Document ID: EPA-HQ-OPP-2016-0049-0023
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2016-12-23T05:00Z

EPA REGISTRATION DIVISION - COMPANY NOTICE OF FILING OF PESTICIDE
PETITION  

EPA Registration Division (RD) Contact: [RD]

Docket ID Number: EPA-HQ-OPP-2016-0049

Interregional Research Project No.4 (IR-4)

Pesticide Petition Number: 6E8505

	EPA has received a pesticide petition (PP# 6E8505) from Interregional
Research Project No. 4, Rutgers, The State University of New Jersey, 500
College Road East, Suite 201 W, 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 a tolerance
for residues of the fungicide oxathiapiprolin,
1-[4-[4-[5-(2,6-difluorophenyl)-4,5-dihydro-3-isoxazolyl]-2-thiazolyl]-1
-piperidinyl]-2-[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]-ethanone,
in or on Cacao bean, bean at 0.10 parts per million (ppm), Cacao bean,
roasted bean at 0.15ppm, Cacao bean, cocoa powder at 0.15 ppm, Cacao
bean, chocolate at 0.15 ppm. 

EPA proposes to use the oxathiapiprolin/citrus residue data with a
proposed MRL tolerance of 0.06 ppm on citrus (RAC).  IR-4 is proposing
that the 0.06 ppm oxathiapiprolin citrus MRL be used to support a U.S.
oxathiapiprolin tolerance of 0.1 ppm on Cacao bean, bean and an
established use pattern on the Orondis and Orondis OD product labels in
the U.S.  The proposed MRL tolerance of 0.1 ppm on Cacao bean, bean is
conservative since there is a higher surface area to mass ratio in
citrus fruit (orange 7-8 cm wide; lemon 7-12 cm; grapefruit 10-15 cm) as
compared to cacao fruit (15.2 to 25.4 cm long and 7.6 to 10.2 cm in
diameter).  In addition, both of these commodities contain inedible
peels that are not directly consumed.  Because cacao beans are processed
into cocoa commodities, IR-4 also proposes oxathiapiprolin tolerances of
0.15 ppm for Cacao bean, roasted bean, 0.15 ppm for Cacao bean, cocoa
powder and 0.15 ppm for Cacao bean, chocolate (based on maximum
theoretical concentration factors, the ratio of the percent of dry
matter in the processes commodity to the percent of dry matter in the
RAC, given 40% dry matter for the cacao bean, 95% dry matter for the
roasted bean, 97% dry matter for cocoa powder and 99% dry matter for
chocolate).

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 support granting of the petition.
Additional data may be needed before EPA rules on the petition.

A. Residue Chemistry

	1. Plant metabolism. The metabolism of oxathiapiprolin is adequately
understood to support the proposed tolerances. Studies in grape, lettuce
and potato when treated at the label rates showed no significant
metabolites. The metabolism of oxathiapiprolin in plants was similar
regardless of the crop or the treatment regime. Oxathiapiprolin was the
principle residue in most crop fractions at various sampling points up
to crop maturity. The overall metabolism of oxathiapiprolin in rotated
crops (cereals, root vegetables, leafy vegetables) was consistent with
metabolism seen in the primary crops.

	2. Analytical method. Adequate analytical methodology, high-pressure
liquid chromatography with MS/MS detection, is available for enforcement
purposes.

	3. Magnitude of residues. Field trials to meet the United States
requirements were carried out in orchards (citrus). The trials covered a
wide range of locations, climates and soil types and the data obtained
reflect the commercial use of the oxathiapiprolin-containing products in
the major US crop growing regions.  The results of these field trials
substantiate oxathiapiprolin as the major residue at harvest in the crop
commodities. Oxathiapiprolin is likewise the relevant residue in
processed commodities.

