
Consumer Product Safety Commission's (CPSC's) final rule prohibiting 
children's toys and childcare articles that contain more than 0.1 
percent of five specific ortho-phthalates (82 FR 49938, October 27, 
2017). Other comments also cited the CHAP report's finding that the 
diet (separate from exposure from children's toys and childcare 
articles) is a major route of exposure to phthalates as a reason why 
FDA should also address the use of phthalates. These comments argued 
that, because maximum use levels of certain phthalates in toys have 
been used to assess risk to children during early development, FDA 
should take action against uses of phthalates in food contact 
applications that contribute to exposure for pregnant women and the 
developing fetus, as well as for nursing mothers and babies.
    (Response 2) The CHAP report included a risk assessment regarding 
the use of 14 phthalates and 6 phthalate alternatives in children's 
toys and childcare articles. While the report was a result of 
significant scientific analysis, the report was conducted primarily for 
the purpose of evaluating the safety of certain phthalates and 
phthalate alternatives in children's toys and childcare articles, and 
the regulatory recommendations in that report apply to those particular 
uses of phthalates. Notably, the CHAP report was not designed to 
evaluate the safety of phthalates for food contact uses, which is the 
subject of this petition. In evaluating the safety of substances for 
food contact uses, FDA is required by statute to consider the safety of 
a substance for the particular food contact use (see sections 409(b) 
and (h)(1) of the FD&C Act (providing that sponsors may submit 
petitions or notifications with respect to the ``intended use'' of the 
substance)). In addition, we are directed by statute to consider food-
related uses in assessing safety (see section 409(c)(5) of the FD&C 
Act) (providing that in determining safety, the Secretary shall 
consider among other relevant factors ``the probable consumption of the 
additive and of any substance formed in or on food because of the use 
of the additive'')). Accordingly, safety assessments conducted for 
purposes other than evaluating the safety of food contact uses cannot 
directly determine the safety of food contact uses. As appropriate, FDA 
may consider the underlying evidence reviewed in such assessments. But 
FDA's statutory responsibility is to evaluate safety in accordance with 
the FD&C Act and in consideration of the specific intended uses for 
which we have jurisdiction.
    (Comment 3) Some comments discussed actions taken with regard to 
phthalates by other government entities (such as CPSC's final rule 
prohibiting phthalates in children's toys and childcare articles if 
they contain more than 0.1 percent of five ortho-phthalates (82 FR 
49938) and the European Union's (EU's) plastic regulation (Commission 
Regulation 10/2011, Plastic Materials and Articles Intended to Come 
into Contact with Food, 2011 O.J. (L 12)). Some comments referred to 
the EU regulation as an unequivocal ban on the use of almost all ortho-
phthalates in food contact materials intended for fatty and infant 
foods. In addition, the comments pointed to FDA's Center for Drug 
Evaluation and Research's (CDER's) removal of two phthalates from its 
inactive ingredients database (77 FR 72869, December 6, 2012), and 
FDA's Center for Devices and Radiological Health's (CDRH's) draft 
guidance on medical devices made with polyvinyl chloride (PVC) 
containing DEHP (67 FR 57026, September 6, 2002). The comments argued 
that FDA should take similar action by banning the use of all 
phthalates in contact with food.
    (Response 3) Each of the governmental actions described in the 
comments were taken based on different applicable legal standards, and 
the safety considerations and assessments that supported those actions 
were not conducted in accordance with FDA's food additive safety 
standards under section 409 of the FD&C Act. In this action, FDA is 
responding to the specific claims made in the petition about the 
applicability of the safety standard in section 409 of the FD&C Act to 
a purported class of 28 ortho-phthalates, and we have evaluated those 
claims in accordance with the requirements for food additive petitions 
and applicable regulations.
    We also note that other regulatory actions and government bodies 
identified in the comments have not limited or banned the use of all 28 
ortho-phthalates that are the subject of the petition. For example, the 
actions taken by Congress and CPSC to limit the use of eight phthalates 
(DEHP, DBP and BBzP, DINP, di-n-pentylphthalate (DPENP), dihexyl 
phthalate (DHEXP), dicyclohexyl phthalate (DCHP), and diisobutyl 
phthalate (DIBP)) in children's toys and childcare articles was not a 
total ban on the use of these substances, but a ban above the specific 
use level of 0.1 percent in the articles. While Congress also put an 
interim ban on DINP, DIDP, and DnOP, the CHAP report later recommended 
to lift the interim ban for DnOP and DIDP as these compounds are not 
likely to be antiandrogenic. The CHAP report also recommended that no 
action be taken on dimethyl phthalate (DMP) and diethyl phthalate 
(DEP).
    The EU's plastic regulation (Commission Regulation 10/2011, 2011 
O.J. (L 12)) authorizes six phthalates (DBP, BBP, DEHP, DINP, diallyl 
phthalate (DAP), and DIDP) for use in food contact plastic materials 
and articles. These phthalates have different

