Document ID: EPA-HQ-OPP-2007-0894-0002
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2007-09-28T04:00Z

EPA Registration Division contact: Susan Stanton; (703) 305-5218

 

Notice of Filing of Pesticide Petitions

Interregional Research Project Number 4 (IR-4)

Petitions 5E4491 (Mint) and 7E7247 (Hops)

EPA has received pesticide petitions (PP#s 5E4491 and 7E7247) from
Interregional Research Project Number 4 (IR-4), 500 College Road East,
Suite 201 W, Princeton, NJ 08540, proposing, 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 180.262 by establishing tolerances for residues of
ethoprop in or on the raw agricultural commodities mint, hay (PP#5E4491)
and hop, dried cone (PP#7E7247) at 0.02 parts per million (ppm).  EPA
has determined that the petitions contain 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 petitions. Additional data
may be needed before EPA rules on the petitions.

A. Residue Chemistry

	1. Plant metabolism.

The qualitative nature of the residue in plants and animals is
adequately understood. The metabolic pathway for degradation of ethoprop
primarily involves hydrolysis of the S-propyl groups as well as
formation of the O-methyl and S-methyl metabolites. The residues of
concern for tolerance enforcement are ethoprop per se while the residues
of concern for risk assessment are ethoprop
((O-ethyl-S,S-dipropylphosphorodithioate),
O-ethyl-S-methyl-S-propylphosphoro- dithioate and
O-ethyl-O-methyl-S-propylphosphorothioate. For the cancer assessment two
additional metabolites are added, O-ethyl-S-propylphosphorothioate and
S,S-dipropylphosphoro- dithioate. 

	2. Analytical method. Adequate methods for purposes of enforcement of
ethoprop tolerances in plant commodities, ruminant tissues and milk are
available.

	3. Magnitude of residues. Five residue trials were conducted in Idaho,
Michigan and Oregon to determine ethoprop residue levels in mint. These
states represent approximately 83% of the cumulative production areas of
mint in the United States. Ethoprop residue levels in mint hay were all
<0.01 ppm. A processing study was conducted in Oregon. This state
represents 37% of the mint grown in the United States.  A concentration
factor of 4X was seen for ethoprop residues in mint oil. However, since
there are no measurable residues of ethoprop in mint based on the
residue trials there is no need for a ethoprop tolerance in mint oil.

Three hop residue trials were conducted in Idaho, Oregon and Washington,
covering the appropriate EPA regions.  Hops were harvested 118 to 135
days after application. Analysis of the hops showed that the ethoprop
residues in all samples were below the lowest level of method validation
(LLMV) of 0.02 ppm except for the Oregon trial where residues in one
sample were below the LLMV and residues in the second sample were just
quantifiable at 0.021 ppm. However, in the Oregon trial the test
substance was accidentally overlapped by approximately 14% which may
have contributed to the detectable residues.>

B. Toxicological Profile

1. Acute toxicity. The acute oral LD50 was 47 milligrams/ kilograms/
body weight (mg/kg bw) for both male and female rats.  The acute rat
dermal LD50 was 1280 mg/kg bw for male and 424 mg/kg bw for females. The
acute rabbit dermal LD50 was 8.5 mg/kg bw for male and 424 mg/kg bw for
females. The acute inhalation LC50 was between 0.12 and 0.25 mg/L for
male and female rats.  Due to its acute toxicity, skin and eye
irritation for ethoprop could not be evaluated in rabbits. The dermal
sensitization study in guinea pigs indicated that ethoprop is a moderate
skin sensitizer.  

