EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR

PESTICIDE PETITIONS PUBLISHED IN THE FEDERAL REGISTER

EPA Registration Division contact: Mindy Ondish (703)605

- 0723

Dow AgroSciences LLC

4F8301

EPA has received a pesticide petition ( 4F8301 ) from Dow AgroSciences

, 9330 Zionsville Road, Indianapolis, IN 46268 request ing, 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 by establishing a tolerance for residues of pronam ide (propyzamide) and its metabolite containing the 3,5

- dichlorobenzoyl moiety calculated as 3,5

- dichloro

- N

- (1,1

- dimethyl

- 2

- propynyl) benzamide in or on the food in or on the raw agricultural commodity lettuce, leaf at 1.0 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 FDDCA; however, EPA has not fully evaluated the sufficiency of the submitted data at this time or whethe r 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 Agency has established that the qualitative nature of the residue in plants is adequately underst ood. The 4/16/93 Residue Chapter of the pronamide RED reported that studies with alfalfa and lettuce indicate that pronamide is readily absorbed by plants through the root system, translocated upward, and distributed into the entire plant. The degree of translocation from leaf absorption is not appreciable. Metabolism primarily occurs via conjugation to (malonyl) glucose. No evidence of fragmentation or loss of the chloro substituent of the aromatic ring was observed. The terminal residues of concern a re pronamide and its metabolites containing the 3,5

- dichlorobenzoyl moiety.

2. Analytical method. Adequate enforcement methodology (gas chromatography using electron capture detection) is available to enforce the tolerance expression, this method is published in PAM II, as method I. In addition, an analytical method has been validated using gas chromatography with negative

- ion chemical ionization mass spectrometry (GC/NCI

- MS) for residue analysis of propyzamide.

3. Magnitude of residues. Magnitude of residue studies were conducted in 2005 by USDA’s IR

- 4 Project minor crops program at field sites located within the major growing regions in the U.S. as recommended by the EPA’s guidelines. Magnitude of residue data were collected from ten field trials located in Region 1 (one trial in New York), Region 2 (one trial in Maryland), Region 3 (one trial in Florida), and Region 10 (7 trials in California). The trials were conducted to collect data on the residues of pronamide on leaf lettuce, the active ing redient in Kerb® 50W (50% WP).2

There were two treatments at each trial site. For treatment 02, a single broadcast application was applied at 0.5 lb a.i./A. For treatment 03, one broadcast application was applied at 1.0 lb a.i./A. The applications were m ade post

- plant pre

- emergence or at very early post

- emergency (1 to 17 days after planting) and marketable baby leaf

- lettuce was collected approximately 20 and 25 days after applications.

Magnitude of residue studies were conducted in 2009 by Dow AgroScienc es at field sites located within the major growing regions in the U.S. as recom mended by the EPA’s guidelines . Magnitude of residue data were collected from eight field trials located in Region 2 (one trial in Georgia), Region 3 (one trial in Florida), an d Region 10 (6 trials in California). The trials were conducted to collect data on the residues of pronamide on leaf lettuce, the active ingredient in Kerb® 3.3 SC (396 g a.i./L).

There were four treatments at each trial site. For treatments 02, 03, 04 a nd 05, a single broadcast application was applied at 0.5, 1.0, 1.5 or 2.0 lb a.i./A, respectively. The applications were made pre

- emergence (from 1 day prior to planting to 3 days after planting) and marketable baby leaf

- lettuce was collected approximatel y 25, 35, 45 and 55 days after applications from each treated plot.

B. Toxicological Profile EPA has evaluated the available toxicity data and considered its validity, completeness, and reliability as well as the relationship of the results of the studies to human risk. EPA has also considered the available information concerning the variability of the sensitivities of major identifiable subgroups of consumers, including infants and children. The nature of the toxic effects caused by propyzamide are disc ussed below

.
1. Acute toxicity. Pronamide technical has a low order of acute toxicity via oral, dermal, and inhalation routes of exposure (Toxicity Category III or IV), produces mild irritation to the eyes and skin (Toxicity Category IV), and is not a de rmal sensitizer. No appropriate acute dietary endpoints were available to quantify risk to females 13

- 50 years of age or to the general population from a single

- dose administration of pronamide. Therefore, no acute dietary endpoints were selected which r epresented toxicit ies from a single

- dose exposure.

