Document ID: EPA-HQ-OPP-2023-0308-0009
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2023-11-28T05:00Z

EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR PESTICIDE PETITIONS PUBLISHED IN THE FEDERAL REGISTER  

EPA Registration Division contact: [Reuben Baris at 703-305-7356]

INSTRUCTIONS:  Please utilize this outline in preparing the pesticide petition.  In cases where the outline element does not apply, please insert "NA-Remove" and maintain the outline. Please do not change the margins, font, or format in your pesticide petition. Simply replace the instructions that appear in green, i.e., "[insert company name]," with the information specific to your action.

TEMPLATE:

[BASF Corporation]

[Insert petition number, PP-xxxxxx]

	EPA has received a pesticide petition ([Insert petition number, PP-xxxxxx]) from [BASF Corporation], [26 Davis Drive, Research Triangle Park, NC, 27709] requesting, 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 residues of [the herbicide pendimethalin, including its metabolites and degradates, in or on food commodities. Compliance with the tolerance levels specified is to be determined by measuring only pendimethalin, N-(1-ethylpropyl)-3,4-dimethyl-2,6 dinitrobenzenamine, 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 [fig] at [0.1] parts per million (ppm) and [fig, dried] at [3.0] 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 (M455H025) 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 current enforcement method (method 996/0) 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 an orchard floor use, in order to determine the magnitude of residues in fig commodities. The field trials were carried out using the maximum label rate and two preharvest intervals (PHI) in figs. Based on the residue results in figs for an orchard floor use, the proposed tolerance for Fig is supported.   The field trials also included processing for dried figs which supports the proposed tolerance for Fig, dried..]

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.  The formulated end use product has an acute oral category of III, an acute dermal category of IV, an acute inhalation category of IV, eye and skin irritation category of IV, and has both positive (in mouse local lymph node assay) and negative (in Buehler assay) skin sensitization results.]

	2. Genotoxicty. [Extensive mutagenicity studies conducted to investigate point and gene mutations, DNA damage and chromosomal aberration, 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. Subchronic 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 62.5 mg/kg b.w./day, based on decreased body weight at 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 [14]C-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 Goat metabolite 6 (M455H029 at 13% TRR), no other component exceeded 10% of the TRR in liver.  M455H029 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, M455H025, 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, goat Metabolite 6 (M455H029) was observed in a recent rat metabolism study and is included as an analyte in cow and hen feeding studies.]

	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 primarily 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. [As a starting point for this assessment, the input files from the EPA HED September 19, 2019 dietary assessment DP 449631 were employed.   Both the Dietary Exposure Evaluation Model- Food Consumption Intake Database (DEEM-FCID) version 4.02 and CARES NG version 1.2.2 were used for comparison.  

	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 unrefined and conservative dietary exposure estimates were based on established and proposed tolerance values, and 100% crop treated values.  An updated analysis included all the crops with established tolerance values as of October 2019 and the proposed tolerances for:

      -Fig
      -Fig, dried

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/kg bw/day based on a NOAEL of 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 95[th] percentile, the most highly exposed sub-population in DEEM was infants (<1 year old), and this group utilized 2.10% of the aPAD.  In CARES, the most highly exposed sub-population was also infants (< 1 year old) at the 95[th] percentile; this group utilized 2.12% of the aPAD.  The two dietary models employ the same WWEIA 2005 to 2010 consumption data and are in good agreement.]

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

 Population
 Subgroups
                               Exposure Estimate
                               (mg/kg b.w./day)
                                     DEEM
                                 %aPAD@ 95th%
                                     DEEM
                               Exposure Estimate
                               (mg/kg b.w./day)
                                     CARES
                                 %aPAD@ 95th%
                                     CARES
                                 US Population
                                   0.009066
                                     0.91
                                   0.009069
                                     0.91
                           All infants (< 1 year)
                                   0.021009
                                     2.10
                                    0.02119
                                     2.12
                                 Children 1-2
                                   0.017324
                                     1.73
                                   0.017306
                                     1.73
                                 Children 3-5
                                   0.013031
                                     1.30
                                   0.013029
                                      1.3
                                 Children 6-12
                                   0.009049
                                     0.90
                                   0.009046
                                      0.9
                                  Youth 13-19
                                   0.006298
                                     0.63
                                   0.006307
                                     0.63
                                 Adults 20-49
                                   0.007168
                                     0.72
                                    0.00717
                                     0.72
                                Adults 50+ yrs
                                   0.006474
                                     0.65
                                   0.006465
                                     0.65
                              Females 13 - 49 yrs
                                   0.007205
                                     0.72
                                   0.007212
                                     0.72
 %aPAD = percent of acute population adjusted dose 
 Exposure estimates based on tolerance values and 100 % CT values
 
 

Chronic Dietary (food + water) Exposure Assessment
Dietary exposure estimates were assessed against the chronic Population Adjusted Dose (cPAD) of 0.3 mg/kg b.w./day for all population subgroups. Results of the chronic dietary assessments are listed in Table 2 below. The estimated chronic dietary exposure from crops and animal commodities (both established and proposed tolerances) was <2.35% 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 2 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.  The table below also indicates that the two chronic models of DEEM 4.02 and CARES 1.2.2 agree.

