[Federal Register Volume 82, Number 85 (Thursday, May 4, 2017)]
[Proposed Rules]
[Pages 20847-20859]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2017-08987]
[[Page 20847]]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
21 CFR Parts 170, 177, and 189
[Docket No. FDA-2015-F-0537]
Natural Resources Defense Council et al.; Denial 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, the Agency, or we) is
denying a petition, submitted by the Natural Resources Defense Council,
Center for Food Safety, Clean Water Action, Children's Environmental
Health Network, Center for Science in the Public Interest, Breast
Cancer Fund, Center for Environmental Health, Environmental Working
Group, and Improving Kids' Environment, requesting that we revoke the
Threshold of Regulation (TOR) exemption No. 2005-006 to no longer
exempt from our food additive regulations the use of sodium perchlorate
monohydrate as a conductivity enhancer in antistatic agents for use in
finished articles in contact with dry foods; issue a new FDA regulation
to prohibit the use of perchlorates in antistatic agents for use in
food-contact articles; and amend our food additive regulations to no
longer provide for the use of potassium perchlorate as an additive in
closure-sealing gaskets for food containers.
DATES: This notification is effective May 4, 2017; except as to any
provisions that may be stayed by the filing of proper objections. See
Section VI of this document for information on the filing of
objections. Submit either electronic or written objections and requests
for a hearing by June 5, 2017. Late, untimely filed objections will not
be considered. The https://www.regulations.gov electronic filing system
will accept comments until midnight Eastern Time at the end of June 5,
2017. 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.
ADDRESSES: You may submit either electronic or written objections and
requests for a hearing identified by Docket No. FDA-2015-F-0537, by any
of the following methods:
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 a comment 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): Division of Dockets Management (HFA-305), Food and Drug
Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852.
For written/paper objections submitted to the Division of
Dockets Management, 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-2015-F-0537 for ``Natural Resources Defense Council et al.; Denial
of Food Additive Petition.'' Received objections, those filed in a
timely manner (see DATES), will be placed in the docket, and except for
those submitted as ``Confidential Submissions,'' publically viewable at
https://www.regulations.gov or at the Division of Dockets Management
between 9 a.m. and 4 p.m., Monday through Friday.
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 Division of Dockets Management. 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.gpo.gov/fdsys/pkg/FR-2015-09-18/pdf/2015-23389.pdf.
Docket: For access to the docket to read background documents or
objections 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 Division of
Dockets Management, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852.
FOR FURTHER INFORMATION CONTACT: Hui-Chen (Anita) Chang, Center for
Food Safety and Applied Nutrition (HFS-275), Food and Drug
Administration, 5001 Campus Dr., College Park, MD 20740-3835, 240-402-
1161.
SUPPLEMENTARY INFORMATION:
I. Introduction
In a document published in the Federal Register of March 16, 2015
(80 FR 13508), we announced that we filed a food additive petition (FAP
4B4808) (``petition'') submitted by the Natural Resources Defense
Council, 1152 15th St. NW., Suite 300, Washington, DC 20005; the Center
for Food Safety, 303 Sacramento St., Second Floor, San Francisco, CA
94111; Clean Water Action, 144 I St. NW., Suite 400, Washington, DC
20005; the Center for Science in the Public Interest, 1220 L St. NW.,
Suite 300, Washington, DC 20005; Children's Environmental Health
Network, 110 Maryland Ave. NE., Suite 402, Washington, DC 20002; the
Breast Cancer Fund, 1388 Sutter St., Suite 400, San Francisco, CA
94109-5400; the Center for Environmental Health, 2201 Broadway, Suite
302, Oakland, CA 94612; Environmental Working Group, 1436 U St. NW.,
Suite 100, Washington,
[[Page 20848]]
DC 20009; and Improving Kids' Environment, 1915 West 18th St.,
Indianapolis, IN 46202 (collectively, ``petitioners''). In the March
2015 document, we requested comments on the petition under Sec.
189.1(c) (21 CFR 189.1(c)). The petition included submissions dated
July 31, 2014, October 15, 2014, and December 5, 2014. The October 15,
2014, submission included a resubmission of the entire July 31, 2014,
original petition with the inclusion of some additional information.
The December 5, 2014, submission contained additional information to
that provided in the October 15, 2014, submission. Any references to
specific parts of the petition are to the October 15, 2014, submission
while specific references to the December 5, 2014, submission will
refer to the date of that document.
The petition asked FDA to take three separate regulatory actions:
(1) Revoke its 2005 approval of TOR exemption No. 2005-006 allowing as
much as 1.2 percent sodium perchlorate monohydrate in dry food
packaging; (2) issue a new Sec. 189.301 (21 CFR 189.301) prohibiting
the use of perchlorate as a conductivity enhancer in the manufacture of
antistatic agents to be used in food contact articles; and (3) remove
potassium perchlorate as an allowed additive in sealing gaskets for
food containers in existing Sec. 177.1210 (21 CFR 177.1210). For
accuracy, we will refer to the petition's second request as a request
to issue a new regulation under part 189 because a regulation already
exists at Sec. 189.301. The petition asserted that the allowed food-
contact uses of perchlorate are not safe because there is no longer a
reasonable certainty that the perchlorate is not harmful under the
intended conditions of use considering: (1) The probable consumption of
perchlorate; (2) the cumulative effect of perchlorate after taking into
account pharmacologically-related substances, such as thiocyanate and
nitrate, in the diet; and (3) additional safety factors necessary to
protect the developing brain of fetuses and infants from irreversible
harm. The petition also asserted that new exposure data are available
that support the requested revocation of TOR exemption No. 2005-006.
Both food contact substances that are the subject of the petition--
sodium perchlorate monohydrate and potassium perchlorate--belong to a
class of chemicals termed ``perchlorates.'' Perchlorates are both
naturally-occurring and man-made chemicals with a wide variety of
industrial and some medical applications. Perchlorates are ionic salts
that contain the perchlorate anion (chemical structure
ClO4-). In this notification, the term
``perchlorates'' refers to the class of chemicals while the term
``perchlorate'' refers to the perchlorate ion.
II. Background
A. Statutory and Regulatory Background
The petition asked FDA to take actions related to three different
types of FDA regulations.
1. Food Additive Regulation
The Federal Food, Drug, and Cosmetic 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 (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 ``food contact substance[s]'' (i.e., 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 approve their use (see, e.g., section 301(a) and
(k) (21 U.S.C. 331(a) and (k)) and 409(a) of the FD&C Act).
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.'' When we conclude that a
proposed use of a food additive is safe, we issue a regulation called a
``food additive regulation'' authorizing a specific use of the
substance.
The specific food additive regulation at issue in the petition,
Sec. 177.1210, lists substances allowed as indirect additives (also
called food contact substances) in closures with sealing gaskets for
food containers. Potassium perchlorate is one of the listed substances
authorized for this use under Sec. 177.1210.
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 (the Commissioner), 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))). 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.
FDA has issued administrative regulations for food additive
petitions in part 171. These regulations apply to food additive
petitions requesting either that we authorize the new use of a food
additive or that we amend or repeal an existing food additive
regulation.
2. TOR Exemption
The food additive petition process generally applies to substances
used in food packaging or processing when the proposed use will cause
the substance to become part of the food at a level that exceeds a
minimum ``threshold of regulation'' (see Sec. 170.39 (21 CFR 170.39)).
Our determination that a use of a substance is at or below the
``threshold of regulation'' is referred to as a ``threshold of
regulation'' exemption, or a TOR exemption. Regardless of whether the
use of a substance is at or below the threshold of regulation, we
reserve the right to apply the food additive petition process in those
cases in which available information establishes that the proposed
food-contact use may pose a public health risk (see Sec. 170.39(b)).
We established the procedures set forth in Sec. 170.39 to exempt
certain substances used in food-contact articles (e.g., food-packaging
(such as a cereal bag) or food-processing equipment) that migrate or
may be expected to migrate into food at negligible levels from
regulation as a food additive. Eligible substances must become a
component of food at levels that are at or below the threshold of
regulation, must not have been shown to cause cancer in humans or
animals or be suspected carcinogens, and must meet other criteria in
Sec. 170.39. If we determine the criteria are met, we inform the
requestor by letter that the intended use of a substance in food-
contact articles is exempt from regulation as a food additive.
Therefore, when we issue a TOR exemption, the intended use of the
substance does not require a regulation authorizing its food
[[Page 20849]]
additive use under section 409 of the FD&C Act (also referred to as a
``listing regulation'') or food additive petition (see Sec. Sec.
170.3(e)(2) and 171.8). We issued TOR exemption No. 2005-006 in 2005.
We maintain a list of TOR exemptions on our Web site (Ref. 1).
