Document ID: EPA-HQ-OPP-2010-0905-0002
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2011-02-04T05:00Z

<EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR PESTICIDE
PETITIONS PUBLISHED IN THE FEDERAL REGISTER 

Interregional Research Project Number 4 (IR-4) >

<EPA Registration Division contact: Laura Nollen, (703) 305-7390>

 

Petition Number 0F7796

<	EPA has received a pesticide petition, PP # 0F7796, from Interregional
Research Project Number 4 (IR-4), 500 College Road East, Suite 201 W,
Princeton, NJ 08540, proposing, pursuant to section 408(d) of the
Federal Food, Drug, and Cosmetic Act (FFDCA), 21 U.S.C. 346a(d), to
amend 40 CFR part 180.142 to establish  tolerances for residues of 2,4-D
(2,4-D dichlorophenoxyacetic acid), both free and conjugated, determined
as the acid in or on the raw agricultural commodities teff, bran at 4.0
parts per million (ppm); teff, forage at 25.0 ppm; teff, grain at 2.0
ppm; and teff, straw at 50.0 ppm.  EPA has determined that the petition
contains data or information regarding the elements set forth in section
408 (d)(2) of  FDDCA; however, EPA has not fully evaluated the
sufficiency of the submitted data at this time or whether the data
supports granting of the petition. Additional data may be needed before
EPA rules on the petition.>

<A. Residue Chemistry This petition for teff (a minor crop grain) builds
on the existing registration of 2,4-D for use in wheat.

>

<	1. Plant metabolism. Acceptable wheat, lemon, and potato metabolism
studies have been submitted and reviewed as part of the 2005 EPA RED
(EPA 738-R-05-002).

>

<	2. Analytical method. Per the 2005 EPA RED (EPA 738-R-05-002) page 98,
the 2,4-D Task Force II submitted an adequate GC/ECD enforcement method
for plants (designated as EN-CAS Method No. ENC-2/93) which has been
independently validated.  Adequate radiovalidation data have been
submitted and evaluated for the enforcement method using samples from
the wheat metabolism study.>

<	3. Magnitude of residues. IR-4 submitted a proposal to US EPA ChemSAC
to extrapolate to teff from wheat.  Teff and other cereal grains
including corn (sweet and field), rice, sorghum, wheat, barley, pearl
and proso millet, oats, popcorn, rye, teosinte, and triticale have
similar morphological, cultural practices, taxonomical characteristics,
and share similar pest problems.  Teff is scheduled for inclusion in the
revised Cereal Grains Crop Group 15 to be proposed by IR-4 and the
International Crop Grouping Consulting Committee.  IR-4 proposed that
the 2,4-D tolerances for teff be based on the existing residue
tolerances for 2,4-D (40 CFR 180.142) on wheat, barley, oats, rye, and
millet.  US EPA ChemSAC in a meeting on October 29, 2008 agreed with the
proposal, considering the low acreage of teff grown in the US and the
similarity to other cereal grains.>

<B. Toxicological Profile Per the 2005 RED (EPA 738-R-05-002), the EPA
stated that with very few exceptions, the effects and relative
toxicities of the salt and ester forms of 2,4-D are quite similar to
those of the acid form. Thus, the acid form was selected as being
representative of all members of the 2,4-D reregistration case. The
toxicological profile was reviewed and selected endpoints for 2,4-D were
previously published in the Federal Register of July 27, 2005 (Vol. 70,
Number 143, 43302), per Table 2.  At that time, the EPA determined that
the “toxicological database is sufficient for reregistration” but
included a 10X database uncertainty factor in lieu of a DNT study.  The
toxicity database is now augmented by a new F1-extended one generation
dietary toxicity study in rats (MRID 47972101) which was recently
submitted by the 2,4-D task force and is currently under review at the
EPA.  It is anticipated that the data base UF will be reduced in the
future based on the new study.>

<	1. Acute toxicity.  Per Table 2 of Federal Register of July 27, 2005
(Vol. 70, Number 143, 43302), EPA has established acute endpoints from
two different studies.  For the general population including infants and
children, the NOAEL of 67 mg/kg/day from the acute neurotoxicity study
in rats is currently used in conjunction with a 1,000 X UF to arrive at
an aRfD = aPAD of 0.067 mg/kg/day.  For females 13-50 years of age the
NOAEL of 25 mg/kd/day from the rat developmental toxicity study is
currently used with a UF of 1000 to establish an aRfD = aPAD of 0.025
mg/kg/day for this subpopulation.>

