Document ID: EPA-HQ-OPP-2014-0397-0006
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2015-08-26T04:00Z

COMPANY FEDERAL REGISTER DOCUMENT SUBMISSION TEMPLATE (7/1/2006) 
Pendimethalin: amend tolerances for forage grass CG 17; establish
tolerances for animal matrices, March 2014

EPA Registration Division contact: [Kable Bo Davis at 703-306-0415]

 

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TEMPLATE:

[BASF Corporation]

[Insert petition number, PP-xxxxxx]

	21 U.S.C. 346 EPA has received a pesticide petition ([Insert petition
number, PP-xxxxxx]) from [BASF Corporation], [26 Davis Drive, Research
Triangle Park, NC, 27709] 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 180.361 by establishing a tolerance for the residues
of [the herbicide pendimethalin, including its metabolites and
degradates, in or on animal commodities. Compliance with the tolerance
levels specified is to be determined by measuring only pendimethalin ,
N-(1-ethylpropyl)-3,4-dimethyl-2,6dinitrobenzenamine, and its animal
metabolite 1-(1-ethyl-propyl)-5, 6 dimethyl-7-nitro-1H-benzoimidazole,
calculated as the stoichiometric equivalent of pendimethalin] in or on
the raw agricultural animal commodities [milk] at [0.04] parts per
million (ppm), [cattle, goat, horse, and sheep, fat] at [0.30] parts per
million (ppm), [cattle, goat, horse, and sheep, liver] at [1.5] parts
per million (ppm), [cattle, goat, horse, and sheep, meat] at [0.10]
parts per million (ppm), and [cattle, goat, horse, and sheep, meat
byproducts except liver] at [3.0] parts per million (ppm), and by
amending the established tolerances for the combined residues of [the
herbicide pendimethalin, including its metabolites and degradates, in or
on feed commodities. Compliance with the tolerance levels specified is
to be determined by measuring only pendimethalin,
N-(1-ethylpropyl)-3,4-dimethyl-2,6dinitrobenzenamine, and its
metabolite, 4-[(1-ethylpropyl)amino]-2-methyl-3,5-dinitrobenzyl alcohol,
calculated as the stoichiometric equivalent of pendimethalin] in or on
the raw agricultural commodities of [Grass forage, fodder, and hay crop
group 17, forage] at [1000] parts per million (ppm), and [Grass forage,
fodder, and hay crop group 17, hay] at [2000] parts per million (ppm). 
EPA has determined that the petition contains data or information
regarding the elements set forth in section 408 (d)(2) of the 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

	1. Plant metabolism.  [The qualitative nature of the residues of
pendimethalin in plants is understood based on adequate studies
conducted with 14C pendimethalin on various crops.  Pendimethalin and
its 3,5-dinitrobenzyl alcohol metabolite (CL202347) are the established
residues of concern.]

	2. Analytical method. [Section 408 (b)(3) of the amended FDCA requires
EPA to determine that there is a practical method for detecting and
measuring levels of the pesticide chemical residue in or on food and
that the tolerance be set at a level at or above of the limit of
detection of the designated method.  In plants, the method is aqueous
organic solvent extraction, column clean up, and quantitation by GC. 
The method has a limit of quantitation (LOQ) of 0.05 ppm for
pendimethalin and the alcohol metabolite. In the animal commodity method
D0405, pendimethalin and its metabolites (CL 202347 and Goat Metabolite
6) are extracted from milk and tissue with acidic aqueous methanol. An
aliquot is taken from extract, diluted with water and then cleaned using
a solid phase extraction column. The compounds are eluted from the
column using methanol/water. The eluates are diluted with methanol/water
for analysis via LC/MS/MS. The results are calculated separately by
direct comparison of the sample peak responses to those of external
standards. The method has a limit of quantitation (LOQ) of 0.01 in milk
and 0.05 ppm in tissues for both pendimethalin and the goat metabolite
6.  The method has undergone an independent laboratory validation.]

