Document ID: EPA-HQ-OPP-2007-0536-0002
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2007-08-22T04:00Z

PP#6E7074

Summary of Petition

	EPA has received a pesticide petition (PP 6E7074) from Interregional
Research Project Number 4 (IR-4), 500 College Road, Suit 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 180.421 by establishing a tolerance for residues of fenarimol
[alpha-(2-chlorophenyl)-alpha-(4-chlorophenyl)-5-pyrimidinemethanol] in
or on the raw agricultural commodity hop at 1.0 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 nature of the residue in fenarimol-treated hop has not been
directly determined.  Radioactive metabolism studies with apples and
cherries indicate that fenarimol is the only significant component of
the residue in apples and cherries. The residue of concern in hop is
fenarimol.

 Analytical methodologies used for hop are slight modifications of the
basic PAM II method for fenarimol (Method R039). Residues are extracted
with methanol. Aqueous sodium chloride (5%) is added and the extract is
partitioned with dichloromethane. Residues are cleaned up on a Florisil
or alumina column and detected by GC/ECD.  In hop samples, method
validation recoveries ranged from 72% to 94%, and the limit of detection
was 0.04 ppm. 	

.  Hop:  In 3 IR-4 residue trials, hop was treated 4 times at a rate of
0.22 lb ai/A per application and harvested 9-12 days after the last
application.  Residues of fenarimol up to 0.74 ppm in dried hop cones
were observed.

 Based on these results and for purposes of this petition, it is
appropriate to base the magnitude of total terminal residues and
proposed tolerance only on residues of the parent compound, fenarimol.

B. Toxicological Profile

.  The acute oral lethal dose (LD50) in the rat is 2,500 milligrams per
kilogram (mg/kg) and the acute dermal LD50 in the rabbit is >2,000
mg/kg. The inhalation lethal concentration (LC50) in the rat is >2.04
mg/liter of air, which is the highest obtainable respirable aerosol
concentration. Fenarimol produced no indications of dermal irritation in
rabbits or sensitization in the guinea pig. End use formulations of
fenarimol have similar low acute toxicity profiles.

Fenarimol tested negative in several assay systems for gene mutation,
structural chromosome aberration and other genotoxic effects. In a
micronucleus test in the mouse, fenarimol did produce a significant
increase in the percent of polychromatic erythrocytes with micronucleus
at 24 hours but not at 48 or 72 hours. Moreover, a second test run at a
higher dosage, which produced significant toxicity including death, was
unequivocally negative.

A developmental toxicity study in rabbits was negative for teratogenic
effects at all doses tested (0, 5, 10, and 35 mg/kg). A developmental
toxicity study in rats demonstrated hydronephrosis at 35 mg/kg (doses
tested were 0,5, 10, and 35 mg/kg). A second developmental toxicity
study in rats, with a postpartum evaluation, again demonstrated
hydronephrosis at 35 mg/kg. Maternal toxicity (decreased body weight)
was also observed at the 35 mg/kg/day dose level. The no observed effect
 level (NOEL) for hydronephrosis and maternal toxicity is 13 mg/kg.



Subchronic toxicity. NA 

A 2-year chronic toxicity and carcinogenicity study in rats fed diets
containing 0, 50, 130, or 350 ppm (equivalent to 2.5, 6.5, or 17.5
mg/kg/ day) resulted in a systemic NOEL of 130 ppm, equivalent to 6.5
mg/kg/day. An increase in fatty liver changes was observed in rats fed
diets containing 350 ppm. There were no carcinogenic effects observed
under the conditions of the study.

A second 2-year carcinogenicity study was conducted in rats fed diets
containing 0, 12.5, 25, or 50 ppm, equivalent to 0, 0.63, 1.25, or 2.5
mg/ kg/day. There was no apparent effect on  survival, which was reduced
in all treatment groups due to chronic respiratory disease. An increased
incidence of fatty changes in the liver was observed at the top dose
level of 50 ppm, and the NOEL was established as 25 ppm (1.2 mg/kg/day)
in this study. A third 2-year carcinogenicity study was conducted at the
same dose levels as above. The incidence of liver lesions was similar in
the treated and control groups;  thus the NOEL for liver effects in this
study was greater than 50 ppm (2.5 mg/kg/day).

A 2-year feeding study was conducted in mice fed diets containing
concentrations of 0, 50, 170, or 600 ppm, equivalent to 0, 7, 24.3, or
85.7 mg/kg/day.  The 600 ppm dose level was shown to increase liver
weight. There was no increase in cancer, and no toxicologically
significant treatment related effects were observed at any dose level.
The NOEL was determined to be 600 ppm (85.7 mg/kg/ day).

In a 1-year chronic toxicity study, dogs were fed diets containing 0,
1.25, 12.5, or 125 mg/kg/day.  The NOEL was 12.5 mg/kg/day based upon an
increase in serum alkaline phosphatase, increased liver weights, an
increase in p-nitroanisole o-demethylase activity, and mild hepatic bile
stasis at the high dose level (125 mg/kg/day).  Based on the chronic
toxicity data, the chronic Reference Dose (RfD) for fenarimol is
established at 0.0006 mg/kg/day. The RfD for fenarimol is based on a
2-year chronic feeding study in rats with a NOEL of 6.5 mg/kg/day and an
uncertainty factor of 1000.

