Document ID: EPA-HQ-OPP-2007-0106-0002
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2007-04-04T04:00Z

EPA Registration Division contact: Barbara Madden 703-305-6463

 

Interregional Research Project Number 4 (IR-4)

PP# 6E7129

	21 U.S.C. 346 EPA has received a pesticide petition (6E7129) 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 180.361 by establishing tolerances for 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 commodity Brassica, head and stem,
Subgroup 5A at 0.05 parts per million (ppm), grape at 0.05 ppm,
asparagus at 0.1 ppm and artichoke, globe at 0.05 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. This summary was
prepared by BASF Corporation, the registrant.   

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
carried out in order to determine the magnitude of residues in the
Brassica head and stem, artichoke, asparagus and grape commodities.  EPA
has determined that the petition contains data or information regarding
the above aforementioned crops.  Field trials were conducted in the
required regions.  Field trials were carried out using the maximum
number of applications, the maximum label rate and shortest pre-harvest
interval (PHI).>

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 (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. Subchronic toxicity. Subchronic (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 subchronic 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 subchronic
oral 92-day thyroid function study, the subchronic 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. Although not relevant to this petition, 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 and no tolerances for pendimethalin residues of
concern in livestock commodities are needed. 

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 (0.03
mg/kg b.w./day) is based on the thyroid hormone related endpoint in
rats, as noted in the subchronic 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 widely used as a pre-emergent
herbicide 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 and the U.S. EPA document DP Number D329627. 

This analysis included the crops with established tolerance values as of
October 2006 and the proposed uses on asparagus, grape, artichoke, and
Brassica head and stem, Crop Subgroup 5A.

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 were not
included for meat, milk, eggs, and poultry since it has been determined
that there is no likelihood of residues in these animal commodities and
therefore, tolerance have not been 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 9 % of the cPAD for all subpopulations.  Additional
refinements such as the use of anticipated residues and percent crop
treated values for the established and proposed new crops 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

U.S. Population	0.001121	3.36

All Infants (< 1 year)	0.001804	5.41

Children 1-2 years	0.002983	8.95

Children 3-5 years	0.002536	7.61

Children 6-12 years	0.001636	4.91

Youth 13-19 years	0.001063	3.19

Females 13-49 years	0.000894	2.68

Adults 20-49 years	0.000906	2.72

Adults 50+ years	0.000783	2.35

%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 March 3, 2006.  The pendimethalin water
values were calculated using PRZM-EXAMS and SCI-GROW2.  The modeled
acute and chronic surface water concentrations were 38.8 and 4.8 ug/L,
respectively.  The modeled groundwater concentration was 0.024 ug/L.  

Drinking water contributions were assessed based on the a pendimethalin
water concentration of 4.8 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	0.000101	0.3

All Infants (< 1 year)	0.000332	1.0

Children 1-2 years	0.000150	0.5

Children 3-5 years	0.000141	0.4

Children 6-12 years	0.000097	0.3

Youth 13-19 years	0.000073	0.2

Females 13-49 years	0.000094	0.3

Adults 20-49 years	0.000094	0.3

Adults 50+ years	0.000099	0.3

%cPAD = percent of chronic population adjusted dose 

Exposure based on the maximum estimated water concentration of 4.8 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 1863 (children 1-2 years) and 5513 (US
population) for the EC formulation and 886 (children 1-2 years) and 3067
(US population) for the CS formulation, respectively.  These MOEs are
greater than the target MOE of 300, which indicates there is no safety
concern.  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/day)	Water
Exposure (mg/kg/day)	Residential Exposure (mg/kg/day)	Total Exposure
(mg/kg/day)	MOE2

US	10	300	0.001121	0.000101	0.000592	0.001814	5513

Child

1-2 yr old	10	300	0.002983	0.00015	0.002235	0.005368	1863

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	0.001121	0.000101	0.002038	0.00326	3067

Child

1-2 yr old	10	300	0.002983	0.00015	0.008148	0.011281	886

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	0.001121	0.000101	0.001222	3.7

All Infants (< 1 yr old)	0.03	0.001804	0.000332	0.002136	6.4

Children 1-2 years	0.03	0.002983	0.00015	0.003133	9.4

Children 3-5 years	0.03	0.002536	0.000141	0.002677	8.0

Children 6 – 12 years	0.03	0.001636	0.000097	0.001733	5.2

Youth 13-19 years	0.03	0.001063	0.000073	0.001136	3.4

Females 13-49 years	0.03	0.000894	0.000094	0.000988	3.0

Adults 20-49 years	0.03	0.000906	0.000094	0.001	3.0

Adults + 50	0.03	0.000783	0.000099	0.000882	2.6

]

herbicide and Pendulum® AquaCap™ herbicide are 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

Table 7.	Summary of residential exposure to pendimethalin following the
use of the Pendulum® AquaCap™ 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

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