[[Page 31077]]

use restrictions, specific migration limits, and specific type(s) of 
food the articles containing these substances may contact. The EU's 
regulation authorizes certain phthalates and does not ban the use of 
all other phthalates for food contact applications.
    The removal of DEHP and DBP from CDER's database of inactive 
ingredients in drug products followed the publication of CDER's 
guidance document, ``Limiting the Use of Certain Phthalates as 
Excipients in Center for Drug Evaluation and Research-Regulated 
Products'' (77 FR 72869). While CDER's guidance was informed by 
concerns about the safety of DBP and DEHP, the guidance was limited to 
the use of those substances as excipients in drug and biologic 
products, and the guidance specifically states that the recommendations 
in the document do not address the use of DBP or DEHP in other types of 
FDA-regulated products. As an additional matter, the guidance 
document--like all FDA guidance documents--is non-binding and sets 
forth policy and regulatory recommendations only (see 21 CFR 10.115). 
In addition, the CDRH draft guidance is not a ban on the use of DEHP. 
Instead, the draft guidance (which was never finalized and has since 
been withdrawn) would have suggested labeling DEHP content and would 
have recommended that device manufacturers consider replacing DEHP for 
a small subset of medical devices where PVC containing DEHP may come in 
contact with the tissue of a sensitive patient population in a manner 
and for a period of time that may result in concerns about aggregate 
exposure to DEHP. The draft guidance did not address exposure to DEHP 
from any other use of PVC, such as food contact applications.
    (Comment 4) Most comments supported banning all 28 ortho-phthalates 
even in the absence of scientific evidence of harm because of concern 
that banning only some phthalates could lead to substitution with other 
phthalates or alternatives that may carry unknown risks.
    (Response 4) Consistent with section 409 of the FD&C Act, FDA 
evaluates the safety of all food additives against the same safety 
standard of reasonable certainty of no harm and does not make safety 
determinations based on the comparison of one chemical to its potential 
substitute. The 28 ortho-phthalates that are the subject of the 
petition were approved via the food additive petition process and 
included an evaluation using the same safety standard as other food 
contact substances. Any ``substitute'' phthalate used as a food contact 
substance would also undergo any required premarket safety review and 
would be required to meet FDA's safety standard.
    In response to the comments arguing that FDA should take action 
even if there is uncertainty about the data, FDA regulates food 
additives in accordance with the FD&C Act. Under the FD&C Act, food 
additives may not be used unless it can be demonstrated that there is a 
reasonable certainty that no harm will result from their use.
    (Comment 5) Several comments supported the petitioners' position 
that all 28 phthalates should be considered and regulated as a single 
class because, in the commentors' view, the phthalates are chemically 
and pharmacologically related. The comments also stated that exposure 
to phthalates should be considered cumulatively based on the 
antiandrogenic effects seen in rats treated with certain phthalates and 
that a single ADI should be established for the asserted class. The 
comments agreed with the petition's argument that adverse effects and 
the 3 [micro]g/kg bw/day ADI proposed for DEHP should be attributed to 
the entire asserted class, and that current exposure levels for 
phthalates exceeds this level.
    Conversely, one comment stated that the antiandrogenic effect 
identified is species-specific and that some studies have reported 
that, unlike the observations made in studies testing rat fetus tissue, 
antiandrogenicity is not observed in human fetus tissue when exposed to 
phthalates in the same way.
    (Response 5) FDA has addressed the petitioners' three assertions in 
sections II (A, B, and C). FDA has also addressed the human relevance 
to the antiandrogenicity effect reported from rat studies in section 
II.B and in Ref. 4.
    (Comment 6) Some comments stated that FDA should consider purported 
economic costs of human health impacts (such as healthcare expenses due 
to illness and lost productivity) associated with exposure to chemicals 
generally, including phthalates.
    (Response 6) FDA does not agree that it is necessary to evaluate 
the potential economic impact of the regulated uses of the 28 ortho-
phthalates that are the subject of the petition. The economic costs for 
which the comment wants FDA to conduct estimates are health related 
(i.e., costs to the healthcare system that result from asserted health 
problems caused by phthalates). At the time FDA authorized the 28 
ortho-phthalates that are the subject of the petition, FDA found them 
to be safe. The comments did not explain why FDA is under an ongoing 
obligation to develop cost estimates for substances that FDA has found 
to be safe. If new data and information accrue such that FDA determines 
that any approved additives are in fact unsafe, FDA will take 
appropriate action by revoking the approvals for such additives or 
otherwise ensuring that the additives are not used.
    (Comment 7) Several comments stated that if FDA does not grant the 
petition, we should require disclosure of the use of phthalates in food 
packaging directly on the label so consumers who wish to avoid or limit 
exposure to phthalates are able to make an informed decision.
    (Response 7) The petition did not request that FDA establish 
requirements for the labeling of products manufactured with phthalates. 
We note that manufacturers may voluntarily label their products as 
phthalate-free, as long as such labeling is truthful and not 
misleading.
    For FDA to require labeling on food packages regarding the use of 
phthalates, FDA would consider the standards in: (1) Section 
409(c)(1)(A) of the FD&C Act, providing that regulations for food 
additives prescribe the conditions necessary to provide for the safe 
use of the ingredient, and (2) the standard under section 201(n) of the 
FD&C Act that any such declaration constitutes a material fact with 
respect to the consequences that may result from the use of the food. 
The comments did not provide evidence to address either of these 
standards, and based on the current record, we do not find it 
appropriate to take such action in response to these comments.
    (Comment 8) Some comments urged FDA to consider the effects 
phthalates have on the environment and wildlife. The comments stated 
that the use of these chemicals could result in the contamination of 
soil, air, and drinking water.
    (Response 8) The comments did not provide any information or 
relevant data to substantiate the asserted environmental effects of 
phthalates from their use as food additives. Therefore, these comments 
are unsupported. To the extent the comments suggested that FDA conduct 
an environmental assessment or impact statement under the National 
Environmental Policy Act (NEPA), 42 U.S.C. 4321 et seq., we note that 
NEPA does not require Agencies to conduct such assessments or impacts 
unless there is a major Federal action. Agency decisions that maintain 
the status quo do not constitute major Federal actions (see, e.g., 40 
CFR 1508.1(q); Fund for Animals, Inc. v. Thomas, 127 F.3d 80 (D.C. Cir. 
1997); Defenders of Wildlife v. Andrus, 627 F.2d 1238, 1243-46 (D.C. 
Cir. 1980)).

