Document ID: EPA-HQ-OPP-2014-0161-0002
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2014-05-23T04:00Z

EPA REGISTRATION DIVISION - COMPANY NOTICE OF FILING OF PESTICIDE
PETITION

 

EPA Registration Division contact: Sidney Jackson (703) 305-7610

 

Interregional Research Project Number 4 (IR-4)

Pesticide Petition Number: 4E8239

	

	EPA has received a pesticide petition (4E8239) from the Interregional
Research Project 4 (IR-4), IR-4 Headquarters, Rutgers, The State
University of NJ, 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 to
establish tolerances for combined residues of the herbicide sethoxydim,
2-[1-(ethoxyimino)butyl]-5-[2-(ethylthio)propyl]-3-hydroxy-2-cyclohexen-
1-one (CAS Reg. No. 74051–80–2), and its metabolites containing the
2-cyclohexen-1-one moiety (calculated as the herbicide)] in or on the
following raw agricultural commodities: Berry, low growing, subgroup
13-07H, except strawberry at 2.5 parts per million (ppm), Bushberry,
subgroup 13-07B at 5.0 ppm; Caneberry subgroup 13-07A at 5.0 ppm,
Fescue, forage at 6.0 ppm; Fescue, hay at 4.0 ppm; Fruit, citrus, group
10-10 at 0.5 ppm; Fruit, pome, group 11-10 at 0.2 ppm; Fruit, small,
vine climbing, subgroup 13-07F, except fuzzy kiwifruit at 1.0 ppm;
Rapeseed subgroup 20A at 35 ppm; Sunflower subgroup 20B, except
safflower, seed at 7.0 ppm; Cottonseed subgroup 20C at 5.0; Vegetable,
bulb, group 3-07 at 1.0 ppm; and Vegetable, fruiting, group 8-10 at 4.0
ppm. In addition, IR-4 is proposing that upon approval of the above
petitioned-for tolerances, established sethoxydim tolerances in or on
the following commodities are removed, including: Blueberry at 4.0 ppm;
Borage, seed at 6.0 ppm; Caneberry subgroup 13A at 5.0 ppm; Canola, seed
at 35.0 ppm; Cotton, undelinted seed at 5.0 ppm; Crambe, seed at 35.0
ppm; Cranberry at 2.5 ppm; Cuphea, seed at 35.0 ppm; Echium, seed at
35.0 ppm; Flax, seed at 5.0 ppm; Fruit, citrus, group 10 at 0.5 ppm;
Fruit, pome, group 11 at 0.2 ppm; Gold of pleasure, seed at 35.0 ppm;
Grape at 1.0 ppm; Hare’s ear mustard, seed at 35.0 ppm; Juneberry at
5.0 ppm; Lesquerella, seed at 35.0 ppm; Lingonberry at 5.0 ppm; Lunaria,
seed at 35.0 ppm; Meadowfoam, seed at 35.0 ppm; Milkweed, seed at 35.0
ppm; Mustard, seed at 35.0 ppm; Oil radish, seed at 35.0 ppm; Poppy,
seed at 35.0 ppm; Rapeseed, seed at 35.0 ppm; Salal at 5.0 ppm; Sesame,
seed at 35.0 ppm; Sunflower, seed at 7.0 ppm; Sweet rocket, seed at 35.0
ppm; Vegetable, bulb, group 3 at 1.0 ppm; and Vegetable, fruiting, group
8 at 4.0 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 qualitative nature of the residues in plants
and animals is adequately understood for the purposes of registration.

		2. Analytical method.  Analytical methods for detecting levels of
sethoxydim and its metabolites in or on food with a limit of detection
that allows monitoring of food with residues at or above the level in
these tolerances were submitted to EPA.  The proposed analytical method
involves extraction, partition, and clean-up.  Samples are then analyzed
by gas chromatography with sulfur-specific flame photometric detection. 
The limit of quantitation is 0.05 ppm.

