 

COMPANY FEDERAL REGISTER DOCUMENT SUBMISSION TEMPLATE (7/1/2006) 
Pendimethalin: amend tolerances for alfalfa, February 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 amending the established tolerances for the
combined residues of [the herbicide pendimethalin,
N-(1-ethylpropyl)-3,4-dimethyl-2,6dinitrobenzenamine, and its 3,
5-dinitrobenzyl alcohol metabolite (CL 202347)] in or on the raw
agricultural commodities of [alfalfa, forage] at [80] parts per million
(ppm) and [alfalfa, hay] at [150] 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 14 C pendimethalin on various crops.  Pendimethalin and
its 3,5-dinitrobenzyl alcohol metabolite (CL202347) are the 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.]

	3. Magnitude of residues. [Field trials in major growing areas were
conducted in order to determine the magnitude of residues in the alfalfa
commodities. Field trials were carried out using the maximum number of
applications, the maximum label rate and shortest pre-harvest interval
(PHI) in alfalfa at 14 days. EPA has determined that the petition
contains data or information regarding the above aforementioned crops.]

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.  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
rates, about 70% of the radioactivity is excreted in feces and 20% is in
the urine within 24 hours.  Within 96 hours, the radioactivity found in
the tissues was 0.3 ppm or less, except fat which is 0.9 ppm.  The major
portion of the radioactivity that was excreted in the feces was
identified as the parent compound.]

	7. Metabolite toxicology. [The main pendimethalin plant metabolite, CL
202347, has been tested for toxicity.  The acute oral toxicity in mice
was determined to be 2140 mg/kg bw.  An Ames assay showed the metabolite
to be non-mutagenic.]

	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

	1. Dietary 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.]

	i. Food. [An assessment was conducted to evaluate the potential risk
due to chronic 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. 

This analysis included all the crops with established tolerance values
as of January 2014, 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), and the proposed newly amended tolerances alfalfa.  

Acute Dietary (food + drinking water) Exposure Assessment

An acute dietary risk assessment for females age 13 – 49 years old is
not required by EPA because there is no relevant toxicological endpoints
for population sub-group.  EPA has determined that an acute dietary
assessment is required for all other populations. 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.  The most highly
exposure sub-populations was infants (< 1 year old) and utilized only
1.8% aPAD.  

Chronic Dietary (food + water) Exposure Assessment

The chronic dietary exposure estimates were based on established and
proposed tolerance values, and 100% CT values. Default process factors
were used with consumption data from the USDA Continuing Survey of Food
Intake by Individuals (CSFII 1994 - 1996, 1998).  The EPA Food Commodity
Ingredient Database (FCID) was also used in Exponent's Dietary Exposure
Evaluation Module (DEEM-FCID) software.  

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 less than 2.0% of
the cPAD for all subpopulations. Additional refinements such as the use
of anticipated residues 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 safety
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	0.001984	0.6

All infants (< 1 year)	0.003665	1.1

Children 1-2	0.006786	2.0

Children 3-5	0.005115	1.5

Children 6-12	0.002989	0.9

Youth 13-19	0.001679	0.5

Adults 20-49	0.001535	0.5

Adults 50+ yrs	0.001438	0.4

Females 13 - 49 yrs	0.001502	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 February 23, 2012. The estimated acute and
chronic surface water concentrations were 80.5µg/L and 6.2µg/L,
respectively. The estimated groundwater concentration was 0.036µg/L.
The estimated drinking water exposure was included in the dietary
assessment.   

Acute Aggregate Exposure and Risk (Food and water)

The acute dietary assessment was conducted including food and drinking
water exposure.  Residential exposure is not included in the acute
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.  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 was 125.  These MOEs are greater
than the target MOE of 30, which indicates there is no safety concern
from the aggregate exposure from pendimethalin.  The results of the
analysis are shown in Tables 2. 

Table 2. 	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	0.001984	0.078	0.079984	125

Child

1-2 yr old	10	30	0.006786	0.102	0.108786	92

1 Target MOE is 30.

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

Chronic Aggregate Exposure and Risk (food and water)

The aggregate chronic risk includes residues of pendimethalin from food
and water (Table 1). Exposures from residential uses are not included in
the chronic aggregate assessment.  The results demonstrate there are no
safety 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.  ]

	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 3 reflects the
most recent EPA human health risk assessment published on July 25, 2012.
 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. 

Table 3.	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	313

Child 1-2 	Turf-residential	Dermal	0.06	167

 	 	Hand to mouth	0.042	238

 	 	Object to mouth	0.0013	7692

 	 	soil ingestion	0.000065	153846

 	 	Granular injestion	0.071	141

Adult	Turf-golf	Dermal	0.0037	2703

Children 11-16	Turf-Golf	Dermal	0.0043	2326

Children 6-11	Turf-Golf	Dermal	0.0051	1961

Adult	Gardening	Dermal	0.078	128

Children 6-11	Gardening 	Dermal	0.053	189

]

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 no harm will result to the general population
or any subpopulation from aggregate exposure to pendimethalin residues.]

	2. Infants and children. [Based on these risk assessments, there is a
reasonable certainty that no harm will result to infants or children, or
any subpopulation from aggregate exposure to pendimethalin residues.]

F. International Tolerances

	[There is 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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