	3. Magnitude of residues. [Field trials in major growing areas were
conducted in order to determine the magnitude of residues in forage
grass (MRID 47471701) commodities. Field trials were carried out using
the maximum number of applications, the maximum label rate and shortest
pre-harvest interval (PHI) in forage grass at 0 day. Decline data
indicated the average half-lives on the order of 10 days in grass forage
and hay.  Two dairy cattle feeding studies are available to account for
secondary transfer of pendimethalin residues occur from treated
feedstuffs to bovine matrices.  A recent dairy cattle feeding study was
conducted for 29 days with a pendimethalin concentration of 760
mg/kg-feed to cover the proposed use in grasses.  This study also
included a 10-day depuration phase to observe the withdrawal of the
compound from milk and tissues following the last dosing interval. 
Observed residue levels of pendimethalin and goat metabolite 6 in milk
and animal tissues support the proposed tolerances in animal matrices. 
A previous feeding study (MRID 46591234) was conducted three levels of
10, 30 and 100 mg/kg-feed; at these lower exposure levels, no residues
in milk or any tissue were noted above the LOQ for pendimethalin, or two
metabolite analytes at the highest dose level tested of 100 ppm.  EPA
has determined that the petition contains data or information regarding
the above aforementioned crops and animal feeding study.]

B. Toxicological Profile 

	1. Acute toxicity.  [Pendimethalin technical demonstrates low acute
toxicity via the oral, dermal, and inhalation routes of exposure.  The
acute toxicity studies place technical pendimethalin in toxicity
category III for the acute oral, category IV for acute dermal, and
category IV for acute inhalation.  The acute reference dose is based on
reduced motor activity at Day 0 in the acute neurotoxicity study.
Technical pendimethalin is category IV for skin irritation and category
III for eye irritation. Pendimethalin did not cause skin sensitization
in guinea pigs.  Two formulated end use products are registered for use
on crops, an Emulsifiable Concentrate (EC) and an Encapsulated
Suspension (CS).  The EC has an acute oral category of III, acute dermal
category of III, an acute inhalation category of III, eye and skin
irritation of III, and is not a dermal sensitizer.  The CS has an acute
oral category of IV, an acute dermal category of IV, an acute inhalation
category of IV, eye and skin irritation category of IV, and is not a
dermal sensitizer.]

	2. Genotoxicty. [Extensive mutagenicity studies conducted to
investigate point and gene mutations, DNA damage and chromosomal
aberration, both using in vitro and in vivo test systems demonstrate
pendimethalin to be non-genotoxic. 

Pendimethalin has been classified as a Group C "possible human
carcinogen," based on a statistically significantly increased incidence
of benign follicular cell adenomas of the thyroid gland in male and
female rats at 5000 ppm (250 mg/kg b.w./day) (highest concentration
tested).  For risk assessment, OPP recommends using the RfD (non-linear)
approach for quantification of human risk.  The Agency Committee has
determined that the hypothesis, that benign thyroid tumors associated
with pendimethalin are due to a thyroid-pituitary imbalance, can be
supported.  Finally, pendimethalin's mechanism of threshold oncogenic
activity only occurs at high doses in rats, a mammalian species that is
expected to be much more sensitive than humans to the induction of
thyroid tumors via conditions which result in hypothyroidism.]

	3. Reproductive and developmental toxicity. [Pendimethalin is not a
selective developmental toxicant.  There is no indication of increased
susceptibility following prenatal/postnatal exposure to pendimethalin.  

In a developmental (teratology) toxicity study in the rat, the results
demonstrated that the NOAELs for both maternal toxicity and fetal
(prenatal)/developmental toxicity were 500 mg/kg b.w./day (highest dose
tested) (HDT).  In addition, there were no indications of any
teratogenic effects in the rat fetuses at 500 mg/kg b.w./day (HDT). 
Therefore, pendimethalin is considered to be neither a developmental
toxicant nor a teratogenic agent in the rat.  