		3. Magnitude of residues.  IR-4 received a request from the
Agricultural Experiment Stations of Oregon and Idaho for the minor use
of sethoxydim on fine fescue (Creeping Red (Festuca rubra), Chewings
(Festuca nigrescens), and Hard Fescue (Festuca ovina)) for the control
of annual and perennial grasses in fine fescue grass grown for seed. 
The nature of the residues of sethoxydim is adequately understood and an
acceptable analytical method is available for enforcement purposes.  The
registration of this use would provide the growers with a safe and
effective herbicide for the control of annual and perennial grasses, yet
would not expose human beings or the environment to unreasonable adverse
effects.  Therefore, tolerances are proposed for fescue, forage at 6.0
ppm and fescue, hay at 4.0 ppm based on the OECD tolerance calculator.

IR-4 received a request from the Agricultural Experiment Station of
Oregon and North Carolina for the minor use of sethoxydim on blueberry
(highbush and lowbush) for the control of grass weeds and to reduce the
pre-harvest interval from 30 days to 1 day.  The nature of the residues
of sethoxydim is adequately understood and an acceptable analytical
method is available for enforcement purposes.  The registration of this
use would provide the growers with a safe and effective herbicide for
the control of grasses, yet would not expose human beings or the
environment to unreasonable adverse effects.  There is an existing
blueberry tolerance of 4.0 ppm for sethoxydim with a 30 day PHI.  Based
on the results of that study, IR-4 proposes the removal of the tolerance
for blueberry (representative crop for the Bushberry subgroup 13-07B),
Juneberry, Lingonberry and Salal and the establishment of a subgroup
tolerance for the Bushberry subgroup 13-07B at 5.0 ppm.  IR-4 proposes
to change the pre-harvest interval for highbush blueberry to 1 day,
while leaving the lowbush pre-harvest interval at 30 days.

In addition, IR-4 proposes the establishment of tolerances for the
following revised crop groups based on existing tolerances that are
shown in brackets:

Caneberry subgroup 13-07A [Caneberry subgroup 13A at 5.0 ppm];

Berry, low growing, subgroup 13-07G [Strawberry at 10 ppm];

Berry, low growing, subgroup 13-07H, except strawberry [Cranberry at 2.5
ppm];

Fruit, citrus, group 10-10 [Fruit, citrus, group 10 at 0.5 ppm];

Fruit, pome, group 11-10 [Fruit, pome, group 11 at 0.2 ppm];

Fruit, small, vine climbing, subgroup 13-07F, except fuzzy kiwifruit
[Grape at 1.0 ppm];

Rapeseed subgroup 20A [Borage, seed at 6.0 ppm; Canola, seed at 35.0
ppm; Crambe, seed at 35.0 ppm; Cuphea, seed at 35.0 ppm; Echium, seed at
35.0 ppm; Flax, seed at 5.0 ppm; Gold of pleasure, seed at 35.0 ppm;
Hare’s ear mustard, seed at 35.0 ppm; Lesquerella, seed at 35.0 ppm;
Lunaria, seed at 35.0 ppm; Meadowfoam, seed at 35.0 ppm; Milkweed, seed
at 35.0 ppm; Mustard, seed at 35.0 ppm; Oil radish, seed at 35.0 ppm;
Poppy, seed at 35.0 ppm; Rapeseed, seed at 35.0 ppm; Sesame, seed at
35.0 ppm; and Sweet rocket, seed at 35.0 ppm];

Sunflower subgroup 20B, except safflower [Sunflower, seed at 7.0 ppm];

Cottonseed subgroup 20C [Cotton, undelinted seed at 5.0];

Vegetable, bulb, group 3-07 [Vegetable, bulb, group 3 at 1.0 ppm]; and

Vegetable, fruiting, group 8-10 [Vegetable, fruiting, group 8 at 4.0
ppm].]

B. Toxicological Profile

		1. Acute toxicity.  Sethoxydim has favorable acute toxicity.  The
acute toxicity studies place technical sethoxydim in toxicity category
III for acute oral, dermal and inhalation toxicity.  Sethoxydim is
category IV for both eye and skin irritation, and it is not a dermal
sensitizer.

