[Federal Register Volume 81, Number 249 (Wednesday, December 28, 2016)]
[Rules and Regulations]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2016-31215]
ENVIRONMENTAL PROTECTION AGENCY
40 CFR Part 180
[EPA-HQ-OPP-2015-0776 and EPA-HQ-OPP-2015-0831; FRL-9955-82]
Methyl Isobutyrate and Isobutyl Isobutyrate; Exemption From the
Requirement of a Tolerance
AGENCY: Environmental Protection Agency (EPA).
ACTION: Final rule.
SUMMARY: This regulation establishes exemptions from the requirement of
a tolerance for residues of methyl isobutyrate (CAS Reg. No. 547-63-7)
and for residues of isobutyl isobutyrate (CAS Reg. No. 97-85-8) when
used as inert ingredients (solvents) applied to growing crops or raw
agricultural commodities after harvest. Jeneil Biosurfactant Company
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 methyl
isobutyrate and isobutyl isobutyrate when used in accordance with the
DATES: This regulation is effective December 28, 2016. Objections and
requests for hearings must be received on or before February 27, 2017,
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-2015-0776 and EPA-HQ-OPP-2015-
0831, 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: [email protected].
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-2015-0776 and EPA-HQ-OPP-2015-0831 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 February 27, 2017. Addresses for mail and
hand delivery of objections and hearing requests are provided in 40 CFR
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-2015-0776 and EPA-
HQ-OPP-2015-0831, 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
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 March 16, 2016 (81 FR 14030) (FRL-9942-
86), EPA issued a document pursuant to FFDCA section 408, 21 U.S.C.
346a, announcing the filing of two pesticide petitions (PP IN-10848 &
PP IN-10850) by Jeneil Biosurfactant Company, 400 N. Dekora Woods
Blvd., Saukville, WI 53080. The petitions requested that 40 CFR 180.910
be amended by establishing two exemptions from the requirement of a
tolerance: One for residues of methyl isobutyrate (CAS Reg. No. 547-63-
7) (PP IN-10848) and one for isobutyl isobutyrate (CAS Reg. No. 97-85-
8) (PP IN-10850), when used as inert ingredients (solvents) applied to
growing crops or raw agricultural commodities after harvest. That
document referenced a summary of each petition prepared by Jeneil
Biosurfactant Company, the petitioner, which are available in the
respective dockets (PP IN-10848 in docket ID number EPA-HQ-OPP-2015-
0776 and PP IN-10850 in docket ID number EPA-HQ-OPP-2015-0831), http://www.regulations.gov. Comments were received in response to the notice
of filing, requesting the denial of these petitions based only
generally on a concern for the use of ``toxic chemicals'' in or on
food. Because the commenters did not provide any information upon which
to evaluate these specific inert ingredient tolerance exemptions and
because EPA has determined that such exemptions would be safe, EPA is
not denying the petition as requested.
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
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
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 exemption 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. Section 408(b)(2)(C) of FFDCA requires EPA to
give special consideration to exposure of infants and children to the
pesticide chemical residue 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 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 methyl isobutyrate and isobutyl
isobutyrate including exposure resulting from the exemption established
by this action. EPA's assessment of exposures and risks associated with
methyl isobutyrate and isobutyl isobutyrate 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 methyl isobutyrate and isobutyl
isobutyrate 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.
Methyl isobutyrate and isobutyl isobutyrate are rapidly metabolized
through hydrolysis to form an alcohol and carboxylic acid in the body.
Many of the supporting data for methyl isobutyrate comes directly from
the closely related and similarly metabolized compound isobutyl
isobutyrate. Where separate information for methyl isobutyrate and
isobutyl isobutyrate is available, the studies will be presented along
with information for their common metabolite isobutanol.
An LD50 value of 16,000 milligrams/kilogram body weight
(mg/kg bw) was determined in rats for methyl isobutyrate. The
LC50 of methyl isobutyrate was 25.5 milligrams per Liter
(mg/L) in mice. The acute oral LD50 for isobutyl isobutyrate
value in rats and mice was >6,400 mg/kg. The acute inhalation
LC50 (6 hour exposure duration) was between 3.88 and 31.94
mg/L isobutyl isobutyrate in rats. The dermal LD50 value for
isobutyl isobutyrate in guinea pigs was >8,550 mg/kg.
No repeat-dose studies of methyl isobutyrate were identified in a
search of the toxicological literature. In an 18-week oral gavage study
in rats with isobutyl isobutyrate, there were no treatment related
effects in hematology, clinical chemistry parameters, urinalysis,
histological examination, behavior, appearance, body weight, or food/
water consumption. The NOAEL was 1,000 mg/kg/day; the highest dose
tested. In a 90-day oral toxicity study in rats with isobutanol,
treatment related effects were seen only at 1,000 mg/kg bw/day, and
included hypoactivity, which was significant during week one and
decreased markedly after week 4, and lower body weight gain (18% below
that of control rats) in males during week one. The NOAEL was 316 mg/kg
In a 90-day study toxicity study in rats exposed to isobutanol in
drinking water, no effects on body weight, food/water consumption, and
clinical signs of toxicity and organ weights (livers, kidneys, adrenal
glands, and testes) were observed at doses up to 1,450 mg/kg/day. The
NOAEL for isobutanol was 1,450 mg/kg/day.
