United States Office of Prevention, Pesticides
Environmental Protection and Toxic Substances
Agency (7505P)
<&EPA Pesticide
Fact Sheet
Name of Chemical: Meptyldinocap
Reason for Issuance: New Chemical
Tolerance Established
Date Issued: September 2009
Description of Chemical
Generic Name: 2-(l-methylheptyl)-4,6-dinitrophenyl (2E)-2-butenoate
Common Name: Meptyldinocap
Trade Name Used: GF-1478 Fungicide
In Foreign Countries:
Chemical Class: Dinitrophenol
EPA Chemical Code: 036000
Chemical Abstracts
Service (CAS) Number: 131 -72-6
Registration Status: Not Registered in the U.S.; Import Tolerance Established
Pesticide Type: Fungicide
U.S. Producer: Dow AgroSciences, LLC
9330 Zionsville Road
Indianapolis, IN 46268
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Tolerances Established
An import tolerance for the combined residues of meptyldinocap (2-(l-methylheptyl)-4,6-
dinitrophenyl (2£)-2-butenoate) and 2,4-DNOP (2,4-dinitro-6-(l-methylheptyl)phenol)
expressed as meptyldinocap for use on grapes at 0.2 ppm was established in the 40 CFR
§180.648.
Use Patterns and Formulation
Meptyldinocap is a new dinitrophenol fungicide and is one of six isomers found in the older
fungicide dinocap. Meptyldinocap is used on grapevines in the United Kingdom, Italy, Romania,
Hungary, Tunisia, and Chile to control powdery mildew. Meptyldinocap is proposed for use in
these countries as a 350 g/L emulsifiable concentrate (EC) formulation labeled for multiple foliar
applications per season. Meptyldinocap interferes with fungal respiration by acting as an
uncoupler of oxidative phosphorylation, and has been placed in Group 29 by the Fungicide
Resistance Action Committee (FRAC). There are currently no meptyldinocap products
registered in the U.S. A summary of the use pattern in foreign countries is provided in Table 1
below.
Table 1 Maximum Application Rate of Meptyldinocap on Grapes in Several European
Countries and Tunisia
App. Timing, Type,
and Equip.
Broadcast foliar - BBCH
growth stage 13 to 8 1(3
leaves unfolded; beginning
of ripening); broadcast
application by ground
equipment
Formulation
3 50 g/L EC
App. Rate
(kg ai/ha)
0.21
Max. No.
App. per
Season
4
Max. Seasonal
App. Rate
(kg ai/ha)
0.84
PHI
(days)
21
Use Directions and
Limitations
Retreatment interval (RTI) =
10 days, RTI of 5 days when
used as an eradicant late in
the season (only two
applications may be made as
a late season eradicant )
Maximum Application Rate of Meptyldinocap on Grapes in Chile
Broadcast foliar - swollen-
bud to preflower and
postharvest; broadcast
application by ground
equipment
350 g/L EC
preharvest -
0.21
postharvest -
0.41
3
not indicated
60
m = 7 days.
Product Chemistry
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Table 2 Nomenclature of Meptyldinocap
Structure
Common name
Company experimental name
IUPAC name
CAS name
CAS registry number
Molecular weight
End-use product (EP)
o
HjC'^^-^'^O CH3
Q^y'Lx'x/x/x/cH,
NO2
Meptyldinocap (also referred to as 2,4-dinitro-6-(l-methylheptyl) crotonate)
DE-126;RH-23,163
(RS)-2-(l -methylheptyl)-4,6-dinitrophenyl crotonate
2-( 1 -methvlheptyl)-4,6-dinitrophenyl (2£)-2-butenoate
131-72-6
364.40
350 g/L EC (GF-1478 Fungicide; 33.2% EC)
Table 3 Physicochemical Properties
Melting point
PH
Relative density
Water solubility (mg/L) at 20°C
Solvent solubility (g/L) at 25°C
Vapor pressure (Pa) at 25°C
Dissociation constant, pKa
Octanol/water partition coefficient,
Log(Kow) at 20.5°C
UV/visible absorption spectrum
(maxima, molar extinction coefficient)
-22.5°C
not applicable
1.11
0.151
Acetone >252
Ethyl acetate >256
1,2-Dichloroethane >252
Xylene >256
n-Heptane >251
Methanol >253
7.92 x 10"6
Does not dissociate in aqueous solutions.
6.55 ±0.33
acidic: 240 nm (e= 16727), 310 nm (e=2155)
basic: 260 nm (e=6376), 372 nm (e=12980), 405 nm (e=10969)
neutral: 240 nm (e= 16727), 310 nm (e=2155)
Toxicology Profile
Table 4 Acute Toxicity Profile - Technical Meptyldinocap
Guideline No.
