Document ID: EPA-HQ-OPP-2014-0397-0003
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2014-12-17T05:00Z

EPA REGISTRATION DIVISION - COMPANY NOTICE OF FILING FOR PESTICIDE PETITION

Docket ID Number: EPA-HQ-OPP-2014-0397

EPA Registration Division contact: Sidney Jackson (703) 305-7610

Interregional Research Project Number 4 
Pesticide Petition Number: 4E8282
      EPA has received a pesticide petition (PP#) number 4E8282 from the Interregional Research Project Number 4 (IR-4), IR-4 Project Headquarters,  Rutgers, The State University of New Jersey, 500 College Road East, Suite 201 W, Princeton, NJ 08450  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 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-2,6dinitrobenzenamine, 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 caneberry, subgroup 13-07A at 0.1 parts per million (ppm), bushberry subgroup 13-07B at 0.1 ppm, and nut, tree, group 14-12 at 0.1 ppm.  In addition, the petitioner proposes that upon approval of the abovementioned tolerances to remove existing tolerances at 40 CFR 180.361 for juneberry at 0.1 ppm, nut, tree, group 14 at 0.1 ppm and pistachio 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 submitted data at this time or whether the data support 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 (CL202347) 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 gas chromatography (GC).  The method has a limit of quantitation (LOQ) of 0.05 ppm for pendimethalin and the alcohol metabolite.

	3. Magnitude of residues. Field trials in major growing areas were conducted in order to determine the magnitude of residues in caneberry and bushberry commodities. Field trials were carried out using the maximum label rate and shortest pre-harvest interval (PHI) in berries at 30 days. No field trial data were generated in order to determine the magnitude of residues in raw agricultural commodities in crop group 14-12 as EPA has determined that the tolerance on this crop commodity may be safely extrapolated from the established tolerances for the crop group 14.  EPA has determined that the petition contains data or information regarding the above aforementioned crops.

B. Toxicological Profile 

	1. Acute toxicity.  Pendimethalin technical demonstrates low acute toxicity via the oral, dermal, and inhalation routes of exposure.  The acute toxicity studies place technical pendimethalin in toxicity category III for the acute oral, category IV for acute dermal, and category IV for acute inhalation.  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.  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 body weight (b.w.)/day) (highest concentration tested).  For risk assessment, OPP recommends using the reference dose (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 no-observed-adverse-effect-levels (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 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.  The lowest-observed-adverse-effect-level (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), the highest concentration tested (HCT).  For the 18-month mouse feeding study, the NOAEL for systemic toxicity was 500 ppm (75 mg/kg b.w./day), based on slightly decreased mean body weights and reduced survival at 5000 ppm (750 mg/kg b.w./day) (HCT).  There were no oncogenic effects up to 5000 ppm (750 mg/kg b.w./day) (HCT).  Lastly, for the 1-year oral (via gelatin capsules) chronic dog study, the NOAEL for systemic toxicity was 200 mg/kg b.w./day, the highest dose tested.

	6. Animal metabolism. Adequate goat and poultry metabolism studies are available for pendimethalin. In the rat, pendimethalin is metabolized mainly through oxidation of the 4-methyl group attached to the benzene ring as well as oxidation of the alkyl side chain of the N-substituted dinitroaniline compound.  When C14-pendimethalin is administered to 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 Metabolite 6 (13% TRR), no other component exceeded 10% of the TRR in liver.  The major metabolite (Metabolite 6) 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, CL 202347, has been tested for acute oral toxicity in the mouse, as well as genotoxicity (Ames assay).  The acute oral lethal dose (LD)50 in the mouse was determined to be 2140 mg/kg b.w., 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, since goat Metabolite 6 was observed in a recent rat metabolism study, it is considered to have been evaluated in the existing mammalian toxicity database for the active ingredient.

	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 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. The updated dietary assessments employed the EPA posted Dietary Exposure Evaluation Model- Food Consumption Intake Database (DEEM-FCID) version 3.18 and the residue input files from their July 2012 dietary assessment DP 401100 for any concentration factors as a starting point.

	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 Tier 1 dietary exposure estimates were based on established and proposed tolerance values, and 100% CT values.  An updated analysis included all the crops with established tolerance values as of May 2014 and: the proposed tolerances for hops, dried cones at 1.0 ppm (pending EPA review, submitted October 2013); the proposed crop group expansion tolerances to replace current existing pendimethalin tolerances including onion-bulb subgroup 3-07A = 0.10 ppm, onion-green subgroup 3-07B = 0.20 ppm, low growing berry subgroup 13-07G = 0.10 ppm, vegetable-fruiting group 8-10 = 0.10 ppm, fruit-citrus group 10-10 = 0.10 ppm, fruit-pome group 11-10 = 0.10 ppm, fruit-stone group 12-12 = 0.10 ppm, and sunflower subgroup = 0.1 ppm (pending EPA review, submitted October 2013); the proposed amended tolerances for alfalfa forage and hay (pending EPA review, submitted February 2014); the proposed tolerances on animal commodities which support the proposed amended tolerances on forage grasses (pending EPA review, submitted March 2014); and the proposed new tolerances on caneberry sub group 13-07A and bushberry sub group 13-07B, and the newly proposed crop group expansion tolerances to replace current existing pendimethalin tolerances on tree nut group 14-12 = 0.10 ppm.

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 active ingredient (ai)/kg b.w./day based on a NOAEL = 100 mg/kg b.w./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 valid sub-population was "Infants (<1 year old)" and this group utilized only 1.8% aPAD.