            
 Table 2. 	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)
                                     DEEM
                                     %cPAD
                                     DEEM
                               Exposure Estimate
                               (mg/kg b.w./day)
                                     CARES
                                     %cPAD
                                     CARES
                                 US Population
                                   0.002022
                                      0.7
                                   0.002023
                                     0.67
                           All infants (< 1 year)
                                   0.003958
                                      1.3
                                   0.004031
                                     1.34
                                 Children 1-2
                                   0.007046
                                      2.3
                                   0.007047
                                     2.35
                                 Children 3-5
                                   0.005148
                                      1.7
                                   0.005148
                                     1.72
                                 Children 6-12
                                   0.002952
                                      1.0
                                    0.02952
                                     0.98
                                  Youth 13-19
                                   0.001660
                                      0.6
                                    0.00166
                                     0.55
                                 Adults 20-49
                                   0.001559
                                      0.5
                                   0.001559
                                     0.52
                                Adults 50+ yrs
                                   0.001512
                                      0.5
                                   0.001512
                                     0.50
                              Females 13 - 49 yrs
                                   0.001534
                                      0.5
                                   0.001534
                                     0.51
 %cPAD = percent of chronic population adjusted dose 
 Exposure estimates based on tolerance values and 100 % CT values
 
 

	ii. Drinking water. [The most recent EPA EFED drinking water exposure assessment from February 12, 2019 DP 448587 was a streamlined assessment which recommended use of the previous assessment published January 8[th], 2015 (DP 421275). The proposed fig use pattern is similar to the assessed and approved grape uses.  Thus, the use of the drinking water estimated from DP 421275 is sufficient for this petition.  The estimated acute and chronic water concentrations from EPA models were 96.4 ug/L and 9.73 ug/L, respectively. These estimated drinking water exposures were included directly in the dietary assessments. The DEEM and CARES critical exposure contribution analysis indicate that estimated model water contributions (indirect and direct) makeup over 75% 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 previously assessed by EPA. This petition does not include any new residential uses.  The previous Residential MOEs (Margin of Exposure) of Table 6.1 in DP 448588 remain applicable and are above the Agency's level of concern. 

Acute Aggregate Exposure and Risk (Food and water)
It has been previously determined by EPA that the acute aggregate assessments include only food and drinking water exposure (DP390457).  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.  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 September 19, 2019; 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 is 92 and 127 for children 1-2 years and adults, respectively.  These numbers align well with the EPA's previous assessment. These MOEs are greater than the EPA established LOC 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 MOE[1]
           Food + Drinking Water Exposure               (mg/kg/day)
                                       
                      Residential Exposure[2] (mg/kg/day)
                          Total Exposure (mg/kg/day)
                                    MOE[3]
                                       
                                 US Population
                                      10
                                      30
                                   0.002022
                                     0.077
                                    0.07902
                                      127
                                     Child
                                  1-2 yr old
                                      10
                                      30
                                   0.007046
                                     0.102
                                   0.109046
                                      92

1 HED's LOC for the MOE is 30.
[2] Residential values are from Table 6.1 of EPA D448588
[3] Aggregate MOE = (NOAEL / (Food + Water + Residential Exposure); See Table 4.5.3 of EPA D448588 for NOAEL values.

Chronic Aggregate Exposure and Risk (food and water)
It has been previously determined by EPA that the chronic aggregate assessments include 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

	[In 2016, EPA's Office of Pesticide Programs released a guidance document entitled, Pesticide Cumulative Risk Assessment:  Framework for Screening Analysis.  This document provides guidance on how to screen groups of pesticides for cumulative evaluation using a two-step approach beginning with the evaluation of available toxicological information and if necessary, followed by a risk-based screening approach.  The EPA has utilized this framework for pendimethalin and determined that although pendimethalin shares some chemical and /or toxicological characteristics with other pesticides, the toxicological database does not support a testable hypothesis for a common mechanism of action.   No further data are required to determine that no common mechanism of toxicity exists for pendimethalin, and other pesticides and no further cumulative evaluation is necessary for pendimethalin.  (DP 448588, Pendimethalin Human Health Risk Assessment, Sept 19, 2019)]

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

	[Canada has default MRLs of 0.1 ppm for pendimethalin in many orchard crop uses that are aligned with the current proposed request.  These Canadian MRLs include fig.  Currently there are no CODEX or Mexican International Maximum Residue Levels (MRLs) established for residues of pendimethalin in fig.]