870.1100
870.1200
870.1300
Study Type
Acute oral (rat)
Acute dermal (rat)
Acute inhalation (rat)
MRID(s)
47289116
47289118
N/A
Results
LD5o > 2000
mg/kg bw (F)
LD5o > 5000
mg/kg bw (M&F)
N/A
Toxicity Category
III
IV
N/A
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870.2400
870.2500
870.2600
Primary eye irritation (rabbit)
Primary dermal irritation (rabbit)
Dermal sensitization (mouse)
47289120
47289122
47289124
Minimally
irritating
Slight irritant
Positive (LLNA)
III
IV
N/A
Table 5 Subchronic, Chronic and Genotoxicity Profile for Meptyldinocap
Guideline No./
Study Type
MRID No. (year)/
Classification /Doses
Results
870.3050
28-Day oral toxicity
(mouse)
47289127 (2005)
Acceptable/non-guideline
0, 100, 200, or 750 ppm
(equivalent to 0/0, 16/19.3,
30.7/40.8, or 117/161.1
mg/kgbw/day [M/F])
NOAEL = 750ppm(117/161.1 mg/kgbw/day [M/F])
LOAEL not observed.
870.3100
90-Day oral toxicity
(rat)
47289128 (2005)
Acceptable/guideline
0, 200, 650, or 2000 ppm
(equivalent to 0/0, 11/13,
37/41, or 113/127 mg/kg
bw/day [M/F])
NOAEL = 650 ppm (37/41 mg/kg bw/day [M/F])
LOAEL = 2000 ppm (113/127 mg/kg bw/day [M/F]), based on
decreased body weight, body-weight gain, and food consumption
in both sexes.
870.3150
90-Day oral toxicity
(dog)
47289129 (2005)
Acceptable/guideline
0, 15, 60, or 120 ppm
(equivalent to 0/0,
0.49/0.48, 1.51/2.14, or
3.58/3.89 mg/kg bw/day
[M/F])
NOAEL = 60 ppm (1.51 mg/kgbw/day [M])
LOAEL =120 ppm (3.58 mg/kg bw/day) based on significant,
sustained increased alanine aminotransferase (ALT) and
aspartame aminotransferase (AST) levels (M).
870.4100
1-year oral toxicity
(dog)
Extension of 90-day
study without a
control group
47289130 (2006)
Acceptable/non-guideline
120 ppm (equivalent to
3.31/3.22 mg/kg bw/day
[M/F])
No effect of treatment at 120 ppm on limited number of
parameters, including ophthalmological measurements.
870.3700
Prenatal
developmental
(mouse)
47289132 (2005)
Acceptable/non-guideline
0, 100, 250, or 500 mg/kg
bw/day)
Maternal NOAEL = 500 mg/kg bw/day
Maternal LOAEL not observed.
Developmental NOAEL = 500 mg/kg bw/day
Developmental LOAEL not observed.
No effect on external or otoconial development.
870.3700
Prenatal
developmental (rat)
47289134 (2005)
Acceptable/guideline
0,50, 150, [or 500
Maternal NOAEL = 50 mg/kg bw/day
Maternal LOAEL =150 mg/kg bw/day based on decreased body
weights, body-weight gains, and food consumption.
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Table 5 Subchronic, Chronic and Genotoxicity Profile for Meptyldinocap
Guideline No./
Study Type
MRID No. (year)/
Classification /Doses
Results
(terminated)] mg/kg
bw/day)
Developmental NOAEL =150 mg/kg bw/day
Developmental LOAEL not observed.
Developmental toxicity was not observed, including effects on
otoconial development.
870.3700
Prenatal
developmental
(rabbit)
47289136 (2005)
Acceptable/guideline
0, 3, 12, or 48 mg/kg
bw/day
Maternal NOAEL =12 mg/kg bw/day
Maternal LOAEL = 48 mg/kg bw/day based on decreased body-
weight gains and food consumption.
Developmental NOAEL = 48 mg/kg bw/day
Developmental LOAEL not observed.
Developmental toxicity was not observed, including effects on
otoconial development.
Special study
Oral developmental
toxicity with non-
methylheptyl isomers
of dinocap (mice)
47289133 (2005)
Acceptable/non-guideline
5 or 10 mg/kg bw/day,
depending on isomer
Developmental toxicity was observed with the 2,6-dinitro-4-(l-
propylpentyl)-phenyl crotonate (4-PP) isomer of dinocap only.
