Document ID: EPA-HQ-OPP-2006-0744-0002
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2006-11-22T05:00Z

COMPANY FEDERAL REGISTER DOCUMENT SUBMISSION TEMPLATE  (7/1/2006)

EPA Registration Division contact: Tony Kish, PM 22  (703)308-9443

 

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TEMPLATE:

E.I. du Pont de Nemours and Company

PP No. (to be assigned)

	EPA has received a pesticide petition (PP No. to be assigned) from the
Interregional Research Project No. 4 (IR-4), 681 U.S. Highway #1 South,
North Brunswick, New Jersey  08902-3390, 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 180.587 by establishing a tolerance for
residues of the fungicide famoxadone in or on the raw agricultural
commodity Caneberries at 11 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 the 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 plant metabolism of famoxadone is adequately understood in 3
distinct crops to support these tolerances: tomatoes, potatoes, and
grapes. These studies showed no significant metabolites  (all < 10%
total radioactive residue (TRR)) in the RACs (tubers, tomato fruit, and
grape berries). The only significant residue in any of the studies was
the parent compound, famoxadone, occurring primarily as surface residues
(grape berries, and tomato fruit). No residues were detected in potato
tubers. Thus, the proposed tolerance expression is for the parent
compound, famoxadone (DPX-JE874) only.

 

	2. Analytical method. 

An analytical enforcement method is available for determining famoxadone
plant residues in or on potatoes, cucurbit vegetables (cucumbers,
melons, and squash), fruiting vegetables (tomatoes, peppers), and head
lettuce using gas-liquid chromatography (GC) with nitrogen phosphorus
detection (NPD). The method is applicable to high and medium moisture,
oily and non-oily crops and related matrices. The limit of quantitation
(LOQ) is 0.02 ppm.

    

The analytical enforcement for use on tomato processed fractions and
also the RAC, tomato, utilizes column switching liquid chromatography
with ultraviolet (UV) detection. The LOQ is 0.02 ppm.

     

The LOQ in each method allows monitoring of crops with famoxadone
residues at or above the levels proposed in these tolerances.

	3. Magnitude of residues. 

Caneberries

Magnitude of residue data were collected from field trials conducted in
Washington (region 12), Oregon (region 12), California (region 10) and
Canada (regions 5 and 12).  Residues of famoxadone ranged from 0.41 to
6.6 ppm.

B. Toxicological Profile

	1. Acute toxicity.  

A battery of acute toxicity tests on technical famoxadone places it in
the following Toxicity Categories:

Oral LD50		Rat		> 5000 mg/kg				Category IV

Dermal LD50		Rabbit		>2000 mg/kg				Category III

Inhalation LC50	Rat		>5.3 mg/L				Category IV

Eye irritation		Rabbit		Moderately irritating			Category  III

Dermal irritation	Rabbit		Moderately irritating			Category  III

Dermal sensitization	Guinea Pig	Not a Sensitizer			

In an acute neurotoxicity test, famoxadone was not neurotoxic to rats. 
The no observed adverse effect level (NOAEL) was 1,000 mg/kg in males,
based on systemic toxicity at 2,000 mg/kg.  The NOAEL in females was
2,000 mg/kg, the highest dose tested (HDT).

	2. Genotoxicty. 

Famoxadone was tested in a battery of assays to evaluate genotoxicity
and chromosome aberrations with the following results. Based on the
weight-of-evidence, famoxadone is not considered to be genotoxic or
clastogenic.

Bacterial gene mutation           		Salmonella and E. Coli    	Negative

Mammalian gene mutation in vitro  	CHO/HGPRT           		Negative

Mammalian chromosome aberrations	 Human Lymphocytes		Positive without
activation

in vitro							Negative with activation

Mammalian chromosome aberrations 	Mouse micronucleus  		Negative

in vivo

Unscheduled DNA synthesis in vitro 	Primary rat hepatocytes	Negative

Unscheduled DNA synthesis in vivo 	Primary rat hepatocytes 	Negative

	3. Reproductive and developmental toxicity. 

The results of a series of studies indicated that there were no
reproductive or developmental hazards associated with famoxadone.