2. Genotoxicty. Results of the battery of genotoxicity studies indicate that pronamide is not a genotoxic agent.

3. Reproductive and developmental toxicity. There was no quantitative or qualitative evidence of increased susceptibility in the fetuses or the offspring of rats or rabbits following pre

- and/or postnatal exposure to pronamide. In the prenatal developmental toxicity study in rabbits and the multigeneration reproduction study in rats, any o bserved toxicity to the fetuses or offspring occurred at equivalent or higher doses than did toxicity to parental animals. In the rat developmental toxicity study, the highest dose of pronamide tested exceeded the doses tested in both the rabbit developmen tal toxicity study and the rat multigeneration reproduction study without demonstrating toxicities in either maternal animals or fetuses

.3

4. Subchronic toxicity. For risk assessments based on short

- term (1

- 30 days) incidental oral, dermal and inhalation e xposures, a dose of 8.46 mg/kg/day was established by EPA for us e in risk assessment s

. Dermal Toxicity Study (2005) : A 28

- day dermal toxicity study (MRID 46885701) in F344/DuCrl rats was conducted in ten male and ten female Fischer 344 rats per group

. Th e rats were dermally exposed at a semi

- occluded skin test site to 0, 100, 500, or 1000 mg pronamide technical/kilogram body weight/day (mg/kg/day), six hours/day, for at least 28 consecutive days. The dermal application of pronamide to male Fischer 344 ra ts at dose levels of 500 or 1000 mg/kg/day for 28 days resulted in lower body weights and body weight gains that were dose related. These lower body weights were also associated with lower feed consumption and alterations in the absolute and relative weig hts of various organs; however, there were no microscopic effects noted in any of these tissues indicative of systemic toxicity. The only treatment

- related, histopathologic effect consisted of a slight or very slight hyperplasia of the epidermis and an in creased incidence of very slight inflammation of the dermis at the dermal test site in several males and females given 1000 mg/kg/day. The minimal alteration of the skin at the test site was interpreted to be a protective, adaptational change to repeated exposures of pronamide and was not considered to be an adverse effect. The NOEL for systemic toxicity was 100 mg/kg/day for males, based on the body weight decrements that occurred at 500 and 1000 mg/kg/day. The NOEL for systemic toxicity for females was 1000 mg/kg/day. The NOAEL at the dermal test site was 1000 mg/kg/day. Although there were no systemic target organ effects , a conservative overall NOAEL for this dermal toxicity study is 100 mg/kg/day based on the decreased body weight and body weight gain in males at 500 mg/kg/day.

Immunotoxicity study (2010) : Dietary administration of pronamide to male CD

- 1 mice for 28 consecutive days at concentrations of 15, 75, and 250 mg/kg/day did not result in a test substance

- related decrease in the serum prim ary IgM antibody response to the T

- cell dependent antigen, sRBC. Furthermore, no test substance

- related effects were observed on spleen and thymus weights or hematological parameters. Therefore, the ov erall NOEL for suppression of the humoral immune resp onse was considered to be the targeted concentration of 250 mg/kg/day pronamide. Test substance

- related higher liver weights noted in the 75 and 250 mg/kg/day pronamide

- treated groups confirmed exposure levels were sufficient to induce general toxicity ba sed on the known effects of pronamide in rodents.

