EPA Registration Division contact: Andrew Ertman; 703-308-9367

PP #2E8051

EPA has received a pesticide petition (2E8051) from IR-4, IR-4 Headquarters, 

Rutgers, The State University of New Jersey, 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 by 

establishing a tolerance for residues of fenoxaprop-ethyl, .( [ (±)-ethyl 2- [ 4- [ ( 6 -

chloro-2-benzoxazolyl)oxy]phenoxy]propanoate) and its metabolites 2-[4-[ ( 6:-

chloro-2-benzoxazolyl) oxy] phenoxy] propanoic acid and 6-chloro-2,3-

dihydrobenzoxazol-2-one, each expressed as the parentcompound in or on the raw 

agricultural commodities grass, hay at 0.15 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. Plant metabolism studies with fenoxaprop-ethyl were 

performed in wheat, cotton and peanuts. The metabolism in all plants was very 

similar. The main reactions involved were rapid cleavage of the ethyl ester to form 

fenoxaprop acid. Next, the benzoxazolyloxy linkage is cleaved, resulting in the 

formation of AE F054014 (6-chloro-2,3-dihydro-benzoxazol-2-one).

2. Analytical method. Tolerances are being proposed in grass hay for the 

combined residues of fenoxaprop-ethyl and its metabolites fenoxaprop-acid and AE 

F05414. The analytical method involves reflux with acid to convert fenoxaprop-ethyl

and fenoxaprop acid to AE F05414, derivatization followed by SPE clean-up. 

Quantitation is by gas chromatography-mass spectrometry ( GC/MS).

3. Magnitude of residues. Four residue field trials were conducted in 

Washington and Oregon representing regions 11 and 12. Trials were conducted on 

bluegrass, fescue (two separate varieties) and ryegrass. No residues greater than the 

lowest limit of method validation (LLMV, 0.05 ppm) were observed for any of the 

three analytes in any sample.

B. Toxicological Profile

1. Acute toxicity. Fenoxaprop-P-ethyl has very low acute toxicity to mammals

irrespective of the route of exposure (oral, percutaneous or inhalation exposure). It

is non-irritating to eyes and skin, and is not a skin sensitizer (Buehler) Overall, it is 

classified as Toxicity Classification III. The oral LD50 in rats is greater than greater 

than 2000 mg/kg. The dermal LD50 value in rats is greater than 2000 mg/kg. The

inhalation LC50 for a four-hour exposure (nose only) is greater than 1.224 mg/L. In 
the acute oral toxicity study, clinical signs were observed within 1 to 24 hours with 

recovery within thirteen days after exposure. No clinical signs nor body weight 

changes or necropsy findings were observed in the dermal toxicity study conducted 

in rats. In the acute inhalation toxicity study, non-specific clinical signs were 

observed with recovery within five days after exposure. Fenoxaprop-p-ethyl is a 

member of the arloxy phenoxy-propionate class of herbicides, based on structural 

similarity of the arloxy phenoxy-propionate herbicides, knowledge of the mode of 

action for these compounds, and lack of neurotoxicity for this class, the acute 

neurotoxicity study is not required for fenoxaprop-P-ethyl.

2. Genotoxicty. Genotoxicity potential was evaluated in a series of tests

including in vitro and in vivo tests. There was no indication of gene mutation either

in the presence or absence of metabolic activation in both the bacterial reverse

mutation and mammalian gene mutation tests. The in vitro chromosome aberration

test and the in vivo mouse micronucleus test were also both negative. These studies

demonstrate that fenoxaprop-P-ethyl has no genotoxic potential.

3. Immunotoxicity. Immunotoxicity potential was evaluated in a four week

study in female rats. Following immunization with SRBC antigen, mean anti-SRBC 

IgM concentrations were similar to the untreated control group at all dose levels 

tested.

The high dose of 630 ppm (47 mg /kg bw/day) was determined to be the NOEL for 

immunotoxicity for females. Fenoxaprop-P-ethyl is therefore, not considered to be 

immunotoxic.

4. Reproductive and developmental toxicity. In a rat two-generation

fenoxaprop-ethyl reproduction study, the parental systemic NOAEL was 5 ppm 

(0.25 mg/kg/day ) based on decreased in total lipids in F1 males and females and 

total cholesterol in F1 males. The reproductive LOAEL of 1.5 mg/kg/day was based 

on reduced pup body weights (F1a). The US EPA determined that the fenoxapropethyl reproduction study and chronic toxicity studies may be used to bridge with 

fenoxaprop-p-ethyl. In a rat developmental toxicity study, the NOAEL was 32

mg/kg/day both in the dam (based on a reduction in body weight gain, food 

consumption and heart weight) and in terms of fetal development (based on delayed 

ossification of the cranial bones and the absence of any other findings). No evidence 

of a teratogenic effect was observed at any dose level tested.

In a rabbit developmental toxicity study, the NOAEL was 32 mg/kg/day

both in the dam (based on decreased food consumption, stagnation of body weight 

gains during the treatment period, and increased kidney weights) and in

terms of fetal development (visceral and skeletal effects observed at the high dose).