	2. Genotoxicty.  The potential for genetic toxicity of ethoprop was
evaluated in several in vitro and in vivo assays. Ethoprop is devoid of
mutagenic activity in the Ames and Chinese Hamster Ovary-HGPRT assays
with and without metabolic activation.  Ethoprop was also negative in a
DNA repair assay with primary rat hepatocytes.  A negative response was
observed in both the in vitro chromosome aberration and in vitro sister
chromatid exchange assays without metabolic activation while a weakly
positive result was observed in both assays in the presence of metabolic
activation.  The weakly positive effect was observed only at cytotoxic
concentrations and was considered to be a secondary effect of
cytotoxicity.  In addition, no biologically significant dose-response
was observed in either assay.  A rat bone marrow cytogenic assay was
clearly negative in both sexes under acute and subchronic treatment
conditions.  A dominant lethal study in rats demonstrated that ethoprop
was not clastogenic.  Therefore, the weight of evidence clearly
demonstrates that ethoprop is not genotoxic.

	3. Reproductive and developmental toxicity.  Ethoprop has been tested
for reproductive toxicity in rats (2 studies) and developmental toxicity
in both rats and rabbits (2 studies in each species).  In a
three-generation reproduction study, 10 male and 20 female Fisher 344
rats were administered 0, 60.5, 131, or 262 ppm ethoprop in the diet. 
No NOEL for general toxicity to the parental animals was observed due to
decreased body weight gains at all doses tested.  No reproductive
effects were noted at any dose level tested.  For the offspring, a NOEL
of 131 ppm was established based on effects seen on the Lactation Index.
 In a two-generation reproduction study, 28 Sprague-Dawley rats per sex
per dose were administered 0, 1, 30, or 150 ppm (reduced from 300 ppm
due to excessive toxicity) of ethoprop in the diet.  The NOEL for
general toxicity in the adult animals was 1 ppm based on plasma and
brain cholinesterase inhibition at 30 ppm.  No reproductive effects were
noted at any dose level tested.  For the offspring, a NOEL of 30 ppm was
obtained (body weight effects at the top dose), indicating no increased
risk to the offspring in the absence of indications of overt adult
toxicity.

In a developmental study in rats, ethoprop was administered by gavage at
doses of 0, 0.16, 1.6, or 16 mg/kg for gestation days 6-15.  At 16
mg/kg/day, decreased body weight gain during gestation and increased
incidence of fetal wastage were observed.  At 1.6 mg/kg/day, a slight
increase in extra ribs (11 fetuses versus 2 in the controls) was
observed.  The significance was difficult to interpret due to the low
number of litters delivered at the top dose (12 litters versus 22 in
controls). A clear NOEL for developmental toxicity was established at
0.16 mg/kg/day.  In a second developmental study, rats were dosed by
gavage at 0, 2, 9, or 18 mg/kg/day on days 6 through 15 of gestation. 
The maternal NOEL was 2 mg/kg/day and the LOEL was 9 mg/kg/day based on
a slight but statistically significant depression of body weight gain at
9 mg/kg/day during the first 3 days of treatment.  The developmental
toxicity NOEL was 18 mg/kg/day due to the absence of any toxicological
effects on the fetus.

In a rabbit developmental study, ethoprop was administered by gavage at
doses of 0, 0.125, 0.5, or 2 mg/kg for gestation days 6-18. No evidence
of maternal or fetal toxicity was observed in the study. A NOEL for
maternal and developmental toxicity of 2 mg/kg/day was established.  In
a second developmental study, rabbits were dosed by gavage at 0, 0.625,
1.25, or 2.5 mg/kg/day on days 6 through 18 of gestation.  No evidence
of maternal or fetal toxicity were observed in this study despite the
fact that in a previously conducted rangefinding study, maternal
mortality was observed at doses of 5 and 10 mg/kg/day. A NOEL for
maternal and developmental toxicity of 2.5 mg/kg/day was established.

Therefore, based on the multi-generation reproduction studies in rats,
ethoprop is not considered a reproductive toxicant and shows no evidence
of endocrine effects.  The data from the developmental toxicity studies
on ethoprop show no evidence of a potential for developmental effects
(malformations or variations) at doses that are not maternally toxic. 
Based on the most current developmental toxicity studies, the NOEL for
maternal toxicity in rats was 2 mg/kg/day and for developmental toxicity
was 18 mg/kg/day.  In rabbits the NOEL for both maternal and
developmental toxicity was 2.5 mg/kg/day.