In a 90-day isobutanol inhalation study, no differences were found
in body weight, food consumption, ophthalmoscopic examination, clinical
observation, clinical chemistry, neurobehavioral observations, organ
weights, gross pathology, and histopathology. The NOAEL for repeat-dose
effects including neurotoxicity was 2,500 ppm.
In two prenatal developmental toxicity studies via inhalation,
female rats and Himalayan rabbits were exposed to vapor of isobutanol.
In rats, no mortality or significant differences in clinical signs,
body weight development, or gross pathology between controls and
treated groups and no effects on development were noted. The maternal
and developmental rat NOAELs were 3,030 ppm. In rabbits, no mortality
or significant differences in clinical signs, body weight development,
or gross pathology between controls and treated groups and no effects
on development were noted. The maternal no observed adverse effect
level (NOAEL) for rabbits was 758 ppm. Fetuses exhibited no signs of
developmental changes in response to isobutanol. Therefore, the
developmental NOAEL was 3,030 ppm, the highest dose.
In a 2-generation reproduction study in rats with isobutanol via
inhalation, no exposure-related effects were observed on F0 and F1
parental survival or on F0 and F1 reproductive performance, body
consumption and food efficiency in males or females. The NOAEL for
isobutanol for parental systemic, reproductive and neonatal toxicity is
2,500 ppm (7,380 mg/m\3\ the maximum concentrations exposed).
There were no adequate studies on the carcinogenic potential of
methyl isobutyrate or isobutanol isobutyrate. Methyl isobutyrate did
not significantly induce chromosome loss in mitotically growing
Saccharomyces cerevisiae. The structurally similar isobutyl isobutyrate
did not induce reverse mutations at concentrations as high as 5,000
microgram/milliliter (ug/mL). An evaluation of the structure of methyl
isobutyrate for alerts to genotoxicity yields no identifiable
structures of concern. Based on negative results in genotoxicity assays
and an extensive history of exposure to isobutyl isobutyrate,
carcinogenic potential of this compound is likely to be low. Methyl
isobutyrate was not genotoxic in one study and it does not contain
reactive substructures of concern and isobutyl isobutyrate was also
negative in genotoxic assays and in extensive exposure history;
therefore the carcinogenic potential of both compounds is low.
Metabolism of aliphatic esters such as methyl isobutyrate and
isobutyl isobutyrate proceeds rapidly through hydrolysis to form an
alcohol and carboxylic acid. These are reactions of the
carboxylesterases or esterases, which predominate in hepatocytes but
are present in most tissues throughout the body, including small
intestine, colon, kidney, trachea and lung. Hydrolysis of methyl
isobutyrate is extensive and will form methanol and isobutyric acid.
Isobutyric acid is metabolized to propionic acid which, in turn, is
converted to succinic acid and ultimately to glucose and glycogen.
Methanol is oxidized and excreted ultimately as CO2 and
water. In male rats injected intravenously with isobutyl isobutyrate,
the parent compound decreased rapidly in blood and was undetected after
166 seconds. The half-life was calculated at 11.1 seconds. Isobutanol
and isobutyric acid levels increased rapidly, with the acid
consistently higher than the alcohol, suggesting that the former is a
metabolic product of the alcohol in addition to the parent compound.
Isobutyric acid will be conjugated and excreted or will undergo [beta]-
oxidation in the fatty acid metabolic pathway.
B. Toxicological Points of Departure/Levels of Concern
Once a pesticide's toxicological profile is determined, EPA
identifies toxicological points of departure (POD) and levels of
concern to use in evaluating the risk posed by human exposure to the
pesticide. For hazards that have a threshold below which there is no
appreciable risk, the toxicological POD is used as the basis for
derivation of reference values for risk assessment. PODs are developed
based on a careful analysis of the doses in each toxicological study to
determine the dose at which no adverse effects are observed (the NOAEL)
and the lowest dose at which adverse effects of concern are identified
(the LOAEL). Uncertainty/safety factors are used in conjunction with
the POD to calculate a safe exposure level--generally referred to as a
population-adjusted dose (PAD) or a reference dose (RfD)--and a safe
margin of exposure (MOE). For non-threshold risks, the Agency assumes
that any amount of exposure will lead to some degree of risk. Thus, the
Agency estimates risk in terms of the probability of an occurrence of
the adverse effect expected in a lifetime. For more information on the
general principles EPA uses in risk characterization and a complete
description of the risk assessment process, see http://www.epa.gov/pesticides/factsheets/riskassess.htm.
