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 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 by establishing a tolerance for residues of pronamide (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 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 Agency has established that the qualitative nature of the 

residue in plants is adequately understood. 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 are 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 ingredient in Kerb® 50W (50% WP).
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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 made 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 AgroSciences 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 eight field trials located in 

Region 2 (one trial in Georgia), Region 3 (one trial in Florida), and 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 and 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 approximately 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 discussed 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 dermal 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 represented toxicities 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 observed 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 

developmental toxicity study and the rat multigeneration reproduction study without 

demonstrating toxicities in either maternal animals or fetuses.
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4. Subchronic toxicity. For risk assessments based on short-term (1-30 days) 

incidental oral, dermal and inhalation exposures, a dose of 8.46 mg/kg/day was 

established by EPA for use in risk assessments. 

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.

The 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 rats 

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 

weights 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 increased 

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 primary 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 overall 

NOEL for suppression of the humoral immune response 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 based 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 and 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 group and included slow respiration 

and animals that were cold to touch. One female from the 600 mg/kg dose group was 

found moribund on day 2 and was euthanized. Treatment-related observations in the
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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-related 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 hindlimb 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 group 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 pronamide 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 highdose males and females. There were no effects on any parameter that would suggest a 

neurotoxic effect, and the subchronic dietary NOEL for pronamide neurotoxicity 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-species 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 nonneoplastic histologic changes in the liver (centrilobular hypertrophy and hepatocellular 

eosinophilic alteration 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 possible 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 carcinogenic 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.
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6. Animal metabolism. The qualitative nature of the residue in animals is 

adequately understood. 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 poultry 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 

modification 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 interpretation 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 is 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 increases 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 

results of the dietary assessment are considered to be conservative (health protective) risk 

estimates. Chronic assessments were conducted to evaluate potential risks due to chronic 
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dietary exposures of the U.S. population and sensitive sub-populations to residues 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 for 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 screening 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 present 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 risk. 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 (TRC) 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 exposure is 77% of the cPAD.

2. Non-dietary exposure. Pronamide no longer is used as a residential use product. 

Use is limited to nurseries, 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 

included 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-occupational 

exposure, the pronamide labels require a 24 hour restricted entry interval or require 

watering-in as soon as possible after application.
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The relevant exposure scenarios for the non-occupational risk assessment are based on 

high contact lawn activities for 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 professional 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 conducted 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 years 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 

effects to human health that may result from dietary, residential, or other nonoccupational 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 have 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 proposed 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 cPAD 
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because the chronic PAD represents the level at or below which daily dietary exposures 

over a lifetime will not pose appreciable risks to human health. 

As no acute dietary endpoints were selected which represented toxicities from a singledose exposure, there is no concern that acute (single daily) exposure will pose 

appreciable risks to human health.

The potential contribution of pronamide from non-residential (recreational) exposure was 

assessed where applicable (short term exposure). Calculated adult MOEs for nonresidential 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 nonresidential 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 studies 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 

increased 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 

population 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 

potential 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. 
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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 term exposures the relevant populations that could 

have non-residential exposures were considered. For children the most sensitive nonresidential exposure scenario was golfing for children aged 6 to <11 years of age. The 

calculated MOE was 880.

Therefore, based 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 review 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 

individual 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