[Federal Register Volume 85, Number 28 (Tuesday, February 11, 2020)]
[Proposed Rules]
[Pages 7698-7708]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2020-02665]
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ENVIRONMENTAL PROTECTION AGENCY
40 CFR Part 180
[EPA-HQ-OPP-2015-0230; FRL-9998-74]
RIN 2070-ZA16
Banda de Lupinus Albus Doce (BLAD); Proposal To Revoke Exemption
and Establish Pesticide Tolerances
AGENCY: Environmental Protection Agency (EPA or Agency).
ACTION: Proposed rule; reproposal.
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SUMMARY: On May 29, 2015, EPA proposed to revoke the current exemption
from the requirement of a tolerance for residues of banda de Lupinus
albus doce (BLAD) in or on all food commodities and to establish
tolerances for residues of BLAD in or on almonds, grapes, strawberries,
and tomatoes. Following the receipt of several comments, the Agency is
reproposing this action in order to clarify its proposed rulemaking. In
addition, since the publication of the initial proposal, the registrant
has requested that the Agency establish tolerances for additional
commodities. The Agency is undertaking this action under the Federal
Food, Drug, and Cosmetic Act (FFDCA).
DATES: Comments must be received on or before April 13, 2020.
ADDRESSES: Submit your comments, identified by docket identification
number EPA-HQ-OPP-2015-0230, by one of the following methods:
Federal eRulemaking Portal: http://www.regulations.gov.
Follow the online instructions for submitting comments. Do not submit
electronically any information you consider to be Confidential Business
Information (CBI) or other information whose disclosure is restricted
by statute.
Mail: OPP Docket, Environmental Protection Agency Docket
Center (EPA/DC), (28221T), 1200 Pennsylvania Ave. NW, Washington, DC
20460-0001.
Hand Delivery: To make special arrangements for hand
delivery or delivery of boxed information, please follow the
instructions at http://www.epa.gov/dockets/where-send-comments-epa-dockets.
Additional instructions on commenting or visiting the docket, along
with more information about dockets generally, is available at http://www.epa.gov/dockets.
FOR FURTHER INFORMATION CONTACT: Anne Overstreet, Deputy Director,
Biopesticides and Pollution Prevention Division (7511P), Office of
Pesticide Programs, Environmental Protection Agency, 1200 Pennsylvania
Ave. NW, Washington, DC 20460-0001; main telephone number: (703) 305-
7090; email address: [email protected].
SUPPLEMENTARY INFORMATION:
I. General Information
A. Does this action apply to me?
You may be potentially affected by this action if you are an
agricultural producer, food manufacturer, or pesticide manufacturer.
The following list of North American Industrial Classification System
(NAICS) codes is not intended to be exhaustive, but rather provides a
guide to help readers determine whether this document applies to them.
Potentially affected entities may include:
Crop production (NAICS code 111).
Animal production (NAICS code 112).
Food manufacturing (NAICS code 311).
Pesticide manufacturing (NAICS code 32532).
B. What should I consider as I prepare my comments for EPA?
1. Submitting CBI. Do not submit this information to EPA through
regulations.gov or email. Clearly mark the part or all of the
information that you claim to be CBI. For CBI information on a disk or
CD-ROM that you mail to EPA, mark the outside of the disk or CD-ROM as
CBI and then identify electronically within the disk or CD-ROM the
specific information that is claimed as CBI. In addition to one
complete version of the comment that includes information claimed as
CBI, a copy of the comment that does not contain the information
claimed as CBI must be submitted for inclusion in the public docket.
Information so marked will not be disclosed except in accordance with
procedures set forth in 40 CFR part 2.
2. Tips for preparing your comments. When preparing and submitting
your comments, see the commenting tips at http://www.epa.gov/dockets/commenting-epa-dockets#tips.
II. This Proposal
A. What is the authority for this action?
EPA is taking this action under section 408(e) of the FFDCA, 21
U.S.C. 346a(e), which allows EPA to issue regulations, including
establishing tolerances and revoking exemptions, on its own initiative.
Under FFDCA section 408(e), the Agency applies the same standards for
establishing tolerances and revoking exemptions found in FFDCA section
408(b) and (c), 21 U.S.C. 346a(b) and (c). FFDCA section
408(b)(2)(A)(i) allows EPA to establish a tolerance (the legal limit
for a pesticide chemical residue in or on a food) only if EPA
determines that the tolerance is ``safe.'' FFDCA section
408(b)(2)(A)(ii) defines ``safe'' to mean that ``there is a reasonable
certainty that no harm will result from aggregate exposure to the
pesticide chemical residue, including all anticipated dietary exposures
and all other exposures for which there is reliable information.'' This
includes exposure through drinking water and in residential settings
but does not include occupational exposure. FFDCA section 408(b)(2)(C)
requires EPA to give special consideration to exposure of infants and
children to the pesticide chemical residue in establishing a tolerance
and to ``ensure that there is a reasonable certainty that no harm will
result to infants and children from aggregate
[[Page 7699]]
exposure to the pesticide chemical residue. . . .''
The relevant portion of FFDCA section 408(c)(2)(A)(i) requires the
Agency to modify or revoke an exemption if the Agency determines it is
not safe, where ``safe'' has the same definition as in FFDCA section
408(b)(2)(A)(ii).
EPA performs a number of analyses to determine the risks from
aggregate exposure to pesticide residues. For further discussion of the
regulatory requirements of FFDCA section 408 and a complete description
of the risk assessment process, see http://www.epa.gov/pesticide-tolerances/setting-tolerances-pesticide-residues-foods.
B. What action is the Agency taking?
EPA is proposing to revoke the existing exemption from the
requirement of a tolerance for residues of the fungicide BLAD in or on
all food commodities that was established in the Federal Register of
March 22, 2013 (78 FR 17600) (FRL-9380-6). In place of the exemption,
EPA is proposing to establish tolerances for residues of the fungicide
BLAD at the level of quantitation (LOQ), i.e., 0.02 parts per million
(ppm), in or on the following commodities: Almond; almond, hulls;
fruit, pome, group 11-10; fruit, stone, group 12-12; grape; hops, dried
cones; strawberry; vegetable, cucurbit, group 9; and vegetable,
fruiting, group 8-10.
EPA is taking this action in response to concerns raised by the
U.S. Food and Drug Administration (FDA) about the potential
allergenicity of BLAD for lupin-sensitive and/or peanut-sensitive
individuals following EPA's promulgation of the tolerance exemption of
BLAD on all food commodities. (Ref. 1). Based on the potential
uncertainty raised by those concerns, EPA sought additional data from
the petitioner and reexamined the safety of the BLAD tolerance
exemption. Following further review of BLAD and an assessment of the
additional data that were provided, EPA has concluded that given the
source of BLAD and the results of bioinformatics analysis, such data do
not disprove the potential for BLAD to pose an allergenicity risk to
lupin-sensitive and peanut-sensitive individuals. As a result, EPA no
longer considers the existing tolerance exemption for residues of BLAD,
which, on its face, permits unlimited residues of BLAD in or on all
food commodities, to be safe. Nevertheless, EPA concludes that the
available residue data and food processing information support a safety
determination for establishing numerical tolerances at the LOQ for
residues of BLAD in or on almond; almond, hulls; fruit, pome, group 11-
10; fruit, stone, group 12-12; grape; hops, dried cones; strawberry;
vegetable, cucurbit, group 9; and vegetable, fruiting, group 8-10.
III. Guidance for Assessing Allergenicity
The Agency considered the following sources of internationally
accepted guidance in assessing the potential allergenicity of BLAD.
Although these documents are primarily concerned with the safety of
foods that have been genetically modified, the allergenicity analysis
is relevant since it outlines a process for evaluating whether the gene
(or protein) engineered into the food has introduced an allergen or
resulted in a food that may be allergenic. EPA considers the
recommended approaches for assessing potential allergenicity to apply
equally to proteins that may be applied directly onto the plant as well
as those directly incorporated into the plant via genetic engineering.
A. Report of Joint FAO/WHO Expert Consultation (2001)
In 2001, the Joint Food and Agriculture Organization of the United
Nations (FAO)/World Health Organization (WHO) Expert Consultation on
Allergenicity of Foods Derived from Biotechnology was held at the
headquarters of the FAO. The 28-expert consultation focused on the
question of allergenicity of genetically modified foods and prepared a
report providing scientific advice for the assessment of allergenicity
of genetically modified foods. (Ref. 2, hereinafter ``2001 FAO/WHO
Report''). The consultation developed a new decision tree identifying
two paths for assessing allergenicity, depending upon whether the
source of the gene is a known allergen. (Id. at 6, 26).
