Document ID: EPA-HQ-OPP-2013-0768-0004
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2014-02-21T05:00Z

EPA REGISTRATION DIVISION - COMPANY NOTICE OF FILING FOR PESTICIDE PETITION 

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

Interregional Research Project Number 4 (IR-4)

Pesticide Petition Number: PP# 3E8212

      EPA has received a pesticide petition (PP# 3E8212) 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 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, calculated as the stoichiometric equivalent of pendimethalin, in or on the raw agricultural commodities berry, low growing subgroup 13-07G at 0.1 ppm parts per million (ppm), fruit, citrus, group 10-10 at 0.1 ppm, fruit, pome, group 11-10 at 0.1 ppm, fruit, stone, group 12-12 at 0.1 ppm, hops, dried cones at 0.1, onion, bulb subgroup 3-07A at 0.1 ppm, onion, green subgroup 3-07B at 0.2 ppm, sunflower subgroup 20B at 0.1 ppm, and vegetable, fruiting, group 8-10 at 0.1 ppm.  In addition, the petitioner proposes based upon the establishment of new tolerances above, removal of existing tolerances at 40 CFR 180.361 on fruit, citrus, group 10 at 0.1 ppm, fruit, pome, group 11 at 0.1 ppm, fruit, stone, group 12 at 0.1ppm, garlic at 0.1 ppm, leek at 0.20 ppm, onion, bulb at 0.1 ppm, onion, green at 0.20 ppm, onion, welsh at 0.20 ppm, shallot at 0.2, strawberry at 0.10 ppm,  sunflower seed at 0.1 ppm and vegetable, fruiting, group 8 at 0.10 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 14 C pendimethalin on various crops.  Pendimethalin and its and its metabolite, 4-[(1-ethylpropyl)amino]-2-methyl-3,5-dinitrobenzyl alcohol
         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 hops commodities. Field trials were carried out using the maximum number of applications, the maximum label rate and shortest pre-harvest interval (PHI). No field trial data were generated in order to determine the magnitude of residues in raw agricultural commodities in crop groups 8, 10, 11, and 12, or in crop subgroups 3-07A, 3-07B or 13-07G, and 20B as EPA has determined that the tolerance on these crop commodities may be safely extrapolated from the established tolerances for the respective crop groupings and crop subgroups. 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.  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 milligram/kilogram body weight (mg/kg b.w.)/day) (highest concentration tested).  For risk assessment, the EPA recommends using the RfD (non-linear) approach for quantification of human risk.  The Agency 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 level (NOAEL)s 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 (HDT).  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 (HDT).  For the dog, the NOAEL for systemic toxicity was 2500 ppm (62.5 mg/kg b.w./day), based on decreased body weight at 10000 ppm (250 mg/kg b.w./day).

	5. Chronic toxicity. The chronic Reference Dose (RfD) was established based on the results of sub-chronic special studies demonstrating the thyroid hormone related endpoint in rats.  The NOAEL of 10 mg/kg b.w./day was established from the collective results of the sub-chronic oral 92-day thyroid function study, the sub-chronic oral 56-day thyroid function study, and the 14-day intrathyroidal metabolism study.  A 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 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) (HDT).  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) (HDT).  There were no oncogenic effects up to 5000 ppm (750 mg/kg b.w./day) (HDT).  Lastly, for the 1-year oral (via gelatin capsules) chronic dog study, the NOAEL for systemic toxicity was 200 mg/kg b.w./day, the highest dose tested.

	6. Animal metabolism. Adequate goat and poultry metabolism studies are available for pendimethalin. The Agency has determined that there is no reasonable expectation of finite pendimethalin residues of concern in animal commodities as a result of use on multiple crops. 

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 (0.3 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

	1. Dietary exposure. Pendimethalin is a pre-emergent herbicide used to control broadleaf and grass weeds in food and non-food crops, as well as non-agricultural use sites including residential lawns. In examining aggregate exposure, FQPA directs EPA to consider available information concerning exposures from the pesticide residue in food 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.

	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.  The current tolerance values are listed in the U.S. 40 CFR § 180.361. 