	4. Subchronic toxicity.   The subchronic toxicity of ethoprop has been
studied in three 21-day dermal studies in rabbits and a 5 month dog
study.  In a 21-day dermal study in rats, the animals were dosed at 0,
0.3, 1.0 or 10 mg/kg/day applied in mineral oil to the intact dorsal
dermal surface. The animals appeared healthy throughout the study with
no significant effects on body weights, food consumption, organ weights
or macroscopic or microscopic findings.  Both sexes had lower plasma and
RBC cholinesterase levels at 1.0 and 10 mg/kg/day.  The NOEL was
therefore 0.3 mg/kg/day. 

In a 21-day dermal study in rabbits, the animals were dosed at 0, 0.05,
0.1, or 1.0 mg/kg/day in 1% aqueous methyl cellulose.  There were no
effects of treatment other than on cholinesterase levels.  Plasma and
RBC cholinesterase levels were significantly reduced at 1 mg/kg/day and
brain cholinesterase was reduced at doses of 0.1 and 1 mg/kg/day. 
Therefore, the NOEL in this study was 0.05 mg/kg/day. In a second 21-day
dermal study in rabbits, the animals were dosed at 0, 0.03, 0.1, or 1
mg/kg/day in 4% carboxymethylcellulose in distilled water on the shaved
dorsal skin.  On the basis of reduced brain, RBC and plasma
cholinesterase in both sexes at 1.0 mg/kg/day, the NOEL in the study was
0.3 mg/kg/day.

In a 5 month dog study, dogs were administered capsules containing
ethoprop dissolved in corn oil at doses of 0.01, 0.025 and 1.0 mg/kg/day
for five months.  Significant decreases in plasma cholinesterase were
seen in both sexes at 0.025 and 1.0 mg/kg/day.  Significant decreases in
red blood cell cholinesterase were seen only in males at 1.0 mg/kg/day. 
There were no effects noted on brain cholinesterase.  No other changes
were noted in any of the other parameters evaluated in the study.  The
NOEL based on the plasma cholinesterase depression was 0.01 mg/kg/day.

Therefore, as previously demonstrated the rabbit is more sensitive to
the cholinesterase inhibiting properties of ethoprop and is not
considered to be an appropriate model for dermal exposure in humans. 
The NOEL in the rat dermal study was 1 mg/kg/day.  In a subchronic dog
study, the NOEL based on plasma cholinesterase depression was 0.01
mg/kg/day.

	5. Chronic toxicity.  Three two-year rat chronic toxicity/oncogenicity
studies, two 18 to 24 month mouse oncogenicity studies, and a 1-year dog
study, were performed with ethoprop. In a combined ethoprop chronic
toxicity/oncogenicity study in F-344 rats, the animals were exposed in
utero and during nursing by administering the test diet at
concentrations of 0, 60.5, 131, and 262 ppm to the F0 parents.  The F1
generation that made up the 2-year phase of the study received doses of
0, 4.5, 9, or 18 ppm for weeks 0-12 and doses of 0, 49, 98, or 196 ppm
from weeks 13-109.  The only finding at the low dose of 49 ppm was a
depression of serum and brain cholinesterase.  The effects noted at 98
and 196 ppm that exhibited a dose response relationship included
depression of serum and brain cholinesterase and reduced body weights. 
No histopathological or tumorogenic effects were observed at any dose
level.

In a second combined chronic toxicity/oncogenicity study, Fischer 344
rats were administered doses of 0, 1.0, 10.0, or 100.0 ppm in the diet
for 24 months.  A NOEL of 1.0 ppm was established in both sexes based on
plasma and RBC cholinesterase depression at 10.0 and 100.0 ppm.  Brain
cholinesterase inhibition was noted only at a dose of 100 ppm in both
sexes.  No histopathological or tumorogenic effects were observed at any
dose level.