    

In a 2-generation rat reproduction study, the NOAEL for both adults and
offspring was 200 ppm (11.3-17.5 mg/kg/day depending on gender and
generation) based on clinical signs, decreased body weights, effects on
nutritional parameters, and liver toxicity in adults and decreased
weight of pups.  Effects on pups occurred only at a maternal effect
level and may have been secondary to altered growth and nutrition in the
dams.  There were no effects on reproduction (mating, fertility,
reproductive organs) up to and including the highest concentration
tested, 800 ppm (44.7-71.8 mg/kg/ day). 

In studies conducted to evaluate developmental toxicity potential,
famoxadone was neither teratogenic nor uniquely toxic to the conceptus. 
In a rat developmental toxicity study, the maternal NOAEL was 250
mg/kg/day based on decreased weight gain and food consumption at 500
mg/kg/day.  The fetal NOAEL was 1,000 mg/kg/day, the HDT.  In rabbits,
the maternal and developmental NOAEL was 350 mg/kg/day based on weight
loss, decreased food consumption, clinical signs, fecal impactions, and
subsequent abortion, resorptions, and post implantation loss at 1,000
mg/kg/day.  These effects were considered related to the physical
properties of the dosing solution at the highest concentration.

	4. Subchronic toxicity. 

Subchronic (90-day) feeding studies were conducted with rats, mice, and
dogs. In addition, the following subchronic feeding studies were
conducted: A 90-day in rats to evaluate neurotoxicity and 28-day feeding
studies in rats and mice to evaluate immunotoxicity.  A 28-day dermal
study was conducted in rats.

    

In a 90-day feeding study in rats, EPA considered the NOAEL to be 50 ppm
(3.3 and 4.2 mg/kg/day in male and females, respectively) based on
changes in weight gain, food consumption and mild hemolytic anemia at
200 ppm (13 and 17 mg/kg/day, respectively).  In a subchronic
neurotoxicity study in rats, there was no evidence of neurotoxicity up
to and including the highest concentration tested, 800 ppm (46.9 and
59.3 mg/kg/day for males and females, respectively).  The NOAEL for
systemic toxicity was 200 ppm (11.7 and 14.4 mg/kg/day in males and
females, respectively) based on body weight and nutritional effects at
800 ppm.

    

In mice, the subchronic NOAEL was 350 ppm (62.4 and 79.4 mg/kg/day in
males and females, respectively), based on hepatotoxicity and mild
anemic effects at higher concentrations.

    

In a 90-day feeding study in dogs, the NOAEL was 40 ppm (1.3 mg/kg/day)
in males.  In females, 40 ppm (1.4 mg/kg/day) was a marginal effect
level for lens lesions.  Effects observed at 300 ppm (10 mg/kg/day) or
higher included lens lesions, body weight and nutritional effects,
hemolytic anemia, and hyperkalemia with associated clinical signs. 

    

Famoxadone was tested in 28-day feeding studies in rats and mice,
designed to evaluate immunotoxicity.  There was no evidence of
immunotoxicity in either species.  The NOAEL for systemic toxicity was
200 ppm (14 and 16 mg/kg/day in males and females, respectively) in rats
and 2,000 ppm (417 mg/kg/day) in female mice.  There were no effects in
males at 7000 ppm (1186 mg/kg/day), the HDT.  

    

In a 28-day repeated dose dermal study, the NOAEL for male rats was 250
mg/kg/day based on changes in liver enzymes at 500 mg/kg/day.  The NOAEL
for female rats was 1,000 mg/kg/day, the HDT.

	5. Chronic toxicity. 

Chronic studies with famoxadone were conducted on rats, mice, dogs, and
monkeys to determine oncogenic potential and/or chronic toxicity of the
compound.  Effects generally similar to those observed in the 90-day
studies were seen in the chronic studies.  

There was no evidence of carcinogenicity in the lifetime feeding studies
in rats and mice.  In rats, the chronic NOAEL was 200 ppm (8.4
mg/kg/day) in male rats and 40 ppm (2.2 mg/kg/day) in female rats based
on body weight changes, nutritional effects, slight hemolytic anemia,
and mild hepatotoxicity at higher dietary concentrations.  In mice, the
chronic NOAEL was 700 ppm (96 and 130 mg/kg/day for males and females,
respectively) based on slight hepatotoxicity in males and females and
amyloidosis in females at 2,000 ppm (274 and 392 mg/kg/day in males and
females, respectively).

