[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
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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).
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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)
``Comparative Pharmacokinetics and Subacute Toxicity of Di-(2-
ethylhexyl) Phthalate (DEHP) in Rats and Marmosets: Extrapolation of
Effects in Rodents to Man,'' Environmental Health Perspectives, 65,
299-307.
15. Pugh, G. Jr., J.S. Isenberg, L.M. Kamendulis, et al. (2000)
``Effects of Di-isononyl Phthalate, Di-2-ethylhexyl Phthalate, and
Clofibrate in Cynomolgus Monkeys,'' Toxicological Sciences,
56(1):181-188.
*16. Schecter, A., M. Lorber, Y. Guo, et al. (2013) ``Phthalate
Concentrations and Dietary Exposure from Food Purchased in New York
State,'' Environmental Health Perspectives, 121(4): 473-494.
[[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