[Federal Register Volume 76, Number 120 (Wednesday, June 22, 2011)]
[Rules and Regulations]
From the Federal Register Online via the Government Printing Office [www.gpo.gov]
[FR Doc No: 2011-15466]
ENVIRONMENTAL PROTECTION AGENCY
40 CFR Part 180
2-methyl-2,4-pentanediol; Exemption from the Requirement of a
AGENCY: Environmental Protection Agency (EPA).
ACTION: Final rule.
SUMMARY: This regulation establishes an exemption from the requirement
of a tolerance for residues of 2-methyl-2,4-pentanediol (CAS Reg. No.
107-41-5) when used as an inert ingredient as a solvent in pesticide
formulations 40 CFR 180.910 and 180.930 for use on crops (pre-harvest
and post-harvest) and for direct application on animals without
limitations. 2-methyl-2,4-pentanediol is commonly referred to as
``hexylene glycol''. The FB Sciences, Inc., 153 N. Main Street, Suite
100, Collierville, TN 38017 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 2-methyl-2,4-pentanediol.
DATES: This regulation is effective June 22, 2011. Objections and
requests for hearings must be received on or before August 22, 2011,
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: EPA has established a docket for this action under docket
identification (ID) number EPA-HQ-OPP-2010-0330. All documents in the
docket are listed in the docket index available at http://www.regulations.gov. Although listed in the index, some information is
not publicly available, e.g., Confidential Business Information (CBI)
or other information whose disclosure is restricted by statute. Certain
other material, such as copyrighted material, is not placed on the
Internet and will be publicly available only in hard copy form.
Publicly available docket materials are available in the electronic
docket at http://www.regulations.gov, or, if only available in hard
copy, at the OPP Regulatory Public Docket in Rm. S-4400, One Potomac
Yard (South Bldg.), 2777 S. Crystal Dr., Arlington, VA. The Docket
Facility is open from 8:30 a.m. to 4 p.m., Monday through Friday,
excluding legal holidays. The Docket Facility telephone number is (703)
FOR FURTHER INFORMATION CONTACT: Mark Dow, Registration Division
(7505P), Office of Pesticide Programs, Environmental Protection Agency,
1200 Pennsylvania Ave., NW., Washington, DC 20460-0001; telephone
number: (703) 305- 5533; e-mail address: email@example.com.
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.
Potentially affected entities may include, but are not limited to:
Crop production (NAICS code 111).
Animal production (NAICS code 112).
Food manufacturing (NAICS code 311).
Pesticide manufacturing (NAICS code 32532).
This listing is not intended to be exhaustive, but rather provides
a guide for readers regarding entities likely to be affected by this
action. Other types of entities not listed in this unit could also be
affected. The North American Industrial Classification System (NAICS)
codes have been provided to assist you and others in determining
whether this action might apply to certain entities. If you have any
questions regarding the applicability of this action to a particular
entity, consult the person listed under FOR FURTHER INFORMATION
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.gpoaccess.gov/ecfr.
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-2010-0330 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
August 22, 2011. 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 that does not contain any 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 a copy of
your non-CBI objection or hearing request, identified by docket ID
number EPA-HQ-OPP-2010-0330, by one of the following methods:
Federal eRulemaking Portal: http://www.regulations.gov.
Follow the on-line instructions for submitting comments.
Mail: Office of Pesticide Programs (OPP) Regulatory Public
Docket (7502P), Environmental Protection Agency, 1200 Pennsylvania
Ave., NW., Washington, DC 20460-0001.
Delivery: OPP Regulatory Public Docket (7502P),
Environmental Protection Agency, Rm. S-4400, One Potomac Yard (South
Bldg.), 2777 S. Crystal Dr., Arlington, VA. Deliveries are only
accepted during the Docket Facility's normal hours of operation (8:30
a.m. to 4 p.m., Monday through Friday, excluding legal holidays).
Special arrangements should be made for deliveries of boxed
information. The Docket Facility telephone number is (703) 305-5805.
