EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR

PESTICIDE PETITIONS PUBLISHED IN THE FEDERAL REGISTER

EPA Registration Division contact: Andrew Ertman , (703) 30 8

- 9367

Interregional Research Project Number 4 (IR

- 4)

PP #1E7878

21 U.S.C. 34 6 EPA has received a pesticide petition ( PP #1E7878 ) from IR

- 4 Project Headquarters, Rutgers, The State University of NJ

, 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 a tolerance for the combined residues of the herbicide pendimethalin, N

- (1

- ethylpropyl)

- 3,4

- dimethyl

- 2,6dinitrobenzenamine, and its 3, 5

- dinitrobenzyl alcohol metabolite (CL 20234 7) in or on the raw agricultural

commodit ies lettuce , leaf at 3

. 0 parts per million (ppm )

, Brassica, leafy greens, subgroup 5B at 0.2 ppm, turnip greens at 0.2 ppm, melons subgroup 9A at 0.1 ppm, vegetable
, soybean , succulent at 0.1 ppm, and small fruit vi ne climbing subgroup 13

- 07E, except grape at 0.1 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 submit ted 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 req uires 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 t he 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 area s were carried out in order to determine the magnitude of residues in the leaf lettuce, Brassica leafy greens, melons, and small fruit vining commodities. No field trial data were generated in order to determine the magnitude of residues in turnip greens a nd vegetable soybean commodities, as EPA has determined that the tolerance thesecrop commodities may be safely extrapolated from the proposed tolerances on leafy

Bra s sica greens (subgroup 5B) and from the established tolerances on beans for turnip green a nd vegetable soybean (edamame), respectively. EPA has determined that the petition contains data or information regarding the above aforementioned crops. Field trials were conducted for the representative crops of Brassica leafy greens subgroup 5B (mustar d greens), melons subgroup 9A (cantaloupe), and small fruit vine climbing subgroup 13

- 07E (kiwifruit) spread across the US. Field trials were carried out using the maximum number of applications, the maximum label rate and shortest pre

- harvest interval (P HI)

.

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 o f 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 mutagen icity 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 h uman 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 recommen ds 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)/developmentaltoxicity 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 reprodu ctive 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 decrease d 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, th ere 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 fo r 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 NOA EL 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 demon strating 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 int rathyroidal 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

ext rapolation 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 A djusted 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 (approximat ely 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 pp m (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

a vailable 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

.

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 an d 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 disr uption

. 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 ab ove, 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. Dietar y 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 ava ilable 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 oth er indoor uses). The potential foraggregate 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 pend imethalin. The current tolerance values are listed in the U.S. 40 CFR § 180.361.

This analysis included all the crops with esta blished tolerance values as of April

2011

, and the proposed new tolerances for lettuce , leaf at 4 .0 ppm, Brassica leafy

greens (subgroup 5B) at 0.2 ppm, turnip greens at 0.2 ppm, melons (subgroup 9A) at 0.1 ppm, vegetable

, soybean
, succulent at 0.1 ppm, and small fruit vine climbing (subgroup 13

- 07E, except grape) at 0.1 ppm.

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 Su rvey 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 wo rst

- 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 establi shed 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 die tary 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 ch ronic dietary exposure assessment considering crops with established and proposed tolerances for pendimethalin.

Population Subgroups Exposure Estimate (mg/kg b.w./day) %cPAD

US Population 0.001857 5.57
All infants (< 1 year) 0.003139 9.42

Children 1

- 2 0.006097 18.29Children 3

- 5 0.00481 14.43

Children 6

- 12 0.002925 8.78

Youth 13

- 19 0.001735 5.21

Adults 20

- 49 0.001354 4.06
Adults 50+ yrs 0.001217 3.65

Females 13

- 49 yrs 0.001326 3.98
%cPAD = percent of chronic population adjusted dose Exposure e stimates 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 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 October 27, 2009

. The pendimethalin water values were calculated using PRZM

- EXAMS and SCI

GROW2. The modeled chronic surface water concentrations were 6. 0 ug/L, while

t he modeled g roundwater concentration was 0.0 36 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, us ing 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 a ssessment 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 as sessment 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 exposu re from turf use. Post application exposure from the turf use is considered short

- term. The aggregate MOE from food, water, and residential exposure are 11 74 (children 1

- 2 years) and

3 883 (US population) for the EC formulation and 6 93 (children 1

- 2 years ) and 2 487 (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

MOE 1 Food

Exposure (mg/kg/d ay) Water

Exposure (mg/kg/day) Residential

Exposure (mg/kg/day) To tal

Exposure (mg/kg/day) MOE 2

US 10 300 0.001857 0.00012625 0.000592 0.00257525 3883

Child

1

- 2 yr old 10 300 0.006097 0.0001875 0.002235 0.0085195 1174

1 Target MOE is 300.

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

Table 4. E stimated short/intermediate term aggregate exposure and risk of

pendimethalin for the CS formulation.

Population NOAEL

(mg/kg/day) Target

MOE 1 Food

Exposure (mg/kg/day) Water

Exposure (mg/kg/day) Residential

Exposure (mg/kg/day) Total

Exposure (mg/kg/day ) MOE 2

US 10 300 0.001857 0.00012625 0.002038 0.00402125 2487

Child

1

- 2 yr old 10 300 0.006097 0.0001875 0.008148 0.0144325 693

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 pendimethalinPopulation 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 0.001857 0.00012625 0.00198325 5.9 All Infants (< 1 yr old) 0.03 0.003139 0.000415 0.003554 10.7

Children 1

- 2 years 0.03 0.006097 0.0001875 0.0062845 18.9

Children 3

- 5 years 0.03 0.00481 0.00017625 0.00498625 15.0

Children 6

– 12 years 0.03 0.002925 0.00012125 0.00304625 9.1

Youth 13

- 19 years 0.03 0.001735 0.00009125 0.00182625 5.5

Females 13

- 49 years 0.03 0.001326 0.0001175 0.0014435 4.3

Adults 2 0

- 49 years 0.03 0.001354 0.0001175 0.0014715 4.4

Adults + 50 0.03 0.001217 0.00012375 0.00134075 4.0

2. Non

- dietary exposure

. The systemic exposure from the use of pendimethalin on residential turf was calculated following the current EPA Standard Op erating 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® AquaCapTM 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 (N OAEL/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 subgro ups.

Table 7. Summary of residential exposure to pendimethalin following the use of

the Pendulum ® AquaCap TM herbicide formulation including the r oute Populatio

n 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 absorptionspecific and aggregate exposure assessment results for the population subgroups.

D. Cumulative Effects

Exposure to Substances with Commo n 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, pend imethalin 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 Det ermination

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 Interna tional Maximum Residue Levels (MRL's) established for residues of pendimethalin in these crops at

this time

. Populatio

n 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

- appli cation 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