This analysis included all the crops with established tolerance values as of October 2012, and the proposed new tolerances for hops, dried cones at 1.0 ppm.  Also, proposed new crop group tolerances to replace current existing pendimethalin tolerances.  The current existing tolerances to be replaced are garlic at 0.1 ppm, leek at 0.20 ppm, onion-bulb at 0.10 ppm, onion-green at 0.20 ppm, shallot at 0.20 ppm, onion-welsh at 0.20 ppm, strawberry at 0.10 ppm, vegetable-fruiting group 8 at 0.10 ppm, fruit, citrus group 10 at 0.10 ppm, fruit, pome group 11 at 0.10 ppm, fruit-stone group 12 at 0.10 ppm, and sunflower seed at 0.1 ppm.  The proposed new crop group tolerances are onion, bulb subgroup 3-07A at 0.10 ppm, onion-green subgroup 3-07B at 0.20 ppm, berry, low growing subgroup 13-07G at 0.10 ppm, vegetable-fruiting group 8-10 at 0.10 ppm, fruit-citrus group 10-10, fruit, pome group 11-10 at 0.10 ppm, fruit, stone group 12-12 at 0.10 ppm, and sunflower subgroup at 0.1 ppm.  

Acute Dietary (food + drinking water) Exposure Assessment
An acute dietary risk assessment for females, age 13  -  49 years old, is not required by EPA because there is no relevant toxicological endpoints for population sub-group.  EPA has determined that an acute dietary assessment is required for all other populations. The acute population adjusted dose (aPAD) is 1 mg ai/kg bw/day based on a NOAEL = 100 mg/kg bw/day and a total safety factor of 100.  The acute dietary exposure to pendimethalin residues was low for all populations.  The most highly exposure sub-populations was infants (< 1 year old) and utilized only 1.8% aPAD.  

Chronic Dietary (food + water) Exposure Assessment
The chronic dietary exposure estimates were based on established and proposed tolerance values, and 100% crop treated (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.  

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 (both established and proposed tolerances) was less than 2.0% of the cPAD for all subpopulations. Additional refinements such as the use of anticipated residues and percent crop treated values for the established crop uses would further reduce the estimated chronic dietary exposure. The results in Table 1 below demonstrate there are no safety concerns for any subpopulation based on established and new uses, and that the results clearly meet the FQPA standard of reasonable certainty of no harm.
            
            Table 1. Summary of Chronic Dietary Exposure (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
                                   0.001984
                                      0.6
                           All infants (< 1 year)
                                   0.003665
                                      1.1
                                 Children 1-2
                                   0.006786
                                      2.0
                                 Children 3-5
                                   0.005115
                                      1.5
                                 Children 6-12
                                   0.002989
                                      0.9
                                  Youth 13-19
                                   0.001679
                                      0.5
                                 Adults 20-49
                                   0.001535
                                      0.5
                                Adults 50+ yrs
                                   0.001438
                                      0.4
                              Females 13 - 49 yrs
                                   0.001502
                                      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 were 80.5 microgram per liter (ug/L) and 6.2ug/L, respectively. The estimated groundwater concentration was 0.036ug/L. The estimated drinking water exposure was included in the dietary assessment.   

Acute Aggregate Exposure and Risk (Food and water)
The acute dietary assessment was conducted including food and drinking water exposure.  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 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.  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 margin of exposure (MOE) from food, water, and residential exposure for children 1-2 years old was 92 and for adults was 125.  These MOEs are greater than the target MOE of 30, which indicates there is no safety concern from the aggregate exposure from pendimethalin.  The results of the analysis are shown in Tables 2. 

Table 2. 	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
                                   0.001984
                                     0.078
                                   0.079984
                                      125
                                     Child
                                  1-2 yr old
                                      10
                                      30
                                   0.006786
                                     0.102
                                   0.108786
                                      92

1 Target MOE is 30.
[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 1). 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.  

	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 3 reflects the most recent EPA human health risk assessment published on July 25, 2012.  The residential assessment was conducted using the updated Standard Operating Procedures for Residential Pesticide Exposure Assessment.  The calculated MOEs are all greater than the MOE level of concern. 

Table 3.	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
                                      313
Child 1-2 
                               Turf-residential
                                    Dermal
                                     0.06
                                      167
 
                                       
                                 Hand to mouth
                                     0.042
                                      238
 
                                       
                                Object to mouth
                                    0.0013
                                     7692
 
                                       
                                soil ingestion
                                   0.000065
                                    153846
 
                                       
                              Granular injestion
                                     0.071
                                      141
Adult
                                   Turf-golf
                                    Dermal
                                    0.0037
                                     2703
Children 11-16
                                   Turf-Golf
                                    Dermal
                                    0.0043
                                     2326
Children 6-11
                                   Turf-Golf
                                    Dermal
                                    0.0051
                                     1961
Adult
                                   Gardening
                                    Dermal
                                     0.078
                                      128
Children 6-11
                                  Gardening 
                                    Dermal
                                     0.053
                                      189
]

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 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.