No evidence of a teratogenic effect was observed at any dose level tested.

5. Subchronic toxicity. Subchronic studies showed that the liver is the major

target organ in rats and mice. In addition to the liver, the kidney (females) was also 

a target organ in mice. In the female mouse, moderate to marked renal tubular
injury was observed at the high dose. In dogs, a decrease in bodyweight gain and an 

increase in ASAT and total protein for the males as well as a decrease in ALAT for 

both sexes were observed at the highest dose tested (2000 ppm, ca. 81 mg/kg bw). 

The rat was the most sensitive species followed by the mouse with the dog

being the least sensitive. Overall, the lowest NOAEL was observed in the

subchronic rat study. In this study, the NOAEL for the rat was established at 0.75

mg/kg bw/day. Fenoxaprop-p-ethyl is a member of the arloxy phenoxy-propionate 

class of herbicides, based on structural similarity of the arloxy phenoxy-propionate 

herbicides, knowledge of the mode of action for these compounds, and lack of 

neurotoxicity for this class, the subchronic neurotoxicity study is not required for 

fenoxaprop-P-ethyl.

6. Chronic toxicity. The US EPA determined that the fenoxaprop-ethyl 

chronic toxicity studies may be used to bridge with fenoxaprop-p-ethyl. In a two 

year dog study No treatment related effects 'were seen on mortality, behavior, 

clinical findings, food consumption, hematology, kidney and liver function, or 

urinalysis. Neurologic, ophthalmologic, otologic, dental, and mucosal health were 

similar in the treated and control animals. In addition, dosing did not cause 

toxicologically important effects on organ weights, organ-to-body weight ratios, or 

gross and histopathological findingsThe NOEL was 15 ppm (0.375 mg/kg/day) and 

the LOEL, based on decreases in body weight gain, was 75 ppm (1.875 mg/kg/day).

In the rat, at the end of the combined chronic toxicity and carcinogenicity study 

treatment did not affect mortality, behavior, clinical findings, body weight, food 

consumption, hematology, kidney and liver function, or urinalysis. In addition, 

dosing did not causetoxicologically important effects on organ weights, organ-tobody weight ratios, or gross and histopathological findings. For chronic toxicity, the 

NOEL was 30 ppm {1.5 mg/kg/day) and the LOEL was 180 ppm (9 mg/kg/day) 

based on decreased serum lipids and cholesterol in the males. Under the conditions 

of this study, there was no evidence of carcinogenic potential.

In a mouse carcinogenicity study the target organ was the liver. Treatment had no 

effect on mortality. Clinical observations indicated an increased incidence of swollen 

abdomen in both sexes at the mid and high dose from week 55 onward. In males 

only, absolute liver weight and relative liver weight was increased. Histopathology 

revealed alterations in the liver characterized as hepatocellular hypertrophy, single 

cell necrosis, pigmentation in macrophages and lipofuscin deposit at mid dose 

(males) and high (males and females) . For chronic toxicity, the NOEL was 40 ppm 

(5.7 mg/kg/day), and the LOEL was 115 ppm (16.6 mg/kg/day) based on 

histopathological findings in the liver.

There was evidence of carcinogenicity at the highest dose tested. Statistically (p <0. 

05) significant increases were seen in liver and adrenal gland tumors. 

7. Animal metabolism. In the rat, fenoxaprop-P-ethyl is rapidly absorbed and 

excreted. Based on a comparison of the radioactivity excreted after oral and 

intravenous treatment, the oral absorption rates can be estimated at about 84% for 

the male rats and roughly 96% for the female rats indicating an almost complete 

oral absorption. Fenoxaprop-P-ethyl was extensively metabolized with unchanged
parent compound found only in low percentages of the recovered dose. The

metabolism of fenoxaprop-P-ethyl in male and female rats was similar and included 

hydrolysis of the ethyl ester, followed by cleavage to afford the (D+)-2-(4-

(hydroxyphenoxy)-propionic and 6-chloro-2,3-dihydro-(benzoxazol-2-one), 

hydroxylation, conjugation and sulphatation. In ruminants and poultry, 

fenoxaprop-ethyl is rapidly excreted and the principal route of metabolism is 

similar to that described for the rat above. Fenoxaprop-ethyl residues do not 

accumulate in animal tissues, milk or eggs.

8. Metabolite toxicology. Not applicable as parent is the compound of

concern.

9. Endocrine disruption. There is no evidence to suggest that fenoxaprop-Pethyl has any primary endocrine disruptive potential. Reproductive and 

developmental findings provided no evidence of an enhanced sensitivity of the 

young. Bayer CropScience will conduct any studies that may be required under 

EPA’s Endocrine Disrupter Screening Program.