		2. Genotoxicty.  Sethoxydim was negative for inducing mutations in
both an in vitro Ames test and an in vitro mammalian cell mutation
assay.  Sethoxydim also demonstrated no chromosomal effects in an in
vivo sister chromatid exchange (Chinese hamster bone marrow) assay.  An
additional in vitro study investigating unscheduled DNA synthesis showed
no effects.  In total, sethoxydim has been tested in five genetic
toxicology assays consisting of in vitro and in vivo studies.  It can be
stated that sethoxydim did not show any mutagenic, clastogenic or other
genotoxic activity when tested under the conditions of the studies
mentioned above.  Therefore, sethoxydim does not pose a genotoxic hazard
to humans.

		3. Reproductive and developmental toxicity. The reproductive and
developmental toxicity of sethoxydim was investigated in a 2-generation
rat reproduction study as well as in rat and rabbit developmental
toxicity studies.  In the reproduction study, a decreased pup body
weight and tail abnormalities were observed at the highest dose tested. 
There were no effects on reproduction or evidence of parental toxicity. 
The NOAEL is >150 mg/kg bw/day for reproductive toxicity and 30 mg/kg
bw/day for developmental toxicity.

In the rat study, maternal toxicity observed at the two highest doses
consisted of some clinical signs including irregular gait and decreased
activity.  Developmental changes were also noted at the two highest
doses and consisted of decreased fetal weights, tail abnormalities and
skeletal variations.  The maternal and developmental NOAEL’s were 180
mg/kg bw/day.

 

In the rabbit teratology study, maternal toxicity observed at high dose
consisted of decreased food consumption and body weight gain.  An
increased incidence of incompletely ossified 6th sternebrae was the only
sign of developmental toxicity.  The NOAEL for both maternal and
developmental toxicity was 320 mg/kg bw.

		4. Subchronic toxicity.  The subchronic toxicity of sethoxydim was
investigated in 90-day feeding studies with rats and mice, a six-month
feeding study in dogs and a 21-day dermal administration study in rats
and a 4-week inhalation study in rats.  Generally, mild toxicity was
observed.  At high dose levels in feeding studies, general findings were
decreased food consumption and body weight gain and liver changes
indicative of an adaptive response to treatment.  In addition,
hemosiderosis of the spleen was observed at the highest dose tested in
dogs.  The lowest NOAEL in the subchronic feeding studies was 20 mg/kg
bw/day in the 90-day dog study.

In the 21-day repeat dose dermal study, no systemic effects were noted
up to the highest dose tested of 1000 mg/kg bw/day.  The 4-week
inhalation toxicity study had a NOEC of 0.3 mg/l based on increased
liver weight, clinical chemistry and liver histopathology at 2.4 mg/l.

		5. Chronic toxicity.  The NOAEL in the chronic dog study was 17.5
mg/kg bw/day based on effects observed at the high dose consisting of
increased hemosiderosis in the spleen and depressed myeloid
erythropoiesis in the sternal bone marrow, increased absolute and
relative liver weights and increased serum liver enzymes.

	

In a rat chronic/oncogenicity study, sethoxydim was administered at
doses up to 143 mg/kg bw/day in males and 204 mg/kg bw/day in females. 
Body weight gain decreases and liver toxicity in the form of
hepatocellular hypertrophy were observed at the higher doses tested. 
The NOAEL’s for the chronic/oncogenicity study in rats were 12 mg/kg
bw/day in males and 66 mg/kg bw/day in females.  There was no evidence
of carcinogenicity in rats.

Sethoxydim was also tested for oncogenic potential in mice.  Body weight
gains were decreased in both sexes at the high dose.  In addition, liver
toxicity occurred at the two highest doses tested in males.  This
included an early onset of liver effects including hepatocellular
hypertrophy and fatty degeneration.  The NOAEL’s are 13.8 mg/kg bw/day
for males and 44 mg/kg bw/day for females.  There was no evidence that
sethoxydim produced a carcinogenic effect in mice.

		6. Animal metabolism.  In a rat metabolism study with sethoxydim,
excretion was shown to be extremely rapid and tissue accumulation was
negligible.  Of the administered dose, 78% was excreted in urine and
20.1% in feces.  Sethoxydim is extensively metabolized with very little
excretion of parent.