In a developmental (teratology) toxicity study in the rabbit, the
results demonstrated the NOAEL for maternal toxicity was 30 mg/kg
b.w./day, based on increased clinical signs of toxicity and decreased
body weight gain during the treatment period at 60 mg/kg b.w./day (HDT).
 The NOAEL for fetal (prenatal)/developmental toxicity was 60 mg/kg
b.w./day (HDT).  In addition, there were no indications of any
teratogenic effects in the rabbit fetuses at 60 mg/kg b.w./day. 
Therefore, pendimethalin is considered to be neither a developmental
toxicant nor a teratogenic agent in the rabbit.

A two-generation reproductive toxicity study in the rat demonstrated an
absence of increased sensitivity for the developing offspring to
pendimethalin.  The NOAEL for parental toxicity was 500 ppm
(approximately 38.5 mg/kg b.w./day), based on reduced food consumption
and decreased body weight/weight gain at 2500 ppm (mid-dietary
concentration).  The NOAEL for pup/offspring toxicity was also 500 ppm,
based on decreased pup body weight gain at 2500 ppm.  Lastly, the NOAEL
for reproductive toxicity was 2500 ppm (approximately 194 mg/kg
b.w./day), based on reduced mean live litter size at 5000 ppm (highest
concentration tested) (HCT).  These reductions in mean live litter size
and pup body weight gain were only observed at dietary concentrations
that were parentally toxic.  As such, there is no evidence that prenatal
or postnatal exposure to pendimethalin results in an increased
sensitivity to developing offspring.]

	4. Sub-chronic toxicity. [Sub-chronic (90-day) feeding studies were
conducted in rats and dogs.  For the rat, the NOAEL for systemic
toxicity was 500 ppm (41 mg/kg b.w./day), based on slightly decreased
body weight, increased absolute and relative liver weights, and liver
histopathology (hepatocellular hypertrophy) in males and females at 5000
ppm (HCT).  For the dog, the NOAEL for systemic toxicity was 2500 ppm
(62.5 mg/kg b.w./day), based on decreased body weight at 10000 ppm (250
mg/kg b.w./day).]

	5. Chronic toxicity. [The chronic Reference Dose (RfD) was established
based on the results of sub-chronic special studies demonstrating the
thyroid hormone related endpoint in rats.  The NOAEL of 10 mg/kg
b.w./day was established from the collective results of the sub-chronic
oral 92-day thyroid function study, the sub-chronic oral 56-day thyroid
function study, and the 14-day intrathyroidal metabolism study.  A LOAEL
of 31 mg/kg b.w./day was based on hormonal and histopathological changes
in the thyroid gland.  The chronic RfD was calculated to be 0.3 mg/kg
b.w./day using an Uncertainty Factor (UF) of 30X (3X for interspecies
extrapolation and 10X for intraspecies variability).  EPA/HED currently
recommends a FQPA Safety Factor of 1X.  Therefore, the chronic
Population Adjusted Dose (PAD) is 0.3 mg/kg b.w./day.

Chronic toxicity studies were conducted in rats, mice, and dogs.  For
the 2-year rat feeding study, the NOAEL for systemic toxicity was 500
ppm (25 mg/kg b.w./day), based on decreased body weight gain
(approximately 20-30%), increased clinical signs of toxicity, increased
relative liver weights, and slight but statistical increase in the
incidence of benign follicular cell adenomas of the thyroid gland in
males and females at 5000 ppm (250 mg/kg b.w./day) (HCT).  For the
18-month mouse feeding study, the NOAEL for systemic toxicity was 500
ppm (75 mg/kg b.w./day), based on slightly decreased mean body weights
and reduced survival at 5000 ppm (750 mg/kg b.w./day) (HCT).  There were
no oncogenic effects up to 5000 ppm (750 mg/kg b.w./day) (HCT).  Lastly,
for the 1-year oral (via gelatin capsules) chronic dog study, the NOAEL
for systemic toxicity was 200 mg/kg b.w./day, the highest dose tested.]

