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EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR 

PESTICIDE PETITIONS PUBLISHED IN THE FEDERAL REGISTER 

EPA Registration Division contact: William Cutchin; 703-305-7990

TEMPLATE:

Bayer CropScience

3F8182

EPA has received a pesticide petition (3F8182) from Bayer CropScience

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 the tolerances

for residues of aluminum tris(O-ethylphosphonate) in or on the raw agricultural 

commodity Pepper/Eggplant, subgroup 8-10B, at 0.01 parts per million (ppm) and 

Non-bell (chili) pepper dried fruits at 0.01 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 metabolism of fosetyl-al in plants is adequately 

understood. Adequate data on the nature of the residues in plants, including 

identification of major metabolites and degradates of fosetyl-al, are available. 

Radiolabeled studies on the uptake, translocation and metabolism in plants show 

that the chemical proceeds through hydrolytic cleavage of the ethyl ester. The major 

residues are fosetyl-al, phosphorus acid, and ethanol. The tolerances are established 

for the parent only, that is fosetyl-al as specified in 40 CFR 180.415.

2. Analytical method. An enforcement method for plant commodities has been 

validated on various commodities. It has undergone successful EPA validation and 

has been submitted for inclusion in PAM II. The animal method has also been 

approved as an adequate enforcement method.

3. Magnitude of residues. Magnitude of residue data in/on bell and non-bell 

(chili) pepper fresh fruits and non-bell (chili) pepper dried fruits were determined 

from fourteen field trials conducted in Mexico (6 trials), Peru (3 trials) and 

California (5 trials). Prior to transplant, all seedlings were grown in greenhouse 

trays and received three foliar spray applications ranging from 8.09 to 8.69 lbs 

fosetyl-al/A/application (9.07 to 9.74 Kg fosetyl-al/A/application) with a 10-day 

treatment interval. Total foliar application rates ranged from 24.5 to 25.4 lbs 
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fosetyl-al/A (27.5 to 28.4 Kg fosetyl-al/A). Following transplant of the previously 

treated seedlings, plants received either 3 drench applications or 3 chemigation 

applications ranging from 0.83 to 0.84 lb fosetyl-al/A/application (0.93 to 0.94 Kg 

fosetyl-al/ha/application) with a 10 day treatment interval and 5-day PHI. Total 

combined seasonal application rates for both treatment regimens (foliar + drench 

and foliar + chemigation) ranged from 27.0 to 27.8 lbs fosetyl-al/A (30.3 to 31.2 Kg 

fosetyl-al/ha). Duplicate composite samples of bell and non-bell pepper, fresh fruits 

were collected from the treated plots at 4- to 5-day pre-harvest intervals (PHIs). In 

the non-bell/chili pepper trials, samples of fresh non-bell peppers to be dried were

collected at the same intervals as samples for fresh non-bell peppers. These samples 

were allowed to dry either outside, inside at room temperature, or in a lowtemperature drying oven for 7 to 20 days, according to typical local agricultural 

practices. Six of the trials were conducted as decline trials with fresh fruit samples 

collected at 0, 2, 4, 5, 7 and 9 to 10 days. 

Residue values for dried non-bell (chili) peppers were calculated by multiplying 

residue values measured in fresh non-bell (chili) peppers by a processing factor 

determined from the dry weight of each of the respective non-bell chili pepper 

samples. Fosetyl residues, quantitated as fosetyl-al only, in bell pepper, fresh fruits,

non-bell (chili) pepper, fresh fruits and non-bell (chili) pepper, dried fruits were 

<0.01 ppm.

B. Toxicological Profile

1. Acute toxicity. A complete battery of acute toxicity studies for fosetyl-Al 

technical has been conducted. The lethal dose LD50 from the acute oral rat is 

5.4 g/kg and the LD50 from an acute dermal rabbit study is >2 g/kg. The

LC50 for a rat inhalation study is >1.73 mg/L. The acute oral rat and primary 

dermal irritation studies indicate category IV toxicity. A guinea pig dermal 

sensitization study shows fosetyl-Al is not a skin sensitizer. The primary eye

irritation study in rabbits shows fosetyl-Al to be an eye irritant with Category I 

toxicity.

