Document ID: EPA-HQ-OPP-2007-0303-0002
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2007-06-27T04:00Z

EPA Registration Division contact: Sidney Jackson, Phone (703) 305-7610

Interregional Research Project No. 4 (IR-4)

PP#: 7E7187

	EPA has received pesticide petitions (PP) [7E7187] from the IR-4
Project Hedquarters, 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
180.553 by establishing a tolerance for residues of the fungicide,
fenhexamid, (N-2,3-dichloro-4-hydroxyphenyl)-1-methyl cyclohexane
carboxamide) in or on the following raw agricultural commodity: 
asparagus at 0.02 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 FFDCA; however, EPA has not fully evaluated
the sufficiency of the submitted data at this time or whether the data
support granting of the petition.  Additional data may be needed before
EPA rules on the petition.

A. Residue Chemistry                                       

.  The qualitative nature of fenhexamid residues in plants is adequately
understood.

.  An adequate method for purposes of enforcement of the proposed
fenhexamid tolerances in plant commodities is available.  

3.  Magnitude of Residues.  The magnitude of residues for fenhexamid on
the proposed commodity is adequately understood.

B. Toxicological Profile

.  The acute oral toxicity study resulted in a lethal dose (LD50) of >
5,000 mg/kg for both sexes.  The acute dermal toxicity in rats resulted
in an LD50 of > 5,000 mg/kg for both sexes. The acute inhalation was
investigated in two studies in rats. Inhalation by aerosol at the
maximum technically possible concentration of 0.322 milligram/liter
(mg/L) resulted in no deaths or symptoms (LC50 > 0.322 mg/L). A dust
inhalation study resulted in an LC50 > 5.057 mg/L.  Fenhexamid was not
irritating to the skin or eyes after a 4-hour exposure period. The
Buehler dermal sensitization study in guinea pigs indicated that
fenhexamid is not a sensitizer. Based on these results fenhexamid
technical is placed in toxicity Category IV and does not pose any acute
dietary risks.

.  The potential for genetic toxicity of fenhexamid was evaluated in six
assays including two Ames tests, an HGPRT forward mutation assay, a
unscheduled DNA synthesis (UDS) assay, an in vitro chromosomal
aberration assay in Chinese hamster ovary (CHO) cells, and a
micronucleus test in mice. The compound was found to be devoid of any
mutagenic activity in each of these assays; including those tests that
investigated the absence or presence of metabolic activating systems. 
The weight of evidence indicates that fenhexamid technical does not pose
a risk of mutagenicity or genotoxicity.

.  

   	 i. In a 2-generation reproduction study (one mating per
generation), 30 Sprague-Dawley rats per sex per dose were administered
0, 100, 500, 5000, or 20000 ppm of fenhexamid in the diet. The
reproductive toxicity no observed adverse effect level (NOAEL) was
20,000 ppm. The neonatal NOAEL was 500 ppm, and the lowest observed
adverse effect level (LOAEL) was 5,000 ppm based on decreased pup body
weight. The parental toxicity NOAEL was 500 ppm based on lower adult
pre-mating body weights at 5,000 and 20,000 ppm, lower gestation body

weights at 20,000 ppm, lower lactation body weights at 5,000 and 20,000
ppm, and statistically significant changes in clinical chemistry
parameters, terminal body weights, and organ weights at 5,000 and 20,000
ppm. Based on this study, it is clear that the only toxic effects in the
neonates occurred at parentally toxic doses.

    	ii. In rats, fenhexamid was administered by gavage at doses of 0 or
1000 mg/kg for gestation days 6-15. No maternal toxicity,
embryotoxicity, fetotoxicity, or teratogenic effects were observed at
the limit dose of 1000 mg/kg/day. Therefore, the NOAEL for maternal and
developmental toxicity was 1000 mg/kg/day.

   	 iii. In rabbits, fenhexamid was administered by gavage at doses of
0,100, 300, and 1000 mg/kg for gestation days 6-18. Body weight gain and
feed consumption of the dams were reduced at the two top doses. One
abortion occurred in each of the top two dose groups and two total
resorptions occurred in the top dose group. The placental weights were
slightly decreased at 300 mg/kg/day and above. In the 1000 mg/kg/day
group, slightly decreased fetal weights and a slightly retarded skeletal
ossification were observed. All other parameters investigated in the
study were unaffected. Therefore, the NOAELs for maternal and
developmental toxicity were 100 mg/kg/day in this study.

    	Based on the 2-generation reproduction study in rats, fenhexamid is
not considered a reproductive toxicant and shows no evidence of
endocrine effects. The data from the developmental toxicity studies on
fenhexamid show no evidence of a potential for developmental effects
(malformations or variations) at doses that are not maternally toxic.
The NOAEL for both maternal and developmental toxicity in rats was 1000
mg/kg/day, and for rabbits the NOAEL for both maternal and developmental
toxicity was 100 mg/kg/day.