Acute Neurotoxicity Studies ( 2011 ) : Ten male and ten female F344/DuCrl rats per group were given a single, oral gavage dose of 0, 40, 200, or 600 mg pronamide/kg body weight to evaluate the potential for acute neurotoxicity. Males of the 600 and females of the 200 and 600 mg/kg dose groups had a slight decrease in body weight following treatment. Treatment

- related clinical findings on day 2 were limited to males and/or females of the 600 mg/kg dose group a nd included decreased activity, decreased or absent feces, incoordinated gait, and red periocular soiling. Other clinical signs on day 2 were present only in females of the 600 mg/kg dose grou p and included slow respiration and animals that were cold to to uch. One female from the 600 mg/kg dose group was found moribund on day 2 and was euthanized. Treatment

- related observations in the4

functional observational battery ( FOB ) were present only on day 1 in males and females of the 200 and 600 mg/kg dose groups. The pattern of clinical effects on day 1 was suggestive of CNS depression and/or general systemic toxicity following acute, bolus dosing. There were no treatment

- relate d observations in any dose group during the day 8 or 15 FOB. There were no treatment

- related observations in males or females of the 40 mg/kg group at any FOB time point. Females of the 200 and 600 mg/kg dose groups had a decrease in both forelimb and hind limb grip performance on day 1. Males of the 200 and 600 mg/kg dose groups and females of the 40, 200, and 600 mg/kg dose groups had an increase in landing foot splay on day 1. Males and females of the 200 and 600 mg/kg dose groups had a decrease in rectal temperature on day 1. There was also a decrease in total motor activity in males and females from all dose groups on day 1. There were no
treatment

- related effects on grip performance, landing foot splay, rectal temperature or motor activity in any dose g roup on day 8 or 15. There were no treatment

- related gross or histopathologic findings in the central or peripheral nervous system. Based on the increase in landing foot splay in female rats and the decrease in motor activity seen in male and female rats at 40 mg/kg on day 1 , a NOEL was not determined. The NOEL for neuropathology was 600 mg/kg, the highest dose level tested.

Subchronic Neurotoxicity Study (2011): A subchronic neurotoxicity study was conducted to assess the effects of dietary exposure to p ronamide at levels of 0, 40, 200, and 1000 ppm in male and female F344/DuCrl rats for at least 90 days. The NOEL for general toxicity was 40 ppm based on the decrease in body weight of the mid

- and high

dose males and females. There were no effects on any parameter that would suggest a neurotoxic effect, and the subchronic dietary NOEL for pronamide neurotoxic ity in male and female rats was 1000 ppm

.
5. Chronic toxicity. A chronic reference dose (cRfD) of 0.08 mg/kg/day has been determined on the basis of the two

- year chronic toxicity/carcinogenicity study in rats and the application of an uncertainty factor of 100 (10x for interspecies extrapolation and 10x for intra

- spec ies variation). The NOAEL in this study was 8.46 mg/kg/day and the LOAEL was 42.59 mg/kg/day based upon increased relative liver weight and the non

neoplastic histologic changes in the liver (centrilobular hypertrophy and hepatocellular eosinophilic alter ation in males and females), thyroid (follicular cell hypertrophy in males and females) and ovaries (sertoliform tubular hyperplasia in females). The 3x FQPA safety factor was applied to the chronic dietary risk assessment because there is evidence of pos sible endocrine effects (thyroid, testes, ovaries, adrenal glands, pituitary gland, thymus) identified in subchronic/chronic studies conducted across species

. Overall, the weight of the evidence supports the conclusion that pronamide is not genotoxic and the MoAs for pronamide

- induced rodent tumors are dose responsive with a clear threshold and are not relevant to humans. Therefore, based on the EPA’s 2005 Guidelines for Carcinogen Risk Assessment, pronamide should be classified as “Not likely to be carci nogenic to humans”. Importantly, a margin of exposure risk assessment based on a chronic reference dose of 0.08 mg/kg/day would be protective of human health

.5

6. Animal metabolism. The qualitative nature of the residue in animals is adequately understoo d. Studies involving lactating goats and laying hens indicate that the primary route of elimination is by excretion (urine and feces). Minimal residues were distributed to goat and poultry muscle. The major metabolites in the eggs, liver, and fat of pou ltry are pronamide and 3,5