<	2. Genotoxicty. Per the 2005 RED (EPA 738-R-05-002), based on the
overall pattern of responses observed in both in vitro and in vivo
genotoxicity tests, 2,4-D was not mutagenic, although some cytogenic
effects were observed. Per Table 1 of Federal Register of July 27, 2005
(Vol. 70, Number 143, 43302), several genotoxicity studies have been
conducted.  In the Ames tests, no evidence of bacterial mutation in S
typhimurium. strains TA1535, TA1537, TA1538, TA98, TA100, with and
without S9 were observed.  No significant increase in bone marrow
polychromatic erythrocytes were found in the in vivo erythrocyte
micro-nucleus assay.  No evidence of increased chromosome aberrations in
human lymphocytes in the in vitro chromosome aberration study with human
lymphocytes.  Equivocal results (+ at top 2 doses, with results similar
to dimethyl sulfoxide (DMSO control) were noted in the cytogenetics in
vivo chromosome aberration study with rat bone marrow. No evidence of
induction of unscheduled DNA synthesis has been noted. 2,4-D is
considered “Not likely to pose a cancer risk” based on the lack of
carcinogenicity in a rat carcinogenicity study and a mouse
carcinogenicity study.>

<	3. Reproductive and developmental toxicity. Per the 2005 RED (EPA
738-R-05-002), the toxicity database for 2,4-D includes acceptable
developmental and reproductive toxicity studies for use in risk
assessment.  However, the recently submitted F1-extended one generation
dietary toxicity study in rats (MRID 47972101) provides a new and
detailed evaluation of the potential effects of
2,4-dichlorophenoxyacetic acid (2,4-D) on the reproductive function, as
well as potential effects on numerous endpoints in the first generation
offspring, including survival, growth and the development of nervous,
immune and reproductive systems.  Across life stages, the 2,4-D extended
one generation study has established a no-observed adverse effect level
(NOAEL) based on systemic toxicity of 100 ppm in males (5.5 mg/kg/day)
and 300 ppm in females (20.6 mg/kg/day in non-pregnant P1 adults).

Regarding reproductive effects, there was no indication of reproductive
toxicity by 2,4-D in the new study. 2,4-D had no effects on estrous
cyclicity or reproductive indices, including mating, fertility, time to
mating, gestation length, pre- and post-implantation loss and
corporalutea number. Litter sizes, pup survival, sperm parameters,
ovarian follicle counts and reproductive organ histopathology were
unaffected by 2,4-D.  Pup growth was affected during lactation, but only
at a dose causing parental toxicity and resulting in nonlinear renal
clearance. Overall, 2,4-D is not a reproductive toxin.  

There was no evidence of developmental neurotoxicity related to 2,4-D
exposure. There were no exposure-related effects on brain histopathology
at any age. Functional observational battery (FOB) parameters (hand-held
and open-field observations, grip performance, landing foot splay,
rectal temperature), motor activity and acoustic startle response (ASR)
were assessed in these animals on post natal date (PND) 54-59. The
offspring adults were perfused for central and peripheral nervous system
neuropathology. In addition, brain weights, gross brain measurements and
morphometric measurements were evaluated. There were no exposure-related
effects on FOB parameters, motor activity or ASR. Habituation
(behavioral response to a stimulus) was not affected at any dose of
2,4-D. Gross and morphometric brain measurements also were not affected.
There was no exposure-related neuropathology in PND 22 or 60 animals,
including no effects on brain myelin (assessed by special staining).
Thus 2,4-D exposure shows no evidence of DNT.>

<	4. Subchronic toxicity. Per Table 2 of Federal Register of July 27,
2005 (Vol. 70, Number 143, 43302), the short-term incidental oral and a
short-term dermal endpoints are currently established based on the rat
developmental toxicity NOAEL = 25 mg/day with an associated LOAEL of 75
based on decreased maternal body-weight gain and skeletal abnormalities.
 The intermediate-term incidental oral and dermal endpoints are
established based on the subchronic rat oral toxicity NOAEL of 15
mg/kg/day with an associated LOAEL = 1000 mg/kd/day based on decreased
body weight/body-weight gain, alterations in some hematology (decreased
platelets (both sexes)) and clinical chemistry (decreased T3 (females)
and T4 (both sexes)) parameters, and cataract formation.  The LOC for
Residential MOEs is 1000.>