B. Toxicological Profile

	1. Acute toxicity.  Based on EPA criteria, technical oxathiapiprolin is
classified with an overall Toxicity Category IV (Tox Cat IV). This
compound is considered a Tox Cat IV based on no observed for acute oral,
dermal or inhalation toxicity up to the OPPTS testing guidelines limit
dose levels tested. Oxathiapiprolin is not an eye or skin irritant and
it is not a dermal sensitizer. 

No evidence of neurotoxicity was observed in an acute neurotoxicity
study conducted with oxathiapiprolin in rats. The no-observed-effect
level (NOEL) and no-observed-adverse-effect-level (NOAEL) in an acute
neurotoxicity study where 2000 milligram (mg) oxathiapiprolin/kilogram
bodyweight (kg bw), which was the highest dose administered in the
study.

	2. Genotoxicty. Oxathiapiprolin was evaluated in a battery of in vitro
and in vivo genetic toxicology studies. Negative results were obtained
in all studies indicating that oxathiapiprolin does not cause genetic
damage and therefore, does not pose a mutagenic hazard.

	3. Reproductive and developmental toxicity. No effects on fertility
were observed in one- and two- generation reproduction studies in rats.
No effects on development were observed in developmental toxicity
studies in rats and rabbits. Slight delays in sexual maturation were
observed in male rats in the multi-generation reproduction studies, with
a NOAEL of 104 mg/kg bw/day. Decreases in offspring body weight were
also observed in the multi-generation reproduction studies at higher
dose levels.

	4. Subchronic toxicity. Short-term oral feeding studies with
oxathiapiprolin were conducted in rats, mice and dogs with durations of
up to 90 days. In addition, a 14 day oral gavage study (conducted as
part of early discovery) and a 28-day dermal study were performed. No
adverse effects were observed in any of these studies. In all cases, the
NOAELs were greater than or equal to 1000 mg/kg bw/day. Non–adverse
findings observed in these studies were limited to changes in organ
weights, clinical chemistry parameters and liver cytochrome P450
isozymes.

Oxathiapiprolin showed no evidence of immunotoxicity in a 28-day feeding
study in mice. Additionally, no indications of a potential for
oxathiapiprolin to affect the immune system were noted in the
subchronic/carcinogenicity studies with rats, mice or dogs. Based on
this, oxathiapiprolin does not appear to pose an immunotoxic hazard.

Neurotoxicity endpoints were included in the subchronic (90-day feeding)
study that tested up to 1096/1300 mg/kg bw/day in male/female rats. No
evidence of neurotoxicity was observed in the 90-day dietary toxicity
study in rats. There was also a lack of any treatment related clinical
signs indicative of potential neurotoxicity observed in the repeated
dose studies in mice or dogs.

	5. Chronic toxicity. Based on the results of chronic feeding studies in
rats and mice, oxathiapiprolin was not carcinogenic in either species.
No indications of chronic toxicity were observed in either study. A
one-year toxicity study was also conducted in dogs, with no
toxicologically relevant findings. Possible test substance-related
changes in organ weights and clinical chemistry parameters were
observed.

	6. Animal metabolism. [14C]Oxathiapiprolin was investigated in rats
after single low and high dose administration, and after multiple
treatments at low doses. At the low dose (10 mg/kg bw) absorption was
31-49%, and declined to 5.4-7.7% at the high dose (200 mg/kg bw). Peak
plasma concentrations occurred at 0.25-9.5 hours. Plasma 14C residue
concentrations showed steady-state kinetics in male and female rats
after multiple low does administrations (10 gm/kg bw for 14 days).

Maximum tissue concentrations at Tmax occurred in the liver. Clearance
was rapid for liver and other tissues by 168 hours after dosing. All
tissues at 168 hours, including the carcass, collectively retained
<0.05% of the dose. The pattern of distribution was similar between
sexes and single and multiple dose administration. The low percentage
and concentration values in tissues indicate very low potential for
accumulation. 

Plasma terminal elimination half-lives ranged from 40-51 hours following
single or multiple low-dose administration. Excretion in urine and feces
was >95% complete by 48 hours after single dosing. The pattern of
excretion was similar after multiple dosing. Fecal excretion was the
primary route of elimination (≥90%). Recovery in urine was much lower
(≤2.5%). Essentially no excretion occurred by exhalation.