- dichlorobenzoic acid. The major metabolites in the milk, fat, muscle, and liver of goats are pronamide, 3,5

- dichlorobenzoic acid, and compounds containing the 3,5

- dichlorobenzoyl moiety. The metabolic pathway involves modificat ion of the aliphatic portion of pronamide. The terminal residues of concern are pronamide and its metabolites containing the 3,5

- dichlorobenzoyl moiety

.
7. Metabolite toxicology

. No relevant data

.
8. Endocrine disruption

. Pronamide was one of the chemicals selected for EPA’s Endocrine Disruptor Screening Program (EDSP) based on the exposure potential to humans and environment. A recent battery of 11 EDSP assays was completed for pronamide. To assist with scientific interp retation of the EDSP screening results for pronamide, a weight

- of

- evidence (WoE) evaluation was completed based on the OECD conceptual framework for testing and assessment of potential endocrine

- disrupting chemicals. The conclusion of the WoE evaluation i s that pronamide does not appear to interact directly with the endocrine system, including estrogen, androgen, and thyroid pathways. Across in vivo repeat

- dose toxicity studies, pronamide induces hepatic enzymes, produces hepatocellular hypertrophy and i ncreases liver weights. These changes are coupled with increased metabolic activity and the subsequent inactivation and/or clearance of both steroid and thyroid hormones. Thus, while propyzamide alters some endocrine

- sensitive endpoints in the EDSP Tier 1 assays, indirect effects on the liver likely contribute to these endocrine changes.

C. Aggregate Exposure

1. Dietary exposure. A dietary assessment was conducted using the Dietary Evaluation Model (DEEM

- FCID, ver. 3.14) software which contains food consumption data based on NHANES 2

- day food consumption data for 2003 to 2008 and food translation to RACs, as indicated by EPA/USDA FCID recipe sets of February 2012. This assessment evaluates the potential risks due to chronic dietary exposures of the U. S. population subgroups to residues of pronamide. These analyses cover the proposed tolerance for lettuce, leaf

.

i. Food. a). Acute exposure. No appropriate toxicological endpoint attributable to a single exposure has been established for pronamide

. Since no acute toxicological endpoints have been established, no acute assessment was performed.

b). The current chronic dietary assessment is a refined assessment using the proposed and existing tolerance values, monitoring data from the PDP, relevant processing factors and percent crop treated values to estimate dietary exposure. The result s of the dietary assessment are considered to be conservative (health protective) risk estimates. Chronic assessments were conducted to evaluate potential risks due to chronic6

dietary exposures of the U.S. population and sensitive sub

- populations to residue s of pronamide against the established chronic reference dose (cRfD) of 0.08 mg/kg/day based on a NOAEL of 8.46 mg/kg/day from the combined chronic toxicity/carcinogenicity study in rats and an uncertainty of 100 (10x for intra

- species variation and 10x fo r inter

- species variation). The FQPA Safety Factor (SF) = 3x; therefore, the chronic Population Adjusted Dose (cPAD) = 0.03 mg/kg/day

.

ii. Drinking water

. Water monitoring data exist for pronamide. However, in order to conduct a conservative assessment s creening level exposure levels to water were estimated using the Agency’s water models, PRZM

- EXAMS and PRZM

- GW. The screening concentration in surface water was estimated using the Pesticide Root Zone Model

– Exposure Analysis Modeling System (PRZM

- EXAMS)

. The screening concentration in ground water was estimated using the Pesticide Root Zone Model for Groundwater (PRZM

- GW). These models take into account the use patterns and the environmental profile of the pesticide, but do not include consideration of the impact that processing raw water for distribution as drinking water would likely have on the removal of pesticides from the source water. The primary use of these models is to provide a coarse screen for assessing whether a pesticide is likely to be prese nt in drinking water at concentrations which would exceed human health levels of concern.

a). Acute exposure and risk. No acute dietary endpoint has been established for pronamide. Therefore, no acute assessment was conducted.