If the source of the gene is a known allergen, the analysis focuses
on both sequence homology and specific sera testing. (Id. at 7-8).
Determining sequence homology to a known allergen is the first step for
genes derived from known allergenic sources. The 2001 FAO/WHO Report
notes that significant sequence homology is indicated (and thus a
potential for cross-reactivity between the new protein and a known
allergen) when there is more than 35% identity between the amino acid
sequence of the expressed protein and the known allergen, within a
window of 80 amino acids. (Id. at 10-11).\1\ If the sequence homology
demonstrates similarity to a known allergen, the product is considered
allergenic, i.e., a person sensitive to a known allergen is likely to
be allergic to the new protein as well. (Id. at 7). The 2001 FAO/WHO
Report notes that for proteins derived from known allergenic sources
where sequence homology to a known allergen is demonstrated, ``the
product is considered allergenic, and no further testing is typically
undertaken.'' (Id.)
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\1\ The 2001 FAO/WHO Report also recognizes that potential for
cross-reactivity may require consideration of additional factors
when proteins have less than 35% identity with a known allergen in a
window of 80 amino acids. (Ref. 2 at 11). These considerations are
not discussed in this document since the sequence homology for BLAD
exceeds 35% identity with other known allergens.
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The 2001 FAO/WHO Report provides that for proteins derived from
known allergenic sources where the sequence homology analysis is
negative, a specific serum screen is to be conducted. (Id. at 7). The
2001 FAO/WHO Report recommends using only patients with a level of
sensitization to the allergen source of more than 10 kilointernational
units per liter (kIU/L) of specific immunoglobulin E (IgE), in order to
ensure that the test is conducted with sera from patients sufficiently
allergic to the source material, and cautions that patients who have a
low level of sensitization may not provide useful results for assessing
reactivity to the expressed protein. (Id.) Assuming adequately
sensitive sera are available, the 2001 FAO/WHO Report notes that the
degree of confidence in the results of the specific serum screening
will depend upon the number of sera available for analysis. To achieve
a 95% certainty that a substance is not a major allergen, a negative
result must be obtained with at least 6 relevant sera; 99% certainty,
at least 8 relevant sera; 99.9% certainty, at least 14 relevant sera.
To achieve 95% certainty that a substance is not a minor allergen, a
negative result must be obtained with at least 17 relevant sera; 99%
certainty, at least 24 relevant sera. Larger numbers of sera are
recommended to increase the confidence associated with negative
immunoassay results; using fewer sera carries the risk of a false
negative outcome. (Id.) The 2001 FAO/WHO Report notes that the in vitro
method applied to assess the results should be a validated assay
measuring specific IgE. (Id.)
The 2001 FAO/WHO Report concludes that any positive results from
the sera screen will define the product as likely to be allergenic and
will normally lead to discontinuation of product development. (Id.) A
negative outcome from the sera screen does not necessarily support a
conclusion that the product is not allergenic, however;
[[Page 7700]]
rather, because of the allergenic nature of the source of the
substance, a desire to continue with product development will normally
prompt further analysis to rule out allergenicity concerns (i.e.,
targeted serum screening, analysis of pepsin resistance, and animal
modeling, and in selected cases, in vivo/ex vivo testing (i.e., skin
prick testing, basophil histamine release, and oral challenge)). (Id.
at 7-8).
If the source of the protein is not a known allergen, the 2001 FAO/
WHO Report decision tree advises consideration of four sets of data:
(1) Sequence homology with known allergens; (2) targeted serum testing;
(3) pepsin resistance; and (4) immunogenicity testing in animal models.
(Id. at 8). If the sequence homology reveals a level of homology with a
known allergen, the protein is ``considered to be an allergenic risk .
. . [and n]o further evaluation for allergenicity would typically be
necessary.'' (Id.) If the sequence homology does not identify any
similarities, the 2001 FAO/WHO Report notes that it does not
necessarily mean that the substance is not an allergen. Rather, because
of potential limitations in the databases or limited information on the
relevant allergen, the 2001 FAO/WHO Report recommends that a targeted
serum screen be conducted to test for cross-reactivity of individual
serum samples containing high levels of IgE antibodies specific to a
source broadly related to the source of the substance at issue, e.g.,
if the gene is derived from a monocot, sera from individuals with
allergies to other monocots would be used in the screen. (Id. at 12). A
positive result with one of these sera will indicate that the substance
is likely to be allergenic and further study would not be necessary,
unless further confirmation is sought through in vivo/ex vivo
approaches mentioned above. (Id. at 8). Negative results would then
lead to the analysis of the protein for pepsin resistance (i.e., how
completely the protein degrades in the presence of pepsin during
digestion) and evidence of immunogenicity in appropriate animal models.
(Id. at 12-13). The 2001 FAO/WHO Report recommends that any results of
these analyses be taken into consideration in combination with the rest
of the decision tree criteria. (Id. at 13.)
B. Codex Alimentarius Guidance (2009)
The Codex Alimentarius Guidance is a ``collection of
internationally adopted food standards, guidelines, codes of practice
and other recommendations,'' developed by an intergovernmental body
with more than 180 members, within the framework of the Joint Food
Standards Programme established by the FAO and WHO. (Ref. 3, preface).
Contained within the Codex Alimentarius Guidance, the Guideline for the
Conduct of Food Safety Assessment of Foods Derived from Recombinant-DNA
Plants (``Codex Guideline'') addresses safety and nutritional aspects
of genetically altered foods and recommends an approach for assessing
the safety of foods derived from recombinant-DNA plants and plants
altered by other techniques. (Id. at 7-33).
The Codex Guideline states that all newly expressed proteins in
recombinant-DNA plants should be assessed for their potential to cause
allergic reactions. (Id. at 15). The Codex Guideline describes stepwise
approach to the assessment of the possible allergenicity of newly
expressed proteins. (Id. at 20-23). The initial assessment involves
three steps: (1) Identify the source of the protein; (2) assess the
extent to which a protein is similar in structure to a known allergen;
and (3) evaluate the resistance of the protein to degradation by
pepsin. (Id. at 21-22).
The Codex Guideline states that ``[i]t is important to establish
whether the source is known to cause allergic reactions. Genes derived
from known allergenic sources should be assumed to encode an allergen
unless scientific evidence demonstrates otherwise.'' (Id. at 21). The
Codex Guideline notes ``[t]he transfer of genes from commonly
allergenic foods . . . should be avoided unless it is documented that
the transferred gene does not code for an allergen. . . .'' (Id. at
15). Because there is no single definitive test for predicting allergic
human response, ``[k]nowledge of the source of the introduced protein
allows the identification of tools and relevant data to be considered
in the allergenicity assessment. These include: the availability of
sera for screening purposes; documented type, severity and frequency of
allergic reactions; structural characteristics and amino acid sequence;
physicochemical and immunological properties (when available) of known
allergenic proteins from that source.'' (Id. at 21).
The next piece of the allergenicity assessment is the amino acid
sequence homology, the purpose of which is to determine whether a
protein is similar in structure to a known allergen and thus has
allergenic potential. (Id.) Assessing similarity to known allergens is
done by comparing the new protein to databases of known allergens,
looking for two types of similarity. First, the sequence homology looks
for contiguous identical amino acid segments; the Codex Guideline noted
that ``the size of the contiguous amino acid search should be based on
scientifically justified rationale in order to minimize the potential
for false negative or false positive results,'' whereas the 2001 FAO/
WHO Report recommended moving from 8 to 6 identical amino acid
segments. (Id.) Second, the sequence homology looks for whether there
is a potential for human IgE cross-reactivity between the new protein
and a known allergen. (Id.) The Codex Guideline incorporates the
finding of the 2001 FAO/WHO Report, which concludes that a potential
cross-reactivity is likely when there is more than 35% identity in a
segment of 80 or more amino acids. (Id.) Where there is a negative
sequence homology, it indicates that the protein is not a known
allergen and is unlikely to be cross-reactive with known allergens.
(Id. at 22). A positive sequence homology indicates that the protein is
likely to be allergenic and, in order to be considered further,
specific serum testing (i.e., testing conducted using serum of
individuals who are sensitized to the allergenic source) should be
conducted. (Id.)
The Codex Guideline also recognizes that many food allergens
exhibit resistance to pepsin digestion and thus resistance to pepsin
digestion can be used to assess potential allergenicity. (Id.) If a
protein is resistant to pepsin digestion, it suggests that further
analysis should be conducted to evaluate potential allergenicity;
however, the Codex Guideline notes that lack of resistance does not
necessarily mean that the protein is not an allergen. (Id.)