Our regulations provide that if we receive significant new
information that raises questions about the dietary concentration or
the safety of a substance that is the subject of a TOR exemption, we
may reevaluate the substance (see Sec. 170.39(g)). Our regulations, at
Sec. 170.39(g), state that if we tentatively conclude that the
available information no longer supports an exemption for the use of
the food-contact material from the food additive regulations, we will
notify any persons that requested an exemption for the substance of our
tentative decision and will provide them with an opportunity to show
why the use of the substance should not be regulated under the food
additive provisions of the FD&C Act. If the requestors fail to
adequately respond to the new evidence, we notify them that further use
of the substance in question for the particular use will require a food
additive regulation (see Sec. 170.39(g)). Thus, anyone who seeks to
use such substance as a food additive would need to submit a food
additive petition seeking such a regulation or obtain authorization
through a food contact notification. We also notify other
manufacturers, by means of a notice published in the Federal Register,
of our decision to revoke a TOR exemption issued for a specific use of
a substance in a food-contact article (see Sec. 170.39(g)).
3. Regulation Under Part 189
Our regulations at Sec. 189.1(a) provide that ``food ingredients''
may be prohibited from uses in human food based on a determination that
the food ingredients present a potential risk to the public health or
have not been shown by adequate scientific data to be safe for use in
human food. Additionally, Sec. 189.1(c) provides that the
Commissioner, either on his own initiative or on the petition of any
interested person, may publish a proposal to establish, amend, or
repeal a regulation under this section on the basis of new scientific
evaluation or information. We established part 189 to: (1) Provide, for
reference purposes, a partial listing of substances prohibited from use
in human food and (2) create an administrative process through which we
can prohibit by rulemaking the use of substances in human foods because
of a determination that they present a potential risk to the public
health or have not been shown by adequate scientific data to be safe
for use in human foods (see 39 FR 34172, September 23, 1974).
B. Abandonment of Use of Potassium Perchlorate Authorized Under 21 CFR
Sec. 177.1210
In a document published in the Federal Register on June 30, 2016
(81 FR 42585), we announced that we filed a food additive petition (FAP
6B4816) (``abandonment petition'') that proposed that we amend Sec.
177.1210 to no longer provide for the use of potassium perchlorate as
an additive in closure-sealing gaskets for food containers because the
use has been intentionally and permanently abandoned. Elsewhere in this
issue of the Federal Register, we have published a final rule
concluding that the use of potassium perchlorate authorized under Sec.
177.1210 has been permanently and completely abandoned. The final rule
amends Sec. 177.1210 to no longer authorize the use of potassium
perchlorate as an additive in closure-sealing gaskets for food
containers.
Because the final rule issued in response to the abandonment
petition removes potassium perchlorate as an allowed additive in
sealing gaskets for food containers--thereby taking the third action
requested in the petition--the petition's third request is moot, and it
is neither necessary nor an efficient use of our resources to address
the petitioners' assertions regarding the safety of the food additive
use of potassium perchlorate that is no longer authorized. Where
helpful for clarity, this notification will describe the petition's
arguments regarding the food additive use of potassium perchlorate in
the course of reviewing the petition's requests to revoke TOR exemption
No. 2005-006 and to issue a new regulation under part 189.
C. The Scope of a Food Additive Petition
The petitioners designated their petition as a ``food additive
petition.'' A food additive petition must either propose the issuance
of a regulation prescribing the conditions under which a food additive
may be safely used (see section 409(b)(1) of the FD&C Act), or propose
the amendment or repeal of an existing food additive regulation (see
section 409(i) of the FD&C Act).
Only one of the petition's requested actions falls within the
statutory scope of a food additive petition: Amending Sec. 177.1210 to
remove potassium perchlorate as an allowed additive in sealing gaskets
for food containers, the action we are taking in response to the
abandonment petition. Because the petition's other two requests--the
revocation of TOR exemption No. 2005-006 and the issuance of a
regulation under part 189 prohibiting the use of perchlorate in the
manufacture of antistatic agents to be used in food-contact articles--
are not directed at regulations issued under the food additive petition
process, they are governed by different regulations and are not subject
to the statutory processes for food additive petitions.
TOR substances, i.e., substances used in food-contact articles that
become a component of food at levels that are below the threshold of
regulation and meet the criteria in Sec. 170.39, are exempt from
regulation as food additives and do not require a listing regulation or
food additive petition (see Sec. Sec. 170.3(e)(2) and 171.8). As noted
in the filing notice for this petition, the procedures for reevaluating
and revoking a TOR exemption are set forth in Sec. 170.39(g). These
procedures are distinct from the food additive petition process. A
request to revoke a TOR exemption is the proper subject of a citizen
petition submitted under 21 CFR 10.30.
The petition's request that we issue a new regulation under part
189 also falls outside the scope of a food additive petition. A
proposed part 189 regulation does not propose the issuance of a new
food additive regulation or the amendment or repeal of an existing food
additive regulation (see sections 409(b)(1) and (i) of the FD&C Act).
Under part 189, an interested person can use the citizen petition
process to request a regulation prohibiting a substance from human food
(see Sec. 189.1(c) (referring to 21 CFR part 10, which sets forth
FDA's citizen petition process)).
Although the requests to revoke the approval of TOR exemption No.
2005-006 and to issue a new regulation under part 189 are outside the
scope of a food additive petition, for reasons of administrative
efficiency, we initially considered these requests in conjunction with
the petition's request to amend Sec. 177.1210 to remove potassium
perchlorate as an allowed additive in sealing gaskets for food
containers. Because the food additive use of potassium perchlorate has
been removed from Sec. 177.1210 in response to the abandonment
petition, it is neither necessary nor an efficient use of resources to
address the petition's assertions regarding this use of perchlorate.
Nonetheless, because we considered all of these requests together for
purposes of administrative efficiency, we are addressing the
[[Page 20850]]
petition's requests to revoke the approval of TOR exemption No. 2005-
006 and to issue a new regulation under part 189 in this document.
However, although we are addressing these requests in connection with
our denial of a food additive petition, we emphasize that these
requests are not the proper subject of a food additive petition. Our
denial of these two requests is a final Agency decision, but is not an
order under section 409(c)(1)(B) of the FD&C Act.
D. Background on Perchlorate
Perchlorate can interfere with the normal functioning of the
thyroid gland by competitively inhibiting the transport of iodide into
the thyroid. Iodide is an important component of two thyroid hormones,
T4 and T3, and the transfer of iodide from the blood into the thyroid
is an essential step in the synthesis of these two hormones. Iodide
transport into the thyroid is mediated by a protein molecule known as
the sodium (Na+)-iodide (I-) symporter (NIS). NIS
molecules bind iodide with high affinity, but they also bind other ions
that have a similar shape and electric charge, such as perchlorate. The
binding of these other ions to the NIS can inhibit iodide transport
into the thyroid, which can result in intrathyroidal iodide deficiency
and consequently decreased synthesis of T4 and T3 (73 FR 60262, 60266,
October 10, 2008). In fetuses, infants, and young children, thyroid
hormones are critical for normal growth and development. Id. at 60275.
For example, sustained thyroid hormone decrement in a pregnant mother
could lead to adverse neurodevelopmental effects in the fetus. Id. at
60266. Research in this area is ongoing.
As part of its discussion asserting that new information is
available that raises question as to the safety of the allowed food-
contact uses of perchlorates, the petition cited two reviews on
perchlorate requested by the Environmental Protection Agency (EPA): A
2005 National Research Council (NRC) review (Ref. 2) and the 2013
report of the EPA's Scientific Advisory Board (SAB) (Ref. 3). The 2005
NRC report noted that thyroid iodide uptake inhibition (IUI) is the
only effect that has been consistently documented in humans exposed to
perchlorate. Therefore, as part of its review, the NRC utilized a
hypothetical mode-of-action (MOA) framework, which represents a
continuum of possible biological effects resulting from perchlorate
exposure, to describe the potential pathway of events following
perchlorate exposure. This MOA framework hypothesized that IUI could
induce thyroid hormone changes to an extent that could ultimately
result in neurodevelopmental effects in fetuses and infants. The SAB
utilized a similar MOA framework. In both MOA frameworks, IUI is the
determinant, non-adverse precursor effect, which must occur prior to
any later adverse effect.
1. 2005 NRC Review
The 2005 NRC report was prepared in response to a request from the
EPA that the National Academy of Sciences review the science regarding
potential adverse effects of disruption of thyroid function and provide
recommendations to apply this information to a risk assessment for
environmental contamination from perchlorate. The report recommended
that EPA derive a reference dose (RfD) for perchlorate by applying a
tenfold intraspecies uncertainty factor to a no observed effect level
(NOEL) based on the initiation of IUI as determined in a human study
(Ref. 4). (The RfD is an estimate (with uncertainty spanning perhaps an
order of magnitude) of a daily oral exposure to the human population
(including sensitive subgroups) that is likely to be without an
appreciable risk of deleterious effects during a lifetime. The NOEL is
an exposure level at which there are no statistically or biologically
significant increases in frequency or severity of any effect between
the exposed population and its appropriate control.) The NRC stated
that this approach was conservative and protective of health given that
the NOEL is based on the non-adverse effect of IUI, which precedes the
continuum of possible adverse effects as a result of perchlorate
exposure. According to the NRC, the application of the uncertainty
factor accounts for differences in sensitivity between the healthy
human subjects of the determinant clinical study and ``even the most
sensitive populations'' for perchlorate exposure, which the NRC
identified as fetuses of pregnant women who may have hypothyroidism or
iodide deficiency. (Hypothyroidism is a condition where ``the thyroid
gland does not produce enough thyroid hormones to meet the body's
needs'' (Ref. 5)). EPA adopted the NRC's recommendations resulting in
an RfD of 0.7 micrograms perchlorate/kilogram body weight/day ([mu]g/kg
bw/d) (Ref. 6).