Special study
Oral developmental
and postnatal toxicity
with methylheptyl
isomers of dinocap
and dinocap (mice)
47304907 (1987)
Acceptable/non-guideline
25 mg/kg bw/day
No evidence of developmental toxicity, incl. cleft palate or
torticollis and no effects on fetal body weight, swimming ability,
or otolith development with either methylheptyl isomer or in
combination.
Also published in Rogers et al. 1987.
Teratogenesis, Carcinogenesis, and
Mutagenesis 7:341-346.
870.5100
Bacterial gene
mutation
47289137 (2005)
Acceptable/guideline
0-4690 ug/plate (+/- S9)
Negative
870.5300
Mammalian cell gene
mutation
47289138 (2005)
Acceptable/guideline
0-18.6 |ag/mL (-S9)
0-92.9 lag/mL (+S9)
Negative
870.5375
In vitro mammalian
chromosomal
aberration
47289139 (2005)
Acceptable/guideline
0-929 ug/mL (+/-S9)
Negative
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Table 5 Subchronic, Chronic and Genotoxicity Profile for Meptyldinocap
Guideline No./
Study Type
MRID No. (year)/
Classification /Doses
Results
870.5395
In vivo mouse
erythrocyte
micronucleus assay
47289140 (2005)
Acceptable/guideline
0, 465, 929, or 1858 mg/kg
bw
Negative
870.7485
Metabolism and
pharmacokinetics
47289141 (1996)
Acceptable/non-guideline
29.5 (mice) or 95.5 (rats)
mg/kg bw (single dose)
This study was performed to evaluate
differences in rat and mouse urinary
metabolism (only) of meptyldinocap as a
surrogate for dinocap. Fatty acid (3-oxidation
was the primary metabolic pathway in both
species; more metabolism occurred via fatty
acid a-oxidation in mice (approximately
32.9%) than in the rats (18.0%). A
total of 7 metabolites were identified in
mouse urine that were not identified in
rat urine; however, each compound
represented only 1.23-2.78% of the
total radioactivity isolated in the urine.
Based on these results, 2,4-DNHPC undergoes
esterase-mediated de-esterification followed by
sequential metabolism by cytochrome P-450,
alcohol dehydrogenase, and aldehyde
dehydrogenase to form the carboxylated
metabolite, 2,4-dinitro-6-(l-
methylheptanoate)phenol. Further metabolism
proceeds via the fatty acid pathways, which is
the primary pathway for metabolism of 2,4-
DNHPC in both rat and mouse.
870.7485
Metabolism and
pharmacokinetics
00153615, 47289142
(1976)
Acceptable/non-guideline
49 mg/kg bw/day (7 days;
1 rat/sex)
Absorption: 18-24% administered dose throughout 7 days.
Distribution: largest concentrations of radioactive residues
(excluding the GI tract) included heart, carcass, liver, pelt, and
thymus (0.27-0.85% administered dose).
Metabolism: hydrolysis of the crotonate ester followed by
oxidation of the octyl side chain.
Excretion: primarily through the feces (52-58% administered
dose) and urine (15-20% administered dose) throughout 7 days.
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Table 5 Subchronic, Chronic and Genotoxicity Profile for Meptyldinocap
Guideline
No.
Study Type
MRID No. (year)/
Classification /Doses
Results
870.3050
28-Day oral
toxicity (mouse)
47289127 (2005)
Acceptable/non-guideline
0, 100, 200, or 750 ppm
(equivalent to 0/0, 16/19.3,
30.7/40.8, or 117/161.1
mg/kgbw/day [M/F])
NOAEL = 750 ppm (117/161.1 mg/kgbw/day
[M/F])
LOAEL not observed.
870.3100
90-Day oral
toxicity (rat)
47289128 (2005)
Acceptable/guideline
0, 200, 650, or 2000 ppm
(equivalent to 0/0, 11/13,
37/41, or 113/127 mg/kg
bw/day [M/F])
NOAEL = 650 ppm (37/41 mg/kg bw/day [M/F])
LOAEL = 2000 ppm (113/127 mg/kgbw/day
[M/F]), based on decreased body weight, body-
weight gain, and food consumption in both sexes.
870.3150
90-Day oral
toxicity (dog)
47289129 (2005)
Acceptable/guideline
0, 15, 60, or 120 ppm
(equivalent to 0/0, 0.49/0.48,
1.51/2.14, or 3.58/3.89
mg/kgbw/day [M/F])
NOAEL = 60 ppm(1.51 mg/kgbw/day [M])
LOAEL = 120 ppm (3.58 mg/kg bw/day) based on
significant, sustained increased alanine
aminotransferase (ALT) and aspartame
aminotransferase (AST) levels (M).
