Document ID: EPA-HQ-OPP-2014-0114-0003
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2014-05-23T04:00Z

I.   E.I. du Pont de Nemours and Company

EPA Registration Division Contact :   Erin Malone, (703) 347-0253

PP No. 3F8220

EPA has received a pesticide petition (3F8220) from E.I. du Pont de
Nemours & Company (“DuPont”), 1007 Market Street, Wilmington, DE
19898, proposing pursuant to section 408 (d) of the Federal Food, Drug,
and Cosmetic Act, 21 U.S.C. 346a (d), to amend 40 CFR part 180 to
establish tolerances for residues of 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 the following commodities: grapes (import
tolerance) at 0.9 ppm; vegetable, root and tuber vegetables, tuberous
and corm vegetables (crop subgroup 1C) at 0.01 ppm; bulb vegetables,
onion, bulb (crop subgroup 3-07A) at 0.04 ppm; bulb vegetables, onion,
green (crop subgroup 3-07B) at 2 ppm; fruiting vegetables (crop group
8-10) at 0.2 ppm, dried fruiting vegetables at 0.9 ppm;  cucurbit
vegetables (crop group 9) at 0.2 ppm; Brassica (cole) leafy vegetables,
head and stem Brassica (crop subgroup 5A) at 1.5 ppm; leafy vegetables
(except Brassica vegetables), leafy greens (crop subgroup 4A) at 15 ppm;
peas, edible podded at 1 ppm; peas, succulent, shelled at 0.05 ppm;
ginseng root at 0.4 ppm; and to establish a Guideline Reference Level
for residues of oxathiapiprolin, in or on tobacco, dried leaves at 30
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 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 proposed 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
principal 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. Livestock Metabolism. The metabolism of oxathiapiprolin in ruminants
and poultry is adequately understood to support the proposed tolerances.
 Lactating goat and monogastric hen metabolism studies were conducted.
The metabolism of oxathiapiprolin in the rat was, in general, consistent
with that of the lactating goat (ruminant) and monogastric hen.

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

4. Magnitude of residues. Field trials to meet country (Canada, the
United States) and regional (the EU) requirements were carried out in
vineyards (grape), field or protected vegetables (brassica vegetables,
bulb vegetables, cucurbit vegetables, fruiting vegetables, leafy
vegetables, peas, and potatoes), ginseng and tobacco.  The trials
covered a wide range of locations, climates and soil types globally and
the data obtained reflect the commercial use of the
oxathiapiprolin-containing products in the major crop growing regions.

The results of these field trials substantiate oxathiapiprolin as the
major residue at harvest in all crop commodities except potato tubers
(which were below the limit of quantification).  Oxathiapiprolin is
likewise the relevant residue in processed commodities.  For commodities
of animal origin, there was minimal transfer of oxathiapiprolin residues
from animal feeding-stuffs containing oxathiapiprolin residues to edible
tissues, milk, or eggs.  Livestock feeding studies were not conducted.

B. Toxicological Profile

1. Acute toxicity. Based on EPA criteria, technical oxathiapiprolin is
classified as acute toxicology category IV based on overall results from
several studies. This compound is considered acute toxicology category
IV for acute oral, dermal and inhalation toxicity and eye and skin
irritation. Technical oxathiapiprolin is not a dermal sensitizer. 

No evidence of neurotoxicity was observed in acute study conducted with
oxathiapiprolin in rats. The no-observed-effect level (NOEL) and
no-observed-adverse-effect-level (NOAEL) in an acute neurotoxicity study
were 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 maturation were observed in male
rats in the reproduction studies, with a NOAEL of 104 mg/kg bw/day.  At
much higher doses, decreases in offspring body weight were also
observed.

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, two other studies were performed in rats: a
14-day oral gavage study (conducted as a part of early discovery) and a
28-day dermal study. 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 repeated
dose toxicity 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 intake levels of >1000 mg/kg bw/day in male and
female rats. No evidence of neurotoxicity was observed.  No treatment
related clinical signs indicative of potential neurotoxicity were
observed in 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. Rat 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 dose administrations (10 mg/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
faeces was >95% complete by 48 hours after single dosing.  The pattern
of excretion was similar after multiple dosing.  Faecal excretion was
the primary route of elimination ((90%).  Recovery in urine was much
lower ((2.5%).  Essentially no excretion occurred by exhalation.

Oxathiapiprolin metabolism pathways mainly involved hydroxylation at
various ring carbons and ring opening.  Pyrazole-piperidine bridge
cleavage followed by further oxidation resulted in pyrazole metabolites.

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

The residue of concern is parent oxathiapiprolin only.

No acute dietary risk assessment was needed since there is no acute
toxicity endpoint.

The chronic studies in dogs, rats, and mice were considered, but not
used, as a basis for the chronic reference dose (cRfD), since no adverse
findings occurred in these studies. The lowest NOAEL was observed in the
multigeneration reproduction study in rats.  Therefore, the cRfD 1.04
mg/kg/day is based on the NOAEL of 104 mg/kg bw/day from the
multigeneration reproduction study in rats and a 100-fold safety factor.
 

1. Dietary exposure

i. Food. There is no population in the chronic risk assessment for
oxathiapiprolin with an exposure greater than 1% of the chronic
reference dose.

ii. Drinking water. No acute dietary endpoint was identified. Therefore,
an acute drinking water risk assessment was not necessary. 

Chronic drinking water exposure values were calculated for
oxathiapiprolin using EPA screening concentration models for ground
water and surface water. The groundwater concentrations for
oxathiapiprolin were less than those in surface water, so surface water
values were used in the dietary risk assessment.  

When the surface water concentration was included for drinking water in
the chronic aggregate assessment to evaluate chronic exposure and risk
from food and drinking water, all populations including the general U.S.
population and all subpopulations had an exposure less than 1 % of the
chronic reference dose (cRfD), indicating a significant margin of safety
and reasonable certainty that oxathiapiprolin residues in drinking water
will not contribute significantly to the aggregate chronic human health
risk. 

2. Non-dietary exposure. The Margin of Exposure (MOE) estimated for
inhalation while smoking treated tobacco leaves indicates that there are
no inhalation intake concerns.  Since there are no residential or home
uses non-dietary exposure has not been assessed.

D. Cumulative Effects

A determination has not been made that oxathiapiprolin has a common
mechanism of toxicity with other substances. Oxathiapiprolin does not
appear to produce a common toxic metabolite with other substances. A
cumulative risk assessment was, therefore, not performed for this
analysis.

E. Safety Determination

1. U.S. population. Based on risk assessments performed using worst-case
exposure assumptions there is a reasonable certainty that no harm will
result to the general population from the aggregate exposure to
oxathiapiprolin.  No additional safety factors are warranted.

2. Infants and children. Based on the risk assessments performed using
worst-case exposure assumptions there is a reasonable certainty that no
harm will result to infants and children from the aggregate exposure to
oxathiapiprolin.  No additional safety factors are warranted.

F. INTERNATIONAL TOLERANCES

No tolerances have been established to date for oxathiapiprolin.

Pesticide Petition to Establish Tolerances for Oxathiapiprolin