    

In a 1-year feeding study in dogs, the only effect observed was lens
lesions at 300 ppm (8.8 and 9.3 mg/kg/day for males and females,
respectively). The NOAEL for these lesions was 40 ppm (1.2 mg/kg/day in
both sexes).  In a 1-year gavage study, the NOAEL in cynomolgus monkeys
was 100 mg/kg/day in both males and females based on slight hemolytic
anemia in both sexes at the 1,000 mg/kg/day dose level. There were no
other effects observed at any level.  No eye lesions were found at any
dose level.

	6. Animal metabolism. 

Famoxadone was rapidly eliminated in the rat, primarily by fecal
excretion and to a lesser extent in the urine.  Absorption and
metabolism of famoxadone was limited.  There was no accumulation in
organs or tissues.  Parent famoxadone was the major component recovered.
Hydroxylated parent compound and sulfated cleavage products were also
recovered to a much lesser extent.

	7. Metabolite toxicology. 

There are no metabolites of toxicological significance to mammals.

	8. Endocrine disruption. 

Chronic, lifespan, and multi-generational bioassays in mammals and acute
and subchronic studies on aquatic organisms and wildlife did not reveal
endocrine effects. Any endocrine-related effects would have been
detected in this definitive array of required tests. The probability of
any such effect due to agricultural uses of famoxadone is negligible.

C. Aggregate Exposure

Famoxadone is a fungicide currently registered in the United States for
use on cucurbits, head lettuce, peppers, potatoes and tomatoes, with
proposed uses on grapes and hops submitted previously. This tolerance
petition proposes the following new uses in the United States:
caneberries. There are no residential uses.

	1. Dietary exposure.

For the chronic dietary endpoint, EPA selected the marginal effect level
of 1.4 mg/kg/day for lens lesions from the subchronic dog study and
added an additional uncertainty factor of 10x for no NOEL and use of a
subchronic study.  With inter- and intraspecies factors the total
uncertainty factor is 1000x for a chronic RfD of 0.0014 mg/kg/day.  No
acute dietary endpoint was selected since no effects attributable to a
single oral exposure were identified in toxicology studies with
famoxadone.

	i. Food. 

Chronic Dietary Exposure Assessment 

Chronic dietary exposure, resulting from the proposed use of famoxadone
on cucurbit vegetables, fruiting vegetables, head lettuce, potatoes,
grapes, hops, and caneberries is well within acceptable limits for all
sectors of the population. The chronic module of the Dietary Exposure
Evaluation Model with the Food Commodity Intake Database (DEEM-FCIDTM),
Exponent, Inc., 2003, Version 2.14 was used to conduct the assessment
with a chronic RfD of 0.0014 mg/kg/day. The analysis employed
overall-mean field-trial values and employed crop treated percentages
based on 5 year annual averages for currently labeled crops and
projections of the 5 year annual averages for proposed crops.

    

For the general U.S. population, the estimated chronic dietary exposure
to famoxadone is 0.000146 mg/kg/day, corresponding to 10% of the chronic
RfD. The exposure for the potentially most highly exposed subgroup in
the population, adults 20-49 years, is 0.000188 mg/kg/day or 14% of the
chronic RfD. The table below lists the results of this analysis, which
indicate large margins of exposure for each population subgroup from
chronic exposure to famoxadone. Since the %RfD for each population
subgroup are well below 100%, the chronic dietary safety of famoxadone
clearly meets the standard of reasonable certainty of no harm.

Results of Chronic Dietary Analysis with Famoxadone

 PRIVATE  

Population Group	Maximum Dietary Exposure (mg/kg/day)	

% RfD

U.S. population	0.000146	10

All infants (<1 yr.)	0.000027	2

Children (1-2 yr.)	0.000158	11

Children (3-5 yr.)	0.000145	10

Children (6-12 yr.)	0.000101	7

Youth (13-19 yr.)	0.000094	7

Adults 20-49 years	0.000188	14

Adults 50+ years	0.000117	8

Females 13-49 years	0.000120	9

                                                           			

Acute Dietary Exposure

Based on the results of toxicity studies, including an acute
neurotoxicity study, no endpoint attributable to a single oral dose of
famoxadone was identified.

	ii. Drinking Food.