II. Petition for Exemption
In the Federal Register of June 8, 2010 (75 FR 32466) (FRL-8827-8),
EPA issued a notice pursuant to section 408 of FFDCA, 21 U.S.C. 346a,
announcing the filing of a pesticide petition (PP 0E7693) by FB
Sciences, Inc., 153 N. Main Street, Ste. 100, Collierville, TN 38017.
The petition requested that 40 CFR 180.910 and 180.930 be amended by
establishing an exemption from the requirement of a tolerance for
residues of 2-methyl-2,4-pentanediol (CAS Reg. No.107-41-5) when used
as an inert ingredient as a solvent in pesticide formulations applied
to crops pre-harvest and post-harvest and to animals without
limitations. That notice referenced a summary of the petition prepared
by FB Sciences, Inc., 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
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 tolerance is ``safe.'' Section 408(b)(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 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 section 408(c)(2)(A) of FFDCA, 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 2-methyl-2,4-pentanediol
including exposure resulting from the exemption established by this
action. EPA's assessment of exposures and risks associated with 2-
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 2-methyl-2,4-pentanediol 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.
2- methyl-2,4-pentanediol (CAS Reg. No. 107-41-5) is an aliphatic
alcohol also known as: Hexylene glycol; diolane; and 1,1,3-
trimethyltrimethylene-diol. Non-pesticidal uses of 2-methyl-2,4-
pentanediol include use as a chemical intermediate, a selective solvent
in petroleum refining, a component of hydraulic fluids, a solvent for
inks, as an additive to cement, textile dye vehicles, a lubricant and
fuel additive, and as an ingredient in cosmetics and hair care
products. The Food and Drug Administration (FDA) has approved of the
use of 2-methyl-2,4-pentanediol as an indirect food additive such as in
adhesives in contact with food under 21 CFR parts 175-178.
2-methyl-2,4-pentanediol is not acutely toxic to rats via the oral
route of exposure. An Organization for Economic Cooperation and
Development (OECD)-SIDS (2001) report indicates LD50 ranges
from 2-4.47 g/kg. Acute dermal toxicity is low with dermal doses up to
2,000 milligrams/kilogram (mg/kg) that did not cause death (as cited in
OECD-SIDS, 2001). It is irritating to the skin and eyes, but not a skin
sensitizer in guinea pigs. It has low inhalation toxicity, with an
LC50 of 160 parts per million (ppm) (0.772 mg/L), which is
in excess of the saturated vapor concentration.
In a 90-day subchronic toxicity study, 2-methyl-2,4-pentanediol was
administered by oral gavage to rats at dose levels of 50, 150, or 450
mg/kg/bw/day. In this study the functional observational battery, blood
chemistry, hematological parameters and histopathological examinations
were conducted. A functional observational battery test gave no
indication of neurotoxicity. In both sexes, hyperplasia,
hyperkeratosis, inflammatory cell infiltration and edema of the mucosa
and submucosa of the stomach were observed starting at 150 mg/kg/day.
These changes were indicative of a local irritative effect resulting
from the oral gavage procedure. Hepatocellular hypertrophy with
increased liver weight was observed at 450 mg/kg/day in both sexes, and
in males at 150 mg/kg/day. In the absence of degenerative or necrotic
changes these findings were considered to be adaptive responses. At 150
and 450 mg/kg/day, increased kidney weights and increased incidence of
acidophilic globules in the tubular epithelium in males were suggestive
of male rat specific alpha-2-microglobulin nephropathy, which is not
considered as an effect relevant to humans. Observed changes were
either fully or partially reversible over the 4-week recovery period.
There were no adverse effects on the reproductive organs. No effects
were observed at 50 mg/kg/day. A NOAEL of 450 mg/kg/day was determined
for systemic toxicity because the effects described were either
produced by irritation from the oral gavage procedure, or were
considered adaptive responses. A range-finding 14-day study gave
No guideline reproduction studies were available for assessment,
however, no adverse effects on reproductive organs (including testes,
prostate, seminal vesicles, epididymis, ovaries, vagina, and uterus)
were observed in the 90-day gavage study in which rats were
administered 2-methyl-2,4-pentanediol at doses up to 450 mg/kg/day.