2. Genotoxicty. Fosetyl-Al is neither mutagenic nor genotoxic. The genetic 

toxicity potential of fosetyl-Al was assessed in several assays. Eight mutagenicity 

tests performed with fosetyl-Al were negative. The tests included two Ames assays 

with S. typhimurum, two phase induction assays using E. coli, two micronucleus

studies in mice, one DNA repair assay using E. coli and one mutation assay in 

Saccharomyces cereviseae.

3. Reproductive and developmental toxicity. Fosetyl-Al is not a reproductive 

toxicant and shows no evidence of estrogertic or androgenic related effects.

a. In a three generation reproduction study, fosetyl-Al was administered to rats 

at dietary levels of 0, 6,000, 12,000 or 24,000 ppm. No adverse effects on 

reproductive performance or pup survival were observed in any dose group. 

The lowest-observed adverse effect level (LOAEL) was established at 12,000 

ppm based on effects on animal weights and urinary tract changes. The no-
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observed adverse effect level (NOAEL) for all effects was 6,000 ppm.

b. A teratology study in rats dosed via oral gavage at 500, 1,000 or 

4,000 mg/kg/day showed a developmental NOAEL of 1,000 mg/kg. At 

4,000 mg/kg, there was maternal toxicity as evidenced by effects on animal 

weights, maternal deaths, increased resorptions and delayed fetal

ossification.

c. A rabbit teratology study showed no toxic effects at oral doses up to 

500 mg/kg. Effects of fosetyl-Al on fetal development were observed only in 

the rat at a dose producing severe maternal toxicity. In the absence of 

maternal toxicity, no adverse effects on fetal development were observed, i.e. 

at 1000 mg/kg/day in rats or at 500 mg/kg/day in rabbits.

4. Subchronic toxicity. In subchronic studies, no significant toxicity was

observed even at doses exceeding the limit of 1000 mg/kg/day.

a. A 21-day dermal study in rabbits showed mild to moderate skin irritation 

and a NOAEL of 1.5 g/kg/day.

b. A 90-day feeding study in rats showed a NOAEL of >5000 ppm; the LOAEL 

was 25,000 ppm with extramedullary hematopoiesis in the spleen.

c. A 90-day dog feeding study showed a NOAEL of 10,000 ppm and a LOAEL 

at 50,000 ppm, at which the test animals had a lower serum potassium level 

than untreated animal.

5. Chronic toxicity. Chronic toxicity studies have been conducted in dogs and 

rats:

a. Dog: Fosetyl-Al was fed to dogs for two years at concentrations qf 0, 10,000, 

20,000, and 40,000 ppm. The NOAEL was 10,000 ppm, equivalent to 

250 mg/kg/day. The NOAEL was 20,000 ppm bused on a slight degenerative 

effect on the testes. These testicular changes, as well as a few scattered 

clinical changes, were seen in the high dose dogs. No effects were observed in

the urinary tract.

b. Rat: Fosetyl-Al was administered via admixture in the diet to CD rats at 

target levels of 0, 2,000, 8,000, and 30,000/40,000 ppm for approximately two

years. Based on these levels, respective doses were 100, 400 and 2000/1500 

mg/kg/day. After two weeks at 40,000 ppm, this dietary level was reduced to 

30,000 ppm due to the occurrence of red coloration of the urine and a 

decrease in body weight gain. Although these findings were no longer 

apparent after Week 2, analytical verification of dietary levels revealed that 

the highest dietary level ranged from approximately 38,000 to 61,000 ppm 

during the first 32 weeks of the study. No significant differences in body 

weight or food consumption were noted at 2,000 or 8,000 ppm. No

biologically significant differences were observed in ophthalmoscopy, 

hematology, clinical chemistry or urinalysis for treated and control animnls.