Subchronic toxicity.    

  	  i. Fenhexamid was administered in the diet to rats for 13 weeks at
doses of 0, 2500, 5000, 10000, and 20000 ppm. The NOAEL was 5000 ppm
(415 mg/kg/day in males and 549 mg/kg/day in females). Reversible liver
effects were observed at 10,000 ppm.

   	 ii. Fenhexamid was administered in the diet to mice for
approximately 14 weeks at doses of 0, 100, 1000, and 10000 ppm. The
NOAEL was 1000 ppm (266.6 mg/kg/day in males and 453.9 mg/kg/day in
females).  Increased feed and water consumption and kidney and liver
effects were observed at 10,000 ppm.

  	  iii. Fenhexamid was administered in the diet to beagle dogs for 13
weeks at doses of 0, 1000, 7000, and 50000 ppm. The NOAEL was 1000 ppm
(33.9 mg/kg/day in males and 37.0 mg/kg/day in females). Increased Heinz
bodies were observed at 7000 ppm. 

.  

    	i. Fenhexamid was administered in the feed at doses of 0, 500,
3500, or 25000 ppm to 4 male and 4 female beagle dogs per group for 52
weeks. A systemic NOAEL of 500 ppm (an average dose of 17.4 mg/kg/day
over the course of the study) was observed based on decreased food
consumption and decreased body weight gain at 25000 ppm, decreased
erythrocyte, hemoglobin and hematocrit values at 25000 ppm, increased
Heinz bodies at 3500 ppm and above, and a dose-dependent increase of
alkaline phosphatase at 3500 ppm and above. There were no treatment
related effects on either macroscopic or histologic pathology.

   	 ii. A combined chronic/oncogenicity study was performed in Wistar
rats. Fifty animals/sex/dose were administered doses of 0, 500, 5000, or
20000 ppm for 24 months in the feed. A further 10 animals/sex/group
received the same doses and were sacrificed after 52 weeks. The doses
administered relative to body weight were 0, 28, 292, or 1280 mg/kg/day
for males and 0, 40, 415, or 2067 mg/kg/day for females. The NOAEL in
the study was 500 ppm (28 mg/kg/day for males and 40 mg/kg/day for
females) based on body weight decreases in females at 5000 ppm and
above, changes in biochemical liver parameters in the absence of

morphological changes in both sexes at 5000 ppm and above, and caecal
mucosal hyperplasia evident at 5000 ppm and above.

    	The NOAEL in the chronic dog study was 17.4 mg/kg/day based on body
weight, hematology and clinical chemistry effects. The lowest NOAEL in
the 2-year rat study was determined to be 28 mg/kg/day based on body
weight, clinical chemistry parameters in the liver, and caecal mucosal
hyperplasia.

.  i.  A lactating goat was dosed at 10 milligrams (mg) 14C- fenhexamid
per kilograms/bodyweight on 3 consecutive days at 24-hour intervals.
Fenhexamid was rapidly and almost completely absorbed, distributed and
eliminated (24.9% in urine, 38.6% in feces, and 0.03% in milk). The
half-life of biliary-fecal elimination (primary pathway) was 0.5 hours.
The primary residues in tissues were unreacted fenhexamid, its
glucuronide derivative and the 4-hydroxy derivative.  

  ii.  Rats were administered radiolabeled fenhexamid (a single oral low
dose of 1 mg/kg, a single oral high dose of 100 mg/kg, or 15 repeated
low doses of 1 mg/kg/day).  Radiolabeled fenhexamid was rapidly
eliminated and tissue residues declined rapidly.  After 48 hours the
total radioactivity residue in the body excluding the GI tract, was <
0.3% of the administered dose in all dose groups. Excretion was rapid
and almost complete with feces as the major route of excretion.
Approximately 62-84% of the recovered radioactivity was found in feces,
and 15-36% in urine within 48 hours post-dosing. Metabolite
characterization studies showed that the main components detected in
excreta were the unchanged parent compound (62-75%) and the glucuronic
acid conjugate of the parent compound (4-23%). The proposed major
pathway for biotransformation is via conjugation of the aromatic
hydroxyl group with glucuronic acid. Identification of radioactive
residues ranged from 88% to 99% and was independent of dose and sex.

. As the primary residues found in rats and goat were the parent
compound fenhexamid and its glucuronic acid conjugate, no additional
metabolite toxicology studies are warranted.

.  Fenhexamid has no endocrine-modulation characteristics as
demonstrated by the lack of endocrine effects in developmental,
reproductive, subchronic, and chronic studies.

C. Aggregate Exposure

.