870.4100
1-year oral toxicity
(dog)
Extension of 90-
day study without a
control group
47289130 (2006)
Acceptable/non-guideline
120 ppm (equivalent to
3.31/3.22 mg/kg bw/day
[M/F])
No effect of treatment at 120 ppm on limited
number of parameters, including ophthalmological
measurements.
870.3700
Prenatal
developmental
(mouse)
47289132 (2005)
Acceptable/non-guideline
0, 100, 250, or 500 mg/kg
bw/day)
Maternal NOAEL = 500 mg/kg bw/day
Maternal LOAEL not observed.
Developmental NOAEL = 500 mg/kg bw/day
Developmental LOAEL not observed.
No effect on external or otoconial development.
870.3700
Prenatal
developmental (rat)
47289134 (2005)
Acceptable/guideline
0, 50, 150, [or 500
(terminated)] mg/kg bw/day)
Maternal NOAEL = 50 mg/kg bw/day
Maternal LOAEL = 150 mg/kg bw/day based on
decreased body weights, body-weight gains, and
food consumption.
Developmental NOAEL =150 mg/kgbw/day
Developmental LOAEL not observed.
Developmental toxicity was not observed, including
effects on otoconial development.
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Table 5 Subchronic, Chronic and Genotoxicity Profile for Meptyldinocap
Guideline
No.
Study Type
MRID No. (year)/
Classification /Doses
Results
870.3700
Prenatal
developmental
(rabbit)
47289136 (2005)
Acceptable/guideline
0, 3, 12, or 48 mg/kgbw/day
Maternal NOAEL = 12 mg/kg bw/day
Maternal LOAEL = 48 mg/kg bw/day based on
decreased body-weight gains and food consumption.
Developmental NOAEL = 48 mg/kg bw/day
Developmental LOAEL not observed.
Developmental toxicity was not observed, including
effects on otoconial development.
Special
study
Oral developmental
toxicity with non-
methylheptyl
isomers of dinocap
(mice)
47289133 (2005)
Acceptable/non-guideline
5 or 10 mg/kg bw/day,
depending on isomer
Developmental toxicity was observed with the 2,6-
dinitro-4-(l-propylpentyl)-phenyl crotonate (4-PP)
isomer of dinocap only.
Special
study
Oral developmental
and postnatal
toxicity with
methylheptyl
isomers of dinocap
and dinocap (mice)
47304907 (1987)
Acceptable/non-guideline
25 mg/kg bw/day
No evidence of developmental toxicity, incl. cleft
palate or torticollis and no effects on fetal body
weight, swimming ability, or otolith development
with either methylheptyl isomer or in combination.
Also published in Rogers et al. 1987.
Teratogenesis, Carcinogenesis, and
Mutagenesis 7:341-346.
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Table 5 Subchronic, Chronic and Genotoxicity Profile for Meptyldinocap
Guideline
No.
870.5100
870.5300
870.5375
870.5395
870.7485
Study Type
Bacterial gene
mutation
Mammalian cell
gene mutation
In vitro mammalian
chromosomal
aberration
In vivo mouse
erythrocyte
micronucleus assay
Metabolism and
pharmacokinetics
MRID No. (year)/
Classification /Doses
47289137 (2005)
Acceptable/guideline
0-4690 ug/plate (+/- S9)
47289138 (2005)
Acceptable/guideline
0-18.6 (4,g/mL (-S9)
0-92.9 (4,g/mL (+S9)
47289139 (2005)
Acceptable/guideline
0-929 ug/mL (+/-S9)
47289140 (2005)
Acceptable/guideline
0, 465, 929, or 1858 mg/kg
bw
47289141 (1996)
Acceptable/non-guideline
29.5 (mice) or 95.5 (rats)
mg/kg bw (single dose)
Results
Negative
Negative
Negative
Negative
This study was performed to evaluate
differences in rat and mouse urinary
metabolism (only) of meptyldinocap as a
surrogate for dinocap. Fatty acid (3-oxidation
was the primary metabolic pathway in both
species; more metabolism occurred via fatty
acid a-oxidation in mice (approximately
32.9%) than in the rats (18.0%). A
total of 7 metabolites were identified in
mouse urine that were not identified in
rat urine; however, each compound
represented only 1.23-2.78% of the
total radioactivity isolated in the urine.
Based on these results, 2,4-DNHPC undergoes
esterase-mediated de-esterification followed by
sequential metabolism by cytochrome P-450,
alcohol dehydrogenase, and aldehyde
dehydrogenase to form the carboxylated
metabolite, 2,4-dinitro-6-(l-
methylheptanoate)phenol. Further metabolism
proceeds via the fatty acid pathways, which is
the primary pathway for metabolism of 2,4-
DNHPC in both rat and mouse.