In a third combined chronic toxicity/oncogenicity study, Sprague-Dawley
rats were administered dose of 0, 1, 60, and 400 ppm in the diet for 104
weeks.  A NOEL of 1 ppm (0.05 mg/kg/day) was established in both sexes
based on plasma, RBC, and brain cholinesterase depression at 60.0 and
400.0 ppm.  No indication of carcinogenicity was observed at any dose
level.

Male and female B6C3F1 mice were administered ethoprop in the diet at 0,
0.2, 2 or 30 ppm for 104 weeks.  RBC, plasma, and brain cholinesterase
levels were inhibited at dose levels of 2 and 30 ppm.  A NOEL of 0.2 ppm
was established in the study.  A slight increase in hepatocellular
carcinomas in females at 30 ppm was considered to be within normal
variability and was not considered to be the result of treatment. In a
second mouse study, male and female B6C3F1 mice were administered
ethoprop in the diet at 0, 15, 30 or 60 ppm for 78 weeks.  RBC and
plasma cholinesterase levels were inhibited at all dose levels.  There
was no evidence of any histopathological effect, including oncogenicity,
associated with treatment at any dose level.

A chronic dog study was also conducted in which ethoprop was
administered via capsule to beagle dogs for 52 weeks at doses of 0,
0.025, 1, and 10 mg/kg/day.  One high dose animal was sacrificed in a
moribund condition.  Plasma cholinesterase inhibition was seen at doses
of 1 and 10 mg/kg/day.  RBC and brain cholinesterase and hepatotoxicity
were observed at 10 mg/kg/day.

All of the available data demonstrate that ethoprop is not carcinogenic
in animals (rats, mice or dogs).  The major effect of ethoprop is
cholinesterase inhibition.  The dog study established the lowest NOEL of
0.01 mg/kg/day based on plasma cholinesterase depression.

6. Neurotoxicity.  The possibility of acute delayed neurotoxicity and
acute and subchronic neurotoxicity of ethoprop has been studied.  The
acute delayed neurotoxicity of ethoprop has been investigated in adult
domestic hens.  Sixty three hens were administered a single 6.5 mg/kg
dose in corn oil.  To protect against acute cholinergic effects, these
hens also received either atropine or atropine and 2-PAM immediately
prior to and at 24 hour intervals after the ethoprop dose.  At study
termination, tissues were perfused in situ and sections of the brain,
spinal cord, and sciatic and tibial nerve were processed for
histopathological examination.  Ethoprop did not produce acute delayed
neurotoxicity.  

In a rat study groups of 17 male and 17 female Sprague Dawley rats were
treated once by gavage with ethoprop at dose levels of 0, 5, 50, or 75
mg/kg bw for males and 0, 5, 25, or 50 mg/kg bw for females in order to
assess its potential acute neurotoxicity by evaluating motor activity,
functional observation battery (FOB), and cholinesterase depression. The
NOEL based on the FOB results was 5 mg/kg in both sexes.  Based on motor
activity, the NOEL was 5 mg/kg in males and 25 mg/kg in females.  Based
on RBC cholinesterase activity, the NOEL was 5 mg/kg in males and below
5 mg/kg in females.  The NOEL for plasma cholinesterase was 5 mg/kg for
both sexes.  The NOEL for Day 15 brain cholinesterase effects and
neuropathologic effects is greater than 75 mg/kg in males and greater
than 50 mg/kg in females.