Calculi in the urinary bladder were observed for several male and female 

rats in the high dose group. Non-neoplastic findings consisted of epithelial 

hyperplasia and inflammation in the urinary bladders of males at

30,000/40,000 ppm. Increased incidences of hydronephrosis, inflammation, 

and epithelial hyperplasia in the kidney were also observed in males from the 
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high dose group. Females from the same group exhibited increased 

incidences qf epithelial hyperplasia in the urinary bladder and 

hydronephrosis in the kidney. The NOAEL in the chronic rat study was 

8,000 ppm (400 mg/kg/day). The lowest NOAEL for chronic effects of 

fosetyl-Al is 10,000 ppm (250 mg/kg/day) based on the dog study. This 

NOAEL is based on minor changes at 20,000 ppm. In the rat, calculi in the

urinary bladder and related histopathological changes in the bladder and 

kidneys of males and females were observed at 30,000/40,000 ppm.

6. Chronic Toxicity and Carcinogenicity Long-term feeding studies were 

conducted with technical grade fosetyl-al in mice and rats and with monosodium 

phosphite, the primary urinary metabolite of fosetyl-al, in rats. These studies, in 

addition to a mechanistic study in rats, are described below:

a. Rat. Fosetyl-al was administered via admixture in the diet to CD rats at 

target levels of 0, 2,000, 8,000, and 30,000/40,000 ppm for approximately 2 

years. After 2 weeks at 40,000 ppm, this dietary level was reduced to 30,000 

ppm due to the occurrence of red coloration of the urine and a decrease in 

body weight gain. Although, these findings were no longer apparent after 

week 2, analytical verification of dietary levels revealed that the highest 

dietary level ranged from approximately 38,000 to 61,000 ppm during the 

first 32 weeks of the study. Calculi in the urinary bladder were observed for 

several male and female rats at 30,000/40,000 ppm. Microscopic examination 

revealed transitional cell carcinomas and papillomas in the urinary bladders 

of high dose males. In addition, a statistically significant increase in adrenal 

pheochromocytomas (benign and malignant combined) was observed in 

males at 8,000 and 30,000/40,000 ppm. The adrenal slides were

independently reread by two consulting pathologists who found no

significant dose-related increases in the incidence of pheochromocytomas or 

hyperplasia. The NOAEL for fosetyl-al in the chronic rat study was 8,000 

ppm.

A subsequent mechanistic study in rats conducted with dietary levels of

8,000, 30,000 and 50,000 ppm demonstrated that the massive doses of 30,000 

and 50,000 ppm fosetyl-al alter calcium/phosphorous homeostasis resulting 

in severe acute renal injury, similar to that observed in the chromic rat 

study, and the formation of calculi in kidneys, ureters, and bladder. Under 

conditions of chronic exposure, these effects could lead to the formation of 

bladder tumors as seen in the chronic rat study. At 8,000 ppm, no evidence of 

renal injury was observed, a result consistent with the absence of bladder 

tumors. Thus, the bladder tumors induced by fosetyl-al were the result of 

acute renal injury followed by a chronic toxic reaction rather than a true 

carcinogenic effect. An carcinogenicity study in rats was conducted with 

monosodium phosphite administered via dietary mixture at levels of 2,000, 

8,000, and 32,000 ppm. No evidence of carcinogenicity was observed in this 

study.

b. Mouse. A 2-year feeding/carcinogenicity study was conducted in mice fed 

diets containing fosetyl-al at 0, 2,500, 10,000, or 20,000/30,000 ppm. The 
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20,000 ppm dose was increased to 30,000 ppm during week 19 of the study. 

The NOAEL for all effects was 20,000/30,000 ppm (3,000/4,500 mg/kg/day).

There were no carcinogenic effects observed under the conditions of this 

study.

c. EPA's Carcinogenicity Peer Review Committee (CPRC) concluded in their 

report of June 29, 1993 that the pesticidal use of fosetyl-al is unlikely to pose 

a carcinogenic hazard for humans given that: (a) Tumors develop in rats 

under extreme conditions that are unlikely to be achieved other than under 

laboratory conditions (at a dose in excess of the EPA dose limit for 

carcinogenicity studies); (b) tumors in rats are believed to develop only at 

doses that produce stones; (c) human dietary exposure to fosetyl-al is only 

about one-500,000th of the NOAEL for stone formation in the rat (the most 

sensitive experimental model); and (d) the dose of fosetyl-al which can be 

absorbed dermally by applicators is also probably too low to result in stone 

formation. Therefore, a cancer dietary exposure analysis for fosetyl-al is not

performed.