Famoxadone is highly unlikely to contaminate ground water resources due
to its immobility in soil, low water solubility, high soil sorption,
moderate soil half-life, and resulting low ground and surface water
exposure.  Chronic drinking water exposure analyses were calculated
using EPA screening concentration models for ground water (SCI-GROW ver.
2.3) and surface water (EXPRESS ver. 1.00.00.12 containing PRZM-EXAMS). 
Results indicate that a reasonable certainty exists that famoxadone
residues in drinking water will not contribute significantly to the
aggregate human risk.

The predicted chronic concentration for famoxadone under worst-case
conditions was 0.006459 parts per billion (ppb) in ground water and
0.0342 ppb in surface water.  When the higher surface water
concentration was included in the dietary risk assessment there was
little change from the food only chronic risk assessment; the following
table provides the results.

Results of Chronic Dietary Analysis Including Water with Famoxadone

 PRIVATE  

Population Group	Maximum Dietary Exposure (mg/kg/day)	

% RfD

U.S. population	0.000147	11

All infants (<1 yr.)	0.000029	2

Children (1-2 yr.)	0.000159	11

Children (3-5 yr.)	0.000146	10

Children (6-12 yr.)	0.000101	7

Youth (13-19 yr.)	0.000094	7

Adults 20-49 years	0.000189	14

Adults 50+ years	0.000117	8

Females 13-49 years	0.000121	9

Since the %cRfD for each population subgroup is well below 100%, the
chronic dietary safety of famoxadone, including the contribution of
drinking water, clearly meets the standard of reasonable certainty of no
harm.

	2. Non-dietary exposure.

Famoxadone products are not labeled for residential non-food uses,
thereby eliminating the potential for residential exposure.
Non-occupational, non-dietary exposure for famoxadone has not been
estimated because the proposed products are limited to commercial crop
production. Therefore, the potential for non-occupational exposure is
insignificant.

D. Cumulative Effects

 EPA's consideration of a common mechanism of toxicity is not necessary
at this time because there is no indication that toxic effects of
famoxadone should be cumulative with those of any other chemical.
Famoxadone is a member of a new class of fungicides that acts by
inhibition of mitochondrial respiration. Famoxadone's biochemical mode
of action on fungi and toxicological profile in animals appear to be
unique.

    

Given the distinct chemical, biological and toxicological profile,
famoxadone's low acute toxicity, absence of genotoxic, oncogenic,
developmental or reproductive effects and low exposure potential, the
expression of cumulative human health effects with any other natural or
synthetic pesticide is not anticipated.

E. Safety Determination

	1. U.S. population. 

Based on the completeness and reliability of the toxicity data and the
conservative exposure assessments, there is a reasonable certainty that
no harm will result from the aggregate exposure of residues of
famoxadone including all anticipated dietary exposure and all other
non-occupational exposures.  No additional safety factors are warranted.

	2. Infants and children.

Based on the completeness and reliability of the toxicity data, the lack
of toxicological endpoints of special concern, the lack of any
indication of greater sensitivity of children, and the conservative
exposure assessment, there is a reasonable certainty that no harm will
result to infants and children from the aggregate exposure to residues
of famoxadone from all anticipated sources of dietary and
non-occupational exposure. Accordingly, there is no need to apply an
additional safety factor for infants and children.

F. International Tolerances

1. EU

MRL's established for famoxadone are available at the following link:

http://europa.eu.int/comm/food/plant/protection/pesticides/index_en.htm

2. CODEX

MRL's for famoxadone were adopted as final (CXL) at the July 2005 CODEX
alimentarius meeting, however these MRL's have not yet been updated into
the database.  MRL's established for famoxadone will eventually be
available at the following link: 

http://faostat.fao.org/faostat/collections?hasbulk=0&subset=FoodQuality&
&language=EN

3. Canada

Famoxadone MRL's are established by Canada (finalized on April 20, 2005)
and are available in the link below:

http://www.pmra-arla.gc.ca/english/legis/maxres-e.html - proposedmrls 

Pesticide Petition for Tolerance                                        
                 	AGRICULTURAL COMMODITIES

for Famoxadone                                                          
                       Caneberries

Copyright by E.I. du Pont de Nemours and Company

Wilmington, DE 19880-0038 (July 2006)