Document ID: EPA-HQ-OPP-2018-0163-0003
Agency: epa
Document Type: Rule
Title: Tolerance Exemptions: Glycine Betaine
Posted Date: 2019-02-07T05:00Z

[Federal Register Volume 84, Number 26 (Thursday, February 7, 2019)]
[Rules and Regulations]
[Pages 2456-2459]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2019-01307]

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ENVIRONMENTAL PROTECTION AGENCY

40 CFR Part 180

[EPA-HQ-OPP-2018-0163; FRL-9987-42]

Glycine betaine; Exemption From the Requirement of a Tolerance

AGENCY: Environmental Protection Agency (EPA).

ACTION: Final rule.

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SUMMARY: This regulation establishes an exemption from the requirement 
of a tolerance for residues of glycine betaine (CAS Reg. No. 107-43-7) 
when used as an inert ingredient (plant nutrient) in pesticide 
formulations applied to growing crops only. SciReg, Inc., on behalf of 
Fine Agrochemicals Ltd, submitted a petition to EPA under the Federal 
Food, Drug, and Cosmetic Act (FFDCA), requesting establishment of an 
exemption from the requirement of a tolerance. This regulation 
eliminates the need to establish a maximum permissible level for 
residues of glycine betaine.

DATES: This regulation is effective February 7, 2019. Objections and 
requests for hearings must be received on or before April 8, 2019, and 
must be filed in accordance with the instructions provided in 40 CFR 
part 178 (see also Unit I.C. of the SUPPLEMENTARY INFORMATION).

ADDRESSES: The docket for this action, identified by docket 
identification (ID) number EPA-HQ-OPP-2018-0163, is available at http://www.regulations.gov or at the Office of Pesticide Programs Regulatory 
Public Docket (OPP Docket) in the Environmental Protection Agency 
Docket Center (EPA/DC), West William Jefferson Clinton Bldg., Rm. 3334, 
1301 Constitution Ave. NW, Washington, DC 20460-0001. The Public 
Reading Room is open from 8:30 a.m. to 4:30 p.m., Monday through 
Friday, excluding legal holidays. The telephone number for the Public 
Reading Room is (202) 566-1744, and the telephone number for the OPP 
Docket is (703) 305-5805. Please review the visitor instructions and 
additional information about the docket available at http://www.epa.gov/dockets.

FOR FURTHER INFORMATION CONTACT: Michael Goodis, Registration Division 
(7505P), Office of Pesticide Programs, Environmental Protection Agency, 
1200 Pennsylvania Ave. NW, Washington, DC 20460-0001; main telephone 
number: (703) 305-7090; email address: RDFRNotices@epa.gov.

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. How can I get electronic access to other related information?

    You may access a frequently updated electronic version of 40 CFR 
part 180 through the Government Printing Office's e-CFR site at http://www.ecfr.gov/cgi-bin/text-idx?&c=ecfr&tpl=/ecfrbrowse/Title40/40tab_02.tpl.

C. How can I file an objection or hearing request?

    Under FFDCA section 408(g), 21 U.S.C. 346a, any person may file an 
objection to any aspect of this regulation and may also request a 
hearing on those objections. You must file your objection or request a 
hearing on this regulation in accordance with the instructions provided 
in 40 CFR part 178. To ensure proper receipt by EPA, you must identify 
docket ID number EPA-HQ-OPP-2018-0163 in the subject line on the first 
page of your submission. All objections and requests for a hearing must 
be in writing, and must be received by the Hearing Clerk on or before 
April 8, 2019. Addresses for mail and hand delivery of objections and 
hearing requests are provided in 40 CFR 178.25(b).
    In addition to filing an objection or hearing request with the 
Hearing Clerk as described in 40 CFR part 178, please submit a copy of 
the filing (excluding any Confidential Business Information (CBI)) for 
inclusion in the public docket. Information not marked confidential 
pursuant to 40 CFR part 2 may be disclosed publicly by EPA without 
prior notice. Submit the non-CBI copy of your objection or hearing 
request, identified by docket ID number EPA-HQ-OPP-2018-0163, 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 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/contacts.html.
    Additional instructions on commenting or visiting the docket, along 
with more information about dockets generally, is available at http://www.epa.gov/dockets.