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Table 5 Subchronic, Chronic and Genotoxicity Profile for Meptyldinocap
Guideline
No.
Study Type
MRID No. (year)/
Classification /Doses
Results
870.7485
Metabolism and
pharmacokinetics
00153615, 47289142 (1976)
Acceptable/non-guideline
49 mg/kg bw/day (7 days; 1
rat/sex)
Absorption: 18-24% administered dose throughout 7
days.
Distribution: largest concentrations of radioactive
residues (excluding the GI tract) included heart,
carcass, liver, pelt, and thymus (0.27-0.85%
administered dose).
Metabolism: hydrolysis of the crotonate ester
followed by oxidation of the octyl side chain.
Excretion: primarily through the feces (52-58%
administered dose) and urine (15-20% administered
dose) throughout 7 days.
Toxicological Endpoints
Table 6 Meptyldinocap - Summary of Toxicological Doses and Endpoints Used in
Human Health Risk Assessment
Exposure
Scenario
Acute Dietary
(All populations)
Chronic Dietary
(All populations)
Cancer
Point of
Departure
Uncertainty /FQPA
Safety Factors
RfD, PAD, LOC
for Risk
Assessment
Study and Relevant Toxicological
Effects
An endpoint of concern (effect) attributable to a single dose was not identified in the database.
Quantification of acute risk to all populations was not required.
NOAEL =
1.51
mg/kg
bw/day
UFA = lOx; UFH =
lOx
UFFQpA = 3x;
(includes UFS)
cRfD = cPAD =
0.005 mg/kg
bw/day
90-day oral (dog; dietary)
LOAEL = 120 ppm (3.58 mg/kg
bw/day) based on sustained increased
alanine aminotransferase (ALT) and
aspartame aminotransferase (AST)
levels in males
Carcinogenicity studies with meptyldinocap were not performed. Classification of dinocap: "Group
E, Evidence of non-carcinogenicity in humans"
Abbreviations:
UF = uncertainty factor
UFA = extrapolation from animal to human (interspecies)
UFH = potential variation in sensitivity among members of the human population (intraspecies)
UFFQPA = FQPA Safety Factor
UFS = extrapolation from subchronic to chronic exposure
NOAEL = no observed adverse effect level
LOAEL = lowest observed adverse effect level
RfD = reference dose (a = acute, c = chronic) = NOAEL + (UFA x UFH)
PAD = population adjusted dose = RfD -^ UFFQPA.
10
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Food Quality Protection Act Considerations:
EPA has determined that an FQPA SF of 3X is necessary to protect the safety of infants and
children given that the point-of-departure for estimating chronic human risk was chosen from a
subchronic study. Use of a 3X SF, in the form of an uncertainty factor for subchronic-to-chronic
extrapolation, with the NOAEL of 1.5 mg/kg/ bw/day from a 90-day toxicity study in dogs yields
an effective NOAEL of 0.5 mg/kg/ bw/day for meptyldinocap. EPA concludes that reliable data
support this FQPA SF based upon the following considerations:
1) The adjusted NOAEL for meptyldinocap is virtually identical to the NOAEL used for the
cRfD for dinocap (0.4 mg/kg bw/day). Use of a larger SF for meptyldinocap would yield
a lower point of departure than that for dinocap, which would be inappropriate, given that
meptyldinocap is a significantly less toxic chemical than dinocap. Evidence showing the
lower toxicity of meptyldinocap include:
• Meptyldinocap is one of six isomers contained in dinocap. Toxicological studies
have isolated the teratogenic isomer in dinocap, and it is not meptyldinocap.
• Meptyldinocap is considered less toxic than dinocap based on the lack of
developmental and ocular toxicities with meptyldinocap at approximately 5X the
doses contained in dinocap.
• A comparison of subchronic studies in the mouse for dinocap with similar studies
for meptyldinocap indicated that dinocap caused liver toxicity and death, whereas
toxicity was absent with meptyldinocap following treatment for 28 days at a
higher dose.
• Unlike dinocap, there is no evidence of offspring susceptibility with
meptyldinocap in any of four developmental toxicity studies across three species
tested.
• Unlike dinocap, there was no evidence of neurotoxicity or neuropathology in any
of the submitted studies for meptyldinocap.
• Unlike dinocap, there was no effect of treatment on mortality, clinical signs,
ophthalmological examinations, or select gross or microscopic pathology in dogs
treated for one year with meptyldinocap. The dinocap cRfD was based on a
chronic study in dogs.