<	5. Chronic toxicity. In the rat chronic toxicity study, a LOAEL of 75
mg/kg/day was observed based on decreased body-weight gain (females) and
food consumption(females), alterations in hematology(decreased RBC, HCT,
and HGB (females),platelets (both sexes)) and clinical chemistry
parameters (increased creatinine (both sexes), alanine and aspartate
aminotransferases (males), alkaline phosphatase (both sexes), decreased
T4 (both sexes), glucose (females), cholesterol (both sexes), and
triglycerides (females).  Per Table 2 of Federal Register of July 27,
2005 (Vol. 70, Number 143, 43302), the NOAEL = 5 mg/kg/day from this
study and a UF = 1000, EPA has currently established an cRfD = cPAD =
0.005 mg/kg/day for all populations.  This NOAEL is also used for the
long-term inhalation and dermal endpoints with a “LOC for MOE” of
1000.

>

<	6. Animal metabolism. The absorption, distribution, metabolism and
excretion of 2,4-D has been studies in rats.  Per Table 1 of Federal
Register of July 27, 2005 (Vol. 70, Number 143, 43302), 2,4-D
elimination (85.5%-93.7%) is primarily via urine with 3.6%-10.5% of dose
eliminated via the feces. At the high-dose level, it appears that a
nonlinear region (decreased clearance) is being reached in the
disposition of 2,4-D. Parent 2,4-D was the major metabolite found in
urine (72.9%-90.5% of the oral dose), with small amounts of
uncharacterized compounds (0.6%-1.3% and 0%-0.7%) being found in the
urine.  

Per the 2005 RED (EPA 738-R-05-002), EPA has noted that the mechanisms
responsible for renal clearance of 2,4-D have been investigated in
several species.  2,4-D is actively secreted by the proximal tubules.
This mechanism of renal clearance is consistent with results seen with
other phenoxy acids. It has been suggested that observed dose dependent,
non-linear, pharmacokinetics of 2,4-D are primarily due to the
saturation of this renal secretory transport system. Due to a limited
capacity to excrete organic acids, the dog is more sensitive to the
effects of 2,4-D than the rat with respect to repeated dosing.>

<	7. Metabolite toxicology. 2,4-dichlorophenol (2,4-DCP) is a known
plant and animal metabolite is 2,4-D.  However, per the EPA RED (EPA
738-R-05-002), EPA has concluded that 2,4-D alone is the residue of
concern.>

<	8. Endocrine disruption. The recently submitted F1-extended one
generation dietary toxicity study in rats (MRID 47972101) included
numerous endpoints to assess for endocrine effects. Endocrine-sensitive
endpoints included estrous cyclicity, reproductive indices, organ
weights/pathology, and sperm parameters. Anogenital distance, nipple
retention, and puberty onset were assessed in offspring; quantitative
ovarian follicle counts in a subset of offspring.  2,4-D did not alter
estrogen- or androgen-sensitive endpoints. There were no effects on
estrogen-sensitive endpoints including vaginal opening, estrous
cyclicity, uterine weights or histopathology, or quantitative ovarian
follicle counts. There were no significant, exposure-related changes in
reproductive organ weights in offspring. Other androgen-sensitive
endpoints, including anogenital distance (AGD) and nipple retention,
which are considered very sensitive endpoints, sperm parameters and
testicular and accessory sex gland histopathology, were not altered.
Based on this data and other studies, 2,4-D shows no evidence of being
an endocrine disruptor interacting with either estrogen or androgen at
doses at or below those resulting in nonlinear renal clearance. 