Therefore, OECD SIDS concluded that no additional studies are required
under the SIDS program regarding fertility. EPA agrees with this
conclusion by the OECD.
In a developmental toxicity study, pregnant rats were administered
30, 300, or 1,000 mg/kg/bw/day of 2-methyl-2,4-pentanediol by gavage in
5 mL/kg of vehicle on gestation days (GD) 6-15. The NOAEL for maternal
toxicity was 300 mg/kg/day based on a statistically significant
reduction in group mean body weight gain and food consumption at 1,000
mg/kg/day. There was a marginal, non-statistically significant
reduction in fetal body weight at 1,000 mg/kg/day. Marginally higher
incidences of fetal variations, some of which were statistically
significant (occipitals incompletely ossified, 21.6%; extra
thoracolumbar ribs, 18.7%; and hyoid arch not ossified, 18%), occurred
at 1,000 mg/kg/day. A delay in the normal ossification process was also
observed in fetuses, but this was considered by the study authors to be
related to reduced maternal body weight gain at this dose level. The
NOAEL and LOAEL for maternal and fetal developmental toxicity were
determined to be 300 and 1,000 mg/kg/day, respectively.
In another developmental toxicity study, pregnant rats received
500, 1,200, or 1,600 mg/kg/bw/day of 2-methyl-2,4-pentanediol by gavage
in 10 mL/kg of vehicle on GD 6-17. At 1,200 and 1,600 mg/kg/day, dams
had ataxia and reductions in mean weight gain and food consumption. At
the 1,600 mg/kg/day, pregnant rats had mean weight loss, and one female
aborted prior to the end of the study. Maternal toxicity at these
levels corresponds to decreased fetal body weights and gravid uterine
weights. Additionally, at 1,600 mg/kg/day, there was one abortion and
one whole litter resorption. However, the number of fetal
malformations, such as increased incidence of skeletal variations
(delayed ossification, extra ribs), was not significantly different
from controls. A maternal NOAEL of 500 mg/kg/day was determined by the
Agency, and the same NOAEL was determined in the study for fetal
toxicity. These results support the results of a study described in
this unit and indicate that 2-methyl-2,4-pentanediol has low potential
for developmental toxicity.
2-methyl-2,4-pentanediol is not genotoxic in either mammalian or
non-mammalian cells ``in vitro.'' It was negative for mutagenicity in
the Ames test, yeast cell assay and hamster ovary cell assay.
Ten rats and a rabbit exposed to an aerosol of 2-methyl-2,4-
pentanediol at a concentration of 0.7 mg/L (about 145 ppm) for 7 hr/day
for 9 days survived with mild upper respiratory irritation. No
histopathological effects were reported.
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.
No acute endpoint of concern was identified in the available
toxicity studies. The endpoint of concern for the
chronic reference dose (cRfD) was identified from the developmental
toxicity study in rats. In this study, the NOAEL (500 mg/kg/day) was
based on increased incidence of clinical signs, reductions in mean body
weight gain and food consumption seen at the LOAEL of 1,200 mg/kg/day
and above. This NOAEL was supported by the 90-day gavage toxicity study
in rats (NOAEL 450 mg/kg/day; highest dose tested). There was a lower
NOAEL (300 mg/kg/day) observed in the range finding study in rats based
on a statistically significant reduction in group mean body weight gain
and food consumption, and marginally higher incidences of fetal
variations seen at the LOAEL of 1,000 mg/kg/day. The differences
between the NOAELs of the range finding study and the developmental
toxicity study in rats were considered due to artifacts of dose
selection. An uncertainty factor 100X (10X for intraspecies variability
and 10X interspecies extrapolation) was applied to the NOAEL. No
additional uncertainty factor is necessary for use of the subchronic to
chronic study because the effects were observed at the limit dose of
1,000 mg/kg/day and above. The FQPA factor for increased susceptibility
of infant and children was reduced to 1X. Therefore, the cRfD is equal
to population adjusted dose (cPAD). This endpoint and the dose was also
used for dermal and inhalation exposure assessment for all exposure
scenarios. Inhalation and dermal absorption was assumed to be 100%.