II. Petition for Exemption

    In the Federal Register of May 18, 2018 (83 FR 23247) (FRL-9976-
87), EPA issued a document pursuant to FFDCA section 408, 21 U.S.C. 
346a, announcing the filing of a pesticide petition (PP IN-11101) by 
SciReg, Inc., 12733 Director's Loop, Woodbridge, VA 22192 on behalf of 
Fine Agrochemicals Ltd. The petition requested that 40 CFR 180.920 be 
amended by establishing an exemption from the requirement of a 
tolerance for residues of glycine betaine (CAS Reg. No. 107-43-7) when 
used as an inert ingredient (plant nutrient) in pesticide formulations 
applied to growing crops. That document referenced a summary of the 
petition prepared by SciReg, Inc., on behalf of Fine Agrochemicals 
Ltd., the petitioner, which is available in the docket, http://www.regulations.gov. There were no comments received in response to the 
notice of filing.

III. Inert Ingredient Definition

    Inert ingredients are all ingredients that are not active 
ingredients as defined in 40 CFR 153.125 and include, but are not 
limited to, the following types of ingredients (except when they have a 
pesticidal efficacy of their own): Solvents such as alcohols and 
hydrocarbons; surfactants such as polyoxyethylene polymers and fatty 
acids; carriers such as clay and diatomaceous earth; thickeners such as

[[Page 2457]]

carrageenan and modified cellulose; wetting, spreading, and dispersing 
agents; propellants in aerosol dispensers; microencapsulating agents; 
and emulsifiers. The term ``inert'' is not intended to imply 
nontoxicity; the ingredient may or may not be chemically active. 
Generally, EPA has exempted inert ingredients from the requirement of a 
tolerance based on the low toxicity of the individual inert 
ingredients.

IV. Aggregate Risk Assessment and Determination of Safety

    Section 408(c)(2)(A)(i) of FFDCA allows EPA to establish an 
exemption from the requirement for a tolerance (the legal limit for a 
pesticide chemical residue in or on a food) only if EPA determines that 
the tolerance is ``safe.'' Section 408(c)(2)(A)(ii) of FFDCA 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. The FFDCA requires EPA to consider the factors 
in subparagraphs (b)(2)(C) and (D) when making this safety 
determination. 21 U.S.C. 346a(c)(2)(B). Section 408(b)(2)(C) of FFDCA 
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 exposure to the pesticide 
chemical residue . . . .'' EPA establishes exemptions from the 
requirement of a tolerance only in those cases where it can be clearly 
demonstrated that the risks from aggregate exposure to pesticide 
chemical residues under reasonably foreseeable circumstances will pose 
no appreciable risks to human health. In order to determine the risks 
from aggregate exposure to pesticide inert ingredients, the Agency 
considers the toxicity of the inert in conjunction with possible 
exposure to residues of the inert ingredient through food, drinking 
water, and through other exposures that occur as a result of pesticide 
use in residential settings. If EPA is able to determine that a finite 
tolerance is not necessary to ensure that there is a reasonable 
certainty that no harm will result from aggregate exposure to the inert 
ingredient, an exemption from the requirement of a tolerance may be 
established.
    Consistent with FFDCA section 408(c)(2)(A), and the factors 
specified in FFDCA section 408(c)(2)(B), EPA has reviewed the available 
scientific data and other relevant information in support of this 
action. EPA has sufficient data to assess the hazards of and to make a 
determination on aggregate exposure for glycine betaine including 
exposure resulting from the exemption established by this action. EPA's 
assessment of exposures and risks associated with glycine betaine 
follows.