2. 2013 EPA SAB Report
The 2013 SAB report was developed in response to a request by EPA
for guidance on a suitable approach to utilize relevant available
information to derive a maximum contaminant level goal (MCLG) for
perchlorate in drinking water. The Safe Drinking Water Act defines an
MCLG as the level of a contaminant in drinking water ``at which no
known or anticipated adverse effects on the health of persons occur and
which allows for an adequate margin of safety.'' 42 U.S.C. 300g-
1(b)(4). An MCLG is a nonenforceable public health goal. EPA generally
derives an MCLG using the RfD and specific chemical exposure factors.
(Ref. 7). Rather than this default approach, the SAB recommended that
EPA expand existing physiologically-based pharmacokinetic/
pharmacodynamics (PBPK/PD) models to relate perchlorate exposure, in
combination with iodide intake, beyond IUI to downstream MOA framework
effects, such as resultant thyroid hormone perturbations and potential
adverse neurodevelopmental outcomes. The SAB also recommended that the
sensitive populations for exposure to perchlorate that EPA should
consider when determining an MCLG are the fetuses of hypothyroxinemic
pregnant women (hypothyroxinemia means that the free thyroxine (fT4)
value is at lower end of the normal range with normal levels of thyroid
stimulating hormone (Ref. 8)) and infants exposed to perchlorate
through either water-based formula preparations or the breast milk of
lactating women.
III. Review of the Petition
The petition asserted that the original request for TOR exemption
No. 2005-006 contained errors that should have made the request
ineligible for a TOR exemption under Sec. 170.39. The petition also
asserted that we made additional errors in exempting the proposed use
of sodium perchlorate monohydrate from regulation as a food additive.
The petition also identified four categories of ``significant new
information that raises questions about the dietary concentration or
the safety of a substance that [FDA] has exempted from regulation,''
that it contends warrant reevaluation of TOR exemption No. 2005-006
under Sec. 170.39(g). Lastly, the petition asserted that infants are
likely to be disproportionately impacted by perchlorate, and that we
have an obligation under Executive Order 13045 (see 62 FR 19885, April
23, 1997) to address risks to infants from perchlorate exposure. The
petition also requested that FDA issue a new regulation under part 189
to prohibit the use of perchlorate as a conductivity enhancer in the
manufacture of antistatic agents to be ``applied to food contact
articles.''
We will first address the petition's arguments regarding the review
of TOR exemption No. 2005-006, then address
[[Page 20851]]
the petition's arguments based on ``significant new information,'' then
subsequently address the assertions pertaining to our obligation under
Executive Order 13045, and finally, the request that we issue a new
regulation under part 189.
A. Arguments Regarding Review of TOR Exemption No. 2005-006
The petition claimed that multiple errors were made in the original
calculation of dietary exposure resulting from the use allowed by the
TOR exemption No. 2005-006 and that assumptions used in that
calculation were either improperly applied or have been shown to be
flawed based on new information available after the TOR exemption
became effective. The petition stated further that if these alleged
errors were addressed, the dietary exposure resulting from the use
allowed by the TOR exemption No. 2005-006 would exceed the TOR
exemption criteria.
We describe the background for TOR exemption No. 2005-006 in
section III.A.1. The issues raised in the petition concerning alleged
errors in the original calculation and assumptions used in that
calculation, as well as our responses to those issues, are discussed in
sections III.A.2 through III.A.6.
1. Background for TOR Exemption No. 2005-006
Our regulations, at Sec. 170.39(a)(2), provide the exposure
criteria for a TOR exemption. As stated in Sec. 170.39(a)(2)(i), the
use of a substance will be exempted from regulation as a food additive
if the use in question is shown to result in or may be expected to
result in dietary concentrations at or below 0.5 parts per billion
(ppb), corresponding to dietary exposure levels at or below 1.5
[micro]g of substance/person/day (based on a diet of 1,500 grams (g) of
solid food and 1,500 g of liquid food per person per day). As noted in
section II.A.2, Sec. 170.39(g) sets forth the procedures for
reevaluating and revoking a TOR exemption.
We have issued guidance documents to help interested parties when
preparing premarket submissions for food contact substances. Our
guidance document specific to chemistry recommendations for food
contact substances (Ref. 9) (``chemistry guidance'') provides
recommendations for: (1) Migration protocols to determine or estimate
the concentration of a food contact substance in the specific food that
contacts a given food-contact article containing the substance as a
result of the intended use of that substance (``the migration of a
substance'') and (2) how to use this information to calculate the
resultant total dietary exposure to the substance as a result of its
intended use. Our chemistry guidance provides general protocols for
food-contact articles intended for single use, as well as general
recommendations for articles intended for repeated use.
The chemistry guidance also provides recommended migration
protocols for certain specific use applications, including articles
intended for use only with non-fatty, dry foods (termed ``Food Type
VIII'' in our chemistry guidance). Specific to non-fatty, dry foods,
the recommended protocol includes an assumption that a food contact
substance migrates into non-fatty, dry foods at a level of 50 [micro]g
substance per kilogram food, or 50 ppb. To determine total dietary
exposure to a substance as a result of its intended use, the chemistry
guidance recommends the application of a consumption factor to the
concentration in food determined from the migration protocol. The
consumption factor describes the fraction of the daily diet expected to
contact a specific type of packaging material. Consumption factors are
derived using information on the types of food consumed, the types of
food contacting each packaging surface, the number of food packaging
units in each food packaging category, the distribution of container
sizes, and the ratio of the weight of food packaged to the weight of
the package (Ref. 9).
The request for TOR exemption No. 2005-006 was submitted to FDA by
Ciba Specialty Chemicals Corporation (Ciba) on June 17, 2005. Although
Ciba calculated exposure for sodium perchlorate monohydrate, in this
document we convert Ciba's exposure numbers to exposure to the
perchlorate anion (the substance of toxicological concern is the
perchlorate anion and EPA's RfD for perchlorate is expressed on a
perchlorate anion basis). To determine the concentration of perchlorate
anion (i.e., ``perchlorate'') in food that contacts finished articles
containing sodium perchlorate monohydrate as a result of TOR exemption
No. 2005-006, Ciba applied the percentage of sodium perchlorate
monohydrate in the finished food-contact article to the 50 ppb
migration concentration assumption for non-fatty, dry foods listed in
our chemistry guidance. This resulted in a sodium perchlorate
monohydrate concentration in food of 0.6 ppb, which corresponds to a
concentration of 0.4 ppb for perchlorate in food. To determine a total
dietary concentration for perchlorate as a result of this specific use,
Ciba then applied our consumption factor for substances that may be
used in all polymers but only for specific uses (0.05) to this
concentration value. This resulted in a total dietary concentration for
sodium perchlorate monohydrate of 0.03 ppb, or 0.02 ppb for
perchlorate. For comparison against the TOR exemption exposure criteria
stipulated in Sec. 170.39(a)(2)(i), Ciba subsequently multiplied this
total dietary concentration by FDA's assumption that an individual
consumes 3 kg of food per day. This resulted in a dietary exposure of
0.09 [micro]g sodium perchlorate monohydrate/person/day, or 0.063
[micro]g perchlorate/person/day. A review that we conducted before TOR
exemption 2005-006 became effective determined that the provided
information demonstrated that the use would result in a dietary
exposure below the 1.5 [micro]g/person/day TOR exemption criteria (Ref.
10).
2. Issues Pertaining to Calculations Based on FDA's Chemistry Guidance
The petition asserted that Ciba deviated from the recommendations
provided in FDA's chemistry guidance when calculating the exposure to
perchlorate that results from the intended use for the TOR exemption
No. 2005-006. Specifically, the petition asserted that applying the
percentage of sodium perchlorate monohydrate in the finished food-
contact article to the 50 ppb migration concentration assumption
deviates from the recommended migration protocol for non-fatty, dry
foods and improperly made Ciba's intended use for sodium perchlorate
monohydrate eligible for a TOR exemption. Furthermore, the petition
said that the original TOR exemption submission did not account for the
recommendations presented in FDA's chemistry guidance for substances in
food-contact articles intended for repeated-use.
a. Applying the percentage of sodium perchlorate in the finished
food-contact article to the 50 ppb migration concentration assumption.
The petition asserted that Ciba ``varied'' from our chemistry guidance
when it ``inserted the amount of perchlorate in the formulation (4%)
and the amount of formulation in the packaging (30%) into'' the
equation for calculating the dietary concentration of sodium
perchlorate monohydrate. Specifically, Ciba applied the percentage of
sodium perchlorate monohydrate in the finished food-contact article (4%
x 30% = 1.2%) to the 50 ppb migration concentration assumption.