	6. Animal metabolism. [Adequate goat and poultry metabolism studies are
available for pendimethalin. In the rat, pendimethalin is metabolized
mainly through oxidation of the 4-methyl group attached to the benzene
ring as well as oxidation of the alkyl side chain of the N-substituted
dinitroaniline compound.  When C14-pendimethalin is administered to
rats, about 70% of the administered radioactivity is excreted via feces
and 20% via urine within 24 hours.  Within 96 hours, the total
radioactive residues (TRR) found in the tissues was 0.3 ppm, except fat
which was 0.9 ppm.  The major portion of the radioactivity that was
excreted in the feces was identified as the unchanged parent compound. 
In the goat metabolism study following administration of radiolabeled
pendimethalin equivalent to 15.35 ppm in the diet for 5 consecutive
days, approximately 94% of the administered radioactivity was recovered
in feces, urine and tissues.  Among the edible tissues, only liver (0.32
ppm) and kidney (0.042 ppm) contained residues >0.01 ppm.  With the
exception of Metabolite 6 (13% TRR), no other component exceeded 10% of
the TRR in liver.  The major metabolite (Metabolite 6) was identified in
feces, bile and urine by LC/MS and high resolution mass spectrometry. 
Only trace levels of unchanged parent were detected.]

	7. Metabolite toxicology. [The main pendimethalin plant metabolite, CL
202347, has been tested for acute oral toxicity in the mouse, as well as
genotoxicity (Ames assay).  The acute oral LD50 in the mouse was
determined to be 2140 mg/kg bw, which is considered to be “slightly
toxic by ingestion in single doses.”  An Ames assay demonstrated that
the plant metabolite is non-mutagenic.  In addition, since goat
Metabolite 6 was observed in a recent rat metabolism study, it is
considered to have been evaluated in the existing mammalian toxicity
database for the active ingredient.]

	8. Endocrine disruption. [It is known that pendimethalin affects the
hypothalamus-pituitary-thyroid axis.  However, as the chronic RfD (0.3
mg/kg b.w./day) is based on the thyroid hormone related endpoint in
rats, as noted in the sub-chronic special studies in Section 5 above,
which additionally demonstrated reversibility of the thyroid effects in
the oral 56-day thyroid function study, these effects are already taken
into consideration in the characterization of potential risks to
humans.]

C. Aggregate Exposure [Pendimethalin is a pre-emergent herbicide used to
control broadleaf and grass weeds in food and non-food crops, as well as
non-agricultural use sites including residential lawns. In examining
aggregate exposure, FQPA directs EPA to consider available information
concerning exposures from the pesticide residue in food and water
(dietary) and all other non-occupational exposures. The primary non-food
sources of exposure are through pesticide use in gardens, lawns, or
buildings (residential and other indoor uses). The potential for
aggregate exposure from all registered and proposed uses is discussed
below.]

	1. Dietary exposure. [The updated dietary assessments employed the EPA
posted Dietary Exposure Evaluation Model- Food Consumption Intake
Database (DEEM-FCID) version 3.18 and the residue input files from their
July 2012 dietary assessment DP 401100 for any concentration factors as
a starting point.]

	i. Food. [An assessment was conducted to evaluate the potential risk
due to dietary exposure of the U.S. population to residues of
pendimethalin.  The current tolerance values are listed in the U.S. 40
CFR § 180.361.  The Tier 1 dietary exposure estimates were based on
established and proposed tolerance values, and 100% CT values.  An
updated analysis included all the crops with established tolerance
values as of March 2014 and: the proposed tolerances for hops, dried
cones at 1.0 ppm (pending EPA review, submitted October 2013); the
proposed crop group expansion tolerances to replace current existing
pendimethalin tolerances including onion-bulb subgroup 3-07A = 0.10 ppm,
onion-green subgroup 3-07B = 0.20 ppm, low growing berry subgroup 13-07G
= 0.10 ppm, vegetable-fruiting group 8-10 = 0.10 ppm, fruit-citrus group
10-10, fruit-pome group 11-10 = 0.10 ppm, fruit-stone group 12-12 = 0.10
ppm, sunflower subgroup = 0.1 ppm (pending EPA review, submitted October
2013); the proposed amended tolerances for alfalfa forage and hay
(pending EPA review, submitted February 2014); and the proposed new
tolerances on animal commodities which support the newly proposed
amended tolerances on forage grasses.