[[Page 31078]]

Our denial of this food additive petition maintains the status quo. To 
the extent that the comments suggested that environmental effects can 
be a basis for withdrawing a food additive petition, we are unaware of 
any such authority under the FD&C Act and the comments did not identify 
any.
    (Comment 9) Some comments agreed with the petitioners' exposure 
estimation that considers cumulative exposure using four datasets from 
different sources, while others disagreed with the approach used to 
estimated exposure. One comment stated that one of petitioners' sources 
for estimating exposure, the 2014 CHAP report, overestimates exposure 
levels because it used outdated NHANES biomonitoring data that does not 
reflect a more recent decline in exposure, as evidenced by a reduction 
in urinary metabolite levels observed in the most recent NHANES data 
(2009-2010 CDC NHANES data, published September 2012).
    (Response 9) As discussed in section II.C, the petition does not 
adequately support the proposed exposure values. We have addressed the 
petitioners' use of exposure data in section II.C.
    (Comment 10) Many comments agreed with the petitioner regarding the 
additional safety factor applied to the NOAEL for DEHP to calculate the 
ADI. The comments stated that a safety factor of 1,000 should be used. 
Conversely, one comment stated that the available data does not support 
the use of a safety factor of 1,000 because the effects identified for 
DEHP in the reference studies are ``mild'' and do not warrant an 
adjustment for severity.
    (Response 10) As discussed in section II.B.2, FDA cannot determine 
the appropriate safety factor without more information than what was 
provided in the petition.

IV. Conclusion

    FAP 6B4815 requested that the food additive regulations be amended 
to provide for the removal of 28 authorized phthalates listed for use 
in contact with food. After reviewing the petition, as well as 
additional data and information relevant to the petitioners' request, 
we determine that the petition provides insufficient information to 
support a finding that there is no longer a reasonable certainty of no 
harm for the proposed class of ortho-phthalates. Therefore, FDA is 
denying FAP 6B4815 in accordance with Sec.  171.100(a).

