Document ID: EPA-HQ-OPP-2016-0049-0008
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2016-05-19T04:00Z

Syngenta Crop Protection, LLC

PP# 5F8441

EPA has received a pesticide petition PP# 5F8441 from Syngenta Crop
Protection, LLC, P.O. Box 18300, 410 Swing Road, Greensboro, NC 27419
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 180.685 by
establishing a tolerance for residues of oxathiapiprolin in or on the
following raw agricultural commodities:

Citrus fruit Crop Group 10-10 at 0.06 parts per million (ppm)

Citrus oil at 2.0 parts per million (ppm)

Citrus pulp at 0.09 parts per million (ppm)

Tuberous and Corm Vegetables, Subgroup 1C at 0.04 parts per million
(ppm)

Potato, wet peel at 0.07 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  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 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), field (potato). 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 mg oxathiapiprolin/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 does (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. Subsequent to the filing of a pesticide petition by
E.I. du Pont de Nemours and Company, Wilmington, DE (DuPont), EPA
established tolerances for 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: Brassica, head and stem (Subgroup 5A); ginseng;
grape; leafy greens (Subgroup 4A); onion, bulb (Subgroup 3-07A); onion,
green (Subgroup 3-07B); pea, edible-podded; pea, succulent shelled;
tomato, dried; vegetable, cucurbit (Group 9); vegetable, fruiting (Group
8-10); and vegetable, tuberous and corm (Subgroup 1C).  With this
Notice-of-Filing, Syngenta is requesting new tolerances for its proposed
uses on potato and citrus (Crop Group 10-10).  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 for those 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 did not subsequently establish any oral, dermal, or inhalation
(acute, chronic, or short-term) endpoints for assessment of consumer
exposures, and in keeping with the EPA’s current policy and practice
with respect to oxathiapiprolin, Syngenta has not conducted any consumer
risk assessments for its proposed uses on citrus fruit (crop group
10-10), tuberous and corm vegetables (subgroup 1C).

i. Food

Acute exposure.  Due to the lack of toxicological endpoints and
Points-of-Departure (PODs), a quantitative acute dietary risk assessment
was not conducted. While dietary exposure to oxathiapiprolin may occur
through food and drinking water, no risks of concern are anticipated due
to the lack of toxicity at anticipated human exposure levels.

Chronic exposure.  Due to the lack of toxicological endpoints and PODs,
a quantitative chronic dietary risk assessment was not conducted. While
dietary exposure to oxathiapiprolin may occur through food and drinking
water, no risks of concern are anticipated due to the lack of toxicity
at anticipated human exposure levels.

Cancer.  A cancer dietary assessment was not conducted.  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.

ii. Drinking water. Due to the lack of toxicological endpoints and PODs,
a quantitative drinking water assessment was not conducted.

2. Non-dietary exposure

Residential Exposure.  There is no residential handler exposure
scenarios associated with the proposed use on turfgrass (i.e., golf
courses and commercial landscapes).  Residential exposures are also
expected for adults and children conducting post-application activities
on treated golf course (turf).  However, since no toxicological
endpoints of concern were identified for oxathiapiprolin and no PODs
were selected, a quantitative residential risk assessment was not
conducted.  Although there is a proposed use on ornamental plants, the
proposed use is only for nurseries and commercial greenhouses.  HED
notes that there are no direct homeowner applications of oxathiapiprolin
to ornamentals; however, treated ornamentals could be purchased at a
retail location for use in a residential setting.  HED considers
post-application exposure resulting from this scenario to be negligible.
 Furthermore, a quantitative residential post-application assessment for
the use of oxathiapiprolin on commercial ornamentals was not performed
because of the lack of potential exposure and the absence of
toxicological endpoints or PODs.

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, E PA 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. For
information regarding EPA's efforts to determine which chemicals have a
common mechanism of toxicity and to evaluate the cumulative effects of
such chemicals, see the policy statements released by EPA's Office of
Pesticide Programs concerning common mechanism determinations and
procedures for cumulating effects from substances found to have a common
mechanism on EPA' s website at:   HYPERLINK
"http://www.epa.gov/pesticides/cumulative" 
http://www.epa.gov/pesticides/cumulative .

E. Safety Determination

1. U.S. population. There is the potential for dietary (food and
drinking water) and residential exposures associated with all current
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
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

Codex Alimentarious Commission has not yet established Maximum Residue
Limits (CXLs) for oxathiapiprolin.

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