Acute Dietary (food + drinking water) Exposure Assessment

No special dietary assessment for females age 13 – 49 years old is
required by EPA because no endpoint was identified for sensitive
populations.  EPA has determined that an acute dietary assessment is
required for the general populations which cover infants and children.
The acute population adjusted dose (aPAD) is 1 mg ai/kg bw/day based on
a NOAEL = 100 mg/kg bw/day and a total safety factor of 100.  The acute
dietary exposure to pendimethalin residues was low for all populations. 
At the 95th percentile, the most highly exposed valid sub-population was
“Infants (<1 year old)” and this group utilized only 1.8% aPAD.

Chronic Dietary (food + water) Exposure Assessment

Dietary exposure estimates were compared against the chronic Population
Adjusted Dose (cPAD) of 0.3 mg/kg b.w./day for all populations
subgroups. Results of the chronic dietary assessments are listed in
Table 1 below. The estimated chronic dietary exposure from crops and
animals (both established and proposed tolerances) was <2.2% of the cPAD
for all subpopulations.  Additional refinements such as the use of
anticipated residues, PDP data and percent crop treated values for the
established crop uses would further reduce the estimated chronic dietary
exposure. The results in Table 1 below demonstrate there are no risk
concerns for any subpopulation based on established and new uses, and
that the results clearly meet the FQPA standard of reasonable certainty
of no harm.

Table 1. Summary of Chronic Dietary Exposure (food + drinking water)
Assessment considering crops with established and proposed
tolerances for pendimethalin. 

Population

Subgroups	Exposure Estimate

(mg/kg b.w./day)	%cPAD

US Population	0.001928	0.6

All infants (< 1 year)	0.003616	1.2

Children 1-2	0.006486	2.2

Children 3-5	0.004922	1.6

Children 6-12	0.002923	1.0

Youth 13-19	0.001635	0.5

Adults 20-49	0.001500	0.5

Adults 50+ yrs	0.001395	0.5

Females 13 - 49 yrs	0.001463	0.5

%cPAD = percent of chronic population adjusted dose 

Exposure estimates based on tolerance values and 100 % CT values

]

	ii. Drinking Water. [The drinking water exposure values used in this
assessment were obtained from the most recent pendimethalin assessment
conducted by EPA published on July 25, 2012. The estimated acute and
chronic surface water concentrations from EPA models were 80.5 µg/L and
6.2 µg/L, respectively. The estimated groundwater concentration was
0.036 µg/L.  These estimated drinking water exposures were included
directly in the dietary assessments. The DEEM critical exposure
contribution analysis calculates estimated model water contributions
(indirect and direct) makeup over 60% of the potential exposure of
pendimethalin for infants within the acute assessment; the modelled
water estimates are understood to be conservative.]

	2. Non-dietary exposure. [The post-application short-term dermal and
incidental oral exposure and risk assessment was determined for
pendimethalin use on residential turf, residential gardens, and golf
course turf. The residential exposure shown in the Table 2 reflects the
most recent EPA human health risk assessment published on July 25, 2012.
 No new uses would impact reuse of this assessment.  The residential
assessment was conducted using the updated Standard Operating Procedures
for Residential Pesticide Exposure Assessment.  The calculated MOEs are
all greater than the MOE level of concern, which is a value of 30. 

Table 2.	Pendimethalin Residential Exposure after the use on Residential
Turf, Residential Gardens, and Golf Course Turf.  