		7. Metabolite toxicology. The most abundant plant metabolites for
sethoxydim are hydroxy derivatives.  Additional toxicology studies were
conducted on 5-OH-MSO2, as a surrogate for all hydroxy metabolites. 
Based on these data, it was concluded that the toxicological potency of
the plant hydroxy metabolites is likely to be equal to or less than that
of the parent compound.

		8. Endocrine disruption.  No specific tests have been conducted with
sethoxydim to determine whether the chemical may have an effect in
humans that is similar to an effect produced by a naturally occurring
estrogen or other endocrine effects.  However, there were no significant
findings in other relevant toxicity studies (i.e., subchronic and
chronic toxicity, teratology and multi-generation reproductive studies)
which would suggest that sethoxydim produces endocrine-related effects.

C. Aggregate Exposure

		1. Dietary exposure.  A dietary assessment was conducted to evaluate
the potential risk due to acute and chronic exposure.  The sethoxydim
chronic reference dose (cRfD) is 0.14 mg/kg bw/day based on the NOAEL of
14 mg/kg bw/day and a 100X safety factor.  The acute reference dose
(aRfD) is 1.8 mg/kg bw/day for all populations including females of
child bearing age, based on a NOAEL of 180 mg/kg bw/day and a 100X
safety factor.

The analysis included all current tolerance values for sethoxydim listed
in U.S. 40 CFR § 180.412 with the proposed changes in this
notification.

The proposed new tolerances are for Fescue, forage at 6.0 ppm and
Fescue, hay.

The proposed revised crop group tolerances based on existing tolerances
are:

Bushberry subgroup 13-07B at 5.0 ppm to replace blueberry, juneberry,
lingonberry, and salal

Caneberry subgroup 13-07A at 5.0 ppm to replace Caneberry subgroup 13A

Berry, low growing, subgroup 13-07G at 10 ppm to replace strawberry

Berry, low growing, subgroup 13-07H, except strawberry, at 2.5 ppm to
replace Cranberry

Fruit, citrus, group 10-10 at 0.5 ppm to replace Fruit, citrus, group 10

Fruit, pome, group 11-10 at 0.2 ppm to replace Fruit, pome, group 11

Fruit, small, vine climbing, subgroup 13-07F, except fuzzy kiwifruit, at
1.0 ppm to replace Grape

Rapeseed subgroup 20A at 35 ppm to replace Borage, seed; Canola, seed;
Crambe, seed; Cuphea, seed; Echium, seed; Flax, seed; Gold of pleasure,
seed; Hare’s ear mustard, seed; Lesquerella, seed; Lunaria, seed;
Meadowfoam, seed; Milkweed, seed; Mustard, seed; Oil radish, seed;
Poppy, seed; Rapeseed, seed; Sesame, seed; and Sweet rocket, seed 

Sunflower subgroup 20B, except safflower, seed at 7.0 ppm to replace
Sunflower, seed

Cottonseed subgroup 20C at 5.0 ppm to replace Cotton, undelinted seed

Vegetable, bulb, group 3-07 at 1.0 ppm to replace Vegetable, bulb, group
3

Vegetable, fruiting, group 8-10 at 4.0 ppm to replace vegetable,
fruiting, group 8.

		i. Food.  Acute Dietary Exposure Assessment

An acute dietary assessment was conducted using tolerance level
residues, 100% crop treatment factors, and default processing factors
for all commodities.

Using the exposure assumptions discussed above, the acute dietary
exposure from food is 6.4% aPAD for the US population.  The most highly
exposed sub-population was children 1-2 years olds which utilized 14.4%
of the aPAD.  The results of the acute dietary assessment are presented
in Table 1.

Table 1.  Results for Sethoxydim Acute Dietary Exposure Analysis
Including both Food and Drinking Water.