Groups of 27 male and 27 female Sprague Dawley rats were treated in the
diet with ethoprop at dose levels of 0, 4, 40, or 400 ppm for 3 months
in order to assess its potential subchronic neurotoxicity by evaluating
motor activity, functional observation battery (FOB), and cholinesterase
depression. The NOEL based on the FOB results was 40 ppm in both sexes. 
Based on motor activity, the NOEL was 40 ppm in males and 400 ppm in
females.  Based on plasma, RBC and brain cholinesterase activity, the
NOEL was 4 ppm in males and below 4 ppm in females.  The NOEL for
neuropathologic effects is greater than 400 ppm in both males and
females.

Therefore, ethoprop has been shown not to be an acute delayed
neurotoxicant.  Due to its cholinesterase inhibiting properties it does
lead to typical behavioral effects from acute and subchronic exposures. 
Ethoprop, however, does not lead to any observable neuropathologic
effects.

	7. Animal metabolism.  Oral administration of ethoprop to the rat
results in rapid absorption, distribution, metabolism and excretion of
the residues. Excretion, which is essentially complete by 48 hours post
dose, is primarily in the urine with some in the feces as well as
respired air. Terminal elimination t1/2 is the blood was 92-135 hours.
Metabolism is by hydrolysis of the S-propyl groups followed by
conjugation. 

	8. Metabolite toxicology.  Available data indicate that several of the
organophosphate metabolites of ethoprop have cholinesterase inhibiting
activity. Available data indicate that the toxicity of these metabolites
has been evaluated in the toxicity studies for the parent compound. 
Therefore no additional toxicity studies were needed for metabolites. 

	9. Endocrine disruption.  In the available toxicity studies on
ethoprop, there was no estrogen or androgen, mediated toxicity. When
additional appropriate screening and/or testing protocols being
considered under the Agency’s EDSP have been developed, ethoprop may
be subjected to further screening and/or testing to better characterize
effects related to endocrine disruption. 

C. Aggregate Exposure

	1. Dietary Exposure.  There are no residential uses for ethoprop;
therefore aggregate exposure consists of dietary (food and drinking
water) exposures.  The acute population adjusted dose (aPAD) of 0.00025
mg/kg bw/day based on an acute NOAEL of 0.025 mg/kg bw/day with an
uncertainty factor of 100 was used to assess acute dietary exposure. 
The chronic population adjusted dose (cPAD) of 0.0001 mg/kg bw/day based
on a chronic NOAEL of 0.01 mg/kg bw/day with an uncertainty factor of
100 was used to assess chronic exposure. The chronic cancer assessment
was based on a Q* of 0.0281.

	i.Food. The current acute and chronic dietary assessments include all
of the current uses for ethoprop as well as the proposed new uses on
mint and hops. No significant contribution was seen from these new uses.
 The US Population utilized 28% of the aPAD (99.9th percentile) and 6%
of the cPAD.  The most highly exposed sub-population for the acute
assessment was Children 1-2 at 78% of the aPAD (99.9th percentile) and
All Infants for the chronic assessment at 15% of the cPAD. The chronic
cancer assessment showed exposure equivalent to a risk of 1.58 x 10-7.
These assessments included human exposure from both food and water.

	ii. Drinking Water.  US EPA’s Standard Operating Procedure (SOP) for
Drinking Water Exposure and Risk Assessments was used to perform the
drinking water assessment.  This SOP uses a variety of tools to conduct
drinking water assessment.   These tools include water models such as
SCI-GROW, FIRST, PRZMS/EXAMS, and monitoring data.  If monitoring data
are not available then the models are used to predict potential residues
in surface and ground water and the highest is assumed to be the
drinking water residue.  In the case of ethoprop monitoring data do
exist and were used in the assessment. A concentration of 202 ppt from a
surface water monitoring study was used in the above assessment. As
noted, the dietary assessments given above included both food and water.

2.  Non-dietary Exposure. Since there are no residential uses of
ethoprop, there are no non-occupational risks from residential
exposures. 