2) Evidence from the meptyldinocap dog study indicates that extending exposure from
subchronic to chronic would not have produced a lower NOAEL. As indicated above,
the extension of the meptyldinocap dog study for an additional 9 months did not result in
effects on mortality, clinical signs, ophthalmological examinations, or select gross or
microscopic pathology as it did with dinocap. Moreover, while levels of serum hepatic
enzymes in dogs in the meptyldinocap study were increased significantly over controls
throughout the 90-day exposure period, the serum hepatic enzyme levels did not become
more severe over time.
11
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Although EPA does not have toxicology studies conducted with meptyldinocap to fulfill
all data requirements, EPA concludes that between the dinocap and meptyldinocap
studies it has a complete database. The dinocap database was incomplete due to a lack of
a developmental neurotoxicity study but such a study is not needed for meptyldinocap
because there was no evidence of neurotoxicity or neuropathology in any of the
submitted studies for meptyldinocap. These results contrast with those of dinocap in
which minor neuropathology was noted in dogs treated with dinocap as a positive control
for 90 days.
EPA began requiring acute and subchronic neurotoxicity testing of all food and non-food
use pesticides on December 26, 2007. Since this requirement went into effect after the
tolerance petition was submitted, these studies are not yet available for meptyldinocap.
In the absence of specific neurotoxicity studies, EPA has evaluated the available toxicity
data to determine whether an additional database uncertainty factor is needed to account
for potential neurotoxicity. Given the lack of neurotoxicity or neuropathology in any
meptyldinocap studies, EPA does not believe that conducting acute or subchronic
neurotoxicity testing will result in aNOAEL less than 1.5 mg/kg/day already established
for the cRfD for meptyldinocap, and an additional uncertainty factor is not needed to
account for the lack of these data. Immunotoxicity testing is also required as a result of
changes made to the pesticide data requirements in December of 2007.
An immunotoxicity study has not been conducted with meptyldinocap. However, an in
vivo immunotoxicity study with additional in vitro measurements (Smialowicz, et al.,
1992) has been conducted with dinocap in mice and published in the open literature.
Immune function, cellularity, organ weights, and histopathology were measured over
several doses in the study. Immunotoxicity was observed at a 30-fold higher dose than
the effective NOAEL used to calculate the cRfD for meptyldinocap. Because a well
conducted immunotoxicity study with dinocap was performed previously, and since
meptyldinocap is considered less toxic than dinocap, the requirement for an
immunotoxicity study with meptyldinocap has been satisfied by the literature study with
dinocap.
3) There is no evidence of offspring susceptibility with meptyldinocap in any of four
developmental toxicity studies across three species tested.
4) There are no residual uncertainties identified in the exposure database for meptyldinocap.
The dietary food exposure assessments were performed based on 100%CT and
tolerance-level residues as well as a very conservative assumption of what meptyldinocap
exposure could occur from use of dinocap. No exposure to meptyldinocap in drinking
water or from residential use is expected because neither meptyldinocap nor dinocap are
registered for use in the United States. The exposure assessment will not underestimate
the exposure and risks posed by meptyldinocap.
12
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Exposure Assessment:
Occupational, residential and drinking water exposures were not assessed since U.S.
registration was not sought for meptyldinocap. Risk estimates were based on dietary (food only)
exposure to meptyldinocap residues on grapes and exposure to meptyldinocap from the currently
established tolerances for dinocap use on apples and grapes under 40 CFR 180.341. The dietary
risk estimates below represent the aggregate risk.
Acute Dietary Risk: An endpoint attributable to a single exposure was not identified, and
therefore, a quantitative acute dietary risk assessment was not performed. Meptyldinocap is not
expected to pose an acute risk.
Chronic Dietary Risk: The chronic dietary exposure assessment (food only) assumed tolerance
level residues and 100% crop-treated for all potential sources of meptyldinocap (exposure to
residues of meptyldinocap on imported grapes, and exposure to meptyodinocap residues from
use of dinocap on imported apples and grapes). Since 22% of technical dinocap is
meptyldinocap and since the proportion of dinocap residues occupied by meptyldinocap is
unknown, the chronic analysis assumed that 100% of the dinocap residues on imported apples
and grapes were meptyldinocap. It is estimated that chronic dietary exposure to meptyldinocap
will utilize 35% of the cPAD for children 1-2 years, the population subgroup receiving the
greatest exposure, and does not exceed the Agency's level of concern.
Cancer: Based on structural similarities and the demonstrated lower toxicity of meptyldinocap
as compared to dinocap, the cancer classification of Group E - Evidence of non-carcinogenicity
in humans for dinocap was extended to meptyldinocap.