The Codex Guideline states that for proteins that originate from a
known allergenic source or that have sequence homology with a known
allergen, testing in immunological assays should be performed where
sera are available. (Id.) The sera should be obtained from individuals
with a ``clinically validated allergy'' to the protein source, and sera
must be obtained from sufficient numbers of individuals to achieve the
necessary level of confidence in the test results regarding the
protein's allergenicity. (Id.) The 2001 FAO/WHO Report notes that, in
the case of a major allergen, a minimum of eight relevant sera is
required in order to achieve a 99% certainty that the new protein is
not an allergen, while in the case of a minor allergen, a minimum of 24
is required. (Id. at n.11). In addition, the ``quality of the sera and
the assay procedure need to be standardized to produce a valid test
result.'' (Id. at 23). ``[A] negative result in in vitro
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immunoassays may not be considered sufficient, but should prompt
additional testing, such as the possible use of skin test and ex vivo
protocols. A positive result in such tests would indicate a potential
allergen.'' (Id.)
IV. Regulatory Background
BLAD is a protein fragment with fungicidal properties. More
specifically, BLAD is a 20 kilodalton (kDa) polypeptide fragment of
[beta]-conglutin, a main storage protein in the flowering plant sweet
lupin (Lupinus albus). BLAD is produced by breakdown of [beta]-
conglutin during day 4 to 12 of the germination process of sweet
lupins. BLAD degrades chitin by catalyzing and successfully removing
the N-acetyl-D-glucosamine terminal monomers, resulting in the
destruction of fungal cells. (Ref. 4).
In the Federal Register of March 22, 2013 (78 FR 17600) (FRL-9380-
6), EPA established an exemption from the requirement of a tolerance
for residues of BLAD in or on all food commodities when applied as a
fungicide and used in accordance with label directions and good
agricultural practices. EPA established this tolerance exemption
following the receipt of a petition from Consumo Em Verde S.A.,
Biotecnologia De Plantas, Parque Technologico de Cantanhede (CEV) in
2012. The Agency's safety finding was based on an assessment of
available data and an assumption that there was a long history of safe
use in human and animal consumption without any adverse effects.
Although the preamble to the March 2013 final rule did not discuss
the potential allergenicity of BLAD, EPA's supporting memorandum for
the establishment of a tolerance exemption examined BLAD's potential
allergenicity, based on the available information EPA had about BLAD at
the time. (Ref. 4). Observing that (i) BLAD comprises an internal
segment of [beta]-conglutin, (ii) [beta]-conglutin exhibits a
relatively strong homology to the other members of the vicilin family,
including well-known allergens contained in peanuts and soybeans, and
(iii) there were a considerable number of studies concerning the
allergenicity of lupin-derived products, EPA conducted an allergenicity
assessment of BLAD. (Id.) EPA examined BLAD under the criteria in the
2001 FAO/WHO Report and the Codex Guideline for assessing proteins not
known to be derived from an allergenic source, which it characterized
as follows: (la) Amino acid residue homology >35%, or (1b) identity in
one or more sets of >6 contiguous amino acid residues, or (1c) cross-
reactivity to known allergens; (2) high resistance to proteolytic
attack; and (3) ingestion of sufficient amounts. (Id.) Although EPA
found that BLAD exhibited a high sequence homology with a well-
established peanut allergen, Ara h 1, EPA concluded that a tolerance
exemption would be safe because, when used according to the proposed
label directions, BLAD's potential exposure and harmful effects to
humans would be negligible, and no adverse effects such as allergenic
reactions would be expected. (Id.)
Following EPA's establishment of this BLAD tolerance exemption,
however, FDA expressed concerns about the potential allergenicity of
BLAD for lupin-sensitive and/or peanut-sensitive individuals. (Ref. 1).
FDA noted that the preamble to the March 2013 final rule did not
discuss allergenicity and disagreed with EPA's statement in the
tolerance exemption preamble about the long history of safe consumption
of sweet lupins. (Id.) FDA noted that BLAD is derived from the lupin
plant and provided information concerning the allergenicity of lupin.
(Id.) Specifically, FDA provided scientific literature indicating that
lupin causes allergic reactions and epidemiological evidence indicating
that lupin is an increasingly significant allergenic hazard in Europe
where it is consumed. (Id.) FDA also referred EPA to the 2005 European
Food Safety Authority (EFSA) official opinion. The EFSA opinion
examined the potential for allergenicity of lupin in response to a
request from the European Commission, which was considering whether to
place lupin on a list of known allergens and require lupin
identification on food labels. (Id.; see also Ref. 5). The EFSA opinion
noted allergic reactions to lupin have been documented in individuals
allergic to peanuts and those with no known allergy to peanuts. (Ref.
5).
FDA also provided information on BLAD's bioinformatics. Using
publicly available sequence information, FDA determined that [beta]-
conglutin, the specific protein from which BLAD is derived, is a major
lupin allergen, Lup an 1. (Ref. 1). FDA further concluded that BLAD has
a high amino acid sequence identity to two major allergens--Lup an 1
and Ara h 1, a major peanut allergen. (Id.) Based on information about
the allergenicity of the source plant and the sequence homology to
major allergens, FDA concluded that, under the Codex Guideline and the
2001 FAO/WHO Report, BLAD would be considered an allergen until proven
otherwise. (Id.)
Taking this new information concerning BLAD's source into account
along with BLAD's bioinformatics, EPA proceeded to analyze BLAD under
the Codex Guideline approach for assessing proteins derived from known
allergenic sources, which emphasizes the need for specific sera testing
to overcome the presumption that the protein will be allergenic. (Ref.
6). This new approach differed from the approach EPA used in its
initial assessment of BLAD; lacking information that the protein was
derived from a known allergenic source, EPA had used the general
assessment approach recommended for proteins that are not known to be
derived from known allergenic sources. (Id.) In addition to using this
new approach, EPA sought FDA's insight on evaluating food allergens as
it evaluated BLAD's potential allergenicity.
Applying the 2001 FAO/WHO Report and Codex Guideline processes for
assessing substances derived from known allergenic sources, EPA
requested that CEV submit additional data to overcome the presumption
that BLAD would pose a potential allergenicity concern. EPA also
required residue chemistry field trials and a residue decline study to
determine likely residue levels of BLAD on treated commodities listed
on the pesticide label. (Id.) Upon receipt of this new information, EPA
reexamined the safety of BLAD.
Based on that reexamination, on May 29, 2015, EPA proposed to
revoke the established tolerance exemption, which, on its face,
contains no numerical limit on permissible residues in or on all food
commodities, and to establish tolerances for residues of BLAD in or on
almonds, grapes, strawberries, and tomatoes at 0.005 ppm (the level of
detection). 80 FR 30640 (May 29, 2015). In essence, the proposal noted
that, since the available allergenicity data did not rule out the
potential of BLAD's allergenicity, the Agency was unable to continue
supporting the safety finding for the BLAD exemption, which set no
numerical limits for exposures to BLAD on all food commodities, which
facilitate the process for identifying residues that might be higher
than expected in instances of pesticidal misuse. Nevertheless, the
Agency determined that, because the available residue data indicate a
lack of detectable residues on certain commodities (i.e., almonds,
grapes, strawberries, and tomatoes), numerical tolerances set at the
level of detection for ensuring negligible residues of BLAD on almonds,
grapes, strawberries, and tomatoes as expected under approved label use
conditions were safe. Id. at 30643-44.
[[Page 7702]]
The Agency received five timely comments on the proposal, as well
as a number of late-filed comments. Of those timely comments, many
expressed confusion about the Agency's basis for its proposal and
challenged whether the proposal was based on the available data. Some
commenters also expressed concerns for the proposal's impact on farmers
and trade. Upon further review of that proposal and following
additional consultation with FDA regarding the commenters' scientific
challenges to the proposal (Refs. 7, 8), the Agency recognized that the
rationale for its May 29, 2015, proposal could have been presented more
clearly. In addition, the registrant requested that additional
commodities be added to this tolerance rulemaking action. Consequently,
in response to the concerns raised in the comments and the request for
additional commodities, the Agency has decided to repropose with
additional explanation addressing the basis for revoking the tolerance
exemption and establishing tolerances set at the LOQ for residues in or
on the commodities identified in the May 29, 2015, proposal, as well as
other commodities requested by the registrant in the interim. This
reproposal supersedes and replaces the proposal issued on May 29, 2015.