We acknowledge that our chemistry guidance does not specifically
discuss a procedure for applying the percentage of
[[Page 20852]]
a substance in the finished food-contact article to the 50 ppb
migration concentration assumption for the food contact substance, but
applying such a percentage to a migration concentration assumption does
not deviate from that guidance. The migration protocol for Food Type
VIII is written at a general level and does not preclude scientifically
appropriate calculations based on the percentage of a food contact
substance when using the 50 ppb migration concentration assumption. We
believe it was scientifically appropriate for Ciba to apply the
percentage of the food contact substance in the finished packaging to
the 50 ppb migration concentration assumption. Ciba's calculation noted
that sodium perchlorate monohydrate represents only a small fraction of
the antistatic agent in which it is used (4 percent), and the
antistatic agent itself represents only a fraction of the finished
food-contact article in which it is used (30 percent). Therefore,
absent contradictory data, it is scientifically reasonable to assume
that sodium perchlorate monohydrate migrates to Food Type VIII at the
level that it is present in the finished food-contact article (i.e.,
1.2 percent of the 50 ppb migration concentration assumption). Such
percentages have been applied to migration concentration assumptions in
other submissions that have been approved or become effective (Ref.
11).
We also note that the chemistry guidance states that dry foods with
the surface containing no free fat or oil typically exhibit little or
no migration, and cites volatile or low molecular weight adjuvants as
examples of substances that would be expected to migrate into non-
fatty, dry foods. Sodium perchlorate monohydrate is an ionic compound
with low volatility and therefore would not be expected to migrate from
food-contact materials into non-fatty, dry foods (Ref. 11). Therefore,
there is no scientific basis to suggest that sodium perchlorate
monohydrate would migrate into non-fatty, dry foods at a higher
percentage of the 50 ppb migration concentration assumption than its
percentage in the food-contact article.
The appropriateness of Ciba's approach of applying the percentage
of sodium perchlorate monohydrate in the finished food-contact article
to the 50 ppb migration concentration assumption is supported by
available analytical data provided in comments to the docket for the
petition. The migration protocol specific to non-fatty, dry foods
provided in our chemistry guidance recommends either the estimation of
the migration of a substance using the 50 ppb migration concentration
assumption or the determination of the actual migration via appropriate
migration studies. Comments submitted to the docket for the petition
include a migration study for sodium perchlorate monohydrate from a
worst-case polymeric resin into a simulant for non-fatty, dry foods
(see Docket Nos. FDA-2015-F-0537, Supplemental Comments from BASF
Corporation (Keller and Heckman LLP) (FDA-2015-F-0537-18), BASF Corp
Migration Report (Redacted) re: Supplemental Comments from BASF
Corporation (Keller and Heckman LLP) (FDA-2015-F-0537-19), BASF
Corporation Appendix A--Analysis Method (Redacted) re: Supplemental
Comments from BASF Corporation (Keller and Heckman LLP) (FDA-2015-F-
0537-20), BASF Corporation Appendix B--Detailed Sample Analysis Data
(Redacted) re: Supplemental Comments from BASF Corporation (Keller and
Heckman LLP) (FDA-2015-F-0537-21), BASF Corporation Appendix C--
Chromatograms (Redacted) re: Supplemental Comments from BASF
Corporation (Keller and Heckman LLP) (FDA-2015-F-0537-22), and BASF
Corporation Appendix D--Spiking Validation at Low Perchlorate
(Redacted) re: Supplemental Comments from BASF Corporation (Keller and
Heckman LLP) (FDA-2015-F-0537-23)). We reviewed this study and
determined that it is adequate to determine worst-case migration of
perchlorate into non-fatty, dry foods as a result of the use specified
in the TOR exemption No. 2005-006 (Ref. 11). As such, the migration
concentration in food for perchlorate as determined from this migration
study can be used to verify the appropriateness of Ciba's approach of
applying the percentage of sodium perchlorate monohydrate in the
finished food-contact article to the 50 ppb migration concentration
assumption.
The migration study reported its results on a basis of grams of
perchlorate per surface area of test sample. To convert this reporting
basis to grams of perchlorate per gram of food, we applied our standard
assumption for the food mass-to-surface area ratio for consumer
packaging (10 g of food contacting each square inch of food-contact
article) to the results of the migration study. This results in a
migration concentration of 0.5 nanogram (ng) perchlorate/g food, or 0.5
ppb. This value is substantially less than the 50 ppb migration
concentration assumption provided in our chemistry guidance and is
essentially equivalent to the 0.4 ppb concentration for perchlorate in
food calculated using Ciba's approach in its TOR submission. The
dietary exposure to perchlorate calculated using the concentration for
perchlorate in food obtained from the migration study (0.075 [mu]g/
person/day) is also essentially equivalent to that calculated using
Ciba's approach (0.063 [micro]g/person/day) and is lower than the TOR
exemption criteria of 1.5 [mu]g/person/day. The results of the
migration study confirm that Ciba's approach to calculating migration
was scientifically appropriate. Both the migration study and Ciba's
approach resulted in dietary exposure figures for sodium perchlorate
monohydrate that were lower than the TOR exemption criteria. Therefore,
the petition's assertion that the intended use of sodium perchlorate
monohydrate would not be eligible for a threshold of regulation
exemption if migration had been properly calculated is unfounded.
b. Calculation of dietary exposure based on migration protocol. As
discussed in section III.A.1, FDA's chemistry guidance discusses
general protocols for food-contact articles intended for single-use
(e.g., a disposable paper cup), as well as for articles intended for
repeated-use (e.g., a reusable ceramic mug). Part I.C.5 of the petition
noted that Ciba's calculation of dietary exposure ``did not rely'' on
the recommended migration protocol in our chemistry guidance for food-
contact articles intended for repeated use. Related to this argument,
in the December 5, 2014, submission, the petitioners asserted that
Ciba's use of a single-use protocol, rather than a repeated-use
protocol, does not account for the release of perchlorate over time
``as the plastic degrades or is flexed.''
Using the single-use protocol results in a higher exposure value
than using the repeated-use protocol because: (1) The factors applied
to the migration value to determine exposure in the single-use protocol
are exaggerative and (2) exposure values from repeated-use articles are
typically very small in comparison to single-use articles. Therefore,
when a food contact substance will be used in both single- and
repeated-use articles, it is more conservative and protective to use
the single-use protocol to determine exposure than it is to use the
repeated-use protocol. Accordingly, where, as here, a food contact
substance is intended to be used in both single- and repeated-use food-
contact articles, we use the single-use protocol to determine exposure.
We only use the repeated-use protocol for food contact substances that
are only used in repeated-use food-contact articles. As Ciba's intended
use
[[Page 20853]]
of sodium perchlorate monohydrate was not limited to repeated-use food-
contact articles, its use of the single-use protocol, rather than the
repeated-use protocol, was appropriate.
i. Background on migration protocols. The migration protocols in
the chemistry guidance provide recommendations on: (1) How to determine
the total migration of a substance from a given food-contact surface
area (migration value) and (2) how to use that migration value to
determine dietary exposure to the migrating substance based upon the
mass of food the food-contact surface area will come into contact with
and the percentage of the diet that mass of food constitutes. The
single-use and repeated-use protocols both provide similar
recommendations on how to determine the total amount of migration of a
substance from a given food-contact surface area; however, they differ
in the assumptions used to determine dietary exposure from that
migration value. Specifically, to determine dietary exposure, the
single-use protocol applies the following factors to the migration
value: (1) FDA's standard assumption of the amount of food in contact
with a given surface area of a single-use articles (10 g of food
contacting each square inch of food-contact article); (2) food-type
distribution factors to account for the variable nature of the food
contacting each food-contact article (when applicable); and (3)
consumption factors (i.e., the fraction of the daily diet expected to
contact a specific type of packaging material). Ciba's calculation did
not use food-type distribution factors, and we will not discuss such
factors further. By comparison, the repeated-use protocol recommends
that dietary exposure be determined by applying to the migration value
an estimate of the total mass of food contacting a known food-contact
surface area over the service life of the article.
ii. Use of the single-use protocol for substances in both single-
and repeated-use articles. We consider the exposure calculated from the
single-use protocol to address the exposure to a food contact substance
used in both single- and repeated-use articles for several reasons,
including that: (1) The factors applied to the migration value to
determine exposure in the single-use protocol are exaggerative and (2)
exposure values from repeated-use articles are typically very small in
comparison to single-use articles.
We consider the factors applied to the migration value to determine
exposure in the single-use protocol to be exaggerative for several
reasons. For instance, the use of a consumption factor in the single-
use protocol assumes that the food contact substance will be used in
all food-contact articles that utilize the specific type of material to
which the consumption factor applies (as discussed in section III.A.1,
consumption factors are specific to a material--e.g., glass, paper, or
plastic--in that the consumption factor describes the fraction of the
daily diet expected to contact packaging that utilizes that type of
material). This is an exaggerative assumption. Food contact substances
are used in food-contact articles to perform a specific technological
function. It is highly unlikely that all food-contact articles that use
the type of packaging material to which a specific consumption factor
applies will require that technological function. In addition, the use
of a consumption factor does not account for the use of alternative
food contact substances that perform the same technological function.