Population

Subgroups	95th Percentile Exposure Estimate

(mg/kg bw/day)	%aPAD

US Population	0.115813	6.4

All infants (< 1 year)	0.207434	11.5

Children 1-2	0.258563	14.4

Children 3-5	0.223652	12.4

Children 6-12	0.140949	7.8

Youth 13-19	0.085054	4.7

Adults 20-49	0.082702	4.6

Adults 50+ yrs	0.078437	4.4

Females 13 - 49 yrs	0.082104	4.6

Chronic Dietary Exposure Assessment

The chronic population adjusted dose (cPAD) used for US and all
sub-populations is 0.14 mg/kg bw/day.  Using the exposure assumptions
discussed above, sethoxydim chronic dietary exposure from food for the
US population was 31.9% of the cPAD.  The most highly exposure
subpopulation was children 1 - 2 years old which utilized 94.4% cPAD.  
The results of the chronic dietary assessment are presented in Table 2.

Table 2.  Summary of Chronic Dietary Exposure Assessment Considering
Crops with Established and Proposed Tolerances for Sethoxydim and
Drinking Water.

Population

Subgroups	Exposure Estimate

(mg/kg bw/day)	%cPAD

US Population	0.044671	31.9

All infants (< 1 year)	0.093969	67.1

Children 1-2	0.132143	94.4

Children 3-5	0.105162	75.1

Children 6-12	0.063504	45.4

Youth 13-19	0.036358	26.0

Adults 20-49	0.035444	25.3

Adults 50+ yrs	0.035608	25.4

Females 13 - 49 yrs	0.035204	25.1

]

		ii. Drinking water.  The drinking water values used in this assessment
were based on the EPA document “Sethoxydim Drinking Water Assessment
(Tier 1) for Reregistration Eligibility Decision” February 7, 2005. 
The estimated drinking water concentrations (EDWCs) for total sethoxydim
residues are 1.5 ppb for ground water and 130 ppb (acute) and 16 ppb
(chronic) for surface water.  These water concentration where included
in the dietary assessment conducted above.

Acute Aggregate Exposure and Risk (Food and water)

The aggregate acute risk includes residues of sethoxydim from food and
water.  Exposures from residential uses are not included in the acute
aggregate assessment.  Table 1 above shows the aggregate assessment for
sethoxydim.

 Chronic Aggregate Exposure and Risk (food and water)

The aggregate chronic risk includes residues of sethoxydim from food and
water.  Exposures from residential uses are not included in the chronic
aggregate assessment.  Table 2 above shows the aggregate exposure from
food and water.

Short- and Intermediate Term Aggregate Exposure and Risk (Food, Water
and Residential Exposure)

Short- and intermediate-term aggregate exposure takes into account
residential exposure plus chronic exposure from food and water. 
Sethoxydim is only used for spot treatment in residential environments. 
The EPA has stated that exposure from spot treatment is negligible and a
exposure risk assessment is not required.  Therefore, the aggregate risk
is the sum from chronic food and water.  The chronic aggregate risk
assessment has shown that there is no concern. Therefore, it is
concluded with reasonable certainty that no harm will occur from
short-term aggregate exposure of sethoxydim.

		2. Non-dietary exposure.  Sethoxydim is only used for spot treatment
in gardens, flower beds, recreational areas, and around building and
structures.  The EPA has determined that for sethoxydim, the
quantification of dermal exposure risk assessment is not required
because of lack of dermal and prenatal toxicity in rabbits, and the low
dermal absorption of sethoxydim.  The EPA has also stated that the
residential post-application exposure from spot treatment is negligible.
 Therefore based on the lack of dermal toxicity and negligible exposure
potential, a non-dietary exposure assessment was not conducted.

D. Cumulative Effects

		The EPA is currently developing methodology to perform cumulative risk
assessments.  At this time, there is no available data to determine
whether sethoxydim has a common mechanism of toxicity with other
substances or how to include this pesticide in a cumulative risk
assessment.  Unlike other pesticides for which EPA has followed a
cumulative risk approach based on a common mechanism of toxicity,
sethoxydim does not appear to produce a toxic metabolite common to other
substances.

E. Safety Determination

		1. U.S. population.  Based on this risk assessment, BASF concludes
that there is a reasonable certainty that no harm will result to the
general population from the aggregate exposure to sethoxydim residues.

		2. Infants and children.  Based on this risk assessment, BASF
concludes that there is a reasonable certainty that no harm will result
to infants or children from the aggregate exposure to sethoxydim
residues.

F. International Tolerances

		There are no CODEX maximum residue levels established or proposed for
residues of sethoxydim.