A. Toxicological Profile

    EPA has evaluated the available toxicity data and considered their 
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. Specific information on the studies received and the nature 
of the adverse effects caused by glycine betaine as well as the no-
observed-adverse-effect-level (NOAEL) and the lowest-observed-adverse-
effect-level (LOAEL) from the toxicity studies are discussed in this 
unit.
    Glycine betaine is naturally present in numerous foods including 
beets, spinach, grains, seafood, and eggs. Its presence has also been 
reported in bacteria, animals, and plants. It is produced in the human 
body from choline and the amino acid glycine and acts as a methyl group 
donor and osmolyte.
    Glycine betaine has low acute oral toxicity. Acute dermal, 
inhalation, and dermal irritation studies for glycine betaine were not 
submitted. Glycine betaine was shown to be non-irritating to the eyes. 
In skin sensitization studies in mice, glycine betaine was not skin 
sensitizer. Although a dermal irritation study is not available, 
studies have shown that glycine betaine is found in human skin cell and 
sweat excreted from the body indicating that the chance for dermal 
irritation is minimal. In addition, a percutaneous dermal absorption 
study showed that only 0.1% of the applied dose permeated through the 
epidermis. This would make dermal toxicity unlikely.
    Repeat dose oral toxicity studies on glycine betaine in rats 
include: Two 28-day studies, a 90-day study, and a combined chronic 
toxicity/carcinogenicity study. No adverse effects of treatment were 
seen in any of the studies up to the limit dose of 1000 Milligrams/
kilograms/day (mg/kg/day). Some effects (e.g., increased liver weights, 
hepatocellular vacuolation, and increased Gamma Glutamyl Transferase 
(GGT) levels) were seen at varying dose levels, but only at extremely 
high doses (>=4000 mg/kg/day) were these effects seen in combination 
and therefore, considered a potential effect of treatment. One of the 
28-day rat oral toxicity studies included a 28-day reversal period 
where animals were fed the control diet and evaluated on day 56. The 
study showed that after the reversal period the liver weights were 
comparable to control and the vacuoles were gone.
    The full study reports for studies referenced above were not 
available and therefore, the Agency could not determine if these 
effects (e.g., increased liver weights, hepatocellular vacuolation, and 
increased GGT levels) were a true result of toxicity from the subject 
chemical or if they were within normal range of historical controls of 
the test animal or an effect of the excessive dosing. According to the 
summaries provided through the European Chemicals Agency (ECHA) 
database as part of the Registration, Evaluation, Authorization, and 
Restrictions of Chemical (REACH) program and the Cosmetic Ingredient 
Review (CIR) on betaine, betaine is tolerated at very high levels and 
its effects are reversible. This was also the finding of an article in 
Food and Chemical Toxicology which reviewed the two 28-day studies and 
the 90-day study. Although the study reviews did not treat these 
effects as adverse, and determined the NOAEL to be the highest dose 
tested in each case (4000-7143 mg/kg/day), in the absence of 
confirmatory data, the Agency has taken the conservative approach and 
treated these as an effect of treatment. The target organ in these 
studies appeared to be the liver.
    While no developmental or reproductive studies were conducted with 
glycine betaine, it was seen to be beneficial in preventing neural tube 
defects and has been used in children as young as 24 days old as a 
treatment for homocystinuria. There was no evidence of carcinogenicity 
in any of the studies presented including the combined chronic/
carcinogenicity study and studies on mutagenicity and cytotoxicity. In 
addition, no neuropathological changes or effects were reported in any 
of the studies. The Agency does not believe glycine betaine will be 
carcinogenic or neurotoxic.

B. Toxicological Points of Departure/Levels of Concern

    Available toxicity studies on glycine betaine indicate that it has 
a very low acute, subchronic, and chronic toxicity.

[[Page 2458]]

No adverse effects were seen in any of the studies presented at the 
limit dose of 1000 mg/kg/day, effects seen above the limit dose level 
are not used for endpoint selection; therefore, no endpoint of concern 
has been selected for acute, subchronic, or chronic toxicity.

C. Exposure Assessment

    1. Dietary exposure from food and feed uses. In evaluating dietary 
exposure to glycine betaine, EPA considered exposure under the proposed 
exemption from the requirement of a tolerance. EPA assessed dietary 
exposures from glycine betaine in food as follows:
    Dietary exposure to glycine betaine may occur from eating foods 
naturally containing glycine betaine and foods treated with pesticide 
formulations containing glycine betaine as an inert ingredient. 
Because, at the limit dose, no endpoint of concern was identified, a 
quantitative dietary exposure assessment for glycine betaine was not 
conducted.
    2. Dietary exposure from drinking water. Since a hazard endpoint of 
concern was not identified for the acute and chronic dietary 
assessment, a quantitative dietary exposure risk assessment for 
drinking water was not conducted, although exposures may be expected 
from use of pesticide formulations containing glycine betaine on food 
crops.
    3. From non-dietary exposure. The term ``residential exposure'' is 
used in this document to refer to non-occupational, non-dietary 
exposure (e.g., textiles (clothing and diapers), carpets, swimming 
pools, and hard surface disinfection on walls, floors, tables). Glycine 
betaine may be used as inert ingredient in pesticide products that are 
registered for specific uses that may result in indoor or outdoor 
residential. Additional non-dietary exposure may occur from use of 
glycine betaine in pharmaceutical products and cosmetics. However, 
since there are no toxicological effects of concern at the limit dose 
in available studies, a quantitative assessment of residential (non-
occupational) exposures and risks is not necessary.
    4. Cumulative effects from substances with a common mechanism of 
toxicity. Section 408(b)(2)(D)(v) of 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 glycine betaine to share a common mechanism of 
toxicity with any other substances, and glycine betaine does not appear 
to produce a toxic metabolite produced by other substances. For the 
purposes of this tolerance action, therefore, EPA has assumed that 
glycine betaine 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 http://www.epa.gov/pesticides/cumulative.