For short-term (<35 day) risk assessments to females 13 - 50 years old,
the Agency selected a LOAEL of 35 mg/kg/day based upon decreased
fertility and dystocia in rats and an uncertainty factor of 3000.

. Metabolism studies conducted in rats show fenarimol is rapidly
metabolized and excreted. Major metabolic pathways were oxidation of the
carbinol-carbon atom, the phenyl rings and the pyrimidine ring.

. NA

.  In a 3-generation reproduction study with rats and in subsequent
special studies, fenarimol was determined to be a weak inhibitor of
aromatase. Rats dosed at 0, 12.5, 25 or 50 ppm (equivalent to 0, 0.625,
1.25 or 2.5 mg/ kg/day) demonstrated decreased fertility in males at 25
ppm and delayed parturition and dystocia in females at 25 and 50 ppm.
The NOEL for reproductive effects was 12.5 ppm (0.625 mg/kg/day). The
infertility effect in males is considered to be a species-specific
effect mediated by the inhibition of aromatase, an enzyme which
catalyzes the conversion of testosterone to estradiol. Estradiol plays
an essential role in the developmental and maintenance of sexual
behavior in rats.

Multigeneration reproduction studies in guinea pigs and mice were
negative for reproductive effects at the highest dose levels tested, 35
mg/kg/day and 20 mg/kg/day, respectively. A NOEL of 35 mg/kg/day for
reproductive effects relevant to humans was established based on the
NOEL from the multigeneration reproduction study in guinea pigs.

C. Aggregate Exposure

.  For the purposes of assessing the potential dietary exposure from use
on hop, an estimate of aggregate exposure is determined by basing the
TMRC from previously established tolerances and the proposed tolerance
on hop at 1.0 ppm while assuming that 100% of these crops have a residue
of fenarimol at the tolerance level.

Exposure of humans to residues could also result if such residues are
transferred to meat, milk, poultry or eggs.  Since there is no livestock
feed commodity associated with hop, there is no reasonable expectation
that measurable secondary residues of fenarimol will occur in meat,
milk, poultry or eggs under the terms of the proposed use.  Other
established tolerances for fenarimol on food or feed crops in the United
States are established under 40 CFR part 180.421.  The use of a
tolerance level and 100% of crop treated clearly results in an
overestimate of human exposure and a safety determination for use on hop
that is based on conservative exposure assessment.	

.  Based upon the available environmental studies conducted with
fenarimol wherein its properties show little potential for mobility in
soil and extremely rapid photolysis in water, there is no anticipated
exposure to residues of fenarimol in drinking water.

. The proposed uses on hop involve application of fenarimol to crops
grown in an agricultural environment. Thus, the potential for
non-occupational, non-dietary exposure to the general population is not
expected to be significant.

D. Cumulative Effects

There is no evidence that there is a common mechanism of toxicity with
any other chemical compound or that potential toxic effects of fenarimol
would be cumulative with those of any other pesticide chemical. Thus it
is believed that it is appropriate to consider only the potential risks
of fenarimol in its exposure assessment.

E. Safety Determination

.  It is concluded that aggregate exposure to fenarimol will utilize
less than 2% of the chronic RfD for the U.S. general population and less
than 14% of the acute RfD for females 13 - 50 at the 99.9 percentile
level.  EPA generally has no concern for exposures below 100% of the RfD
because the RfD represents the level at or below which daily aggregate
dietary exposure over a lifetime will not pose appreciable risks to
human health. It is concluded that there is a reasonable certainty that
no harm will result from aggregate exposure to fenarimol residues in or
on hop. 

. In assessing the potential for additional sensitivity of infants and
children to residues of fenarimol, data from developmental toxicity
studies in rats and rabbits and a multigeneration reproduction study in
the rat are considered. The developmental toxicity studies are designed
to evaluate adverse effects on the developing organism resulting from
pesticide exposure during prenatal development to one or both parents.
Reproduction studies provide information relating to effects from
exposure to the pesticide on the reproductive capability and potential
systemic toxicity of mating animals and on various parameters associated
with the well-being of offspring.

FFDCA section 408 provides that EPA may apply an additional safety
factor for infants and children in the case of threshold effects to
account for pre- and post-natal toxicity and the completeness of the
data base. Based on the current toxicological data requirements, the
data base for fenarimol relative to pre- and post-natal effects for
children is complete. Further, for fenarimol, the NOEL in the chronic
feeding study which was used to calculate the RID (6.5 mg/kg/day used by
EPA or 1.2 mg/kg/ day used by The World Health Organization) is already
lower than the NOELs from the developmental studies in rats and rabbits.

Concerning the multi-generation reproduction study, the effects on
reproduction are considered to be specific effect caused by aromatase
inhibition. The aromatase enzyme promotes normal sexual behavior in rats
and mice, but not in guinea pigs or primates, including humans. A NOEL
of 35 mg/kg/day for reproductive effects relevant to humans was
established based on the NOEL from the multigeneration reproduction
study in guinea pigs. In addition, a NOEL of 13 mg/kg/ day for
developmental effects was established based upon the NOEL from the
teratology study in rats. Therefore, it is concluded that an additional
uncertainty factor is not needed and that the RfD at 0.065 mg/kg/day is
appropriate for assessing risk to infants and children.

F. International Tolerances

 ADVANCE \d5 There is no Codex or national maximum residue level
established for fenarimol on hop.

 PAGE  5 

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