There were no thyroid effects at low and mid dose levels and no
biologically significant effects on thyroid endpoints at all life stages
examined. There were no adverse pathological alterations, thus, slight
thyroid changes seen in a satellite group of pregnant females were
considered adaptive, non-adverse responses. The only altered thyroid
endpoints occurred at an exposure level that clearly resulted in
nonlinear renal clearance.>

<C. Aggregate Exposure This proposal is based on bridging uses and
tolerances from wheat to teff.  Wheat use is covered by the exposure
assessments within the EPA 2005 RED.  The proposed additional use of
2,4-D on teff would not have changed the results of those assessments.>

<	1. Dietary exposure. Tolerances for: Wheat, bran at 4.0 ppm, Wheat,
forage at 25 ppm Wheat, grain at 2.0 ppm are included in the EPA Final
Rule (72 52017, Sept. 12, 2007).  The exposure assessment supporting
these tolerances values is found in the 2005 RED.  The existing exposure
assessment for wheat is sufficient to cover any teff exposure, because
the exposure from the proposed use on teff is already covered by the
existing EPA dietary assessment for small grains.  If the consumer
switches to consumption of teff in place of traditional grains, the
dietary exposure assessment is unchanged, hence the information from the
2005 RED is reiterated below.

>

<	i. Food. Per the 2005 Reregistration Eligibility Decision for 2,4-D
(EPA738-R-05-002) regarding acute food, exposure estimates to the
general U.S. population were 18% and 17% of the aPAD using both DEEM and
Lifeline, respectively.  The most highly exposed population subgroup
using both DEEM and Lifeline was children 1-2 years of age; exposures
were 33% and 32% of the aPAD, respectively.  Calculated exposure to
females 13-49 years of age was 31% of the aPAD using DEEM and 42% of the
aPAD using Lifeline; these higher calculated percentages for women of
child-bearing age are due to the 2.7x lower toxicological point of
departure for developmental effects applicable to Females 13-49 years of
age.  These acute dietary (food) exposure estimates are all less than
the Agency’s level of concern (100% of aPAD).

For chronic exposure the EPA RED concludes that exposures to the general
U.S. population were 4.1% and 3.8% of the cPAD, using DEEM and Lifeline,
respectively.  Calculated food exposures to children 1-2 years of age,
the most highly exposed population subgroup, was 8.5% of the cPAD using
DEEM and Lifeline.>

<	ii. Drinking water. Drinking water estimates were included in the
previous DEEM model estimates listed in Federal Register of July 27,
2005 (Vol. 70, Number 143, page 43307).  The resulting exposure
estimates were 10% of the cPAD for the U.S. population, 24% of the cPAD
for all Infants (< 1 year old), and 18% of the cPAD for children 1–2
years old.>

<	2. Non-dietary exposure. Per Federal Register of July 27, 2005 (Vol.
70, Number 143, 43302), there are no residential uses for 2,4-D that
result in chronic residential exposure to2,4-D. 2,4-D is currently
registered for uses that could result in short-term residential
exposure.  Short-term turf exposures were calculated only for females
13–49 and children 1–6, because these population subgroups have the
highest exposure and are protective of the other subgroups. EPA
published potential turf exposure values of 0.024 mg/kg/day for females
and 0.021 mg/kg/day for children 1-6, respectively.

>

<D. Cumulative Effects. For the purposes of this tolerance action, it is
not assumed that 2,4-D has a common mechanism of toxicity with other
substances.>

<E. Safety Determination>

<	1. U.S. population. Per the Federal Register of July 27, 2005 (Vol.
70, Number 143, 43302) aggregate risk assessments for the general
population were conservatively covered by calculations for females
13–49 and children 1–6, because these population subgroups have the
highest exposure and are protective of the other subgroups. EPA
determined, the short-term aggregate MOEs which include turf exposure
are not of concern because the MOEs equal or exceed the target MOE of
1,000.

>

<	2. Infants and children. In the Federal Register of July 27, 2005
(Vol. 70, Number 143, 43302) and after evaluating hazard and exposure
data for 2,4-D, EPA removed the default 10X FQPA safety factor, but
retained a database uncertainty factor (UFDB) of 10X in lieu of a
developmental neurotoxicity (DNT) study in rats for 2,4-D.  This FQPA
decision was based on the existing toxicity database for 2,4-D at that
time which includes acceptable developmental and reproductive toxicity
studies.  The new extended F1-generation study in rats is anticipated to
result in the removal of the 10X UFDB in the future.>

<F. International Tolerances>

<	There are no known tolerances specifically for teff elsewhere in the
world.  According to Homologa (  HYPERLINK "http://www.homologa.com" 
www.homologa.com ), there are many international MRLs established for
wheat: Argentina, Australia and Brazil have established 0.2 ppm, Japan
and Mexico list 0.5 ppm, CODEX and the US list 2 ppm and the EU, Russian
Federation and Switzerland list 0.05 ppm.>

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