V. Aggregate Risk Assessment and Determination of Safety
A. Toxicological Profile
EPA has evaluated the available toxicity data and considered its
validity, completeness, and reliability as well as the relationship of
the results of the studies to human risk. EPA has also considered
available information concerning the variability of the sensitivities
of major identifiable subgroups of consumers, including infants and
children.
As noted in the preamble to the March 22, 2013, final rule, all of
the toxicity data requirements have been fulfilled. The toxicological
profile of BLAD has not changed since that rule; therefore, EPA is
relying on the toxicity findings in that document and supporting
documents to support its continuing conclusion that BLAD does not
present any toxic concerns. 78 FR at 17601-02 and Ref. 4.
As noted in Unit IV., upon receiving new information about BLAD's
source from FDA, EPA reexamined the potential allergenicity of BLAD for
lupin-sensitive and peanut-sensitive individuals, using the approach
recommended in the 2001 FAO/WHO Report and in the Codex Guideline: (1)
Identify the source of the protein; (2) assess the extent to which a
protein is similar in structure to a known allergen; and (3) for
substances derived from a known allergenic source and that have
sequence homology with a known allergen, test sera of a sufficient
number of individuals who are sensitized to the allergenic source.
(Refs. 2, 3).
BLAD is a fragment of the [beta]-conglutin protein produced in the
sweet lupin (Lupinus albus). There are several sources indicating that
lupin is a major allergen. First, EFSA has issued a number of science
opinions recognizing lupin as causing allergic reactions in peanut-
sensitive individuals and IgE sensitization in individuals with no
known allergy to peanuts. (Refs. 5, 9). Based on the EFSA reports, the
European Commission added lupin to the list of major allergens that
must be identified on food labels. (Ref. 10). FDA also considers lupin
to be a food allergen and, based on reports of allergic reactions to
lupin (some severe), has issued advisory statements to alert consumers
to the potential for allergic reactions to foods containing lupin,
especially those individuals with a peanut allergy. (Refs. 8, 11, 12).
In addition, both EFSA and FDA cite to extensive scientific literature
indicating that exposure to lupin causes allergic reactions in peanut-
sensitive individuals (indicating cross-reactivity), as well as in the
general population. (Refs. 1, 5, 8). After considering this
information, EPA has concluded that lupin, from which BLAD is derived,
is a known allergen.
EPA also assessed BLAD for any sequence homology to known
allergens. EPA determined that BLAD exhibits a high sequence homology
(58%) when compared to Ara h 1, a recognized allergen known for causing
allergic reactions (sometimes severe) in peanut-sensitive individuals.
(Ref. 4). In addition, FDA informed EPA that BLAD is also 86% identical
and 91% similar in amino acid sequence (with no gaps) to Lup an 1.0101,
the [beta]-conglutin derived from Lupinus angustifolius. (Ref. 8). Lup
an 1 has been recognized as a food allergen in the World Health
Organization/International Union of Immunological Sciences database,
(Ref. 13), and EFSA considers Lup an 1 to be the major lupin allergen.
(Ref. 9 at 165). Given that BLAD is derived from a known allergen and
has a high sequence homology to two known allergens, EPA required
additional testing to further assess BLAD's potential allergenicity,
consistent with the Codex Guideline recommendation to seek specific
serum testing or immunological assays where sera are available.
In response, CEV agreed to conduct studies that test for
allergenicity, including a skin prick (in vivo) test on individuals
sensitive to Ara h 1 and in vitro immunological testing on serum from
those individuals. (Ref. 14). After identifying several patients who
reported having an allergy, a skin prick test (SPT) was conducted in
order to establish a sampling population that was sensitive to lupins
and/or peanuts. (Ref. 15). Sera from 30 individuals \2\ who were found
in the SPT to have a sensitivity to the lupin and/or peanut extract
were used to evaluate the capacity of cross-reactivity to BLAD in these
sensitive individuals. (Ref. 6). The IgE-specific in vitro immunoblot
(ELISA) testing results did not indicate any IgE binding to BLAD, i.e.,
the results indicated that BLAD did not react with the tested patients'
sera. (Id.; Ref. 15).
---------------------------------------------------------------------------
\2\ The initial serum study selected 26 patients who reacted to
the lupin and/or peanut in the SPT. After EPA expressed concern
about some of the results of the study, sera from additional
patients were included in the study. (Refs. 6, 15).
---------------------------------------------------------------------------
While the lack of reactivity indicates that BLAD may not cause an
allergic response in the tested patients, EPA has determined, as
discussed below, that this study is not sufficient to overcome the
presumption of allergenicity for BLAD among the general population of
lupin-sensitive and/or peanut-sensitive individuals, given the
protein's source and sequence homology. (Ref. 16). As noted in Unit
III.B., according to the Codex Guideline, ``a negative result in in
vitro immunoassays may not be considered sufficient, but should prompt
additional testing, such as the possible use of skin test and ex vivo
protocols.'' (Ref. 3 at 23). The critical issues are the availability
of sera from a sufficient number of individuals, the quality of the
sera, and the standardization of the assay procedure. (Id. at 22-23.)
Both EPA and FDA have reviewed the submitted data to determine
whether it supports a conclusion that BLAD is not an allergen. Because
of FDA's initial concerns about BLAD and in light of FDA's experience
evaluating food allergens, EPA discussed the submitted data with FDA
and considered FDA's analysis of the sera testing in EPA's own
assessment of the data. FDA identified several concerns about the
sufficiency of the quantity and quality of the sera used in the
testing, which raise questions about the scientific reliability of the
data for proving that BLAD is not an allergen. As an initial matter,
FDA noted that the sera testing method ``is not the most robust for
disproving allergenicity to a potential allergenic food ingredient.''
(Ref. 8 at 4-5). FDA explained that the
[[Page 7703]]
``most reliable or `gold standard' method for assessing whether or not
a food or food protein will be clinically reactive is clinical testing
by oral food challenge in a well-characterized group of food allergic
individuals.'' (Id. at 5). One of FDA's concerns about the serum test
itself relates to the level of characterization of the recruited
patients' clinical history. (Id.) FDA notes that it typically
encourages submitters of in vitro sera testing to test a
``statistically significant number of sera from well-characterized food
allergic individuals.'' (Id.) In reviewing the BLAD sera study, FDA
found such characterization lacking, in that characterization consisted
of recruited patients' own clinical history of reactions to lupin or
peanut and a skin prick test. (Id.) FDA further explained why this
level of clinical history characterization raises uncertainty about
whether sera were obtained from an appropriately sensitive population
of allergic individuals:
[W]ithout confirmation of allergy by observed positive food
allergen challenge, there remain uncertainties about how truly reactive
these patients are to the food allergen and how representative they are
of the population of potential reactors to the allergen. For example,
depending on when the last allergic reactions occurred, a patient may
have outgrown their food allergy yet still be sensitized (having
specific IgE) to the allergen. Also, some subjects may have associated
non-specific reactions, e.g., an outbreak of hives/urticaria, to a food
they had eaten or were sensitized to, even though they are not truly
reactive to the food. Skin prick tests are also prone to false positive
results, especially with findings of small wheal and flare responses
(<4 mm) (Bernstein et al., 2008), which were the findings seen in a
number of patients in the applicant's study. Inclusion of patients who
are not validated to be clinically reactive to the allergen in question
impacts the robustness and statistical power of the data. In the
applicant's study, FDA found poorly characterized information about the
recruited patients' reaction histories. (Id. at 5-6).
In addition, FDA expressed a concern about the level of IgE
response in the recruited patients:
In addition, IgE-specific level responses to lupin and/or peanut
were not found to be robust in most patients, with levels reported to
be low (less than 2 kU/L) in the majority of subjects. In clinical
practice to determine if a patient with mild or unclear allergic-type
symptoms to the food is allergic, most specialists would consider food
challenge for a patient with peanut IgE levels less than 2 kU/L, as 50%
of peanut-allergic individuals with a median measurement of 2 kU/L are
reported to have negative challenges (Nowak-Wegrzyn et al., 2009; Perry
et al., 2004). Although patients could still be clinically allergic at
low levels of IgE, for peanut, universally accepted clinical cut-off
IgE levels to predict likely clinical peanut allergy have been reported
at much higher levels, i.e., 14 to 15 kU/L. Patients with specific IgE
at or above these predictive levels of 14 to 15 kU/L have a 90-95%
likelihood of reacting to peanut during peanut challenge (Nowak-Wegrzyn
et al., 2009; Sampson and Ho, 1997; Sampson, 2001). IgE cut-off levels
for predicting lupin reactivity have not been established. FDA also
found that only about one third of total patients in the applicant's
sera study had evidence of IgE to Ara h 1 peanut protein, the relevant
allergen in the diagnostic work-up for determining whether BLAD would
pose a potential cross-reactive hazard for peanut-allergic individuals.