b). Chronic exposure and ri sk. Tier I screening level exposure assessments were conducted using PRZM

- EXAMS and PRZM

- GW. The models were run with input data for pronamide and all pronamide metabolites containing the3,5

- dichlorobenzoyl moiety following the Total Residue of Concern (T RC) approach previously used by the Agency. The highest calculated water concentration was for ground water at 411 ppb. As a conservative approach, this water concentration was used in the DEEM

- FCID dietary risk assessment for all direct and indirect water sources. The refined DEEM

- FCID exposure for food and water using the proposed tolerance for lettuce, leaf (1.0 ppm) and established tolerances, monitoring data, processing factors and percent crop treated data resulted in an estimated exposure for the U .S . general population of 32 % of the cPAD. For the most highly exposed population sub

- group, all infants, the estimated exp osure is 77% of the cPAD

.

2. Non

- dietary exposure

. Pronamide no longer is used as a residential use product. Use is limited to nurse ries, greenhouses, Christmas tree plantations and turf grown for seed or sod and non

- residential sites including golf courses, industrial and office building sites, stadium fields or professional athletic fields. Since residential use on turf is not inclu ded in the product use label and labeled uses are restricted to industrial, work and professional sport locations, it is considered that potential exposure to children has been removed except for golfing scenarios. Additionally, to minimize non

- occupation al exposure, the pronamide labels require a 24 hour restricted entry interval or require watering

- in as soon as possible after application

.7

The relevant exposure scenarios for the non

- occupational risk assessment are based on high contact lawn activities f or adults (the envisaged scenario is from contact with treated turf in stadiums and professional athletic fields so the exposed population is limited), mowing turf (adults

– no exposure to children will occur due to the restricted use in stadium and profes sional athletic fields) and golf course re

- entry (adults and children 6 to <11 years of age). The route of exposure is dermal. The predominant population at risk is adults. The Agency’s Level of Concern (LOC) is 300.

A 28

- day dermal toxicity study was c onducted in 2005. The lowest NOEL from the study was 100 mg/kg/day. The point

- of

- departure used in the exposure assessment was 100 mg/kg/day and a conservative 100% dermal absorption was assumed. The calculator used was taken from the US EPA website and is based on the Residential SOPs issued in 2012.

The short

- term Margin of Exposure (MOE) for golf course reentry using two day after treatment (DAT 2) turf transferable residue data from the turf study is 16,000 for adults, 14,000 for children 11 to < 16 y ears of age and 12,000 for children 6 to <11 years of age. For mowing turf the predicted MOE is 63,000 for adults. Exposure to children during mowing is not considered as the use of pronamide is limited to areas (stadium and professional athletic tracks) where children will not be mowing grass. For high contact activities (relevant for adults only) the MOE is 1,300. All predicted exposures exceed the LOC of 300. The Agency generally has no concern for exposures that exceed the LOC.

D. Cumulative Effects

The Food Quality Protection Act (1996) stipulates that when determining the safety of a pesticide chemical, The Agency shall base its assessment of the risk posed by the chemical on, among other things, available information concerning the cumulative effe cts to human health that may result from dietary, residential, or other non

occupational exposure to other substances that have a common mechanism of toxicity.

Pronamide is a pre

- and post

- emergence herbicide used to control annual grasses and broadleaf weeds. At this time, the EPA has not made a determination that pronamide and other substances that may have a common mechanism of toxicity would have cumulative effects.

Therefore, for these tolerance petitions, it is assumed that pronamide does not hav e a common mechanism of toxicity with other substances and only the potential risks of pronamide in its aggregate exposure are considered

. E. Safety Determination

1. U.S. population. Chronic dietary exposure to pronamide from all registered and the propo sed use and drinking water will utilize 32% of the cPAD for the U. S. population. Generally, EPA has no concern for exposures below 100% of the cPAD8

because the chronic PAD represents the level at or below which daily dietary exposures over a lifetime wil l not pose appreciable risks to human health.