7. Animal metabolism. Rat metabolism studies showed that most of the 

radiolabel rapidly appeared in exhaled carbon dioxide. There was also some 

radiolabel excreted in the urine as phosphite, along with a smaller amount as the 

unchanged parent compound. It appears that fosetyl-al is essentially completely 

absorbed after ingestion and extensively hydrolyzed to carbon dioxide which is 

exhaled. The phosphite is excreted in the urine without further oxidation to

phosphate. Aluminum does not appear to be absorbed to a significant extent from 

the gastrointestinal tract.

8. Metabolite toxicology. There are no metabolites of toxicological concern. 

The tolerances are established for the parent only, that is fosetyl-al.

9. Endocrine disruption. No evidence of estrogenic or androgenic effects were 

noted in any study with fosetyl-al. No adverse effects on mating or fertility indices 

and gestation, live birth, or weaning indices were noted in a three-generation rat 

reproduction study at doses well above EPA's limit of 1,000 mg/kg/day. Therefore, 

Bayer CropScience concludes that fosetyl-al does not have any effect on the

endocrine system.

C. Aggregate Exposure

1. Dietary exposure. For all currently registered and proposed uses of fosetylal, acute and chronic food exposure for various subgroups of the U.S. population 

were estimated using the Dietary Exposure Evaluation Model with the Food 

Commodity Intake Database (DEEM-FCID) software Version 3.14. The DEEM 

analysis evaluated the individual food consumption as reported by respondents in 

the USDA’s National Health and Nutrition Examination Survey (NHANES) from 

2003 to 2008 nationwide continuing surveys of food intake by individuals. A Tier 1 

dietary assessment was evaluated based on established tolerances for all registered 

uses and 100% crop treated. For the proposed use on Bell Peppers and Non-Bell 
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Peppers, the proposed tolerance of 0.01 ppm was used in this assessment.

For acute risk, EPA found no appropriate endpoint attributable to a single dose 

exposure was identified in oral acute toxicity studies. Therefore, an acute RfD was 

not established and there was no expectation of acute risk. For chronic risk, EPA 

established the chronic reference dose (RfD) for fosetyl-al at 2.5 mg/kg/day. This 

reference dose (RfD) is based on a NOAEL of 250 mg/kg/day from a 2-year feeding 

study in dogs and the use of a 100 fold safety factor to account for interspecies and

intraspecies differences. Since no dermal or systemic toxicity was seen at the limit 

dose following repeated dermal applications in the 21-day toxicity study using rats, 

no endpoint value was calculated for short and intermediate-term exposure and 

risk. The Agency has concluded that fosetyl-al is unlikely to pose a carcinogenic 

hazard to humans. Therefore, a cancer exposure and risk assessment is not 

appropriate.

i. Food. For food, Tier 1 acute and chronic dietary exposure assessments

were performed. Acute exposure was not required since there was no acute 

reference dose established for this endpoint. The chronic exposure to fosetyl-al 

from food utilizes 4% of the chronic population adjusted dose (cPAD) for the U.S. 

population, 5% of the cPAD for infants, and 12% of the cPAD for children 1-2 years 

old, the subpopulation at greatest exposure. Based on the results of this 

conservative analysis, exposure to fosetyl-al residues from the proposed uses is

expected to be minimal. Bayer CropScience concludes that dietary exposure to 

fosetyl-al resulting from the currently registered uses and the proposed use of the 

product will be well below the Agency's level of concern.

ii. Drinking water. The potential for ground water and/or surface water 

contamination by fosetyl-al and its degradates is expected to be very low, in most 

cases, due to the rapid degradation of the compound in soil to non-toxic degradates 

under both aerobic and anaerobic conditions. Ground water estimations were 

based on “maximum loading” conditions using the SCI-GROW2 screening level 

model. The estimated ground water concentration was 0.006 ppb for all uses. 