Although BLAD was not shown to bind IgE in these subjects, the number
of patients analyzed is too small to draw any meaningful statistical
predictions of lack of allergenicity to BLAD for the general peanut-
allergic population. (Id. at 6).
FDA again noted that ``[r]ecruiting patients who had gone through
and were observed to be reactive to peanut and/or lupin by the `gold
standard' food challenge would have helped to eliminate these
uncertainties about the robustness of the allergic sera
characterization.'' (Id.)
Finally, FDA expressed concern about the quality of the testing
data, including an inadequate description of the methodology used and
poor quality of the sera blot analyses, which further limit the ability
to draw conclusions about the results of the sera testing. (Id.)
EPA gives great weight to FDA's expertise on the issue of
allergenicity, given FDA's role in assessing food safety and their
experience in evaluating foods for potential allergenicity concerns. As
such, EPA has considered many of the concerns raised by FDA in its own
analysis of the submitted data. After its initial conclusion that the
lack of evidence of sera reactivity to BLAD provides an indication that
BLAD may not be an allergen, EPA, taking into consideration FDA's
concerns and the Codex Guideline warning that negative serum testing
results may not be sufficient to disprove allergenicity, reexamined the
adequacy of the submitted sera testing. (Ref. 6).
According to the Codex Guideline, ``the availability of human sera
from a sufficient number of individuals'' and the ``quality of the
sera'' are important to ensure the validity of the test results. For
the present situation, the quality of the sera is the more significant
issue for the BLAD test results. In order to evaluate the quality of
the sera, EPA looks to the 2001 FAO/WHO Report, which cautions that
patients should be carefully selected to ensure an adequate level of
sensitivity to the protein. (Ref. 2 at 7). If patients have a low level
of sensitization, then the usefulness of the sera to predict reactivity
will be compromised. (Id.) In other words, the sera must be from
patients whose allergenicity has been verified and who are sufficiently
sensitive so that the sera will react to the allergen. If sera used is
taken from patients who have not had their allergy verified or who may
have low levels of allergic reaction (i.e., are insufficiently
sensitive to the allergens), the sera may not react to the test
substance, giving a negative result that cannot be extrapolated to the
larger population of allergic or sensitized individuals. This result
would undermine the reliability of the study results for disproving
allergenicity, which can be especially problematic for substances
derived from known allergens or that are similar or identical to known
allergens.
Taking into consideration the need to ensure the quality of the
sera and FDA's concerns about the quality of the sera used in the serum
study, EPA has determined that the study characterization of recruited
patients' clinical history of allergic reactions and lack of
verification of allergenic reactivity raises uncertainties about the
reliability of the study results to conclusively disprove BLAD's
potential to pose an allergenic risk to lupin-sensitive and/or peanut-
sensitive individuals. (Ref. 16). The quality of the sera being used as
a test reagent is a critical issue in ensuring the reliability of the
study results for predicting reactivity. (Id.) The selection of test
subjects based on self-reported clinical symptoms without a food
challenge-confirmed allergy, as well as the potential for false
positives in skin prick tests, raise questions about the selection
process, the adequacy of the IgE levels, and whether the study involved
an adequate number of patients. (Id.) In other words, these facts
introduce uncertainty about the quality of the sera and thus the
reliability of the study results. Consequently, EPA does not consider
this study to be scientifically reliable to overcome the presumption of
[[Page 7704]]
allergenicity for BLAD, given the source of the protein and the
bioinformatics analysis. (Id.)
B. Toxicological Points of Departure/Levels of Concern
The Agency did not identify any points of departure for BLAD. The
toxicity database does not contain any indication of toxic effects as a
basis for any toxicological points of departure or levels of concern.
Moreover, there is no known threshold for allergenicity to BLAD. As a
result, the Agency is not conducting a quantitative assessment of risk
from potential BLAD exposure. Rather, the Agency's assessment of safety
is based on the lack of exposure to BLAD because, as discussed in Unit
V.C., the available residue data indicate that, when applied under
current label rates and using good agricultural practices, there will
be negligible to no detectable residues of BLAD on treated crops.
C. Exposure Assessment
1. Dietary exposure from food and feed uses. BLAD has been approved
for use on several commodities; therefore, EPA evaluated the potential
for BLAD residues on those crops in order to assess exposure.
CEV initially submitted residue data for grape, tomato, and
strawberry. Field trials were conducted applying PROBLAD PLUS (a
fungicide product containing BLAD at 20%) at the maximum product-
labeled application rate (0.75 pounds of active ingredient per acre,
five broadcast foliar applications per season, at 7-day intervals).
Those studies showed that there were no quantifiable residues (where
the LOQ is 0.02 ppm) on any treated grape, tomato, or strawberry
commodities, and the majority of samples showed no residues above the
level of detection (0.005 ppm). (Ref. 15). CEV later submitted
additional field residue studies on cherry, cucumber, and apple that
similarly demonstrated that application consistent with labeled rates
resulted in residues at or below the level of detection of 0.005 ppm.
(Ref. 17).
The Agency also requested that CEV conduct field trials using
exaggerated application rates of 5X and 10X to determine the rate of
BLAD residue degradation. Since the 10X concentration would be
phytotoxic, CEV conducted field trials on tomatoes and strawberries
using only the 5X application rate (3.75 pounds of active ingredient
per acre). The decline curve for the treated commodities indicated a
half-life of 2 days. Based on the measured residue levels in the study
and using a first order degradation model, EPA was able to calculate a
theoretical rate of degradation of 0.4215, which was then used to
predict BLAD residues following treatment. (Ref. 15). Applying this
degradation rate to residue levels observed in field residue data and
taking into consideration the required 1-day interval between
application and harvest of treated crops, the Agency expects that there
will be no residues of BLAD above the level of detection, if any remain
at all, when commodities are treated in accordance with the label.
(Id.) This rapid degradation rate is consistent with the expectation
that BLAD, as a protein fragment, is susceptible to rapid degradation
by environmental factors, such as microbial proteases. (Ref. 17).
Based on the available residue data, the Agency concludes that
residues on grape, tomato, strawberry, apple, cherry, and cucumber will
be below levels of detection and possibly non-existent when used in
accordance with the label at the time of consumption. The Agency has
also concluded that the available data is mutually supportive and is
appropriate for supporting additional tolerances for certain crop
groupings, hops, and almonds. (Id.)
Based on the available representative commodity data, the
registrant requested use on and tolerances for the following crop
groups: Vegetable, fruiting, group 8-10; vegetable, cucurbit, group 9;
fruit, pome, group 11-10; and fruit, stone, group 12-12. Although
residue trials on all the representative commodities for those crop
groups were not completed, the Agency has determined that trials on the
remaining representative commodities are not necessary. The available
residue data are mutually supportive and support a conclusion that any
additional residue data for the other representative commodities would
yield the same results. Given the similarity and consistency of the
residue levels in these studies--in particular the consistency of
results showing residues levels near or below the level of detection--
the similarity in plant morphology between the representative commodity
and the other commodities in the corresponding crop group, and the
additional factors supporting the anticipated lack of exposure to
residues of BLAD (i.e., rapid degradation rate and post-harvest
interval), the Agency concludes that the available data are sufficient
to support these crop groups. (Id.)
In addition, the Agency has concluded that no separate tolerances
are needed for processed commodities of the raw agricultural
commodities contained in these crop groups. (Id.) The rapid degradation
of BLAD by microbes on treated crops combined with the methods for
processing these commodities (e.g., washing and pasteurizing) will
reduce the already low levels of residues on the treated commodities.
The tolerances being established are sufficient to cover residues in
those processed commodities.
Moreover, although no residue field trials were submitted to
support the hops, dried cones tolerance, the Agency has assessed the
potential for exposure to BLAD residues on hops by examining the short
environmental persistence of BLAD and the additional processing steps
to which hops is subject prior to consumption. Following application of
BLAD to hops, at rates that are the same as for other labeled crops,
initial residues of BLAD are expected to rapidly degrade during the
drying phase. The long drying time would also allow a longer time for
microbial degradation of the protein. Furthermore, processing of hops,
which is used as a flavoring and preservative in fermented beverages,
is expected to further mitigate exposure prior to consumption. All of
these factors suggest an elimination of potential residues on hops by
the time of consumption. (Id.)
