Document ID: EPA-HQ-OPP-2014-0540-0002
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2014-11-07T05:00Z

MacroButton macIb01 i  

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.   SEQ CHAPTER \h \r 1 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.   SEQ CHAPTER \h \r 1 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 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 low-temperature 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.    SEQ CHAPTER \h \r 1   SEQ CHAPTER \h \r 1 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.   SEQ CHAPTER \h \r 1   SEQ CHAPTER \h \r 1 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-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.   SEQ CHAPTER \h \r 1   SEQ CHAPTER \h \r 1  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 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 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.   SEQ CHAPTER \h \r 1   SEQ CHAPTER \h \r 1 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.   SEQ CHAPTER \h \r 1 For all currently registered
and proposed uses of fosetyl-al, 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 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.   SEQ CHAPTER \h \r 1   SEQ CHAPTER \h \r 1
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, Bayer CropScience
concludes that the ornamental and turf uses do not add significantly to
the aggregate exposure for fosetyl-al.

D. Cumulative Effects.   SEQ CHAPTER \h \r 1   SEQ CHAPTER \h \r 1
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.   SEQ CHAPTER \h \r 1 Chronic risk estimates
associated with exposure to fosetyl-al 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.   SEQ CHAPTER \h \r 1 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.

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).

 PAGE   

 PAGE   8