 

COMPANY FEDERAL REGISTER DOCUMENT SUBMISSION TEMPLATE (7/1/2006)
Pendimethalin, Increase Alfalfa Forage Tolerance, June 2009  
Pendimethalin: Olives, July 2008

EPA Registration Division contact: [Philip V. Errico at 703-305-6663]

 

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TEMPLATE:

[BASF Corporation]

[ PP-9F7576]

	21 U.S.C. 346 EPA has received a pesticide petition ( PP-9F7576]) 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 combined residues of [the herbicide
pendimethalin, N-(1-ethylpropyl)-3,4-dimethyl-2,6-dinitrobenzenamine,
and its metabolite 4-[(1-ethylpropyl)amino]-2-methyl-3,5-dinitrobenzyl
alcohol] in or on the raw agricultural commodities [alfalfa forage] at
[3.5] 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 metabolite 4-[(1-ethylpropyl)amino]-2-methyl-3,5-dinitrobenzenamine
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 across
the US were carried out in order to determine the magnitude of residues
in alfalfa commodities.  EPA has determined that the petition contains
data or information regarding the above aforementioned crops.  Field
trials were conducted on alfalfa targeting a pendimethalin application
rate of 2 lb ai/A with a 28 day pre-harvest interval (PHI) for alfalfa
forage and hay].

B. Toxicological Profile

	1. Acute toxicity.  [Pendimethalin (BAS 455 H) 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 (BAS 455 H)
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 0.03 mg/kg
b.w./day using an Uncertainty Factor (UF) of 30X (3X for interspecies
extrapolation and 10X for intraspecies variability) and a 10X database
uncertainty factor (UFDB) retained pending receipt of a developmental
thyroid toxicity study.  EPA/HED currently recommends a FQPA Safety
Factor of 1X.  Therefore, the chronic Population Adjusted Dose (PAD) is
0.03 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. The Agency has determined that there is no
reasonable expectation of finite pendimethalin residues of concern in
animal commodities as a result of use on multiple crops.  However,
tolerances for pendimethalin residues of concern in livestock
commodities were proposed in a previous petition. 

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
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 (0.03
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 (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 (BAS 455 H).  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 June 2009, the proposed (pending at EPA) new tolerances forage
grasses, crop group 17, livestock commodities of 0.15 ppm in meat and
0.03 ppm in milk, and olives at 0.1 ppm, and the proposed increased
tolerance for alfalfa forage to 3.5 ppm.  No tolerances are proposed for
poultry or eggs because grass forage and alfalfa forage are not feed
items for poultry.  

Acute Dietary Exposure Assessment

An acute assessment was not needed since the U.S. EPA Toxicological
Endpoint Selection (TES) Committee had previously evaluated the
pendimethalin toxicity data and determined there was no relevant
toxicological endpoints for acute dietary exposure and that a risk
assessment was not required.  

Chronic Dietary 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.  Secondary residues in meat and
milk were included.  Secondary residues for eggs and poultry were not
included since it has been determined that there is no likelihood of
residues in these animal commodities and therefore, a tolerance will not
be required by the EPA.   

Dietary exposure estimates were compared against the worst-case
pendimethalin chronic Population Adjusted Dose (cPAD) of 0.03 mg/kg
b.w./day for all populations subgroups.  Results of the chronic dietary
assessments are listed in the table below.  The estimated chronic
dietary exposure from crops (both established and proposed tolerances)
was less than 20% 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 assessment considering
crops with established and proposed tolerances for pendimethalin. 

Population

Subgroups	Exposure Estimate

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

US Population	0.00207725	6.23

All infants (< 1 year)	0.00396	11.88

Children 1-2	0.0064085	19.23

Children 3-5	0.00508625	15.26

Children 6-12	0.00312325	9.37

Youth 13-19	0.00188925	5.67

Adults 20-49	0.0015675	4.70

Adults 50+ yrs	0.00142875	4.29

Females 13 - 49 yrs	0.0015355	4.61

%cPAD = percent of chronic population adjusted dose 

Exposure estimates based on tolerance values and 100 % CT values



]

	ii. Drinking Water. [There are no established maximum contaminant
levels or health advisory levels for residues of pendimethalin (BAS 455
H) in drinking water.  The drinking water exposure values used in this
assessment were obtained from the most recent pendimethalin assessment
conducted by EPA published on August 2, 2007.  The pendimethalin water
values were calculated using PRZM-EXAMS and SCI-GROW2.  The modeled
chronic surface water concentrations were 6.0 ug/L,  The modeled
groundwater concentration was 0.024 ug/L.  

Drinking water contributions were assessed based on the a pendimethalin
water concentration of 6.0 ug/L for chronic exposure and water
consumption and body weights reported in CSFII, using DEEM-FCID
software.  The chronic estimated water exposure values are summarized in
Table 2.  

Table 2.  	Summary of chronic dietary exposure assessment for drinking
water considering direct and indirect sources. 