V. Objections

    Any persons that may be adversely affected by this notice may file 
with the Dockets Management Staff (see ADDRESSES) either electronic or 
written objections. You must separately number each objection, and 
within each numbered objection you must specify with particularity the 
provision(s) to which you object, and the grounds for your objection. 
Within each numbered objection, you must specifically state whether you 
are requesting a hearing on the particular provision that you specify 
in that numbered objection. If you do not request a hearing for any 
particular objection, you waive the right to a hearing on that 
objection. If you request a hearing, your objection must include a 
detailed description and analysis of the specific factual information 
you intend to present in support of the objection in the event that a 
hearing is held. If you do not include such a description and analysis 
for any particular objection, you waive the right to a hearing on the 
objection.
    It is only necessary to send one set of documents. Identify 
documents with the docket number found in brackets in the heading of 
this document. Any objections received in response to the regulation 
may be seen in the Dockets Management Staff between 9 a.m. and 4 p.m., 
Monday through Friday, and will be posted to the docket at http://www.regulations.gov. We will publish notice of the objections that we 
have received or lack thereof in the Federal Register.

VI. References

    The following references marked with an asterisk (*) are on display 
at the Dockets Management Staff (see ADDRESSES) and are available for 
viewing by interested persons between 9 a.m. and 4 p.m., Monday through 
Friday; they also are 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. In addition, Reference A is also part 
of the administrative record and is on display at the Dockets 
Management Staff. This reference is also available electronically at 
https://www.regulations.gov.

    *1. 2014 Organization for Economic Co-operation and Development 
(OECD) Guidance on Grouping of Chemicals.
    *2. Shibko, S.I. and H. Blumenthal (1973) ``Toxicology of 
Phthalic Acid Esters Used in Food Packaging Material,'' 
Environmental Health Perspectives, 3:131-137.
    *3. FDA Memorandum from R. Bri[ntilde]as to J. Urbelis, May 11, 
2022.
    *4. FDA Memorandum from T-F. Cheng to J. Urbelis, May 11, 2022.
    *5. Phthalates and Cumulative Risk Assessment: The Tasks Ahead; 
National Research Council (US) Committee on the Health Risks of 
Phthalates (NAS Report): Washington (DC): National Academies Press 
(US); 2008.
    *6. 2014 Chronic Hazard Advisory Panel (CHAP) on Phthalates and 
Phthalate Alternatives Final Report.
    *7. OECD: Screening Information Dataset (SIDS) Initial 
Assessment Meeting (SIAM) 19), 19-22 October 2004.
    *8. European Food Safety Authority (EFSA) Panel on Food Contact 
Materials, Enzymes and Processing Aids (2019) ``Update of the Risk 
Assessment of di[hyphen]butylphthalate (DBP), 
butyl[hyphen]benzyl[hyphen]phthalate (BBP), 
bis(2[hyphen]ethylhexyl)phthalate (DEHP), 
di[hyphen]isononylphthalate (DINP) and di[hyphen]isodecylphthalate 
(DIDP) for Use in Food Contact Materials,'' EFSA Journal, 
17(12):5838.
    *9. Canada: Screening Assessment--Phthalate Substance Grouping. 
Environment and Climate Change Canada, Health Canada. December 2020. 
Cat. No.: En14-393/2019E-PDF; ISBN 978-0-660-32979-6.
    *10. FDA, Guidance for Industry, ``Toxicological Principles for 
the Safety Assessment of Food Ingredients: Redbook 2000,'' July 2007 
(available at: https://www.fda.gov/media/79074/download).
    *11. FDA, Guidance for Industry, ``Preparation of Food Contact 
Notifications for Food Contact Substances: Toxicology 
Recommendations,'' October 2021 (available at: https://www.fda.gov/regulatory-information/search-fda-guidance-documents/guidance-industry-preparation-food-contact-substance-notifications-toxicology-recommendations.
    *12. FDA, (2001) ``Safety Assessment of Di(2-ethylhexyl) 
phthalate (DEHP) Released from PVC Medical Devices,'' (available at: 
https://www.fda.gov/media/114001/download).
    13. Kurata, Y., F. Kidachi, M. Yokoyama, et al. (1998) 
``Subchronic Toxicity of Di(2-ethylhexyl)phthalate in Common 
Marmosets: Lack of Hepatic Peroxisome Proliferation, Testicular 
Atrophy, or Pancreatic Acinar Cell Hyperplasia,'' Toxicological 
Sciences, 42:49-56.
    *14. Rhodes, C., T.C. Orton, S. Pratt, et al. (1986) 
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``Effects of Di-isononyl Phthalate, Di-2-ethylhexyl Phthalate, and 
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[[Page 31079]]

    *A. FDA Supplementary Memorandum for Food Additive Petition 
(FAP) 6B4815, J. Urbelis, May 11, 2022.

    Dated: May 11, 2022.
Lauren K. Roth,
Associate Commissioner for Policy.
[FR Doc. 2022-10530 Filed 5-19-22; 8:45 am]
BILLING CODE 4164-01-P