.  Dietary exposure to fenhexamid is limited to the established
tolerances for residues of fenhexamid on grapes (at 4.0 ppm), raisins
(at 6.0 ppm), strawberries (at 3.0 ppm), almond nutmeat (at 0.02 ppm),
almond hulls (at 2.0 ppm), stonefruit except plum, prune, fresh,
post-harvest (at 10.0 ppm), plum, prune, dried (at 2.5 ppm); plum,
prune, fresh (at 1.5 ppm); pear (at 15 ppm), bushberries (at 5.0 ppm),
caneberries (at 20 ppm), pistachios (at 0.02 ppm); cucumber (at 2.0
ppm); fruiting vegetables, except non-bell peppers (at 2.0 ppm);
non-bell pepper (0.02 ppm):  kiwi, post-harvest (at 15.0 ppm); leafy
greens, except spinach (at 30.0 ppm); ginseng (at 0.3 ppm); pomegranate
(3.0 ppm); cilantro (30.0 ppm) and the proposed tolerances through this
petition for asparagus (0.02 ppm)

.  Review of the environmental fate data indicates that fenhexamid is
relatively immobile and rapidly degrades in the soil and water.
Fenhexamid dissipates in the environment via several processes. 
Therefore, a significant contribution to aggregate risk from drinking
water is unlikely.

.  There is no significant potential for non-occupational exposure to
the general public. The proposed uses are limited to agricultural and
horticultural use.

D. Cumulative Effects

	

Consideration of a common mechanism of toxicity is not appropriate at
this time since it has a unique mode of action.  Moreover, there is no
significant toxicity observed for fenhexamid. Even at toxicology limit
doses, only minimal toxicity is observed for fenhexamid. Therefore, only
the potential risks of fenhexamid are considered in the exposure
assessment.

E. Safety Determination

	

.  The percent of the cPAD utilized by all current uses (almonds,
bushberries, caneberries, cucumbers, fruiting vegetables (except
non-bell peppers), grapes, kiwifruits, leafy greens (except spinach),
pears, pistachios, raisins, stonefruits, strawberries) was estimated by
EPA to be 9.9% (Federal Register, September 26, 2003).  Arvesta
Corporation estimated the chronic dietary exposure to fenhexamid
resulting from the use on pome fruit, ginseng, pomegranate, non-bell
pepper (greenhouse transplant) and pomegranate using the DEEM-FCIDTM
software version as had the US EPA and assuming 100 % of the crop
treated and residues equal to the MRL.  The percent cPAD utilized by all
current and proposed uses was estimated to be 18%.    Therefore, the
estimates of dietary exposure indicate adequate safety margins for the
overall U.S. population.

. The percent of the cPAD utilized by all current uses (almonds,
bushberries, caneberries, cucumbers, fruiting vegetables (except
non-bell peppers), grapes, kiwifruits, leafy greens (except spinach),
pears, pistachios, raisins, stonefruits and strawberries) was estimated
by EPA to be 19.6% (infants < 1 year) and 21.8% (children 1 to 2 years)
(Federal Register, September 26, 2003). Arvesta Corporation estimated
the chronic dietary exposure to fenhexamid resulting from the use on
pome fruit, as above. There is no exposure to infants and children from
usind fenhexamid on ginseng, pomegranate, non-bell peppers and cilantro.
The percent cPAD utilized by all current and proposed uses was estimated
to be 61.5% (infants < 1 year) and 60.0% (children 1 – 6 years). 
Therefore, the estimates of dietary exposure indicate adequate safety
margins for children.  In assessing the potential for additional
sensitivity of infants and children to residues of fenhexamid, the
available developmental toxicity and reproductive toxicity studies and
the potential for endocrine modulation by fenhexamid were considered. 
Developmental toxicity studies in two species indicate that fenhexamid
does not impose additional risks to developing fetuses and is not a
teratogen. The 2-generation reproduction study in rats demonstrated that
there were no adverse effects on reproductive performance, fertility,
fecundity, pup survival, or pup development at non-maternally toxic
levels. Maternal and developmental NOAELs and LOAELs were comparable,
indicating no increase in susceptibility of developing organisms. No
evidence of endocrine effects was noted in any study. It is therefore
concluded that fenhexamid poses no additional risk for infants and
children and no additional uncertainty factor is warranted.

F. International Tolerances

 tomato tolerances are in effect in France, Germany, Greece, Italy,
Slovenia, Spain, Turkey (1 ppm) and other EU countries (2 ppm).  Kiwi
tolerances are as follows:  Greece, Italy and Slovenia (10 ppm). 
Stonefruit tolerances already exist in the USA for pre-harvest
applications as well as in Canada (6 ppm), Austria (cherry, 5 ppm; plum,
2 ppm); Belgium (cherry, 5 ppm); Germany and Slovenia (cherry, 5 ppm;
peach and plum, 2 ppm), Italy (cherry, 5 ppm; apricot, peach and plum, 2
ppm); Japan (peach, 1 ppm), Switzerland (cherry, 2 ppm) and the UK
(plum, 1 ppm) and other EU countries (peach and plum, 1 ppm; cherry, 5
ppm).

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