As no acute dietary endpoints were selected which represented toxicities from a single

dose exposure, there is no concern that acute (single daily) exposure will pose appreciable risks to human health.

The po tential contribution of pronamide from non

- residential (recreational) exposure was assessed where applicable (short term exposure). Calculated adult MOEs for non

residential exposures only ranged from 1,300 to 63,000. Aggregated exposures were calculated for adults for both chronic exposures (food and water) and short term exposures (food, water and non

- residential exposure). Estimation of aggregated chronic exposure, from food and water, to the U.S. population resulted in a safe margin of exposure (MOE = 900). For aggregated short term exposures for adults the relevant non

residential exposure scenarios were high turf contact activities and the golfing scenarios. Calculated MOEs were 530 and 850 for the high contact and golfing scenarios, respectively.

Therefore, based on this risk assessment, Dow AgroSciences concludes that there is reasonable certainty that no harm will result to any population from aggregate exposure to pronamide residues from all supported registered and the proposed use

.
2. Infants and children

. EPA uses a weight of evidence approach in determining what safety factor is appropriate for assessing risks to infants and children. This approach takes into account the nature and severity of the effects observed in pre

- and post

- natal stu dies and other information such as epidemiological data. The completeness and adequacy of the toxicity database is also considered. The toxicological database is adequate for FQPA assessment, and there is no indication of quantitative or qualitative incre ased susceptibility of rabbits to in utero exposure or to rats following pre/post

- natal exposure. Also, in the available rat study, no increased susceptibility was seen.

EPA has previously determined that an FQPA safety factor of 3x is applicable to all
p opulation subgroups when assessing dietary exposure scenarios because of evidence of possible endocrine effects.

The most sensitive, relevant, subgroup with the highest chronic food exposure is all infants (<1 year), accounting for 77% of the cPAD.

Using the conservative assumptions described above, the chronic dietary exposure to pronamide including all existing and the proposed use will utilize 77% of the cPAD for all infants (<1 yr old) and 55% of the cPAD for children 1

- 2 years when considering the
po tential aggregate exposure to drinking water.

Estimated short

- term exposures were calculated for the population groups that could have

non

- residential (recreational) exposures. The relevant subpopulations were children 6 to <11 years old and children 11 to <16 years old for the golfing exposure scenario. The calculated non

- residential MOEs ranged from 12,000 to 14,000.9

Aggregated exposures were calculated for children for both chronic exposures (food and water) and short term exposures (food, water and non

- residential exposure). The chronic aggregate risk is resultant from diet, and drinking water exposure, only. Estimation of exposure to children aged 6 to <11 years old resulted in a safe margin of exposure (lowest MOE = 370). For aggregated short ter m exposures the relevant populations that could have non

- residential exposures were considered. For children the most sensitive non

residential exposure scenario was golfing for children aged 6 to <11 years of age. The calculated MOE was 880.

Therefore, b ased on the completeness and reliability of the toxicity data and the conservative exposure assessment, Dow AgroSciences concludes with reasonable certainty that no harm will result to infants and children from the aggregate exposure to pronamide residues from registered and the proposed use

.
F. International Tolerances

Several governing bodies have established Maximum Residue Levels (MRLs) for pronamide in a variety of crops. The related international MRLs are found in the following table based on a re view of MRLs compiled by searches in the USDA MRL database, Homologa , the EU SANCO website , the Australian MRL website and Japan MRL website. Homologa is a third party database used as the source for this table; Dow AgroSciences makes no claim regarding the verification of these values relative to the individu al national authoritative sources

.
Pronamide/Propyzamide Commodity Existing MRL (ppm) Regulatory Authority

Lettuce 1.0 Canada Lettuce, head 1.0 Australia, US Lettuce, leaf 1.0 Australia, US Lettuce (Head lettuce, lollo rosso (cutting lettuce), iceberg lettuce, romaine (cos) lettuce) 1.0 EU

Lettuce (including cos lettuce and leaf lettuce) 0.1 Japan