Population	Scenario-	Route	Exposure  	MOE

Adult	Turf-residential	Dermal	0.032	320

Child 1-2 	Turf-residential	Dermal	0.06	170

 	 	Hand to mouth	0.042	240

 	 	Object to mouth	0.0013	7,700

 	 	soil ingestion	0.000065	150,000

 	 	Granular injestion	0.071	140

Adult	Turf-golf	Dermal	0.0037	2,700

Children 11-16	Turf-Golf	Dermal	0.0043	2,300

Children 6-11	Turf-Golf	Dermal	0.0051	2,000

Adult	Gardening	Dermal	0.078	130

Children 6-11	Gardening 	Dermal	0.053	190

Acute Aggregate Exposure and Risk (Food and water)

It has been previously determined by EPA that the acute aggregate
assessments includes only food and drinking water exposure (DP390457). 
Residential exposure is not included in the acute or chronic aggregate
assessment.  The results showed that the acute aggregate exposure from
pendimethalin residues does not exceed the level of concern for any
population.  

Short- and Intermediate-Term Aggregate Exposure and Risk (food, water,
and residential)

Short-term aggregate risk from pendimethalin takes into account
exposures from dietary consumption (food and water) and residential
exposure from turf use.  Post application exposure from the turf use is
considered short-term.  The residential exposure used in this assessment
is from the most recent EPA human health risk assessment published July
25, 2012, no new residential uses impact the aggregate, so only an
update to the dietary components is needed.  The residential assessment
was conducted using the updated Standard Operating Procedures for
Residential Pesticide Exposure Assessment.  The post-application
residential exposure was determined for the use on residential turf,
residential gardens, and golf course turf.  The highest post-application
exposure from adults was from the garden use and residential turf use
for children 1-2 years old.  The children exposure included dermal and
hand-to-mouth exposure.  The aggregate MOE from food, water, and
residential exposure for children 1-2 years old was 92 and for adults
125.  These MOEs are greater than the target MOE of 30, which indicates
there is no risk concern from the aggregate exposure from pendimethalin.
 The results of the analysis are shown in Tables 3. 

Table 3. 	Estimated short/intermediate term aggregate exposure and risk
of pendimethalin. 

Population	NOAEL (mg/kg/day)	Target MOE1	Food + Drinking Water Exposure 
             (mg/kg/day)

	Residential Exposure (mg/kg/day)	Total Exposure (mg/kg/day)	MOE2

Adult	10	30	0.001928	0.078	0.079928	125

Child

1-2 yr old	10	30	0.006486	0.102	0.108486	92

1 HED’s LOC for the MOE is 30.

2 Aggregate MOE = (NOAEL / (Food + Water + Residential Exposure) 

Chronic Aggregate Exposure and Risk (food and water)

It has been previously determined by EPA that the chronic aggregate
assessments includes only food and drinking water exposure (Table 1),
because exposure is not expected for residential (dermal and inhalation)
exposure pathway (DP390457). Exposures from residential uses are not
included in the chronic aggregate assessment.  The results demonstrate
there are no risk concerns for any subpopulation based on established
and new uses. ]

D. Cumulative Effects

	[Exposure to Substances with Common Mechanism of Toxicity.  The Agency
has not yet published guidelines to determine whether pendimethalin has
a common mechanism of toxicity with other substances or how to include
this pesticide in a cumulative risk assessment.  Unlike other pesticides
for which EPA has followed a cumulative risk approach based on a common
mechanism of toxicity, pendimethalin does not appear to produce a toxic
metabolite produced by other substances.  For the purposes of this
tolerance action, therefore, it is assumed that pendimethalin does not
have a common mechanism of toxicity with other substances.]

E. Safety Determination

	1. U.S. population. [Based on these risk assessments, there is a
reasonable certainty that the aggregate exposure to the general
population or any subpopulation from pendimethalin residues does not
result in an unacceptable risk.]

	2. Infants and children. [EPA has previously recommended the 10X FQPA
safety factor be removed (reduced to 1X) based on reliable data.  Based
on these risk assessments, there is a reasonable certainty that the
aggregate exposure to infants or children, or any subpopulation from
pendimethalin residues does not result in an unacceptable risk.]

F. International Tolerances

	[There are no CODEX, Canadian or Mexican International Maximum Residue
Levels (MRL's) established for residues of pendimethalin in these crops
at this time.]

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