The following example illustrates the exaggerative nature of the use of
a consumption factor: Under the single-use protocol one could use FDA's
consumption factor for colored plastics to determine exposure to a
black pigment intended to be added to plastic food packaging. FDA's
consumption factor for colored plastics describes the fraction of the
daily diet expected to contact packaging that consists of colored
plastic, regardless of the color of that plastic. However, not all
colored plastic is black, and, therefore, a black pigment would not be
added to all colored plastics. In addition, there are multiple black
pigments that are authorized to color food-contact articles. Given that
alternative black pigments are available for the same purpose, it is
unlikely that all black colored plastic packaging would use the
particular black pigment at issue.
We also note that exposure values from repeated-use articles are
typically very small in comparison to single-use articles because
individual repeated-use articles come into contact with significantly
larger amounts of food over their service lifetime than individual
single-use articles. This results in a much greater food mass-to-
surface area ratio for repeated-use articles than the 10 g of food
contacting each square inch of food-contact article assumption for
single-use articles. The greater food mass-to-surface area ratio for
repeated-use articles means that the total amount of migration of a
substance from a given food-contact surface area (the migration value)
is diluted across a much larger amount of food in comparison to a
single-use article, resulting in a significantly lower dietary
concentration.
In conclusion, we consider the exposure to a food contact substance
used in both single- and repeated-use articles to be addressed by the
exaggerative exposure calculated via the single-use protocol.
Therefore, we apply the single-use protocol to food contact substances
intended to be used in both single-use and repeated-use food-contact
articles.
iii. Applying worst-case assumptions to available migration
information. In any event, we note that the migration study described
in section III.A.2.a followed equivalent or more stringent
specifications than those recommended in the single- and repeated-use
protocols. In section III.A.3, we explain that, even if the absolute
worst-case assumptions for both the single- and repeated-use protocols
discussed in the chemistry guidance--that each square inch of food-
contact article will come into contact with 10 g of food, and that the
article will come into contact with all food in a consumer's diet (in
other words, no consumption factors or food type distribution factors
are applied to the migration value)--are applied to the migration value
determined from this study, the calculated dietary exposure to
perchlorate would still fall within the TOR exposure exemption
criteria. As such, the petitioners' assertions that Ciba did not follow
the repeated-use protocol discussed in the chemistry guidance document
and that use of a single-use protocol did not account for the release
(i.e., migration) of perchlorate over time if the finished article
degrades or is flexed, do not support the conclusion that TOR exemption
No. 2005-006 should be revoked.
3. Issues Pertaining to the Use of a Consumption Factor When
Calculating Dietary Exposure
The original calculation of dietary exposure resulting from the use
allowed by the TOR exemption No. 2005-006 used FDA's consumption factor
for substances that may be used in all polymers but only for specific
uses. The petition asserted that the use of a consumption factor in
this instance is inappropriate for a variety of reasons, including that
the consumption factor does not account for the use of sodium
perchlorate monohydrate in all antistatic agents and all polymers, nor
in reusable bulk packaging for raw materials which the petition said
result in finished articles containing sodium perchlorate monohydrate
coming into contact with food ingredients that will later be used in
the production of
[[Page 20854]]
processed foods which are not limited to non-fatty, dry foods.
To address the petition's assertions regarding the appropriateness
of the use of a consumption factor, we used the results of the
migration study provided in comments submitted to the docket for the
petition (discussed in section III.A.2.a) to calculate the dietary
exposure to perchlorate from the use allowed by TOR exemption No. 2005-
006 without the use of a consumption factor (Ref. 11). This approach
overestimates the dietary exposure from the use allowed by TOR
exemption No. 2005-006 because it assumes that finished articles
containing sodium perchlorate monohydrate will come into contact with
all foods in a consumer's diet instead of coming into contact with just
non-fatty, dry foods. This approach also assumes that all food will
come into contact with articles containing sodium perchlorate
monohydrate at the maximum allowed use level, which is a conservative
assumption because it can be expected that not all finished articles
would utilize the substance at the maximum allowed use level. In
addition, this calculation utilizes our food mass-to-surface area ratio
assumption for consumer (single use) packaging, even though it can be
expected that food-contact articles used in food processing and raw
material storage have a much larger food mass-to-surface area ratio
than consumer packaging (see discussion in section III.A.2.b.ii).
Using this conservative approach, we calculated a perchlorate
exposure of 1.5 [micro]g/person/day, which falls within the TOR
exemption criteria specified in Sec. 170.39(a)(2)(i) even without the
use of a consumption factor. This calculation demonstrates that the
assertions raised in the petition pertaining to the use of a
consumption factor do not support a conclusion that TOR exemption No.
2005-006 is no longer supportable under Sec. 170.39(g).
4. Inclusion of Use in Contact With Infant Formula and Food for
Children Younger Than Two Years Old
As discussed in section III.A.1, the original submission for TOR
exemption No. 2005-006 calculated the dietary exposure to perchlorate
from the intended use of sodium perchlorate monohydrate. This
calculation used several factors, including a consumption factor as
well as an assumption of a total food consumption of 3 kg of food per
day. Section I.C.3 of the petition stated that because these factors
are specific to adults, exposure calculated using these factors could
underestimate perchlorate exposure for infants relying on powdered
formula as their sole source of nutrition if sodium perchlorate
monohydrate was used in infant formula packaging as a result of TOR
exemption No. 2005-006. The petition stated that many infants rely on
infant formula as their sole source of nutrition, whereas adults
consume a diverse diet. The petition also stated that infants consume
more food per bodyweight than adults.
a. Section 170.39(a)(2)(i) and the use of specific factors to
calculate exposure. As discussed in section III.A.1, Sec.
170.39(a)(2)(i) requires that dietary exposure be calculated using a
specified assumption of 3 kg of food per day, which is an assumption
for the general adult population. In addition, Sec. 170.39(a)(2)(i)
requires that dietary exposure be expressed on a per person basis
([micro]g/person/day), which does not account for the fact that infants
consume more food per bodyweight than adults. To account for the fact
that infants consume more food per bodyweight than adults, infant
dietary exposure would need to be expressed on a bodyweight basis
([micro]g/kg bodyweight/day). Section 170.39(a)(2)(i) does not preclude
the use of a consumption factor when calculating exposure; as discussed
in section III.A.3, the use of a consumption factor refines exposure by
taking into account the fraction of the daily diet expected to contact
a specific type of packaging material rather than assuming a given food
contact substance will be used in contact with all food in a consumer's
diet. However, in section III.A.3 we also demonstrate that the dietary
exposure to perchlorate that results from the intended use subject to
TOR exemption 2005-006 falls within the TOR exemption criteria even if
that exposure is calculated without the use of a consumption factor.
b. Section 170.39(b) and infant exposure to perchlorate from the
TOR use. Although the intended use for TOR exemption No. 2005-006
results in an exposure of 1.5 [mu]g/person/day or less using the
assumptions specified in Sec. 170.39(a)(2)(i), under Sec. 170.39(b)
we can decline to grant a TOR exemption in those cases where the
available information establishes that the proposed use may pose a
public health risk. In certain circumstances, we believe that infants'
dietary exposure to a substance may be relevant to whether the proposed
use of a substance may pose a public health risk under Sec. 170.39(b).
Therefore, to address the petition's argument that the use of adult-
specific exposure assumptions could underestimate perchlorate exposure
for infants that solely consume reconstituted powdered formula, we
calculated a potential exposure to perchlorate in powdered formula from
the intended use allowed by TOR exemption No. 2005-006. We calculated
this potential infant dietary exposure by applying infant-specific
exposure assumptions articulated in FDA's draft guidance for food
contact notification submissions for food contact substances that
contact infant formula or human milk (Ref. 12), to data from the
migration study provided in comments submitted to the docket for the
petition (discussed in Section III.A.2.). These infant-specific dietary
exposure assumptions include an assumption that an infant (aged 0 to 6
months) consumes 900 g of liquid formula per day (data from the
National Health and Nutrition Examination Survey indicate that the
highest mean intake for infants 0-6-months is for 2-month old infants,
which have an intake of 900 grams/day). FDA also used the corresponding
mean body weight of 2-month olds of 6.3 kg bodyweight/infant. The
infant-specific potential dietary exposure estimate excludes the use of
a consumption factor, because infants aged 0 to 6 months frequently
consume human milk and/or infant formula exclusively. Using this
approach, we calculated a potential infant dietary exposure to
perchlorate in powdered formula from the intended use allowed by TOR
exemption No. 2005-006 of 0.019 [micro]g/kg bodyweight/day (Ref. 11).
As discussed in section III.B, the petition discusses the safety of
perchlorate exposure in the context of the RfD for perchlorate, as well
as a value derived from a preliminary, biologically based dose-response
model. This calculated potential perchlorate exposure for powdered
formula is less than both the RfD for perchlorate (0.7 [micro]g/kg
bodyweight/day) and the value derived from the model (0.42 [micro]g/kg
bodyweight/day). Thus, the petition does not demonstrate that there is
a public health risk to infants under Sec. 170.39(b) as a result of
the intended use of perchlorate allowed by TOR exemption No. 2005-006.