D. Cumulative Effects

Ethoprop is a member of the organophosphate class of insecticides. In
recent communications regarding the cumulative assessment of
organophosphate insecticides, EPA commented that it has completed its
assessment of the cumulative risks from the organophosphate (OP) class
of pesticides as required by the Food Quality Protection Act of 1996. In
addition, the individual OPs have also been subject to review through
the individual-chemical review process. The Agency’s review of
individual OPs has resulted in the issuance of Interim Reregistration
Eligibility Decisions (IREDs) for 22 OPs, interim Tolerance Reassessment
and Risk Management Decisions (TREDs) for 8 OPs, and a Reregistration
Eligibility Decision (RED) for one OP. EPA has concluded, after
completing its assessment of the cumulative risks associated with
exposures to all of the OPs (including ethoprop), that: (1) the
pesticides covered by the IREDs that were pending the results of the OP
cumulative assessment are indeed eligible for reregistration; and (2)
the pesticide tolerances covered by the IREDs and TREDs that were
pending the results of the OP cumulative assessment meet the safety
standard under Section 408(b)(2) of the FFDCA. Thus, with regard to the
OPs, EPA has fulfilled its obligations as to FFDCA tolerance
reassessment and FIFRA reregistration, other than product-specific
reregistration.

E.  Safety Determination

	1. US Population.  Using the conservative exposure assumptions
described above and based on the completeness of the toxicity data, it
can be concluded that aggregate exposure to residues of ethoprop present
a reasonable certainty of no harm.  Exposure from residues in crops and
water utilizes 28% of the aPAD and 6% of the cPAD.  EPA generally has no
concerns for exposures below 100% of the Population Adjusted Doses.  A
chronic cancer assessment indicates that total cancer exposure is
equivalent to a risk of 1.58x10-7. EPA generally has no concerns for
exposures below 3 X 10-6.  Drinking water is included in this
assessment. The conservative nature of these assessments demonstrates a
reasonable certainty of no harm will result from uses of ethoprop for
the US Population.

		2. Infants and children.  In assessing the potential for additional
sensitivity of infants and children to residues of ethoprop, the
available developmental toxicity and reproductive toxicity studies and
the potential for endocrine modulation by ethoprop were considered. 
Developmental toxicity studies in two species indicate that ethoprop is
not a teratogen.  The 2 and 3 generation reproduction studies in rats
demonstrated that there were no adverse effects on reproductive
performance, fertility, fecundity, pup survival, or pup development. 
Maternal and developmental NOELs and LOELS were comparable, indicating
no increase in susceptibility of developing organisms.  No evidence of
endocrine effects was noted in any study.  It is therefore concluded
that ethoprop poses no additional risk for infants and children and no
additional uncertainty factor is warranted.

FFDCA section 408 provides that an additional safety factor for infants
and children may be applied in the case of threshold effects.  Since, as
discussed in the previous section, the toxicology studies do not
indicate that young animals are any more susceptible than adult animals
and the fact that the current RfD already incorporates a 100X
uncertainty factor, an adequate margin of safety is therefore provided
by the RfD established by EPA.  In addition, ethoprop has no
endocrine-modulation characteristics as demonstrated by the lack of
endocrine effects in developmental, reproductive, subchronic, and
chronic studies. Therefore, no additional FQPA safety factor for infants
and children is warranted based on the completeness and reliability of
the database, the demonstrated lack of increased risk to developing
organisms, and the lack of endocrine-modulating effects. 

Based on above conservative exposure assessments the total aggregate
exposure to ethoprop will utilize at most 78% of the acute RfD/PAD
(Children 1-2) and 15% of the chronic RfD/PAD (All Infants) even for
these most highly exposed population subgroup.  In addition, the cancer
assessment shows that the total exposure for the US Population is 1.58 x
10-7, well within the Agency’s level of concern of 3 x 10-6.

F. International Tolerances

		

Although many CODEX Maximum Residue Limits (MRL’s) have been
established for residues of ethoprop in/on crops there are no CODEX
MRL’s for ethoprop on mint or hops at this time.

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