	7. Metabolite toxicology. Oxathiapiprolin is considered to be the only
molecule of toxicological relevance. Toxicology studies conducted with
metabolites support this conclusion. 

	8. Endocrine disruption. No relevant effects were observed on any
endocrine tissue in short- and long-term studies in rats, mice and dogs
to suggest an adverse impact on estrogen or androgen pathways or on
steroid biosynthesis. The reproduction studies in rats provided
sufficient information to fully interpret the effects of oxathiapiprolin
on reproduction. No observations in that study suggested an adverse
effect on estrogen. Additionally, investigational studies were conducted
that suggest no adverse effects on estrogen. The slight delay in
maturation observed in male rats in the reproduction studies may be
exacerbated by weight effects; however, the data suggest that other
factors are involved. Investigational studies did not reveal any adverse
effects on androgens by oxathiapiprolin in rats.

C. Aggregate Exposure

	1. Dietary exposure. EPA has established tolerances for direct or
indirect residues of the fungicide oxathiapiprolin,
1-(4-{4-[(5RS)-5-(2,6-difluorophenyl)-4,5-dihydro-1,2-oxazol-3-yl]-1,3-t
hiazol-2-yl}-1-piperidyl)-2-[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-y
l] ethanone, in or on a number of raw agricultural and processed
commodities (40CFR §180.685).  There are currently pending uses on
potato (Subgroup 1C) and citrus (Crop Group 10-10A) for Syngenta,
sunflower and soybean for DuPont, and basil, asparagus, cane berries
(Subgroup 13-07A), and mustard greens for IR-4.  With this
Notice-of-Filing, Syngenta is proposing new tolerances for an IR-4 use
on cocoa.  There is no expectation of residues of oxathiapiprolin in the
meat, milk, or eggs of ruminants and/or poultry resulting from any
current or proposed uses and no tolerances have been proposed in or on
any livestock commodities at this time.  The EPA stated in its June 25,
2015 human health safety technical review of the DuPont petition (DP
Barcode D417279) that toxicological studies for oxathiapiprolin did not
demonstrate any treatment-related effects and subsequently EPA did not
establish any oral, dermal, or inhalation (acute, chronic, or
short-term) endpoints for assessment of consumer exposures.  In keeping
with the EPA’s current policy and practice with respect to
oxathiapiprolin, Syngenta has not conducted any consumer risk
assessments for the proposed use on cocoa.

	i. Food. Due to the lack of toxicological endpoints and
Points-of-Departure (PODs), quantitative acute dietary risk assessments
were not conducted.

Chronic exposure.  Due to the lack of toxicological endpoints and PODs,
quantitative chronic dietary risk assessments were not conducted. 

Cancer.  Oxathiapiprolin is classified as "not likely to be carcinogenic
to humans."  No treatment-related increase in tumors was observed in
carcinogenicity studies in rats and/or mice.  A cancer dietary
assessment was not conducted

	ii. Drinking water. Due to the lack of toxicological endpoints and
PODs, quantitative drinking water risk assessments were not conducted.

	2. Non-dietary exposure. Residential Exposure: Since no toxicological
endpoints of concern were identified for oxathiapiprolin and no PODs
were selected, quantitative residential risk assessments were not
conducted. 

Occupational Exposure:  Although there is potential for occupational
handler and post-application exposure, risk estimates for OXTP were not
quantitatively assessed because no dermal or inhalation toxicological
endpoints were identified or PODs selected.  The PPE statement on
proposed labels requires handlers to wear baseline clothing (i.e.,
long-sleeved shirt, long pants, shoes plus socks), no chemical-resistant
gloves and no respirator.  No additional PPE recommendations are needed
based on HED’s risk assessment.  The PPE determination and REIs on
proposed labels should be based on the acute toxicity of OXTP.