Population

Subgroups	Exposure Estimate

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

U.S. Population	0.000126	0.4

All Infants (< 1 year)	0.000415	1.2

Children 1-2 years	0.000188	0.6

Children 3-5 years	0.000176	0.5

Children 6-12 years	0.000121	0.4

Youth 13-19 years	0.000091	0.3

Adults 20-49 years	0.000118	0.4

Adults 50+ years	0.000124	0.4

Females 13 – 49 years	0.000118	0.4

%cPAD = percent of chronic population adjusted dose 

Exposure based on the maximum estimated water concentration of 6.0 ug/L



Acute Aggregate Exposure and Risk (Food and water)

An acute assessment was not needed since the U.S. EPA Toxicological
Endpoint Selection (TES) Committee had previously evaluated the
pendimethalin toxicity data and determined there was no relevant
toxicological endpoints for acute dietary exposure and that a risk
assessment was not required.  

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 aggregate MOE from food, water, and
residential exposure are 1132 (children 1-2 years) and 3577 (US
population) for the EC formulation and 678 (children 1-2 years) and 2358
(US population) for the CS formulation, respectively.  These MOEs are
greater than the target MOE of 300, which indicates there is no safety
concern from the aggregate exposure from pendimethalin.  The results of
the analysis are shown in Tables 3 and 4. 

Table 3. 	Estimated short/intermediate term aggregate exposure and risk
of pendimethalin for the EC formulation. 

Population	NOAEL (mg/kg/day)	Target MOE1	Food Exposure (mg/kg/d

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

US	10	300	0.00207725	0.00012625	0.000592	0.0027955	3577

Child

1-2 yr old	10	300	0.0064085	0.0001875	0.002235	0.008831	1132

1 Target MOE is 300.

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

Table 4. 	Estimated short/intermediate term aggregate exposure and risk
of pendimethalin for the CS formulation.  

Population	NOAEL (mg/kg/day)	Target MOE1	Food Exposure (mg/kg/day)	Water
Exposure (mg/kg/day)	Residential Exposure (mg/kg/day)	Total Exposure
(mg/kg/day)	MOE2

US	10	300	0.00207725	0.00012625	0.002038	0.0042415	2358

Child

1-2 yr old	10	300	0.0064085	0.0001875	0.008148	0.014744	678

1 Target MOE is 300.

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 5). 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. 

Table 5. 	Estimated chronic aggregate exposure and risk of pendimethalin
 

Population Subgroup	cPAD (mg/kg/day)	Food Exposure (mg/kg/day)	Water
Exposure (mg/kg/day)	Total Exposure (mg/kg/day)	% cPAD

U.S. Population	0.03	0.00207725	0.00012625	0.0022035	6.6

All Infants (< 1 yr old)	0.03	0.00396	0.000415	0.004375	13.1

Children 1-2 years	0.03	0.0064085	0.0001875	0.006596	19.8

Children 3-5 years	0.03	0.00508625	0.00017625	0.0052625	15.8

Children 6 – 12 years	0.03	0.00312325	0.00012125	0.0032445	9.7

Youth 13-19 years	0.03	0.00188925	0.00009125	0.0019805	5.9

Females 13-49 years	0.03	0.0015355	0.0001175	0.001653	5.0

Adults 20-49 years	0.03	0.0015675	0.0001175	0.001685	5.1

Adults + 50	0.03	0.00142875	0.00012375	0.0015525	4.7



]

	2. Non-dietary exposure. [The systemic exposure from the use of
pendimethalin on residential turf was calculated following the current
EPA Standard Operating Procedures (SOPs) for residential exposure
assessment (EPA 1997b; EPA 1999a), as revised by EPA Policy 12 (EPA,
2001), and using the Residential Exposure Assessment Spreadsheet Tool
(REx), Version 4.0G.  Exposure values were derived from the use of a
product-specific hand press study to estimate hand-to-mouth transfer in
children and a formulation-specific turf transferable residue study to
determine dermal exposure to adults and children.  Residential exposure
to both the Pendulum® 3.3 EC herbicide and Pendulum® AquaCap™
herbicide is presented below.  

The following table provides the route specific and aggregate exposure
assessment results for each population subgroup, along with the
percentage of the cPAD (0.03 mg kg BW/day) utilized, and MOE
(NOAEL/Aggregate systemic Exposure). 

Table 6.	Summary of residential exposure to pendimethalin following the
use of the Pendulum® 3.3 EC herbicide formulation including the route
specific and aggregate exposure assessment results for the population
subgroups.

Population subgroup	Route of Exposure	Route Specific 

Systemic Exposure 

(mg/kg BW/day) 1	Aggregate

Systemic Exposure 

(mg/kg BW/day)	%cPAD	MOE

Adult 

(20-49)	Post-application dermal	0.000592	0.000592	1.8	16892

Child 

(1-6)	Post-application dermal	0.000990	0.002235	6.7	4474

	Post-application 

(Hand to Mouth ingestion)	0.001245



	1 Based 3% dermal absorption



™ herbicide formulation including the route specific and aggregate
exposure assessment results for the population subgroups.

Population subgroup	Route of Exposure	Route Specific 

Systemic Exposure 

(mg/kg BW/day) 1	Aggregate

Systemic Exposure 

(mg/kg BW/day)	%cPAD	MOE

Adult 

(20-49)	Post-application dermal	0.002038	0.002038	6.1	4907

Child 

(1-6)	Post-application dermal	0.003411	0.008148	24.4	1227

	Post-application 

(Hand to Mouth ingestion)	0.004737



	1 Based 3% dermal absorption



]

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

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

