Document ID: EPA-HQ-OPP-2014-0749-0002
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2016-01-15T05:00Z

Interregional Research Project Number 4 (IR-4)

4E8312

	EPA has received a pesticide petition (4E8312) from Interregional
Research Project Number 4 (IR-4), 500 College Road East, Princeton, NJ
08540 requesting, 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 tolerances for residues of clofentezine in or on the raw
agricultural commodities avocado at 0.3 parts per million (ppm); papaya
at 0.3 ppm; fruit, pome, group 11-10 at 0.5 ppm; cherry, subgroup 12-12A
at 1.0 ppm; peach, subgroup 12-12B at 1.0 ppm; and fruit, small, vine
climbing, except fuzzy kiwifruit, subgroup 13-07F at 1.0 ppm.  Upon the
approval of the aforementioned tolerances, IR-4 proposes that the
existing tolerances for apple at 0.5 ppm; pear at 0.5 ppm; cherry at 1.0
ppm; nectarine at 1.0 ppm; peach at 1.0 ppm; and grape at 1.0 ppm be
removed as unnecessary.

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 qualitative nature of clofentezine residues in
plants is adequately understood. The metabolism of clofentezine has been
studied in three crops representative of the use pattern for APOLLO SC:
Apples (pome fruit), peaches (stone fruit), and grapes (vines/small
fruit). In each case, unchanged clofentezine was the major extractable
residue present. Non-extractable residues (fiber-bound) were negligible.
Minor amounts of 2-chlorobenzonitrile, the major photo-degradation
product, were detected, predominantly on the fruit surface. Dissipation
of this component may be a significant route in the degradation of
clofentezine on the surface of these crops. The nature of the residue in
grapes, and in all the other registered crops, is therefore adequately
understood. The residue of concern is the parent, clofentezine.

	2. Analytical method. An adequate method for purposes of enforcement of
the proposed clofentezine tolerance is available. An independent method
validation was successfully completed, and the method was found
acceptable. An extensive database of method validation data using this
method on various crop commodities is available. The Limit of
Quantitation (LOQ) and Minimum Detection Limit (MDL) were determined to
be 0.01 ppm and 0.003 ppm, respectively. The method was forwarded to FDA
for inclusion in PAM-II

	3. Magnitude of residues. Adequate crop field trial data are available
for clofentezine in/on almonds, peaches, nectarines, persimmons, and
grapes following application of a SC formulation containing 0.25 lb
ai/A. The established tolerances range from 0.02 ppm in walnuts to 5.0
ppm in almond hulls (40 CFR §180.446). The magnitude of residues for
the proposed tolerance is adequately understood. The results demonstrate
that the maximum residue of clofentezine in or on avocado was 0.0305
ppm, measured 133 to 140 days after application (0.25 pounds active
ingredient (lb a.i.)/acre).

B. Toxicological Profile

	1. Acute toxicity.  Clofentezine has a relatively low degree of acute
toxicity and irritation potential. It is classified as toxicity category
III for oral, dermal and inhalation toxicity, and toxicity category IV
for eye and skin irritation. The acute oral lethal dose (LD 50) of
clofentezine was determined to be 5,200 milligrams/kilograms (mg/kg) in
rats and mice, 3,200 mg/kg in hamsters, and 2,000 mg/kg in beagle dogs.
The acute rat dermal LD 50 was 2,100 mg/kg. Clofentezine is considered
to be practically non-irritating to eyes and skin but is considered to
be a week skin sensitizer in the guinea pig maximization assay.

	2. Genotoxicty. No evidence of genotoxicity was noted in a battery of
in vitro and in vivo studies. Studies submitted included Ames Salmonella
and mouse lymphoma gene mutation assay, a mouse micronucleus assay, a
rat dominant lethal assay, and a gene conversion and mitotic
recombination assay in yeast. Therefore, the registrant concludes that
clofentezine has no potential to induce genotoxicity.

	3. Reproductive and developmental toxicity. A multigeneration rate
reproduction study was conducted at dietary concentrations of 0, 4, 40,
and 400 ppm. The parental no observed adverse effect level (NOAEL) was
40 ppm based on slightly reduced body weights, increased liver weights
and hepatocellular hypertrophy at 400 ppm. No treatment-related
reproductive effects were noted at any dose level.

In a rat developmental toxicity study, clofentezine was administered by
gavage at dose levels of 0, 320, 1, 280 and 3,200 mg/kg/day during
gestation days 6 to 20. Evidence of maternal toxicity was noted at 3,200
mg/kg/day and consisted of decreased weight gain, increased liver
weights and centrilobular hepatocellular enlargement. No developmental
effects were observed at any dose level.