Surface water estimations were based on environmental fate data and pesticide label 

application using the FIRST model. The estimated surface water concentrations

were 0.0086 ppb (peak) and 0.00003 ppb (annual mean) for proposed uses.

2. Non-dietary exposure. Fosetyl-al is currently registered for residential use 

on turf and ornamental plants. Chronic exposure is not expected for residential 

uses. There is also no expectation of acute risk. No appropriate endpoint 

attributable to a single dose exposure was identified in oral toxicity studies and 

consequently, an acute RfD cannot be calculated. No endpoint value is calculable for 

short- and intermediate-term exposure and a risk analysis cannot be performed

since no dermal or systemic toxicity was seen at the limit dose following repeated 

dermal applications in the 21-day toxicity study using rats. The Agency has 

previously concluded that fosetyl-al is unlikely to pose a carcinogenic hazard to 

human. Therefore, a cancer exposure and risk assessment is not appropriate. Thus, 
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Bayer CropScience concludes that the ornamental and turf uses do not add

significantly to the aggregate exposure for fosetyl-al.

D. Cumulative Effects. Effects associated with fosetyl-al are unlikely to be cumulative

with any other compound. The formation of calculi and bladder tumors in rats is 

the only significant toxicological effect observed with fosetyl-al. These effects were 

observed in rat only at a dose which not only exceeds estimated human exposure by 

several orders of magnitude but is in excess of the OPP dose limit for 

carcinogenicity studies. Therefore, an aggregate assessment based on common 

mechanisms of toxicity is not appropriate as exposure to humans will be well below

the levels producing calculi and bladder tumors in rats. Further, considering the 

rapid elimination of fosetyl-al in the rat metabolism study, any effects associated 

with fosetyl-al are unlikely to be cumulative with any other compound. Based on 

these reasons, only the potential risks of fosetyl-al are considered in the exposure

assessment.

E. Safety Determination

1. U.S. population. Chronic risk estimates associated with exposure to fosetylal in food and water are expected to be well below the Agency's level of concern. 

The Tier I chronic exposure analysis performed for all currently registered and 

proposed food uses show that exposure to fosetyl-al utilizes 4% of the cPAD for the 

U.S. population, 5% of the cPAD for infants, and 12% of the cPAD for children

1-2 years old, the subpopulation at greatest exposure. This analysis was conducted 

assuming 100% crop treated and tolerance level residue values for all crops. The 

contribution of fosetyl-al residues in surface water and ground water to chronic 

aggregate exposure was minimal. Therefore, Bayer CropScience concludes that

even when considering the potential incremental risk resulting from the proposed

use on bell and non-bell peppers, there is a reasonable certainty that no harm will 

result from aggregate exposure to fosetyl-al residues.

2. Infants and children. Infants and children. No indication of increased

susceptibility of rat or rabbit fetuses to in utero and/or postnatal exposure was

noted in the developmental and reproductive toxicity studies. The Agency has

previously determined that no additional safety factor to protect infants and

children is necessary for this product. Using the conservative assumptions

described in the exposure section above, aggregate exposure to fosetyl-al from

currently registered food uses will utilize 5% of cRfD for infants, and up to 12% of 

the cRfD for children 1-2 years old, the subpopulation at greatest exposure. Even 

when considering the potential incremental dietary risk resulting from the proposed 

use on bell and non-bell peppers, the potential for exposure to residues in drinking 

water and from non-dietary, non-occupational exposure, the aggregate exposure to 

fosetyl-al is expected to be well below the level of concern. Bayer CropScience 

concludes that there is a reasonable certainty that no harm will result to infants and 

children from aggregate exposure to fosetyl-al residues.
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F. International Tolerances

No maximum residue limits (MRLs) have been established for residues of fosetyl-al 

in or on bell or non-bell peppers by the Codex Alimentarius Commission (CODEX).