Because the application rates and methods are the same for grape
and almond, the residue data can be translated to almond hulls, and the
Agency has determined that the residues on almond hulls will be similar
to residues found on strawberries, grapes, and tomatoes. (Ref. 18). The
general practice for harvesting almonds, which typically involves 7-10
days of drying before processing, is likely to further reduce residues
on the almond hulls. Also, because BLAD is not applied directly to the
almonds, the Agency expects residues on the almond nutmeat itself to be
even lower.
Because almond hulls are an animal feed item, section 180.6 of
EPA's regulations requires that EPA consider whether residues of BLAD
present on animal feed items will result in residues of BLAD in meat,
milk, eggs, or poultry commodities consumed by humans. 40 CFR 180.6(a).
If there is no reasonable expectation of residues in the livestock
commodities, the Agency can establish a tolerance on the raw
agricultural commodity (in this case, the almond). 40 CFR 180.6(b).
Based on the available information, EPA has concluded that the likely
residues on almond hulls will be at or below levels of detection. Even
if there are any residues remaining on almond hulls that are ingested
by animals, EPA has concluded that there
[[Page 7705]]
is not likely to be any residues in the livestock commodities. (Ref.
18). Due to its molecular size, BLAD is not expected to pass through
biological membranes. Moreover, it is expected to be rapidly digested
instead of accumulating in animal tissues. (Id.) As a result, there is
no reasonable expectation of residues in livestock commodities and thus
no need for associated livestock commodity tolerances.
2. Dietary exposure from drinking water. The Agency expects
residues of BLAD in drinking water to be negligible. Because BLAD is
applied foliarly, there is a chance that it may get into drinking
water, but there is likely to be very little in the environment from
applications. Moreover, what little residue may be present would likely
be subject to potential photolysis and microbial degradation due to its
nature as a protein.
3. From non-dietary exposure. The term ``residential exposure'' is
used in this document to refer to non-occupational, non-dietary
exposure (e.g., for lawn and garden pest control, indoor pest control,
termiticides, and flea and tick control on pets). BLAD is not
registered for any specific use patterns that would result in
residential exposure.
4. Cumulative effects from substances with a common mechanism of
toxicity. Section 408(b)(2)(D)(v) of the FFDCA requires that, when
considering whether to establish, modify, or revoke a tolerance, the
Agency consider ``available information concerning the cumulative
effects of [a particular pesticide's] . . . residues and other
substances that have a common mechanism of toxicity.''
EPA has not found BLAD to share a common mechanism of toxicity with
any other substances, and BLAD does not appear to degrade into any
toxic metabolite or other substance of concern. For the purposes of
this tolerance action, therefore, EPA has assumed that BLAD does not
have a common mechanism of toxicity with other substances. For
information regarding EPA's efforts to determine which chemicals have a
common mechanism of toxicity and to evaluate the cumulative effects of
such chemicals, see EPA's website at https://www.epa.gov/pesticide-science-and-assessing-pesticide-risks/cumulative-assessment-risk-pesticides.
D. Safety Factor for Infants and Children
FFDCA section 408(b)(2)(C) provides that, in considering the
establishment of a tolerance or tolerance exemption for a pesticide
chemical residue, EPA shall apply an additional tenfold (10X) margin of
safety for infants and children in the case of threshold effects to
account for prenatal and postnatal toxicity and the completeness of the
database on toxicity and exposure, unless EPA determines that a
different margin of safety will be safe for infants and children. This
additional margin of safety is commonly referred to as the Food Quality
Protection Act Safety Factor. In applying this provision, EPA either
retains the default value of 10X, or uses a different additional safety
factor when reliable data are available to support the choice of a
different safety factor.
Because the Agency has not identified any threshold effects for
BLAD, this additional safety factor is not applicable for assessing
risk to infants and children.
E. Aggregate Risks and Determination of Safety
EPA has evaluated the available toxicity, allergenicity, and
exposure data and considered its validity, completeness, and
reliability, as well as the relationship of the results of the studies
to human risk. Taking into consideration all available information on
BLAD, EPA cannot conclude that unlimited exposures to BLAD on all food
crops would not pose a risk of allergenicity to lupin-sensitive or
peanut-sensitive individuals. The data submitted on the potential
allergenicity does not overcome the burden for demonstrating that BLAD
is not an allergen, given that BLAD is derived from a known allergenic
source and the bioinformatics analysis demonstrates sequence similarity
with other major allergens. Based on this information, the Agency can
no longer support a safety determination for an unlimited exemption
from the requirement of a tolerance for residues of BLAD on all food
commodities. As a result, EPA is proposing to revoke the current
tolerance exemption for BLAD found in 40 CFR 180.1319.
Although EPA can no longer support the existing tolerance exemption
for BLAD, which, on its face, places no limits on the levels of BLAD
residues on any food commodities, EPA has determined, based on residue
data supporting a conclusion of negligible to no exposure to BLAD
residues on certain crops, that certain limited tolerances would be
safe. That is, there is a reasonable certainty that no harm will result
to the U.S. population, including infants and children, from aggregate
exposure to residues of BLAD when it is applied as a fungicide in
accordance with label directions and good agricultural practices on the
following commodities: Almond; almond, hulls; fruit, pome, group 11-10;
fruit, stone, group 12-12; grape; hops, dried cones; strawberry;
vegetable, cucurbit, group 9; and vegetable, fruiting, group 8-10. Such
exposure includes all anticipated dietary exposures and all other
exposures for which there is reliable information.
Upon consideration of information regarding the likely levels of
exposure to BLAD from approved use patterns, EPA concludes that the
approved uses of BLAD are unlikely to result in residues above the
level of detection when shipped in interstate commerce. Further, based
on expected degradation rates, the Agency expects residue levels at the
time of consumption to be even lower, likely non-existent. The lack of
exposure to detectable residues of BLAD, if there are any residues at
all, is the basis for the Agency's safety finding for these tolerances.
While the Agency, as a general matter, expects users to follow
label directions on pesticide products and that residue data indicate
that application in accordance with the label results primarily in
undetectable residues or levels at or below levels of detection, EPA is
proposing to establish tolerances at the lowest level for measuring
quantifiable residues of BLAD (0.02 ppm). Given the potential severity
of allergic reactions, the Agency believes that setting numerical
tolerances, rather than leaving in effect an unlimited exemption, is
the appropriate regulatory mechanism for monitoring residues and
facilitates the removal of adulterated commodities from the food supply
if residues are found above tolerance levels on any of these
commodities. The expectation of negligible to no residues under proper
use conditions, subject to the mechanisms of enforcement under the
FFDCA and the Federal Insecticide, Fungicide, and Rodenticide Act
(FIFRA), provide assurance that consumers will not be exposed to
residues of BLAD that may cause harm. Therefore, EPA is proposing to
revoke the current exemption and establish tolerances for residues of
BLAD in or on the following commodities at 0.02 ppm: Almond; almond,
hulls; fruit, pome, group 11-10; fruit, stone, group 12-12; grape;
hops, dried cones; strawberry; vegetable, cucurbit, group 9; and
vegetable, fruiting, group 8-10.
VI. Other Considerations
A. Analytical Enforcement Methodology
Adequate enforcement methodology (Enzyme-Linked Immunosorbent Assay
(ELISA: EASI Method No: RA029 and
[[Page 7706]]
RA031)) is available to enforce the tolerance expression.
The method may be requested from: Chief, Analytical Chemistry
Branch, Environmental Science Center, 701 Mapes Rd., Ft. Meade, MD
20755-5350; telephone number: (410) 305-2905; email address:
[email protected].
B. International Residue Limits
In making its tolerance decisions, EPA seeks to harmonize U.S.
tolerances with international standards whenever possible, consistent
with U.S. food safety standards and agricultural practices. EPA
considers the international maximum residue limits (MRLs) established
by the Codex Alimentarius Commission (Codex), as required by FFDCA
section 408(b)(4). The Codex Alimentarius is a joint FAO/WHO food
standards program, and it is recognized as an international food safety
standards-setting organization in trade agreements to which the United
States is a party. EPA may establish a tolerance that is different from
a Codex MRL; however, FFDCA section 408(b)(4) requires that EPA explain
the reasons for departing from the Codex level.
The Codex has not established an MRL for BLAD.
C. Trade and Economic Considerations
The Agency received comments on its May 29, 2015, proposal about
the potential impact of the proposal on trade and farmers. The
commenters alleged that the proposal failed to address possible impacts
on international trade, including the potential to cause other
countries to require or amend MRLs, to develop enforcement procedures
consistent with international regulatory data requirements, and to
impose new and more onerous data requirements. The commenters also
expressed concern about the lack of harmonization with Canada, which
has decided not to regulate residues of BLAD, and pointed to the
potential for disruption in trade between the United States and Canada,
or at least confusion at the border for enforcing the different
standards, as a result. In addition, many commenters expressed concern
that the proposal revoking the exemption would have an adverse impact
on farmers who relied on BLAD as an effective fungicide.