This approach would provide a highly conservative estimate of risk via
the dermal and inhalation routes of exposure.
Table 1--Summary of Toxicological Doses and Endpoints for 2-methyl-2,4-pentanediol for Use in Human Risk
Point of departure and
Exposure/scenario uncertainty/safety RfD, PAD, LOC for risk Study and toxicological
factors assessment effects
Acute dietary (General population No acute endpoint of concern was identified in the available database.
including infants and children).
Chronic dietary (All populations).. NOAEL = 500 mg/kg/day. Chronic RfD = 500 mg/ Developmental Toxicity
Incidental oral short-term and UFA = 10x............. kg/day. Study--rats LOAEL = 1,200
intermediate term. UFH = 10x............. cPAD = 500 mg/kg/day.. mg/kg/day based on reduced
FQPA SF = 1x.......... body weights in maternal
animals, reduced fetal
Dermal short and intermediate term. 100% absorption via
dermal and inhalation
routes; LOC MOE..
Inhalation short and intermediate 100...................
Cancer (Oral, dermal, inhalation).. No evidence of carcinogenicity. SAR analysis negative for carcinogenic
alerts. Not mutagenic in mammalian and non-mammalian mutagenicity assays.
UFA = extrapolation from animal to human (interspecies). UFH = potential variation in sensitivity among members
of the human population (intraspecies). UFL = use of a LOAEL to extrapolate a NOAEL. UFS = use of a short-term
study for long-term risk assessment. UFDB = to account for the absence of data or other data deficiency. FQPA
SF = Food Quality Protection Act Safety Factor. PAD = population adjusted dose (a = acute, c = chronic). RfD =
reference dose. MOE = margin of exposure. LOC = level of concern.
C. Exposure Assessment
1. Dietary exposure from food and feed uses. In evaluating dietary
exposure to 2-methyl-2,4-pentanediol, EPA considered exposure under the
proposed exemption from the requirement of a tolerance. EPA assessed
dietary exposures from 2-methyl-2,4-pentanediol in food as follows:
No acute endpoint of concern was identified in the database.
Therefore, a quantitative acute dietary exposure assessment was not
i. Chronic exposure. In conducting the chronic dietary exposure
assessments, EPA used food consumption information from the United
States Department of Agriculture (USDA) [1994-1996 and 1998] Nationwide
Continuing Surveys of Food Intake by Individuals (CSFII). As to residue
levels in food, no residue data were submitted for 2-methyl-2,4-
pentanediol. In the absence of specific residue data, EPA has developed
an approach which uses surrogate information to derive upper bound
exposure estimates for the subject inert ingredient. Upper bound
exposure estimates are based on the highest tolerance for a given
commodity from a list of high-use insecticides, herbicides, and
fungicides. A complete description of the general approach taken to
assess inert ingredient risks in the absence of residue data is
contained in the memorandum entitled ``Alkyl Amines Polyalkoxylates
(Cluster 4): Acute and Chronic Aggregate (Food and Drinking Water)
Dietary Exposure and Risk Assessments for the Inerts.'' (D361707, S.
Piper, 2/25/09) and can be found at http://www.regulations.gov in
docket ID number EPA-HQ-OPP-2008-0738.
In the dietary exposure assessment, the Agency assumed that the
residue level of the inert ingredient would be no higher than the
highest tolerance for a given commodity. Implicit in this assumption is
that there would be similar rates of degradation (if any) between the
active and inert ingredient and that the concentration of inert
ingredient in the scenarios leading to these highest of tolerances
would be no higher than the concentration of the active ingredient.
The Agency believes the assumptions used to estimate dietary
exposures lead to an extremely conservative assessment of dietary risk
due to a series of compounded conservatisms. First, assuming that the
level of residue for an inert ingredient is equal to the level of
residue for the active ingredient will overstate exposure. The
concentration of active ingredient in agricultural products is
generally at least 50% of the product and often can be much higher.