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 oxathiapiprolin and any other
substances and oxathiapiprolin does not appear to produce a toxic
metabolite produced by other substances.  For the purposes of this
tolerance action, therefore, EPA has not assumed that oxathiapiprolin
has a common mechanism of toxicity with other substances.

E. Safety Determination

	1. U.S. population. There is the potential for dietary (food and
drinking water) and residential exposures associated with all current,
pending, and proposed uses of oxathiapiprolin.  However, due to the lack
of toxicity at the human exposure levels anticipated for oxathiapiprolin
based on the proposed use patterns, no quantitative dietary,
residential, or aggregate exposure assessments are required and no risks
of concern are anticipated.

	2. Infants and children. There is the potential for dietary (food and
drinking water) and residential exposures associated with all current,
pending, and proposed uses of oxathiapiprolin.  However, due to the lack
of toxicity at the human exposure levels anticipated for oxathiapiprolin
based on the proposed use patterns, no quantitative dietary,
residential, or aggregate exposure assessments are required and no risks
of concern are anticipated.

F. International Tolerances

	The following national Maximum Residue Limits (MRLs)* have been
established for oxathiapiprolin:

Commodity	US/Canada/Mexico	Australia	Japan

Amaranth, leafy	15	15

	Arracacha, root	0.01

Arrowroot, tuber	0.01

Artichoke, Chinese, tuber	0.01

Artichoke, Jerusalem, tuber	0.01

Arugula	15

Balsam apple	0.2	0.2

	Balsam pear	0.2	0.2

	Broccoli	1.5	2

	Broccoli, Chinese	1.5	2

	Brussels sprouts	1.5	2

	Cabbage	1.5	2

	Cabbage, Chinese, mustard, gai choy	1.5

Cabbage, Chinese, napa	1.5	15	0.2

Canna, edible, tuber	0.01

Cantaloupe	0.2	0.2

	Cassava, root	0.01

Cauliflower	1.5	2

	Cavalo broccolo	1.5

Chayote, fruit	0.2	0.2

	Chayote, root	0.01

Chervil	15	15

	Chickpea	0.05

Chive, Chinese, leaves	2

Chives	2

Chrysanthemum, edible-leaved	15,  Canada = 0.1

Chrysanthemum, garland	15	15

	Chufa, tuber	0.01

Corn salad	15

Cress, garden	15	15

	Cress, upland	15, Canada = 0.1

Cucumber	0.2	0.2	0.2

* Source: Global MRL Database;   HYPERLINK
"https://www.globalmrl.com/db#query"  https://www.globalmrl.com/db#query
 





Commodity	US/Canada/Mexico	Australia	Japan

Cucumber, Chinese	0.2

Dandelion, leaves	15	15

	Daylily, bulb	0.04

Dock (sorrel)	15	15

	Eggplant	0.5

Eggplant, African	0.5

Eggplant, pea	0.5

Eggplant, scarlet	0.5

Elegans hosta	2

Endive (escarole)	15	15

	Fritillaria, bulb	0.04

Fritillaria, leaves	2

Garden huckleberry	0.5

Garlic, bulb	0.04	1

	Garlic, great headed, bulb	0.04

Garlic, serpent, bulb	0.04

Gerkin, West Indian	0.2	0.2

	Ginger, root	0.01

Ginseng, root	0.15

Goji berry	0.5

Gourd, edible (bottle)	0.2	0.2

	Grape, table	0.7 for US & Mexico IT only, Canada = 0.1a

0.5

Grape, wine	0.7 for US & Mexico IT only, Canada = 0.1a

0.5

Groundcherry	0.5

Kohlrabi	1.5	2

	Kurrat	2

Lady’s leek	2

Leek	2	1

	Leek, wild	2

Lentil	0.05, Canada = 0.1a

Leren, tuber	0.01

Lettuce, head	15	2	0.5

Lettuce, leaf	15	15	0.5

Lily, bulb	0.04

Loofa, angled	0.2	0.2

	Loofa, smooth	0.2	0.2

	Martynia	0.5

a Canada default of 0.1ppm applies.