Under the FFDCA, tolerances and exemptions from the requirement of
a tolerance may be established when EPA determines that they are safe.
21 U.S.C. 346a(b)(2)(A)(i), (c)(2)(A)(i). The FFDCA also requires that
EPA revoke tolerances or exemptions when it determines they are not
safe. Id. This safety assessment is a risk-only assessment, not a risk-
benefit standard. In essence, the statute directs that whether EPA can
leave in effect or establish a tolerance or exemption is based solely
on the Agency's assessment of the risk to human health and not a
balancing of other non-safety factors (e.g., impact on trade or impact
on farmers) with the risk. The FFDCA directs EPA to consider several
factors relevant to the safety of the pesticide residue in food
(aggregated with other sources of exposure to the pesticide residue),
placing particular emphasis on human dietary risk. See, e.g., 21 U.S.C.
346a(b)(2)(B) (addressing an exception to the safety standard for
pesticide residues as to which EPA ``is not able to identify a level of
exposure to the residue at which the residue will not cause or
contribute to a known or anticipated harm to human health''); 21 U.S.C.
346a(b)(2)(C) (requiring special safety findings as to ``infants and
children'' regarding their ``disproportionately high consumption of
foods'' and their ``special susceptibility * * * to pesticide chemical
residues''); 21 U.S.C. 346a(b)(2)(D)(iii) (requiring consideration of
the relationship between toxic effects found in pesticide studies and
human risk); 21 U.S.C. 346a(b)(2)(D)(iv), (vi), and (vii) (requiring
consideration of available information on ``dietary consumption
patterns of consumers,'' ``aggregate exposure levels of consumers,''
and the ``variability of the sensitivities of major identifiable
subgroups of consumers''); 21 U.S.C. 346a(b)(2)(D)(vi) (requiring
consideration of ``non-occupational'' sources of exposure); 21 U.S.C.
346a(b)(2)(D)(viii) (requiring consideration of information bearing on
whether a pesticide ``may have an effect in humans that is similar to
an effect produced by a naturally occurring estrogen or other endocrine
effects''); 21 U.S.C. 346a(l)(2) and (3) (requiring revocation or
suspension of tolerances where associated FIFRA registration is
canceled or suspended ``due in whole or in part to dietary risks to
humans posed by residues of that pesticide chemical on that food'').
The only mention of a factor relevant to trade is found in FFDCA
section 408(b)(4), which, as noted in Unit VI.B., requires EPA to
determine whether an MRL has been established by Codex when
establishing a tolerance and to explain its reasons for departing from
that level, if applicable. 21 U.S.C. 346a(b)(4). Here, as noted above,
Codex has not established any MRLs for BLAD; therefore, there is
nothing to harmonize and no discrepancies to explain. As a matter of
policy and where the Agency can support the safety finding, EPA seeks
to harmonize U.S. tolerances whenever possible with Codex MRLs and the
MRLs of other trading partners, including Canada, consistent with U.S.
food safety standards and agricultural practices. For BLAD, based on
the available information, EPA can no longer maintain the safety
finding to support the unlimited tolerance exemption for BLAD residues
on all commodities. Harmonization with Canada's regulatory approach is
not a legal basis for retaining the exemption under the FFDCA when EPA
concludes that the exemption is not safe.
Notwithstanding the substantive restrictions of the FFDCA, EPA
recognizes the obligations of the United States to comply with the
procedural obligations under the World Trade Organization's Sanitary
and Phytosanitary Measures Agreement (SPS Agreement). Because the
proposal is a regulation subject to the requirements of the SPS
Agreement, EPA intends to comply with the provisions of that Agreement,
including those related to notification and implementation, including
allowing for a 6-month delay in the exemption revocation to provide
exporting countries a period of time to adjust to the U.S. new
tolerances. In any event, the revocation in this proposal is not
discriminatory and is designed to ensure that both domestically
produced and imported foods meet the food safety standard established
by the FFDCA.
VII. Conclusion
EPA proposes to revoke the existing tolerance exemption for
residues of BLAD in or on all food commodities as established in the
Federal Register of March 22, 2013 (78 FR 17600) (FRL-9380-6) under
section 408 of the FFDCA. Based on the available information, EPA can
no longer support the safety finding necessary to maintain the
exemption. Notwithstanding the Agency's conclusions concerning the
unlimited exemption, the Agency has determined that the available
information supports a safety finding for the tolerances for residues
of BLAD in or on almond; almond, hulls; fruit, pome, group 11-10;
fruit, stone, group 12-12; grape; hops, dried cones; strawberry;
vegetable, cucurbit, group 9; and vegetable, fruiting, group 8-10 at
0.02 ppm. Therefore, EPA is proposing to establish tolerances for
residues of BLAD on those commodities.
VIII. References
The following is a listing of the documents that are specifically
[[Page 7707]]
referenced in this document. The docket includes these documents and
other information considered by EPA, including documents that are
referenced within the documents that are included in the docket, even
if the referenced document is not physically located in the docket. For
assistance in locating these other documents, please consult the person
listed under FOR FURTHER INFORMATION CONTACT.
1. U.S. Food and Drug Administration (FDA). Letter from Michael A.
Adams, Ph.D., Deputy Director of Office of Food Additive Safety
(FAS), Center for Food Safety and Applied Nutrition (CFSAN) to
Menyon Adams, Biopesticides and Pollution Prevention Division
(BPPD), Office of Pesticide Programs (OPP), re: Docket Number EPA-
HQ-OPP-2011-1026. May 21, 2013.
2. Food and Agriculture Organization of the United Nations (FAO)/
World Health Organization (WHO). Evaluation of Allergenicity of
Genetically Modified Foods: Report of a Joint FAO/WHO Expert
Consultation on Allergenicity of Foods Derived from Biotechnology.
January 2001.
3. WHO/FAO. Codex Alimentarius: Foods Derived from Modern
Biotechnology. 2009.
4. U.S. Environmental Protection Agency (EPA). Memorandum from
Miachel Rexrode, Ph.D., Senior Biologist (BPPD) to Menyon Adams,
Regulatory Action Leader (BPPD). Request for New Product
Registration for [beta]-Conglutin Section 3 with Tolerance. May 24,
2012.
5. European Food Safety Authority (EFSA). Opinion of the Scientific
Panel on Dietetic Products, Nutrition and Allergies on a Request
from the Commission Related to the Evaluation of Lupin for Labelling
Purposes. (Request No. EFSA-Q-2005-086). The EFSA Journal (2005)
302, 1-11. December 6, 2005.
6. U.S. EPA. Memorandum from John L. Kough, Ph.D., Biologist (BPPD)
to Menyon Adams, Regulatory Action Leader (BPPD). Review of
Allergenicity Decisions on BLAD. December 9, 2015.
7. U.S. EPA. Memorandum from Robert McNally, Director, BPPD, OPP to
Dennis M. Keefe, Ph.D., Director, CFSAN, FAS. Request for Specific
Input from FDA to Assist EPA in Addressing Comments Received in
Response to EPA's Proposal Regarding Banda de Lupinus alba doce
(BLAD). December 7, 2015.
8. U.S. Department of Health and Human Services (HHS). Memorandum
from Stefano Luccioli, MD, Medical Officer, FAS, CFSAN to Dennis
Keefe, Ph.D., Director, FAS, CFSAN. Response to EPA Questions in
Memorandum Dated December 7, 2015, Regarding BLAD Biopesticide.
December 17, 2015.
9. EFSA NDA Panel (EFSA Panel on Dietetic Products, Nutrition and
Allergies), 2014. Scientific Opinion on the Evaluation of Allergenic
Foods and Food Ingredients for Labelling Purposes. EFSA Journal
2014;12(11):3894, 286 pp. doi:10.2903/j.efsa.2014.3894. November 26,
2014.
10. Commission Directive 2006/142/EC (December 22, 2006), amending
Annex IIIa of European Directive 2000/13/EC (March 20, 2000).
11. U.S. FDA. Allergies to a Legume Called Lupin: What You Need to
Know. https://www.fda.gov/consumers/consumer-updates/allergies-legume-called-lupin-what-you-need-know (last checked May 31, 2019).