Further, pesticide products rarely have a single inert ingredient;
rather there is generally a combination of different inert ingredients
used which additionally reduces the concentration of any single inert
ingredient in the pesticide product in relation to that of the active
Second, the conservatism of this methodology is compounded by EPA's
decision to assume that, for each commodity, the active ingredient
which will serve as a guide to the potential level of inert ingredient
residues is the active ingredient with the highest tolerance level.
This assumption overstates residue values because it would be highly
unlikely, given the high number of inert ingredients, that a single
inert ingredient or class of ingredients would be present at the level
of the active ingredient in the highest tolerance for every commodity.
Finally, a third compounding conservatism is EPA's assumption that all
foods contain the inert ingredient at the highest tolerance level. In
other words, EPA assumed 100% of all foods are treated with the inert
ingredient at the rate and manner necessary to produce the highest
residue legally possible for an active ingredient. In summary, EPA
chose a very conservative method for estimating what level of inert
residue could be on food, then used this methodology to choose the
highest possible residue that could be found on food and assumed that
all food contained this residue. No consideration was given to
potential degradation between harvest and consumption even though
monitoring data shows that tolerance level residues are typically one
to two orders of magnitude higher than actual residues in food when
distributed in commerce.
Accordingly, although sufficient information to quantify actual
residue levels in food is not available, the compounding of these
conservative assumptions will lead to a significant exaggeration of
actual exposures. EPA does not believe that this approach
underestimates exposure in the absence of residue data.
ii. Cancer. Chronic and carcinogenicity studies were not available
on 2-methyl-2,4-pentanediol. There is no evidence that 2-methyl-2,4-
pentanediol is carcinogenic. The Agency used a qualitative structure
activity relationship (SAR) database, DEREK Version 11, to determine if
there were structural alerts. No structural alerts were identified. In
addition, it is negative for mutagenicity in mammalian and non-
mammalian mutagenicity assays. 2-methyl-2,4-pentanediol is rapidly
metabolized and excreted as glucuronates. Based on weight-of-evidence
and low toxicity mentioned in this unit, 2-methyl-2,4-pentanediol is
not expected to be carcinogenic. Since the Agency has not identified
any concerns for carcinogenicity relating to 2-methyl-2,4-pentanediol,
a dietary exposure assessment to evaluate cancer risk was not
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 2-methyl-2,4-
pentanediol, a conservative drinking water concentration value of 100
ppb based on screening level modeling was used to assess the
contribution to drinking water for the chronic dietary risk assessments
for parent compound. These values were directly entered into the
dietary exposure model.
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). No
residential uses as a pesticide inert ingredient have been requested
and none are expected. Although 2-methyl-2,4-pentanediol is used in
cosmetics and hair care products, the Agency believes exposure and risk
from these routes of exposure to be negligible. The FDA includes 2-
methyl-2,4-pentanediol (i.e., hexylene glycol) in its list of Indirect
Additives Used in Food Contact Subtances. The exposure to 2-methyl-2,4-
pentanediol through hair color use is considered minimal because it is
a volatile chemical, treatment times are very short and absorption
through the scalp is limited. Based on these considerations, the Agency
concluded that there is no need to conduct aggregate exposure through
use of consumer products. Further, there are no reliable data with
which to estimate such exposures.
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 2-methyl-2,4-pentanediol to share a common
mechanism of toxicity with any other substances, and 2-methyl-2,4-
pentanediol does not appear to produce a toxic metabolite produced by
other substances. For the purposes of this tolerance action, therefore,
EPA has assumed that 2-methyl-2,4-pentanediol 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 Web site at http://www.epa.gov/pesticides/cumulative.
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
2. Prenatal and postnatal sensitivity. The maternal and
developmental effects were only observed at the limit dose of 1,000 mg/
kg/day and above in the developmental toxicity study in rats. Maternal
and fetal toxicity were mainly manifested as decreases in body weights.