DATA GAPS
The petitioner, Dow AgroSciences, has agreed to provide the following additional data:
1. Grape to raisin processing data (OPPTS Guideline Number 860.1520).
2. Submission of analytical standards (meptyldinocap and 2,4-DNOP) to the EPA National
Pesticide Standards Repository.
3. Acute neurotoxicity screening battery study on rats (OPPTS Guideline Number
870.6200a) and subchronic (90-Day) neurotoxicity screening battery study on rats
(OPPTS Guideline Number 870.6200b).
13
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Contact person at USEPA
Mailing address:
Mary L. Waller
Product Manager (21)
Environmental Protection Agency
Office of Pesticide Programs
Registration Division (7505P)
Fungicide Branch
1200 Pennsylvania Avenue NW
Washington, D.C. 20460
Office location and telephone number:
Room S-7319, One Potomac Yard
2777 South Crystal Drive (South Tower)
Arlington, Virginia 22202
Disclaimer: The information in this Pesticide Fact Sheet is a summary only and is not to be used to satisfy
any data requirements for pesticide registration or reregistration.
APPENDIX I:
GLOSSARY OF TERMS AND ABBREVIATIONS
ADNT Acute delayed neurotoxicity
a.i. Active Ingredient
ALT Alanine Aminotransferase
aPAD Acute Population Adjusted Dose
ARI Aggregate Risk Index
AST Aspartame Aminostransferase
BCF Bioconcentration Factor
CAS Chemical Abstracts Service
ChE Cholinesterase
ChEI Cholinesterase inhibition
cPAD Chronic Population Adjusted Dose
%CT Percent crop treated
DAT Days after treatment
DEEM-FCID Dietary Exposure Evaluation Model - Food Consumption Intake Database
DNA Deoxyribonucleic acid
DNT Developmental neurotoxicity
DIT Developmental immunotoxicity
DWLOC Drinking Water Level of Comparison.
EC Emulsifiable Concentrate Formulation
EEC Estimated Environmental Concentration. The estimated pesticide concentration
in an environment, such as a terrestrial ecosystem.
14
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EPA U.S. Environmental Protection Agency
FQPA Food Quality Protection Act
GLC Gas Liquid Chromatography
GLN Guideline Number
LCso Median Lethal Concentration. A statistically derived concentration of a substance
that can be expected to cause death in 50% of test animals. It is usually expressed
as the weight of substance per weight or volume of water, air or feed, e.g., mg/1,
mg/kg or ppm.
LDso Median Lethal Dose. A statistically derived single dose that can be expected to
cause death in 50% of the test animals when administered by the route indicated
(oral, dermal, inhalation). It is expressed as a weight of substance per unit weight
of animal, e.g., mg/kg.
LOAEL Lowest Observed Adverse Effect Level
LOAEC Lowest Observed Adverse Effect Concentration
LOG Level of Concern
LOD Limit of Detection
LOQ Limit of quantitation
mg/kg/day Milligram Per Kilogram Per Day
mg/L Milligrams Per Liter
MOE Margin of Exposure
MRID Master Record Identification (number), EPA's system of recording and tracking
studies submitted
MTD Maximum tolerated dose
NA Not Applicable
NOEC No Observable Effect Concentration
NOEL No Observed Effect Level
NOAEL No Observed Adverse Effect Level
NOAEC No Observed Adverse Effect Concentration
NPDES National Pollutant Discharge Elimination System
OP Organophosphate
OPP EPA Office of Pesticide Programs
OPPTS EPA Office of Prevention, Pesticides and Toxic Substances
PAD Population Adjusted Dose
PAG Pesticide Assessment Guideline
PAM Pesticide Analytical Method
PHED Pesticide Handler's Exposure Data
PHI Preharvest Interval
ppb Parts Per Billion
PPE Personal Protective Equipment
ppm Parts Per Million
PRZM/
EXAMS Tier II Surface Water Computer Model
RAC Raw Agriculture Commodity
RBC Red Blood Cell
RED Reregi strati on Eligibility Decision
REI Restricted Entry Interval
RfD Reference Dose
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SCI-GROW Tier I Ground Water Computer Model
SF Safety Factor
TGAI Technical Grade Active Ingredient
UF Uncertainty Factor
jig micrograms
|ig/L Micrograms Per Liter
|iL/g Microliter per gram
USDA United States Department of Agriculture
WPS Worker Protection Standard
APPENDIX II
Citations Considered to be Part of the Data Base Supporting the Registration of Meptyldinocap.