Chronic Dietary (food + water) Exposure Assessment
Dietary exposure estimates were compared against the chronic Population Adjusted Dose (cPAD) of 0.3 mg/kg b.w./day for all populations subgroups. Results of the chronic dietary assessments are listed in Table 1 below. The estimated chronic dietary exposure from crops and animals (both established and proposed tolerances) was <2.2% 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 1 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.

            
            Table 1. Summary of Chronic Dietary Exposure (food + drinking water) Assessment considering crops with established and proposed tolerances for pendimethalin. 
 Population
 Subgroups
                               Exposure Estimate
                               (mg/kg b.w./day)
                                     %cPAD
                                 US Population
                                   0.001928
                                      0.6
                           All infants (< 1 year)
                                   0.003616
                                      1.2
                                 Children 1-2
                                   0.006486
                                      2.2
                                 Children 3-5
                                   0.004922
                                      1.6
                                 Children 6-12
                                   0.002923
                                      1.0
                                  Youth 13-19
                                   0.001635
                                      0.5
                                 Adults 20-49
                                   0.001500
                                      0.5
                                Adults 50+ yrs.
                                   0.001395
                                      0.5
                             Females 13 - 49 yrs.
                                   0.001463
                                      0.5
 %cPAD = percent of chronic population adjusted dose 
 Exposure estimates based on tolerance values and 100 % CT values

	ii. Drinking Water. The drinking water exposure values used in this assessment were obtained from the most recent pendimethalin assessment conducted by EPA published on July 25, 2012. The estimated acute and chronic surface water concentrations from EPA models were 80.5 ug/L and 6.2 ug/L, respectively. The estimated groundwater concentration was 0.036 ug/L.  These estimated drinking water exposures were included directly in the dietary assessments. The DEEM critical exposure contribution analysis calculates estimated model water contributions (indirect and direct) makeup over 60% 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 determined for pendimethalin use on residential turf, residential gardens, and golf course turf. The residential exposure shown in the Table 2 reflects the most recent EPA human health risk assessment published on July 25, 2012.  No new uses would impact reuse of this assessment.  The residential assessment was conducted using the updated Standard Operating Procedures for Residential Pesticide Exposure Assessment.  The calculated margin of exposures (MOEs) are all greater than the MOE level of concern, which is a value of 30. 

Table 2.	Pendimethalin Residential Exposure after the use on Residential Turf, Residential Gardens, and Golf Course Turf.  
                                  Population
                                   Scenario-
                                     Route
                                  Exposure  
                                      MOE
Adult
                               Turf-residential
                                    Dermal
                                     0.032
                                      320
Child 1-2 
                               Turf-residential
                                    Dermal
                                     0.06
                                      170
 
                                       
                                 Hand to mouth
                                     0.042
                                      240
 
                                       
                                Object to mouth
                                    0.0013
                                     7,700
 
                                       
                                soil ingestion
                                   0.000065
                                    150,000
 
                                       
                              Granular ingestion
                                     0.071
                                      140
Adult
                                   Turf-golf
                                    Dermal
                                    0.0037
                                     2,700
Children 11-16
                                   Turf-Golf
                                    Dermal
                                    0.0043
                                     2,300
Children 6-11
                                   Turf-Golf
                                    Dermal
                                    0.0051
                                     2,000
Adult
                                   Gardening
                                    Dermal
                                     0.078
                                      130
Children 6-11
                                  Gardening 
                                    Dermal
                                     0.053
                                      190

Acute Aggregate Exposure and Risk (Food and water)
It has been previously determined by EPA that the acute aggregate assessments includes only food and drinking water exposure (DP390457).  Residential exposure is not included in the acute or chronic aggregate assessment.  The results showed that the acute aggregate exposure from pendimethalin residues does not exceed the level of concern for any population.  

Short- and Intermediate-Term Aggregate Exposure and Risk (food, water, and residential)
Short-term aggregate risk from pendimethalin takes into account exposures from dietary consumption (food and water) and residential exposure from turf use.  Post application exposure from the turf use is considered short-term.  The residential exposure used in this assessment is from the most recent EPA human health risk assessment published July 25, 2012, 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 for children 1-2 years old was 92 and for adults 125.  These MOEs are greater than the target MOE 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 (mg/kg/day)
                          Total Exposure (mg/kg/day)
                                    MOE[2]
                                       
                                     Adult
                                      10
                                      30
                                   0.001928
                                     0.078
                                   0.079928
                                      125
                                     Child
                                  1-2 yr old
                                      10
                                      30
                                   0.006486
                                     0.102
                                   0.108486
                                      92

1 HED's LOC for the MOE is 30.
[2] Aggregate MOE = (NOAEL / (Food + Water + Residential Exposure) 

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

	Exposure to Substances with Common Mechanism of Toxicity.  The Agency has not yet published guidelines to determine whether pendimethalin has a common mechanism of toxicity with other substances or how to include this pesticide in a cumulative risk assessment.  Unlike other pesticides for which EPA has followed a cumulative risk approach based on a common mechanism of toxicity, pendimethalin does not appear to produce a toxic metabolite produced by other substances.  For the purposes of this tolerance action, therefore, it is assumed that pendimethalin does not have a common mechanism of toxicity with other substances.

E. Safety Determination

	1. U.S. population. Based on these risk assessments, there is a reasonable certainty that 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

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