D. Safety Factor for Infants and Children

    Section 408(b)(2)(C) requires EPA to retain an additional tenfold 
margin of safety in the case of threshold effects to ensure that there 
is a reasonable certainty that no harm will result to infants and 
children from aggregate exposure to the pesticide chemical residue. As 
noted in Unit IV.B., there is no indication of threshold effects being 
caused by glycine betaine at the limit dose. Therefore, due to the lack 
of any toxicological endpoints of concern at the limit dose, EPA is 
conducting a qualitative assessment of glycine betaine which does not 
use safety factors for assessing risk, and no additional safety factor 
is needed for assessing risk to infants and children.

E. Aggregate Risks and Determination of Safety

    Taking into consideration all available information on glycine 
betaine EPA has determined that there is a reasonable certainty that no 
harm to any population subgroup will result from aggregate exposure to 
glycine betaine under reasonable foreseeable circumstances. Therefore, 
the establishment of an exemption from tolerance under 40 CFR 180.920 
for residues of glycine betaine when used as an inert ingredient in 
pesticide formulations applied to growing crops, is safe under FFDCA 
section 408.

V. Other Considerations

Analytical Enforcement Methodology

    An analytical method is not required for enforcement purposes since 
the Agency is establishing an exemption from the requirement of a 
tolerance without any numerical limitation.

VI. Conclusions

    Therefore, an exemption from the requirement of a tolerance is 
established under 40 CFR 180.920 for glycine betaine (CAS Reg. No. 107-
43-7) when used as an inert ingredient (plant nutrient) in pesticide 
formulations applied to growing crops only.

VII. Statutory and Executive Order Reviews

    This action establishes an exemption from the requirement of a 
tolerance under FFDCA section 408(d) in response to a petition 
submitted to the Agency. The Office of Management and Budget (OMB) has 
exempted these types of actions from review under Executive Order 
12866, entitled ``Regulatory Planning and Review'' (58 FR 51735, 
October 4, 1993). Because this action has been exempted from review 
under Executive Order 12866, 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); Executive Order 13045, entitled ``Protection of 
Children from Environmental Health Risks and Safety Risks'' (62 FR 
19885, April 23, 1997); or 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 (PRA) (44 U.S.C. 3501 
et seq.), nor does it 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).
    Since tolerances and exemptions that are established on the basis 
of a petition under FFDCA section 408(d), such as the exemption in this 
final rule, do not require the issuance of a proposed rule, the 
requirements of the Regulatory Flexibility Act (RFA) (5 U.S.C. 601 et 
seq.), do not apply.
    This action directly regulates growers, food processors, food 
handlers, and food retailers, not States or tribes, nor does this 
action alter the relationships or distribution of power and 
responsibilities established by Congress in the preemption provisions 
of FFDCA section 408(n)(4). As such, the Agency has determined that 
this action will not have a substantial direct effect on States or 
tribal governments, on the relationship between the national government 
and the States or tribal governments, or on the distribution of power 
and responsibilities among the various levels of government or between 
the Federal Government and Indian tribes. Thus, the Agency has 
determined that Executive Order 13132, entitled ``Federalism'' (64 FR 
43255, August 10, 1999) and Executive Order 13175,

[[Page 2459]]

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 
or contain any unfunded mandate as described under Title II of the 
Unfunded Mandates Reform Act (UMRA) (2 U.S.C. 1501 et seq.).
    This action 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 (NTTAA) (15 U.S.C. 272 note).

VIII. Congressional Review Act

    Pursuant to the Congressional Review Act (5 U.S.C. 801 et seq.), 
EPA will submit a report containing this rule and other required 
information to the U.S. Senate, the U.S. House of Representatives, and 
the Comptroller General of the United States prior to publication of 
the rule in the Federal Register. This action is not a ``major rule'' 
as defined by 5 U.S.C. 804(2).

List of Subjects in 40 CFR Part 180

    Environmental protection, Administrative practice and procedure, 
Agricultural commodities, Pesticides and pests, Reporting and 
recordkeeping requirements.

    Dated: December 17, 2018.
Michael Goodis,
Director, Registration Division, Office of Pesticides.

    Therefore, 40 CFR chapter I is 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. In Sec.  180.920, add alphabetically the inert ingredient ``Glycine 
betaine (CAS Reg. No. 107-43-7)'' to the table to read as follows:

Sec.  180.920  Inert ingredients used pre-harvest; exemptions from the 
requirement of a tolerance.

* * * * *

------------------------------------------------------------------------
        Inert ingredients               Limits               Uses
------------------------------------------------------------------------
 
                              * * * * * * *
Glycine betaine (CAS Reg. No.     ..................  Plant nutrient.
 107-43-7).
 
                              * * * * * * *
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[FR Doc. 2019-01307 Filed 2-6-19; 8:45 am]
BILLING CODE 6560-50-P