Marginally higher incidences of fetal variations were also observed at
the limit dose or above. There were no guideline reproduction studies
available on 2-methyl-2,4-pentanediol; however, no adverse effects on
reproductive organs (including testes, prostate, seminal vesicles,
epididymis, ovaries, vagina, and uterus) were observed at doses up to
450 mg/kg/day in a 90-day toxicity study in rats. In addition, the
reproductive indices were not affected in the two available
developmental toxicity studies in rats.
3. Conclusion. EPA has determined that reliable data show the
safety of infants and children would be adequately protected if the
FQPA SF were reduced to 1X. That decision is based on the following
i. The toxicity database for 2-methyl-2,4-pentanediol is not
complete but considered as adequate for FQPA assessment given the low
toxicity of 2-methyl-2,4-pentanediol. No guideline reproduction studies
were available for assessment; however, no adverse effects on
reproductive organs (including testes, prostate, seminal vesicles,
epididymis, ovaries, vagina, and uterus) were observed in the 90-day
gavage study in which rats were administered 2-methyl-2,4-pentanediol
at doses up to 450 mg/kg/day. Therefore, OECD SIDS concluded that no
additional studies are required under the SIDS program regarding
fertility. EPA is in agreement
with the OECD conclusion. Chronic studies are also not available, but
the concern for chronic toxicity is low given the low toxicity of 2-
ii. No evidence of clinical signs of neurotoxicity was observed in
the available database. No evidence of neurobehavioral or
neuropathology was seen in a 90-day toxicity study in rats. There is no
indication that 2-methyl-2,4-pentanediol is a neurotoxic chemical and
there is no need for a developmental neurotoxicity study or additional
UFs to account for neurotoxicity.
iii. There is no evidence that 2-methyl-2,4-pentanediol results in
increased susceptibility in rats (as described in this unit).
iv Immunotoxicity studies for 2-methyl-2,4-pentanediol were not
available for review. However, there was no evidence of immunotoxicity
in the available database.
v. There are no residual uncertainties identified in the exposure
databases. The dietary food exposure assessments were performed based
on 100 percent crop treated (PCT) and tolerance-level residues. EPA
made conservative (protective) assumptions in the ground and surface
water modeling used to assess exposure to 2-methyl-2,4-pentanediol in
drinking water. These assessments will not underestimate the exposure
and risks posed by 2-methyl-2,4-pentanediol.
E. Aggregate Risks and Determination of Safety
EPA determines whether acute and chronic dietary pesticide
exposures are safe by comparing aggregate exposure estimates to the
acute (aPAD) and chronic (cPAD). For linear cancer risks, EPA
calculates the lifetime probability of acquiring cancer given the
estimated aggregate exposure. Short-, intermediate-, and chronic-term
risks are evaluated by comparing the estimated aggregate food, water,
and residential exposure to the appropriate PODs to ensure that an
adequate MOE exists.
1. Acute risk. An acute aggregate risk assessment takes into
account acute exposure estimates from dietary consumption of food and
drinking water. No adverse effect resulting from a single oral exposure
was identified and no acute dietary endpoint was selected. Therefore,
2-methyl-2,4-pentanediol is not expected to pose an acute risk.
2. Chronic risk. Using the exposure assumptions described in this
unit for chronic exposure, EPA has concluded that chronic exposure to
2-methyl-2,4-pentanediol from food and water will utilize 3.8% of the
cPAD for the U.S. population and Children 1-2 yrs of age 12.5% cPAD,
the population group receiving the greatest exposure. Based on the
explanation in this unit, regarding residential use patterns, chronic
residential exposure to residues of 2-methyl-2,4-pentanediol is not
3. Short-term risk. Short-term aggregate exposure takes into
account short-term residential exposure plus chronic exposure to food
and water (considered to be a background exposure level).
A short-term adverse effect was identified; however, 2-methyl-2,4-
pentanediol is not currently used as an inert ingredient in pesticide
products that are registered for any use patterns that would result in
short-term residential exposure. Short-term risk is assessed based on
short-term residential exposure plus chronic dietary exposure. Because
there is no short-term residential exposure resulting from use as an
inert ingredient in pesticidal formulations and chronic dietary
exposure has already been assessed under the appropriately protective
cPAD (which is at least as protective as the POD used to assess short-
term risk), no further assessment of short-term risk is necessary, and
EPA relies on the chronic dietary risk assessment for evaluating short-
term risk for 2-methyl-2,4-pentanediol.