5. Consideration of Exposure From Other Sources
The petition asserted that section 409(c)(5)(B) of the FD&C Act and
Sec. 170.3(i)(2) require consideration of cumulative exposure to
perchlorate in the review of TOR exemption No. 2005-006 and that, if
these exposures are considered when calculating the dietary exposure
for the TOR exemption, the resultant exposure may exceed the TOR
exemption criteria of dietary exposure at or below 1.5 [micro]g/person/
day. Specifically, the petition stated that the
[[Page 20855]]
original calculation of dietary exposure resulting from the use allowed
by TOR exemption No. 2005-006 did not consider dietary exposure to
perchlorate as a result of the approved food-contact use of potassium
perchlorate listed in Sec. 177.1210, nor as a result of environmental
contamination of the food supply.
The use of a food contact substance that is exempted from
regulation as a food additive under FDA's TOR regulation is not subject
to the factors that apply to the proposed use of a food additive under
section 409(c)(5)(B) of the FD&C Act and Sec. 170.3(i)(2). Rather,
when we exempt a food-contact use of a substance from regulation as a
food additive, our TOR regulation ensures the safety of this food-
contact use by setting extremely low limits on migration levels so that
its proposed use results in a negligible dietary concentration, and
requiring that the substance not be a carcinogen. A premise of the TOR
regulation is that if a substance meets these requirements, it presents
no other health or safety concerns (see Sec. 170.39(a)(2)). In
determining whether the use of a substance qualifies for a TOR
exemption, cumulative exposure to a substance is not considered under
the TOR regulation because the dietary exposure from the use of a
substance that is at or below the threshold of regulation is
negligible. Thus, Sec. 170.39(a)(2)(i) provides that the only dietary
exposure that is relevant to whether the use of a substance qualifies
for a TOR exemption from regulation as a food additive is the dietary
exposure resulting from the use in question.
We established the threshold of regulation set forth in Sec.
170.39(a)(2)(i) based on available toxicological data showing that it
was feasible to establish a threshold level below which dietary
exposures to substances used in food-contact articles are so negligible
as to pose no public health or safety concerns (see 60 FR 36582, July
17, 1995). In the preamble to the proposed TOR rule, we explained that
our analysis of toxicological data on a large number of representative
compounds demonstrated that the noncarcinogenic toxic effects caused by
the majority of unstudied compounds would be unlikely to occur below
1,000 ppb (58 FR 52719 at 52722, October 12, 1993). To provide an
adequate safety margin, we selected 0.5 ppb as the threshold for
regulation, which is 2,000 times lower than the dietary concentration
at which the vast majority of studied compounds are likely to cause
noncarcinogenic toxic effects (see 58 FR 52719 at 52722). We also
analyzed potency data on a large number of known carcinogens to
determine that the 0.5 ppb dietary concentration level would result in
negligible risk, even in the event that a substance that is exempted
from regulation as a food additive were later shown to be a carcinogen
(see 58 FR 52719 at 52722).
Consistent with Sec. 170.39(a)(2)(i), we do not calculate
cumulative exposure to a substance in evaluating whether the use of the
substance qualified for a TOR exemption. As we explained in an April
2002 guidance for industry entitled, ``Preparation of Food Contact
Notifications for Food Contact Substances: Toxicology
Recommendations,'' at the time the TOR process was established, FDA
determined that, because of the conservative assumptions ordinarily
applied in estimating exposure, the cumulative exposure from a limited
number of trivial food additive uses is not likely to be more than
negligible. Accordingly, in the case of the TOR exposure levels, it was
not necessary to utilize cumulative exposure levels. FDA believes that
the determination made in establishing its TOR is still sound (Ref.
13).
Therefore, contrary to the petition's assertions, under FDA's TOR
regulations, the dietary exposures to perchlorate that are not a result
of the use specified in the TOR exemption No. 2005-006 are not
considered under the exposure criteria for the TOR exemption.
6. Inconsistencies Between the Intended Use Reviewed by FDA and That
Listed on Our Inventory of Effective TOR Exemptions
We maintain an inventory of effective TOR exemptions on our Web
site (Ref. 1). The originating submission for TOR exemption No. 2005-
006 requested a use for sodium perchlorate monohydrate in antistatic
agents at a maximum level of 4 percent by weight. The antistatic agent
would be used in finished plastic at a maximum level of 30 percent by
weight. The finished plastic would be used in contact with non-fatty,
dry foods (Food Type VIII) only. This is the intended use that we
considered in 2005 when we determined that the information provided in
the originating request demonstrated that the use would result in a
dietary exposure at or below the 1.5 [micro]g/person/day criteria. The
petition asserted that this intended use was expanded in the final
letter for the TOR exemption No. 2005-006 to permit the finished
article to be used in contact with all dry foods. The petition also
asserted that the intended use was further expanded in the listing on
our inventory of effective TOR exemptions, to include the use of sodium
perchlorate monohydrate in all types of food contact materials at a
maximum use level of 4 percent by weight in the finished article.
We agree that the intended use for TOR exemption No. 2005-006 was
inaccurately described in the final letter for the TOR exemption No.
2005-006 and the inventory of effective TOR exemptions. On August 17,
2015, we corrected the listing for TOR exemption No. 2005-006 on the
inventory of effective TORs on our Web site to be consistent with the
intended use reviewed by FDA when the TOR exemption became effective
and thereby address the petition's assertions regarding the description
of the intended use for TOR exemption No. 2005-006. We further revised
the listing for TOR exemption No. 2005-006 on September 19, 2016, to
clarify that TOR exemption No. 2005-006 allows the use of perchlorate
in the manufacture of antistatic agents for use in all polymeric food-
contact articles and not only polymeric food packaging.
B. Arguments Based on ``Significant New Information''
Part I.D. of the petition identified the following four categories
of ``significant new information'' that has become available after TOR
exemption No. 2005-006 became effective: ``First, additional research
shows that the endpoint used in the decision was not the most
appropriate or sensitive one to protect fetuses and infants from
permanent brain damage. Second, it is now known that nitrates and
thiocyanates are pharmacologically-related to perchlorate and,
therefore, must be considered in any safety evaluation of perchlorate
as an additive. Third, in 2011, FDA acknowledged that the 50 ppb
migration to dry-food default assumption (``virtually nil'' migration)
may be flawed based on research evidence from Europe. Fourth, FDA has
demonstrated that there is widespread contamination of the food supply
with perchlorate that must be considered.'' The petition asserted that
this new information warrants a reevaluation of TOR exemption No. 2005-
006 under Sec. 170.39(g).
We will first address the petition's arguments regarding
hypothyroxinemia and its proposed acceptable daily intake level, then
discuss the petition's arguments pertaining to perchlorate in the food
supply and pharmacologically related substances, and finally the
arguments pertaining to our 50 ppb migration concentration assumption.
[[Page 20856]]
1. Proposed Acceptable Daily Intake Level Based on Hypothyroxinemia
The petition proposed an acceptable daily intake (ADI) value in
place of the RfD for perchlorate and argues that the exposure from the
TOR use exceeds the ADI proposed in the petition. The petition stated
that the ADI proposed in the petition better accounts for
hypothyroxinemia as a potential result of perchlorate exposure than
does the RfD. However, under our TOR regulations, because a substance
is expected to migrate into food at negligible levels, a non-
carcinogenic endpoint such as hypothyroxinemia is not relevant unless
the use of the substance may pose a public health risk under Sec.
170.39(b). As discussed further in this section, the information in the
petition does not support such a conclusion under Sec. 170.39(b)
because: (1) Even if hypothyroxinemia were relevant, the petition does
not demonstrate that the proposed ADI better accounts for the potential
for perchlorate to cause hypothyroxinemia than the RfD for perchlorate;
(2) the proposed ADI is based on the results of a preliminary model;
and (3) even if it were appropriate to base an ADI on the results of
the preliminary model, the resulting ADI would still be above the
exposure from the TOR use.
a. Summary of petition's discussion on hypothyroxinemia. The
petition asserted that new information, available since TOR exemption
No. 2005-006 became effective, demonstrates that exposure to
perchlorate can result in hypothyroxinemia. As noted in section I.D.2,
hypothyroxinemia means that the fT4 value is at the lower end of the
normal range with normal levels of TSH in the blood. The petition
asserted that the SAB report, which was issued after the TOR exemption
became effective, identified the potentially sensitive population for
perchlorate exposure to be fetuses of hypothyroxinemic pregnant women.
This is in contrast to the NRC report, which identified the potentially
sensitive population for perchlorate exposure to be fetuses of pregnant
women with hypothyroidism or iodide deficiency (both the SAB report and
the NRC report are discussed in section I.D.2). Based upon this
difference, the petition asserted that the RfD, which was based on the
NRC review, does not provide sufficient protection to susceptible
populations. The petition also asserted that IUI, which is the basis of
the RfD, is a less sensitive endpoint than hypothyroxinemia.