Commodity	US/Canada/Mexico	Australia	Japan

Melon, casaba	0.2	0.2

	Melon, citron	0.2

Melon, crenshaw	0.2	0.2

	Melon, golden pershaw	0.2	0.2

	Melon, honey ball	0.2	0.2

	Melon, honeydew	0.2	0.2

	Melon, mango	0.2	0.2

	Melon, Persian	0.2	0.2

	Melon, pineapple	0.2	0.2

	Melon, Santa Claus	0.2	0.2

	Melon, snake	0.2	0.2

	Muskmelon	0.2	0.2

	Naranjilla	0.5

Okra	0.5

Onion, Beltsville bunching	2

Onion, bulb	0.04	0.02

	Onion, Chinese, bulb	0.04	1

	Onion, fresh	2

Onion, green	2	1

	Onion, macrostem	2

Onion, pearl	0.04

Onion, potato, bulb	0.04

Onion, tree, tops	2	1

	Onion, Welsh, tops	2	1

	Orach	15

Parsley 	15

Pea, dwarf	0.05, Canada edible podded = 1

Pea, English	0.05

Pea, field	0.05, Canada = 0.1a

Pea, garden	0.05

Pea, green	0.05

Pea, pigeon	0.05, Canada edible podded = 1

Pea, snow	 edible-podded = 1,  succulent shelled = 0.05, Canada edible
podded only = 1

Pea, sugar snap	edible-podded = 1,  succulent shelled = 0.05, Canada
edible podded only = 1

Pepino	0.5

a  Canada default of 0.1ppm applies.

Commodity	US/Canada/Mexico	Australia	Japan

Pepper, bell	0.5

Pepper, non-bell	0.5

Potato 	0.01

0.05

Pumpkin 	0.2	0.2

	Purslane, garden	15	15

	Purslane, winter	15

Radicchio (red chicory)	15	15

	Roselle (calyx and flower)	0.5

Shallot, bulb	0.04	1

	Shallot, fresh leaves	2

Spinach 	15	15

	Spinach, New Zealand	15	15

	Spinach, vine	15

Squash, summer (crookneck)	0.2	0.2

	Squash, summer (scallop)	0.2	0.2

	Squash, summer (straightneck)	0.2	0.2

	Squash, summer (vegetable marrow)	0.2	0.2

	Squash, summer (zucchini)	0.2	0.2

	Squash, winter (acorn)	0.2	0.2

	Squash, winter (butternut)	0.2	0.2

	Squash, winter (calabaza)	0.2	0.2

	Squash, winter (hubbard)	0.2	0.2

	Squash, winter (spaghetti)	0.2	0.2

	Sunberry	0.5

Sweet potato	0.01

Tanier, corm	0.01

Taro (dasheen), corm	0.01

Tomatillo 	0.5

Tomato 	0.5

0.3

Tomato, dried	3

Tomato, bush	0.5

Tomato, currant	0.5

Tree tomato (tamarillo)	0.5

Turmeric, root	0.01

Watermelon 	0.2	0.2

	Waxgourd 	0.2

Yam bean (jicama), root	0.01

Yam, true, tuber	0.01

Codex Alimentarius Commission has not established any MRLs for
oxathiapiprolin in or on any agricultural commodities. However,
oxathiapiprolin is on the 2016 JMPR Priority List and the following
commodities will be evaluated: grapes, potato (foliar use), dry bulb
onion, green onion, tomato, bell pepper, non-bell pepper, courgette,
cucumber, melon, summer squash, cantaloupe, broccoli, cauliflower, head
cabbage, lettuce, spinach, succulent peas, ginseng and tobacco.

Additional international MRLs or Import Tolerances are expected to be
established in the following countries in 2017 and 2018: EU, Japan,
Australia, China, Hong Kong, Taiwan and Korea.

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