12. U.S. FDA. Frequently Asked Questions on Lupin and Allergenicity.
https://www.fda.gov/food/food-additives-petitions/lupin-and-allergenicity-frequently-asked-questions (last checked May 30,
2019).
13. World Health Organization/International Union of Immunological
Sciences. Allergen Nomenclature. Allergen details for Lup an 1.
http://www.allergen.org/viewallergen.php?aid=421 (last checked May
31, 2019).
14. U.S. EPA. Memorandum from Miachel Rexrode, Ph.D., Senior
Biologist (BPPD) to Linda Hollis, Chief, Biochemical Pesticides
Branch (BPB), BPPD. BLAD Data Requirements. May 15, 2013.
15. U.S. EPA. Memorandum from Miachel Rexrode, Ph.D., Senior
Biologist (BPPD) to Menyon Adams, Regulatory Action Leader (BPPD).
Evaluation of New Serum Testing and Field Residue Decline Study for
BLAD. June 6, 2014. As corrected by the following document: U.S.
EPA. Memorandum from Miachel Rexrode, Ph.D., Senior Biologist (BPPD)
to Menyon Adams, Regulatory Action Leader (BPPD). December 28, 2016.
16. U.S. EPA. Memorandum from John L. Kough, Ph.D., Biologist (BPPD)
to Menyon Adams, Regulatory Action Leader (BPPD) and Linda Hollis,
Branch Chief, BPB, BPPD. Review of FDA Interactions on the
Allergenicity Assessment of Banda de Lupinus alba (BLAD) from CEV.
August 23, 2016.
17. U.S. EPA. Memorandum from John L. Kough, Ph.D., Biologist (BPPD)
to Menyon Adams, Regulatory Action Leader (BPPD). Review of Crop
Groupings for PROBLAD PLUS. June 26, 2019.
18. U.S. EPA. Memorandum from Judy Facey, Ph.D., Associate Branch
Chief (Acting), BPB, BPPD and John L. Kough, Ph.D., Senior Scientist
(BPPD) to Menyon Adams, Regulatory Action Leader (BPPD) and Linda
Hollis, Branch Chief, BPB, BPPD. ChemSAC Conclusion on: Potential
BLAD Residues in Meat or Milk from Almond Hull Feed Consumption
Resulting from Almond Treatment. January 24, 2017.
19. U.S. EPA. Memorandum from Denise Keehner, Division Director,
Biological and Economic Analysis Division, OPP to Public Docket
concerning Tolerance Revocation Rulemaking, Proposed or Final. RFA/
SBREFA Certification for Import Tolerance Revocation. May 25, 2001.
IX. Statutory and Executive Order Reviews
Although this proposed action would revoke an existing exemption
from the requirement of a tolerance, it also would establish new
tolerances that would cover pesticide chemical residues resulting from
existing registered uses under FFDCA section 408(e). The Office of
Management and Budget (OMB) has exempted these types of actions from
review under Executive Orders 12866, entitled Regulatory Planning and
Review (58 FR 51735, October 4, 1993), and 13563, entitled Improving
Regulation and Regulatory Review (76 FR 3821, January 21, 2011). As a
result, this action is not subject to Executive Order 13211, entitled
Actions Concerning Regulations That Significantly Affect Energy Supply,
Distribution, or Use (66 FR 28355, May 22, 2001). Nor does it require
OMB review or any Agency action under Executive Order 13045, entitled
Protection of Children from Environmental Health Risks and Safety Risks
(62 FR 19885, April 23, 1997). Nor is this action considered a
regulatory action subject to review under Executive Order 13771,
entitled Reducing Regulations and Controlling Regulatory Costs (82 FR
9339, February 3, 2017).
This action does not contain any information collections subject to
OMB approval under the Paperwork Reduction Act (44 U.S.C. 3501 et
seq.); does not require any special considerations under Executive
Order 12898, entitled Federal Actions to Address Environmental Justice
in Minority Populations and Low-Income Populations (59 FR 7629,
February 16, 1994); and does not involve any technical standards that
would require Agency consideration of voluntary consensus standards
pursuant to section 12(d) of the National Technology Transfer and
Advancement Act (15 U.S.C. 272 note).
This action directly regulates growers, food processors, food
handlers, and food retailers, but it does not regulate State or tribal
governments. Nor does this action alter the relationships or
distribution of power and responsibilities established in the
preemption provisions of FFDCA section 408(n)(4). Therefore, the Agency
has determined that Executive Orders 13132, entitled Federalism (64 FR
43255, August 10, 1999), and 13175, entitled Consultation and
Coordination with Indian Tribal Governments (65 FR 67249, November 9,
2000), do not apply to this action. In addition, this action does not
impose any enforceable duty, contain any unfunded mandate, or
[[Page 7708]]
otherwise significantly or uniquely affect small governments as
described in the Unfunded Mandates Reform Act (2 U.S.C. 1501 et seq.).
Pursuant to the Regulatory Flexibility Act (5 U.S.C. 601 et seq.),
the Agency previously assessed whether establishment of tolerances,
exemptions from tolerances, raising of tolerance levels, expansion of
exemptions, or revocations might significantly impact a substantial
number of small entities and concluded that, as a general matter, these
actions do not impose a significant economic impact on a substantial
number of small entities. These analyses for tolerance establishments
and modifications and for tolerance revocations were published in the
Federal Register of May 4, 1981 (46 FR 24950) (FRL-1809-5) and December
17, 1997 (62 FR 66020) (FRL-5753-1), respectively, and were provided to
the Chief Counsel for Advocacy of the Small Business Administration.
Taking into account this analysis, and available information concerning
the pesticide listed in this proposed rule, the Agency hereby certifies
that this proposed rule will not have a significant negative economic
impact on a substantial number of small entities. In a memorandum dated
May 25, 2001, EPA determined that eight conditions must all be
satisfied in order for an import tolerance or tolerance exemption
revocation to adversely affect a significant number of small entity
importers, and that there is a negligible joint probability of all
eight conditions holding simultaneously with respect to any particular
revocation. (Ref. 19). Furthermore, for BLAD, the Agency knows of no
extraordinary circumstances that exist as to the present proposed rule
that would change EPA's previous analysis. Any comments about the
Agency's determination should be submitted to EPA along with comments
on the proposed rule and will be addressed prior to issuing a final
rule.
List of Subjects in 40 CFR Part 180
Environmental protection, Administrative practice and procedure,
Agricultural commodities, Pesticides and pests, Reporting and
recordkeeping requirements.
Dated: January 21, 2020.
Richard Keigwin,
Director, Office of Pesticide Programs.
Therefore, it is proposed that 40 CFR chapter I be amended as
follows:
PART 180--[AMENDED]
0
1. The authority citation for part 180 continues to read as follows:
Authority: 21 U.S.C. 321(q), 346a and 371.
0
2. Add Sec. 180.707 to subpart C to read as follows:
Sec. 180.707 Banda de Lupinus albus doce (BLAD); tolerances for
residues.
(a) General. Tolerances are established for residues of the
fungicide banda de Lupinus albus doce (BLAD), including its metabolites
and degradates, in or on the commodities in the table below. Compliance
with the tolerance levels specified below is to be determined by
measuring only BLAD in or on the following commodities.
------------------------------------------------------------------------
Parts per
Commodity million
------------------------------------------------------------------------
Almond...................................................... 0.02
Almond, hulls............................................... 0.02
Fruit, pome, group 11-10.................................... 0.02
Fruit, stone, group 12-12................................... 0.02
Grape....................................................... 0.02
Hops, dried cones........................................... 0.02
Strawberry.................................................. 0.02
Vegetable, cucurbit, group 9................................ 0.02
Vegetable, fruiting, group 8-10............................. 0.02
------------------------------------------------------------------------
(b) Section 18 emergency exemptions. [Reserved]
(c) Tolerances with regional registrations. [Reserved]
(d) Indirect or inadvertent residues. [Reserved]
0
3. Revise Sec. 180.1319 in subpart D to read as follows:
Sec. 180.1319 Banda de Lupinus albus doce (BLAD); exemption from the
requirement of a tolerance.
An exemption from the requirement of a tolerance is established for
the residues of Banda de Lupinus albus doce (BLAD), a naturally
occurring polypeptide from the catabolism of a seed storage protein
([beta]-conglutin) of sweet lupines (Lupinus albus), in or on all food
commodities when applied as a fungicide and used in accordance with
label directions and good agricultural practices. This exemption
expires on [date 6 months after date of publication of final rule in
the Federal Register].
[FR Doc. 2020-02665 Filed 2-10-20; 8:45 am]
BILLING CODE 6560-50-P