In a rabbit developmental toxicity study, clofentezine was administered
by gavage at dose levels of 0, 250, 1,000 and 3,000 mg/kg/day during
gestation days 7 to 28. Slight maternal toxicity (decreased maternal
food consumption and weight gain) and a slight decrease in fetal weight
were noted at 3,000 mg/kg/day. Thus, the NOAEL was considered to be
1,000 mg/kg/day for both maternal and developmental effects.

	4. Subchronic toxicity. In a preliminary 90-day feeding study designed
to select a suitable high dose level for a subsequent chronic rate
study, clofentezine was administered to rats at dietary concentrations
of 0, 3,000, 9,000 and 27,000 ppm. A significant reduction in weight
gain was noted at 9,000 and 27,000 ppm. In addition, a marked,
dose-related hepatomegaly and centrilobular hepatocyte enlargement was
noted in all treatment groups.

In a subsequent 90-day feeding study, clofentezine was administered to
rats at dietary concentrations of 0, 40, 400, and 4,000 ppm. Slightly
reduced weight gain, alterations in several clinical pathology
parameters, increased liver, kidney and spleen weights, and
centrilobular hepatocyte enlargement were noted at 400 and/or 4,000 ppm.
Thus, 40 ppm (2.8 mg/kg/day) was considered to be the NOAEL for this
study.

Clofentezine was administered to beagle dogs for 90 days at dietary
concentrations of 0, 3,200, 8,000 and 20,000 ppm. Increased liver
weights were noted at all dose levels but no histopathological changes
nor any other treatment-related effects were observed.

	5. Chronic toxicity. In a 12-month feeding study, clofentezine was
administered to beagle dogs at dietary concentrations of 0, 50, 1,000,
and 20,000 ppm. An increase in adrenal and thyroid weights, as well as
moderate hepatotoxicity consisting of minimal periportal hepatocyte
enlargement with cytoplasmic eosinophilia, hepatomegaly and increased
plasma cholesterol, triglycerides and alkaline phosphatase levels, were
noted at 20,000 ppm. Evidence of slight hepatotoxicity was also noted at
1,000 ppm. Thus, the NOAEL for this study was considered to be 50 ppm
(1.25 mg/kg/day).

In a 27-month feeding study, clofentezine was administered to rats at
dietary concentrations of 0, 10, 40, and 400 ppm. Effects noted at 400
ppm were limited to the liver and thyroid, primarily of males, and
consisted of increased liver weights, a variety of microscopic liver
lesions (centrilobular hepatocyte hypertrophy and vacuolation, focal
cystic hepatocellular degeneration and diffuse distribution of fat
deposits), increased serum thyroxine levels, and a slight but
statistically significant increase in the incidence of thyroid
follicular cell tumors. The NOAEL was considered to be 40 ppm (2
mg/kg/day).

Clofentezine was not oncogenic to mice when administered for 2 years at
dietary concentrations of 0, 50, 500, and 5,000 ppm. Decreased weight
gain, increased liver weights, and increased mortality were noted at
5,000 ppm. An increased incidence of eosinophilic or basophilic
hepatocytes was noted at 5,000 ppm, and possibly 500 ppm.Show citation
box

Numerous studies were conducted to investigate the mechanism for the
increased incidence of male thyroid follicular tumors that was observed
in the chronic rat study. These studies suggest that the tumors may have
been caused by increased thyroid stimulating hormone (TSH) levels,
which, in turn, resulted from clofentezine's liver toxicity, and were
not attributable to a genotoxic mode of action.

	6. Animal metabolism. The metabolism, tissue distribution and excretion
of clofentezine have been evaluated in a number of species. In all
species, almost all of the administered dose was recovered within 24 to
48 hours after treatment, primarily via the feces. The major route of
metabolism was found to be ring hydroxylation, sometimes preceded by the
replacement of a chlorine atom with a methyl-thio group. Blood and
tissue levels in the fetuses of pregnant rats that had been treated with
clofentezine were much lower than the levels found in the mother,
indicating that clofentezine does not readily pass across the placenta.
In addition, less than 1% of the administered dose was absorbed through
the skin of rats following a 10-hour exposure to the end use formulation
of clofentezine, APOLLO SC.

Following oral dosing of a cow and three goats with 14C-labeled
clofentezine, the residue in milk was identified as a single metabolite,
4-hydroxyclofentezine. Similarly, 4-hydroxyclofentezine has been shown
to be the only metabolite present in fat, liver, and kidney. No
unchanged clofentezine or other metabolites were found. Therefore, the
nature of the residue in animals is adequately understood. The residues
of concern in ruminant commodities and milk are the combined residues of
the parent, clofentezine, and the 4-hydroxyclofentezine metabolite.

	7. Metabolite toxicology. There are no metabolites of toxicological
concern and therefore, no metabolites need to be included in the
tolerance expression and require regulation.