C. Aggregate Exposure

1. Dietary exposure. The toxicological and exposure database for fenoxapropP-ethyl is considered complete. There was no indication of an increased sensitivity 

of the young in any studies including the reproductive and developmental studies in 

rats and rabbits. Therefore, the special FQPA can be reduced to 1X and an 

uncertainty factor of 100 is adequate to account for inter- and intra- species 

variability. Acute and chronic Population Adjusted Doses (aPAD and cPAD) are, 

therefore, the same as the reference doses for the populations and subpopulations of 

interest. Acute dietary exposure was expressed as a percentage of the aPAD of 0.32

mg/kg bw/day based on a NOAEL of 32 mg/kg bw/day in the rat developmental 

toxicity study with an uncertainty factor of 100. Chronic dietary exposure was 

expressed as a percentage of the chronic Population Adjusted Dose (cPAD) of 0.0025

mg/kg bw/day based on a NOAEL of 0.25 mg/kg bw/day in the rat reproductive

study with an uncertainty factor of 100.

i. Food. Since no fenoxaprop-P-ethyl residues were detected on grasses grown 

for seed, there would be minimal change to the previous FQPA human health risk 

for fenoxaprop-P-ethyl in February 1998 (DP Barcode D242374, S. Kizner, 2/3/98). 

Bayer CropScience is not conducting a revised risk assessment for this new use for 

the following reasons: 1.) this label expansion does not involve use on human foods; 

2.) it is unlikely to alter the dietary burden for livestock. There would be negligible 

changes to the results of the 1998 assessment as summarized below.

A Tier 1 acute and chronic dietary risk assessments were conducted to 

evaluate the dietary exposure of the U.S. population and selected subpopulations to 

fenoxaprop residues. The assessment assumed residues would be at tolerance levels 

for fenoxaprop and 100% of the crops were treated. The Tier I acute and chronic 

assessments were conducted using DEEM-FCIDTM, Version 2.14 software. 

Consumption data used in this program were taken from USDA’s CSFII, 1994-
1996, 1998. With these conservative assumptions, acute exposure for food only 

utilizes 0.3% of the aPAD for the Females 13-49. Chronic exposure for food and 

water only utilizes 0.4% of the cPAD for the US Population.

ii. Drinking water. The use of PUMA herbicide on grasses grown for seed 

would have a negligible impact on the estimates of drinking water residues for 

fenoxaprop-P-ethyl. In the human health assessment (2/3/98), EFED used the 

“GENEEC” drinking water model to generate Tier I estimated exposure 

concentrations (EEC) of surface water runoff. The GENEEC screening model 

calculated peak EECs for fenoxaprop-ethyl of 27 ppt and 56-day EEC's of 0.56 ppt. 

For fenoxaprop-acid, the peak EEC was 410 ppt and the 56-day EEC was 87 ppt. 

These drinking water values did not significantly increase dietary exposure. In 

conclusion, the results of the very conservative acute and chronic dietary exposure 

analyses (including food and drinking water) demonstrates that fenoxaprop 

exposure consumes a very small percentage of the risk cup for all scenarios and 

population subgroups examined. Therefore, there is a reasonable certainty that no 

harm will result from exposure to potential residues of fenoxaprop in food and 

water.

2. Non-dietary exposure. The maximum seasonal and single use rate has not 

changed and no new methods of application or field post application activities are 

introduced by the additional crops. Hence, a risk to bystanders, field workers, and 

applicators is not expected to change from the current acceptable levels.

D. Cumulative Effects

Section 408(b)(2)(D)(v) requires that, when considering whether to establish,

modify, or revoke a tolerance, the Agency consider “available information”

concerning the cumulative effects of a particular pesticide’s residues and “other

substances that have a common mechanism of toxicity.” EPA has not made a 

common mechanism of toxicity finding as to fenoxaprop-P-ethyl and any other 

substances and fenoxaprop-P-ethyl does not appear to produce a toxic metabolite 

produced by other substances.

E. Safety Determination

1. U.S. population. Risk assessments for fenoxaprop-P-ethyl are based on a 

complete and reliable toxicity data package and highly conservative assumptions. 

Chronic aggregate dietary exposure (food and water) utilizes <1% of the cPAD for 

the US Population. Acute aggregate dietary exposure (food and water) for the U.S. 

adult population utilizes <1% of the aPAD. Non-occupational non-dietary exposure 

of the U.S. population to fenaxoprop-p-ethyl is not expected to change. Therefore, 

there is a reasonable certainty that no harm will occur to the US Population from 

aggregate exposure (food and drinking water) to residues of fenoxaprop-P-ethyl.

2. Infants and children. The toxicological and exposure database for 

fenoxaprop-P-ethyl is considered complete. There was no indication of an increased 
sensitivity of the young in any studies including the reproductive and developmental

studies in rats and rabbits. Therefore, the special FQPA can be reduced to 1X and 

an uncertainty factor of 100 is adequate. Based on conservative assumptions, 

chronic aggregate dietary exposure (food and water) utilizes <1% of the cPAD for 

Females 13 to 49 yrs. old, the most highly exposed subpopulation. Acute aggregate 

dietary exposure (food and water) utilizes <1% of the aPAD for all subpopulations. 

Non-dietary exposure of children to fenoxaprop-P-ethyl is not anticipated. 

Therefore, there is a reasonable certainty that no harm will occur to infants 

andchildren from aggregate exposure (food and drinking water) to residues of

fenoxaprop-P-ethyl.

F. International Tolerances

No tolerances have been established for fenoxaprop-P-ethyl.