EPA has not identified any toxicological points of departure for
assessing methyl isobutyrate and isobutyl isobutyrate. On the basis of
the metabolism of as methyl isobutyrate and isobutyl isobutyrate
proceeding rapidly through hydrolysis to form an alcohol and carboxylic
acid and ultimately to glucose and glycogen, low acute toxicity for
animals via the dermal, inhalation, and oral routes of exposure, and
low toxicity of the metabolite isobutyl alcohol, no adverse effect is
expected from methyl isobutyrate and isobutyl isobutyrate as a result
of exposure by any route.
C. Exposure Assessment
1. Dietary exposure from food and feed uses. In evaluating dietary
exposure to methyl isobutyrate and isobutyl isobutyrate, EPA considered
exposure under the proposed exemption from the requirement of a
tolerance. EPA assessed dietary exposures from methyl isobutyrate and
isobutyl isobutyrate in food as follows:
Acute and chronic dietary assessments take into account exposure
estimates from dietary consumption of food and drinking water. Because
no adverse effects attributable to a single or repeat exposures to
methyl isobutyrate and isobutyl isobutyrate were seen in the toxicity
databases, quantitative dietary risk assessments are not appropriate.
Due to expected use of methyl isobutyrate and isobutyl isobutyrate in
pesticide formulations applied to growing crops and raw agricultural
commodities after harvest, it is reasonable to expect that there will
be some exposure to these substances from their use in pesticide
products. In addition, FDA has approved the use of methyl isobutyrate
and isobutyl isobutyrate as synthetic flavoring substances in food for
direct human consumption (21 CFR 172.515), so there is expected to be
additional dietary exposure to these substances from non-pesticidal
2. Dietary exposure from drinking water. For the purpose of the
screening level dietary risk assessment to support this request for an
exemption from the requirement of a tolerance for methyl isobutyrate
and isobutyl isobutyrate, a conservative drinking water concentration
value would normally be included in dietary exposure screening level
model. However, because no adverse effects attributable to a single or
repeat exposures to methyl isobutyrate and isobutyl isobutyrate were
seen in the toxicity databases, quantitative dietary risk assessments
are not appropriate.
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).
It is possible that methyl isobutyrate or isobutyl may be used as
an inert ingredient in pesticide products that may result in
residential exposures, although no residential uses are currently
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 or
exemption from 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.''
Because methyl isobutyrate and isobutyl isobutyrate do not have a
toxic mode of action or a mechanism of toxicity, this provision does
D. Safety Factor for Infants and Children
1. In general. Section 408(b)(2)(C) of FFDCA provides that 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 based on reliable data that
a different margin of safety will be safe for infants and children.
This additional margin of safety is commonly referred to as the FQPA
Safety Factor (SF). In applying this provision, EPA either retains the
default value of 10X, or uses a different additional safety factor when
reliable data available to EPA support the choice of a different
Because methyl isobutyrate and isobutyl isobutyrate do not have
threshold effects and because of the lack of safety factors needed for
this qualitative assessment, this provision does not apply to the
assessment of methyl isobutyrate and isobutyl isobutyrate.
E. Aggregate Risks and Determination of Safety
Determination of safety section. Based on the lack of any endpoints
of concern, EPA concludes that there is a reasonable certainty that no
harm will result to the general population or to infants and children
from aggregate exposure to methyl isobutyrate and isobutyl isobutyrate
V. 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.
Therefore, exemptions from the requirement of a tolerance are
established under 40 CFR 180.910 for methyl isobutyrate (CAS Reg. No.
547-63-7) and isobutyl isobutyrate (CAS Reg. No. 97-85-8) when used as
inert ingredients (solvents) in pesticide formulations applied to
growing crops or raw agricultural commodities after harvest.
VII. Statutory and Executive Order Reviews
This action establishes exemptions 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) or Executive Order 13045, entitled ``Protection of
Children from Environmental Health Risks and Safety Risks'' (62 FR
19885, April 23, 1997). 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 exemptions 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, 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
Dated: December 15, 2016.
Daniel J. Rosenblatt,
Acting Director, Registration Division, Office of Pesticide Programs.
Therefore, 40 CFR chapter I is amended as follows:
1. The authority citation for part 180 continues to read as follows:
Authority: 21 U.S.C. 321(q), 346a and 371.
2. In Sec. 180.910, add alphabetically the inert ingredients
``Isobutyl isobutyrate (CAS Reg. No. 97-85-8)''; and ``Methyl
isobutyrate (CAS Reg. No. 547-63-7)'' to the table to read as follows:
Sec. 180.910 Inert ingredients used pre- and post-harvest;
exemptions from the requirement of a tolerance.
* * * * *
Inert ingredients Limits Uses
* * * * * * *
Isobutyl isobutyrate (CAS Reg. None............... Solvent
* * * * * * *
Methyl isobutyrate (CAS Reg. No. None............... Solvent
* * * * * * *
[FR Doc. 2016-31215 Filed 12-27-16; 8:45 am]
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