For the reasons discussed in Unit IV.C.3., short-term aggregate
exposure assessment was not conducted for non-pesticidal uses.
4. Intermediate-term risk. Intermediate-term aggregate exposure
takes into account intermediate-term residential exposure plus chronic
exposure to food and water (considered to be a background exposure
level). An intermediate-term adverse effect was identified; however, 2-
methyl-2,4-pentanediol is not currently used as an inert ingredient in
pesticide products that are registered for any use patterns that would
result in intermediate-term residential exposure. Intermediate-term
risk is assessed based on intermediate-term residential exposure plus
chronic dietary exposure. Because there is no intermediate-term
residential exposure and chronic dietary exposure has already been
assessed under the appropriately protective cPAD (which is at least as
protective as the POD used to assess intermediate-term risk), no
further assessment of intermediate-term risk is necessary, and EPA
relies on the chronic dietary risk assessment for evaluating
intermediate-term risk for 2-methyl-2,4-pentanediol. For the reasons
discussed in Unit IV.C.3., intermediate term aggregate exposure
assessment was not conducted for non-pesticidal uses.
5. Aggregate cancer risk for U.S. population. 2-methyl-2,4-
pentanediol is not expected to pose a cancer risk to humans. Therefore,
aggregate cancer risk was not performed.
6. Determination of safety. Based on these risk assessments, 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 2-methyl-2,4-pentanediol residues.
V. Other Considerations
A. 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.
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 U.N. Food and
Agriculture Organization/World Health Organization 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 a MRL for 2-methyl-2,4-pentanediol.
Therefore, an exemption from the requirement of a tolerance is
established under 40 CFR 180.910 and Sec. 180.930 for 2-methyl-2,4-
pentanediol. (CAS Reg. No. 107-1-41-5) when used as an inert ingredient
in pesticide formulations applied to crops and food animals without
VII. Statutory and Executive Order Reviews
This final rule establishes a tolerance under section 408(d) of
FFDCA 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 final
rule has been exempted from review under Executive Order 12866, this
final rule 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 final rule 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 section 408(d) of FFDCA, such as the tolerance 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 final rule 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 section 408(n)(4) of FFDCA. 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 final rule. In addition,
this final rule does not impose any enforceable duty or contain any
unfunded mandate as described under Title II of the Unfunded Mandates
Reform Act of 1995 (UMRA) (Pub. L. 104-4).
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 of 1995 (NTTAA), Public Law 104-113, section 12(d) (15 U.S.C. 272
VIII. Congressional Review Act
The Congressional Review Act, 5 U.S.C. 801 et seq., generally
provides that before a rule may take effect, the agency promulgating
the rule must submit a rule report to each House of the Congress and to
the Comptroller General of the United States. 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 this final rule in the Federal
Register. This final rule is not a ``major rule'' as defined by 5
List of Subjects in 40 CFR Part 180
Environmental protection, Administrative practice and procedure,
Agricultural commodities, Pesticides and pests, Reporting and
Dated: June 10, 2011.
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, the table is amended by adding alphabetically the
following inert ingredients to read as follows:
Sec. 180.910 Insert ingredients used pre-harvest and post-harvest;
exemptions from the requirement of a tolerance.
* * * * *
Inert ingredients Limits Uses
* * * * * * *
2-methyl-2,4-pentanediol (CAS Without limitation Growing crops and
Reg.. food animals
* * * * * * *
3. In Sec. 180.930, the table is amended by adding alphabetically the
following inert ingredients to read as follows:
Sec. 180.930 Insert ingredients applied to animals: exemption from
the requirement of a tolerance.
* * * * *
Inert ingredients Limits Uses
* * * * * * *
2-methyl-2,4-pentanediol (CAS Without limitation Growing crops and
Reg. No.-107-41-5). food animals
* * * * * * *
[FR Doc. 2011-15466 Filed 6-21-11; 8:45 am]
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