The petition proposed an ADI of 0.042 [micro]g/kilogram bodyweight/
day for perchlorate based on the amount of perchlorate exposure that
may result in hypothyroxinemia in iodide-deficient pregnant women as
reported by FDA scientists in a 2013 Lumen et al. article (Ref. 14).
Lumen et al. summarizes the results of a proof-of concept, biologically
based dose-response (BBDR, also known as a PBPK/PD) model that is
specific to near-term human mothers and fetuses. This model used PBPK/
PD data to predict perchlorate intake levels that could produce thyroid
hormone perturbations at varying levels of maternal iodide intake. The
petition derived its proposed ADI by applying two ten-fold uncertainty
factors to the results presented in the Lumen et al. article. One ten-
fold uncertainty factor is applied to account for intraspecies
variability, while the second tenfold uncertainty factor is applied to
account for the assertion that the perchlorate exposure value provided
in the Lumen et al. article is based on a lowest observed adverse
effect level (LOAEL) rather than a no observed adverse effect level
(NOAEL). (The petition also stated that additional, unquantified
uncertainty factors should be applied to its proposed ADI to account
for deficiencies in the model, but it does not include these factors in
its calculation of the proposed ADI.) The petition subsequently
compared its proposed ADI to a dietary exposure to perchlorate
resulting from the use allowed by TOR exemption No. 2005-006 as
calculated in the petition. As the exposure to perchlorate calculated
in the petition is higher than the derived ADI, the petition asserted
that TOR exemption No. 2005-006 should be revoked.
b. FDA's consideration of the petition's discussion on
hypothyroxinemia. First, the petition contended that its proposed ADI
accounts for the potential for perchlorate to cause hypothyroxinemia
while the RfD for perchlorate does not. However, the petition does not
adequately support its assertion that the RfD for perchlorate fails to
account for the potential for perchlorate to cause hypothyroxinemia
(Ref. 15). The SAB's and NRC's identification of different sensitive
populations for perchlorate exposure is not a basis for concluding that
the RfD provides insufficient protection to the sensitive population
identified by the SAB, nor that the RfD does not account for the
potential for perchlorate to cause hypothyroxinemia. The RfD for
perchlorate is based on the IUI. As previously stated, the basis of the
MOA framework for perchlorate is that IUI must first occur prior to any
resultant thyroid hormone perturbations such as hypothyroxinemia or
hypothyroidism. This contradicts the petition's assertion that IUI is a
less sensitive endpoint than hypothyroxinemia. The NRC and SAB used the
MOA framework for perchlorate in determining their recommendations. The
MOA framework was also used in the development of the Lumen et al. BBDR
model cited by the petitioners (Ref. 14). Furthermore, the tenfold
intraspecies uncertainty factor utilized by the NRC in the derivation
of the RfD is a default value that is intended to account for the
entire range of sensitivity among humans to perchlorate exposure. The
petition did not provide support for its contention that this default,
intraspecies uncertainty factor is not inclusive of fetuses of pregnant
women with hypothyroxinemia.
Second, the 2013 Lumen et al. BBDR model that forms the basis of
the ADI proposed by the petitioners is a preliminary model (Ref. 15)
that FDA believes is not appropriate to use in a quantitative risk
assessment as presented in the petition. Because FDA does not believe
that the model should be used for a quantitative risk assessment due to
the preliminary nature of the analysis, consideration of the
appropriateness of the uncertainty factors proposed by the petitioners
is premature at this time. Since the 2013 Lumen et al. article, we have
worked with EPA scientists to further develop the model cited by the
petitioners. On January 10 and 11, 2017, EPA's contractor conducted an
independent, scientific public peer review of EPA's draft BBDR model
and report. EPA is currently considering peer reviewer comments. EPA
intends to seek peer review of a second report that evaluates methods
to apply the final BBDR model to develop a maximum contaminant level
goal for perchlorate in drinking water (see 81 FR 87553, December 5,
2016).
Third, we note that even if the approach taken in the petition were
appropriate--i.e., to calculate a risk assessment value based on the
results of the preliminary model referenced in the petition, and to
apply both 10-fold uncertainty factors specified in the petition (one
to account for a LOAEL and one to account for intraspecies variability)
to the amount of perchlorate exposure that may result in
hypothyroxinemia in iodide-deficient pregnant women as reported in the
Lumen et al. article--the resultant ADI calculated in the petition is
0.042 [mu]g/kg bodyweight/day. This risk assessment value is higher
than the exposure to
[[Page 20857]]
perchlorate as a result of TOR exemption No. 2005-006 as determined by
Ciba (0.063 [mu]g per chlorate/person/day, which equates to 0.001
[mu]g/kg bodyweight/day utilizing FDA's assumption of 60 kg bodyweight
for adults as described in the chemistry guidance), as well as the
exposures determined from the migration study discussed in section
II.A.2 (for adults: 0.075 [mu]g/person/day which equates to 0.001
[mu]g/kg bodyweight/day; and for infants: 0.019 [mu]g/kilogram
bodyweight/day--see section II.A.4). Therefore, even if deriving a risk
assessment value based on the results presented in the Lumen et al.
article were appropriate, the exposure to perchlorate as a result of
TOR exemption No. 2005-006 is lower than the resulting risk assessment
value, and therefore would not support the assertion by the petitioners
that the results presented in the Lumen et al. article ``raises
questions about the safe level of exposure to perchlorate relied on by
Ciba when the Agency approved TOR No. 2005-006.''
2. Argument Related to Cumulative Dietary Exposure From Perchlorate,
and Substances Pharmacologically Related to Perchlorate, in the Food
Supply
The petition asserted that new information has become available,
since FDA issued the listing regulation for potassium perchlorate in
Sec. 177.1210 and TOR exemption No. 2005-006, that nitrate and
thiocyanate are pharmacologically related to perchlorate, and that
perchlorate contamination of the food supply is widespread. The
petition also asserted that we are required to take into account the
cumulative effect of these substances in the diet.
As discussed in section III.A.5, under Sec. 170.39(a)(2)(i), we do
not calculate cumulative dietary exposure to a substance or
pharmacologically related substances in evaluating whether the use of
the substance qualifies for a TOR exemption from regulation as a food
additive. Under Sec. 170.39(a)(2)(i), the only dietary exposure that
is relevant to whether the use of a substance qualifies for a TOR
exemption from regulation as a food additive is the dietary exposure
resulting from the use in question. Therefore, the petition's argument
regarding cumulative dietary exposure to perchlorate or
pharmacologically related substances does not support a conclusion that
TOR exemption No. 2005-006 is no longer supportable.
3. Alleged Flaws in FDA's 50 ppb Migration Concentration Assumption
The petition stated that FDA, in a 2011 speech by an FDA scientist,
acknowledged potential flaws in the 50 ppb migration concentration
assumption for migration to non-fatty, dry foods (Food Type VIII). To
support this statement, the petition cited a 2011 article which
summarizes the speech given by the FDA scientist (Ref. 16). The
petition also asserted that the 50 ppb migration assumption is
particularly flawed for perchlorate, which is used in packaging to
neutralize the static charge on dry food.
The migration study provided in comments submitted to the docket
for the petition (discussed in section III.A.2.a) found that
perchlorate migrated into a simulant for non-fatty, dry foods at a
concentration of 0.5 ng perchlorate/g food, or 0.5 ppb. As noted, this
value is substantially less than the 50 ppb migration concentration
assumption provided in our chemistry guidance and indicates that the 50
ppb migration concentration assumption does not understate migration
from the intended use of sodium perchlorate monohydrate into non-fatty,
dry foods. As a result, the petition's contentions regarding alleged
flaws in the 50 ppb migration concentration assumption, both generally
and as applied to perchlorate, do not support a conclusion that TOR
exemption No. 2005-006 is no longer supportable.
C. Alleged Disproportionate Impact of Perchlorate on Children's Health
and FDA's Obligation Under Executive Order 13045
Executive Order 13045, ``Protection of Children from Environmental
Health Risks and Safety Risks'' (see 62 FR 19885, April 23, 1997),
provides in part that, ``to the extent permitted by law and
appropriate, and consistent with the agency's mission,'' each Federal
Agency ``shall ensure that its policies, programs, activities, and
standards address disproportionate risks to children that result from
environmental health risks or safety risks,'' which are defined as
``risks to health or to safety that are attributable to products or
substances that the child is likely to come in contact with or ingest
(such as the air we breath [sic], the food we eat, the water we drink
or use for recreation, the soil we live on, and the products we use or
are exposed to).'' The petition asserted that, because perchlorate has
a disproportionate impact on infants, the Executive Order warrants the
use by FDA of additional safety factors beyond those provided in Sec.
170.22 (21 CFR 170.22) when considering the safety of the food-contact
uses of perchlorate. Specifically, the petition contended that safety
factors in addition to the 100-fold safety factor stated in Sec.
170.22 are necessary due to deficiencies in the Lumen et al. BBDR model
(discussed in section III.B.1) and because a pregnant woman's short-
term exposure to perchlorate can cause irreversible harm to the fetal
brain if the woman has low iodine intake.
