Document ID: EPA-HQ-OPP-2007-0893-0002
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2007-09-28T04:00Z

EPA Registration Division contact: Barbara Madden (703)-305-6463	

PP# 7E7232

Summary of Petitions

 to amend 40 CFR part 180 412 by establishing a tolerance for residues
of sethoxydim
(2-[1-(ethoxyimino)butyl]-5-[2-(ethylthio)propyl]-3-hydroxy-2-cyclohexen
-1-one) and its metabolites containing the 2-cyclohexen-1-one moiety
(calculated as the herbicide) in the following crops: cuphea, seed, at
35.0 ppm; echium, seed, at 35.0 ppm; gold of pleasure, seed, at 35.0
ppm; gold of pleasure, meal, at 40.0 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; sesame, seed, at 35.0 ppm; sweet rocket, seed, at 35.0 ppm; crambe,
seed, at 35.0 ppm; crambe, meal, at 40.0 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        

                               

. The qualitative nature of the residues in plants and animals is
adequately understood for the purposes of registration.

. 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 chromotagraphy with sulfur-specific flame photometric detection. 
The limit of quantitation is 0.05 ppm.

. IR-4 received a request from Montana for the use of sethoxydim in or
on rapeseed crops for control of certain perennial and annual grasses. 
Tolerances currently exist for residues of sethoxydim and its
metabolites containing the 2-cyclohexen-1-one moiety in
canola/crambe/rapeseed at 35.0 ppm in the seed and 40.0 ppm in the meal.
 Production practices, growth requirements and physical characteristics
are very similar for the rapeseed crops and canola/crambe/rapeseed.  The
proposed use pattern for sethoxydim in cuphea, echium, gold of pleasure,
hare’s ear mustard, lesquerella, lunaria, meadowfoam, milkweed,
mustard, oil radish, poppy, sesame, and sweet rocket, is the same as the
EPA-approved use pattern for sethoxydim in canola/rapeseed.  IR-4
proposes using the sethoxydim tolerances established on canola/rapeseed,
at 35.0 ppm, and for canola/rapeseed, meal, at 40.0 ppm, as surrogate
data to support tolerances on the other rapeseed crops.

B. Toxicological Profile

.  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.

.  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
exhange (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.

.  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.

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.

. 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.

. 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.

. 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.

. 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

. The sethoxydim chronic reference dose (cRfD) is 0.14 mg/kg bw/day
based on the NOAEL of 14 mg/kg bw/day in the mouse oncogenicity study
and a 100X safety factor.  The acute reference dose (aRfD) is 1.8 mg/kg
b.w./day for the general population and females of child bearing age,
based on a NOAEL from the rat developmental toxicity study of 180 mg/kg
bw/day and a 100X safety factor

An assessment was conducted to evaluate the potential risk due to acute
and chronic dietary exposure of the U.S. population and sub-populations
to residues of sethoxydim and its metabolites containing the
2-cyclohexen-1-one moiety.  Tolerance values have previously been
established and are listed in U.S. 40 CFR § 180.412.  

This analysis included the crops with established tolerance values and
proposed crop tolerances for the additional rapeseed crops.

.  Acute Dietary Exposure Assessment

For crops which have an existing tolerance, the acute dietary exposure
was calculated by the EPA and published in the “Sethoxydim. Acute and
Chronic Aggregate Dietary and Drinking Water Exposure and Risk
Assessment for Section 3 New Use on Borage, Buckwheat, Dill, Okra,
Radish, and Turnip Greens and to Support the Establishment of a Crop
Group Tolerance for Root and Tuber Vegetables (Crop Group 1)”, October
5, 2006.  For the new crops listed in this notice of filing, the acute
assessment was conducted using tolerance level residues and 100% crop
treated factors.

Using the exposure assumptions discussed above, the acute dietary
exposure from food is 3.9 % aPAD for the US population.  The two most
highly exposured subpopulations were children 1-2 years olds.  The %
aPAD utilized by children 1-2 years was approximately 7.0%.  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	99th Percentile Exposure Estimate

(mg/kg bw/day)	%aPAD

US Population	0.0694579	3.9

All infants (< 1 year)	0.1246649	6.9

Children 1-2	0.1261369	7.0

Children 3-5	0.0993839	5.5

Children 6-12	0.0698239	3.9

Youth 13-19	0.0462909	2.6

Adults 20-49	0.0394039	2.2

Adults 50+ yrs	0.0390129	2.2

Females 13 - 49 yrs	0.0386879	2.1

Chronic Dietary Exposure Assessment

For crops which have an existing tolerance, the acute dietary exposure
was calculated by the EPA and published in the “Sethoxydim. Acute and
Chronic Aggregate Dietary and Drinking Water Exposure and Risk
Assessment for Section 3 New Uses on Borage, Buckwheat, Dill, Okra,
Radish, and Turnip Greens and to Support the Establishment of a Crop
Group Tolerance for Root and Tuber Vegetables (Crop Group 1)”, October
5, 2006.  For the new crop listed in this notice of filing, the acute
assessment was conducted using tolerance level residues and 100% crop
treated 

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 6.9% of the cPAD.  The most highly exposure population
sub group was children 1 – 2 years old at 16.4% 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 b.w./day)	%cPAD

US Population	0.0096439	6.9

All infants (< 1 year)	0.0210309	15.0

Children 1-2	0.0229729	16.4

Children 3-5	0.0195919	14.0

Children 6-12	0.0133539	9.5

Youth 13-19	0.0088539	6.3

Adults 20-49	0.0076489	5.5

Adults 50+ yrs	0.0078309	5.6

Females 13 - 49 yrs	0.0074909	5.4

]

.  The drinking water values used in this assessment were based on the
EPA document “Sethoxydim Drinking Water Assessment (Tier 1) for
Reregistration Eligibility Decision”  Feburary 7, 2005.  The estimated
drinking water concentrations (EDWCs) for total sethoxydim residues are
1.5 ppg 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 risk concerns.  Therefore
we can conclude with reasonable certainty that no harm will occur from
short-term aggregate exposure of sethoxydim. 

. 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

.  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.]

. 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 limits or tolerances for sethoxydim
in cuphea, echium, gold of pleasure, hare’s ear mustard, lesquerella,
lunaria, meadowfoam, milkweed, mustard, oil radish, poppy, sesame, or
sweet rocket.

{<HD2>}

{<HD1>}

{<P>}

{</P>}

{<HD2>}

{<P>}

{<E T=’03'>}

{</E>}

{<P>}

{<E T=’03'>}

{</E>}

{<P>}

{<E T=’03'>}

{</E>}

{<HD2>}

{<P>}

{<E T=’03'>}

{</E>}

{<P>}

{<E T=’03'>}

{</E>}

{<P>}

{<E T=’03'>}

{</E>}

{<P>}

{<E T=’03'>}

{</E>}

{<P>}

{<E T=’03'>}

{</E>}

{<P>}

{<E T=’03'>}

{</E>}

{<P>}

{<E T=’03'>}

{</E>}

{<P>}

{<E T=’03'>}

{</E>}

{<HD2>}

{<P>}

{<E T=’03'>}

{</E>}

{<P>}

{<E T=’03'>}

{</E>}

{<P>}

{<E T=’03'>}

{</E>}

{<P>}

{<E T=’03'>}

{</E>}

{<HD2>}

{<P>}

{<HD2>}

{<P>}

{<E T=’03'>}

{</E>}

{<P>}

{<E T=’03'>}

{</E>}

{<HD2>}

{<P>}