	8. Endocrine disruption. Except for the thyroid mechanistic studies
mentioned above, no special studies have been conducted to investigate
the potential of clofentezine to induce estrogenic or other endocrine
effects. However, the standard battery of required toxicity studies has
been completed. These studies include an evaluation of the potential
effects on reproduction and development, and an evaluation of the
pathology of the endocrine organs following repeated or long-term
exposure. Repeated dose studies are generally considered to be of
substantial value as a means for detection of any endocrine effects.
However, with the exception of a slightly increased incidence of thyroid
tumors in male rats, no such effects were noted in any of the repeated
dose toxicity studies with clofentezine. The male rat is known to be
much more susceptible than humans to the carcinogenic effects resulting
from thyroid hormone imbalance and/or increased levels of TSH.
Therefore, the alterations in thyroid hormone and subsequent thyroid
pathological changes, which have been noted following administration of
high doses of clofentezine, are considered to be of minimal relevance to
human risk assessment, particularly considering the low levels of
clofentezine to which humans are likely to be exposed.

C. Aggregate Exposure

	1. Dietary exposure. The chronic dietary exposure estimates from food
and drinking water do not exceed HED’s level of concern. The cancer
dietary exposure estimates from food and drinking water result in a
cancer risk estimate of 2.8 x 10-7.

Tolerances for bean, snap, succulent, dry, seed; for vegetable,
fruiting, group 8; for fruit, pome, group 11; for cherry; and for fruit,
stone, group 12, except cherry have previously been established and the
updates to the crop grouping is not likely to influence assessment
calculations. As avocado is considered minor crops, contribution from
these sources is not likely to have significant impact on this
assessment. 

	i. Food. Clofentezine chronic and cancer dietary risk assessments were
previously conducted using the Dietary Exposure Evaluation Model
DEEM-FCID™, Version 3.16 which uses food consumption data from the
USDA’s NHANES/WWEIA from 2003-2008. A description can be found the
June 6, 2013 Human Health Risk Assessment (PC Code: 125501; Decision
No.: 464564; DP Barcode: D401611). 

	ii. Drinking water. There are no monitoring data currently available
for clofentezine or its residues of concern in drinking water. Estimated
drinking water concentrations (EDWCs) were generated by the
Environmental Fate and Effects Division (EFED) using computer modeling
methods. Tier II EDWCs were generated to support clofentezine use on
almonds, apples, Christmas trees, nectarines, containerized plants,
peaches, pears, persimmons, pecans, and walnuts (R. Parker; D404287;
08/03/2012). The surface water EDWCs are based on the USEPA Pesticide
Root Zone Model (PRZM) and Exposure Analysis Modeling System (EXAMS)
using the EXPRESS shell. Estimated groundwater EDWCs were calculated
using the screening model SCI-GROW (Screening Concentrations in Ground
Water, version 2.3, 07/29/03). The highest surface water EDWCs values
are 7.59 ppb (1-in-10 year acute) and 0.062 ppb (1-in-10 year annual
average). The SCI-GROW groundwater concentration is 0.04 ppb. 

	2. Non-dietary exposure. There are currently no registered residential
uses associated with clofentezine; therefore, a
residential/non-occupational exposure assessment is not required. As a
result, the clofentezine aggregate risk assessment includes only dietary
exposure (food and water).

D. Cumulative Effects Unlike other pesticides for which EPA has followed
a cumulative risk approach based on a common mechanism of toxicity, EPA
has not made a common mechanism of toxicity finding as to clofentezine
and any other substances. For the purposes of this assessment,
therefore, EPA has not assumed that clofentezine has a common mechanism
of toxicity with other substances.

E. Safety Determination

	1. U.S. population. An acute dietary exposure assessment was not
performed as no appropriate endpoints were identified from the available
clofentezine toxicity studies for the acute dietary scenario. A somewhat
refined chronic dietary exposure assessment was previously performed
that directly incorporated potential drinking water residues. The
estimated exposure to the general U.S. population resulted in an
estimated risk of <1% of the chronic population adjusted dose (cPAD).

	2. Infants and children. The estimated exposure to the highest
population subgroup (children 1 < 2 years old) resulted in an estimated
risk of <1% of the chronic population adjusted dose (cPAD).

F. International Tolerances At present, no Canadian, Mexican, or CODEX
maximum residue limits (MRLs) are established for clofentezine on
avocado.

Codex maintains a clofentezine MRL of 0.5ppm set on “stone fruit”
which could impact sweet and tart cherries.

The tolerance for Fruit, small, vine climbing, except fuzzy kiwifruit,
subgroup 13-07F, is set at 1.0ppm. This does not harmonize with the
2.0ppm Codex tolerance. We would like to keep the tolerance at 1.0ppm
because several countries including Japan and Korea also maintain a
1.0ppm tolerance and it would create export issues were the tolerance
changed.

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