We note that Sec. 170.22 pertains to safety factors used in
applying animal experimentation data to man. As the safety arguments
presented in the petition utilize data obtained from human subjects,
and the petition discusses specific safety factors for each argument,
Sec. 170.22 is not relevant to the safety arguments presented in the
petition. Furthermore, in the December 5, 2014, submission the petition
stated that the tenfold safety factor utilized to derive the RfD for
perchlorate is consistent with Executive Order 13045.
With respect to the petition's request to apply additional safety
factors, section III.B.1 explains that FDA believes the results of the
BBDR model are preliminary in nature and not an appropriate basis for a
quantitative risk assessment as presented in the petition. A discussion
of whether or not uncertainty factors should be applied is premature at
this time. For these reasons, we believe that our analysis of the
potential health effects of perchlorate satisfies Executive Order 13045
and that the use of additional safety factors is not necessary.
D. Request To Issue a New Regulation Under 21 CFR Part 189
Part II of the petition asserted that, if FDA were to revoke TOR
exemption No. 2005-006, publication of the notice of revocation in the
Federal Register would be insufficient to alert industry, and therefore
requested that we issue a new regulation under part 189. The requested
regulation would prohibit the use of perchlorates in the manufacture of
antistatic agents to be used in food-contact articles, which is the use
of perchlorate allowed by TOR exemption No. 2005-006.
Because we conclude that TOR exemption No. 2005-006 remains
supportable under Sec. 170.39, we decline to propose a regulation
under part 189 prohibiting this use of perchlorate.
IV. Comments on the Filing Notice
We received very few comments on the petition. Those comments that
discussed the safety of the use of perchlorate in food contact
applications did not provide any additional data to that presented in
the petition.
In this section we discuss the issues raised in the remaining
comments. We preface each comment discussion with a numbered
``Comment'' and each
[[Page 20858]]
response by the word ``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) One comment provided a migration study for sodium
perchlorate monohydrate from a worst-case polymeric resin into a dry
food simulant.
(Response) This study is discussed in section III.A.2.
(Comment 2) Several comments stated that the use of potassium
perchlorate as an additive in closure-sealing gaskets for food
containers has been abandoned.
(Response) The abandonment of potassium perchlorate as an additive
in closure-sealing gaskets is the subject of a separate food additive
petition, 6B4816, which we address elsewhere in this edition of the
Federal Register.
(Comment 3) Another comment stated that the petition's request that
FDA add perchlorate to the list of prohibited substances contained in
part 189 is based upon the identification of a hazard relating to a
class of chemical substances. The comment asserted that an approach to
safety assessment based on hazard identification is a departure from
FDA's practice of evaluating the safety of food contact materials based
on their intended use.
(Response) As we are declining to propose a regulation under part
189 prohibiting the use of perchlorates as a food contact substance in
antistatic agents (see section V), it is not necessary to respond to
this comment.
V. Conclusion
We reviewed the petition and with respect to the petition's first
request, we have determined that the dietary exposure to sodium
perchlorate monohydrate as a result of the use allowed by the TOR
exemption No. 2005-006 does not exceed the TOR exemption criteria in
Sec. 170.39(a)(2)(i) and that the data and information provided do not
support a conclusion that TOR exemption No. 2005-006 is no longer
supportable. With respect to the petition's second request, we decline
to propose a regulation under part 189 prohibiting the use of
perchlorates as a food contact substance in antistatic agents because
proposing such a regulation would be inconsistent with our conclusion
that the data and information provided in the petition do not support a
conclusion that TOR exemption No. 2005-006 is no longer supportable.
With respect to the petition's third request, which is the sole request
that is the proper subject of a food additive petition, the food
additive use of potassium perchlorate has been removed from Sec.
177.1210 in a final rule published elsewhere in this issue of the
Federal Register and we decline to address the petitioners' assertions
regarding the safety of the food additive use. Therefore, we are
denying all three requests, and we are denying the petition in full.
VI. Objections
Any person that may be adversely affected by this order may file
with the Division of Dockets Management (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 Division of Dockets Management between 9 a.m. and 4
p.m., Monday through Friday, and will be posted to the docket at
https://www.regulations.gov. We will publish notice of the objections
that we have received or lack thereof in the Federal Register.
As explained in section II.C, only the petition's request to amend
Sec. 177.1210 is within the scope of a food additive petition under
section 409(b) of the FD&C Act. The remaining two requests are not
within the scope of a food additive petition and our denial of these
requests is not an order under section 409(c)(1)(B) of the FD&C Act.
Therefore, the provision for objections and public hearing under
section 409(f) of the FD&C Act does not apply to these two requests.
VII. References
The following references are on display in the Division of Dockets
Management (see ADDRESSES) and are available for viewing by interested
persons between 9 a.m. and 4 p.m., Monday through Friday; they are also
available electronically at https://www.regulations.gov. FDA has
verified the Web site addresses, as of the date this document publishes
in the Federal Register, but Web sites are subject to change over time.
1. FDA. ``Threshold of Regulation Exemptions.'' Available at https://www.fda.gov/Food/IngredientsPackagingLabeling/PackagingFCS/ThresholdRegulationExemptions/default.htm.
2. National Research Council. 2005. ``Health Implications of
Perchlorate Ingestion.'' Washington, DC. National Academies Press.
ISBN 0-309-09568-9. Available at https://www.nap.edu/catalog/11202/health-implications-of-perchlorate-ingestion.
3. EPA. 2013. ``SAB Advice on Approaches to Derive a Maximum
Contaminant Level Goal for Perchlorate.'' EPA-SAB-13-004. Available
at https://yosemite.epa.gov/sab%5CSABPRODUCT.NSF/
86E44EE7F27EEC1A85257B7B0060F364/$File/EPA-SAB-13-004-unsigned2.pdf.
4. Greer, M.A., G. Goodman, R.C. Pleus, et al. 2002. ``Health Effect
Assessment for Environmental Perchlorate Contamination: The Dose
Response for Inhibition of Thyroidal Radioiodide Uptake in Humans.''
Environmental Health Perspective. 110:927-937.
5. National Institutes of Health, ``Hypothyroidism (Underactive
Thyroid).'' Available at https://www.niddk.nih.gov/health-information/endocrine-diseases/hypothyroidism.
6. EPA. ``Perchlorate (ClO4) and Perchlorate Salts.''
Available at https://cfpub.epa.gov/ncea/iris2/chemicalLanding.cfm?substance_nmbr=1007.
7. EPA. ``White Paper: Life Stage Considerations and Interpretation
of Recent Epidemiological Evidence to Develop a Maximum Contaminant
Level Goal for Perchlorate.'' 2012. Available at https://
yosemite.epa.gov/sab/sabproduct.nsf/
d21b76bff879fa0a8525735a00766807/D3BB75D4297CA4698525794300522ACE/
$File/Final+Perchlorate+White+Paper+05.29.12.pdf.
8. Stedman, T.L. 2006. ``Stedman's Medical Dictionary.''
Philadelphia: Lippincott Williams & Wilkins. 28th ed. ISBN 978-
0781733908.
9. FDA. ``Guidance for Industry: Preparation of Premarket
Submissions for Food Contact Substances: Chemistry
Recommendations.'' Available at https://www.fda.gov/Food/GuidanceRegulation/GuidanceDocumentsRegulatoryInformation/IngredientsAdditivesGRASPackaging/ucm081818.htm.
[[Page 20859]]
10. FDA Memorandum from J. Smith, September 15, 2005.
11. FDA Memorandum from R. Costantino to P. Honigfort, March 31,
2017.
12. FDA. ``Draft Guidance for Industry: Preparation of Food Contact
Notifications for Food Contact Substances in Contact with Infant
Formula and/or Human Milk.'' December 2016. Available at https://www.fda.gov/Food/GuidanceRegulation/GuidanceDocumentsRegulatoryInformation/ucm528215.htm.
13. FDA. ``Guidance for Industry: Preparation of Food Contact
Notifications for Food Contact Substances: Toxicology
Recommendations.'' Available at https://www.fda.gov/Food/GuidanceRegulation/GuidanceDocumentsRegulatoryInformation/ucm081825.htm.
14. Lumen A., D.R. Mattie, and J.W. Fisher. ``Evaluation of
Perturbations in Serum Thyroid Hormones During Human Pregnancy Due
to Dietary Iodide and Perchlorate Exposure Using a Biologically
Based Dose-Response Model.'' Toxicological Sciences. 133(2):320-41,
2013.
15. FDA Memorandum from G. Patton, P. Honigfort, and J. Aungst to
Administrative File, March 31, 2017.
16. Clapp, S., ``FDA Chemist Says Agency's Food Contact Advice is
`Showing Its Age.' '' Food Chemicals News. 53(30): 11-12, 2011.
Dated: April 28, 2017.
Anna K. Abram,
Deputy Commissioner for Policy, Planning, Legislation, and Analysis.
[FR Doc. 2017-08987 Filed 5-3-17; 8:45 am]
BILLING CODE 4164-01-P