MRID
47289100
47289102
47289103
47289104
47289105
47289106
47289107
47289108
47289109
Citation
Dow Agrosciences LLC (2007) Submission of Product Chemistry, Residue,
Toxicity and Environmental Fate Data in Support of the Application for
Registration of GF-1478 and the Petition for Tolerance of Meptyldinocap for Use
on Apples, Wine Grapes, Cucumbers, Tomatoes, Peaches and Strawberries.
Transmittal of 35 Studies
Nelson, R (2007) Group B - Physical/Chemical Properties for GF-1478, A Liquid
End Use Product Containing Meptyldinocap. Project Number: NAFST/07/134.
Unpublished study prepared by Dow Agrosciences LLC. 5 p.
Byrne, S.; Thomas, A.; Hilla, S. (2003) The Nature of the Residue of (Carbon 14)-
2,6-DNOPC (Dinocap) in Apples. Project Number: 020042/01. Unpublished study
prepared by Dow AgroSciences LLC. 128 p.
Dohmeier, D. (1993) Nature of the Residue in Plants: Metabolism of (Carbon 14)
Dinocap in Apples. Project Number: 34/93/21, 34/92/22, TR/34/92/22.
Unpublished study prepared by Rohm and Haas Co. 321 p.
Dohmeier, D. (1994) Nature of the Residue in Plants: Metabolism of (Carbon 14)
Dinocap in Apples: Supplement to Rohm and Haas Technical Report 34-93-21.
Project Number: 34/94/14, TR/34/94/14. Unpublished study prepared by Rohm
and Haas Co. 254 p.
Honeycutt, R. (1976) The Metabolism of (Carbon 14) 2,4-Dinitro-6-(2-Octyl)
Phenyl Crotonate in Cucumber Fruit. Project Number: TR/3423/76/28,
3423/76/28. Unpublished study prepared by Rohm and Haas Co. 29 p.
Foster, D. (2002) Dinocap Method Validation: DNOPC and DNOP Validation of
Methodology for the Determination of DNOPC and DNOP in Apples and Grapes
Using LC-MS/MS. Project Number: GH/C/5503, DOS/220/DOS/220/0222962,
DOS/220/022962. Unpublished study prepared by Huntingdon Life Sciences, Ltd.
74 p.
Foster, D. (2002) Dinocap Independent Laboratory Validation: DNOPC and
DNOP: Independent Laboratory Validation of Methodology for the Determination
of DNOPC and DNOP in Apples and Grapes Using LC-MS/MS. Project Number:
DOS/221/023839. Unpublished study prepared by Huntingdon Life Sciences, Ltd.
83 p.
Howie, D.; Lees, M. (1999) Dinocap: Determination of the Storage Stability at
Residue Levels of Dinocap in Cucumbers, Tomatoes, Peaches, Apples and
16
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MRID
47289112
47289115
47289116
47289117
47289118
47289119
47289120
47289121
47289122
47289123
47289124
47289125
47289127
47289128
47289129
Citation
Strawberries. Project Number: RAS/049, RAS/049/980207,
ER/76/1/TR34/99/141. Unpublished study prepared by Huntingdon Life Sciences,
Ltd. 144 p.
North, L. (2007) Residues of DE-126 in Wine Grapes at Intervals and Harvest
Following Multiple Applications of GF-1478, Southern and Northern Europe -
2006. Project Number: GHE/P/11595, 10001049. Unpublished study prepared by
Agrisearch UK, Ltd., DowElanco GmbH and Agrisearch France SARL. 175 p.
Jones, G. (2006) Residues of Dinocap or DE-126 in Wine Grapes at Intervals and
Harvest Following Multiple Applications of GF-1344 or GF-1478, Northern
Europe - 2005. Project Number: GHE/P/11344, AF/8927/DE, 10001049.
Unpublished study prepared by Agrisearch UK, Ltd., DowElanco GmbH and
Agrisearch France SARL. 147 p.
Merkel, D. (2005) Acute Oral Toxicity Up and Down Procedure in Rats: Dinocap
II. Project Number: 17042, 050197, P320/UDP/DOW. Unpublished study
prepared by Product Safety Laboratories. 28 p.
Merkel, D. (2005) Acute Oral Toxicity Up and Down Procedure in Rats: GF-
1478. Project Number: 17046, 050207, P320/UDP/DOW. Unpublished study
prepared by Product Safety Laboratories. 28 p.
Merkel, D. (2005) Acute Dermal Toxicity Study in Rats - Limit Test: Dinocap II.
Project Number: P322/DOW, 17043, 050198. Unpublished study prepared by
Product Safety Laboratories. 25 p.
Merkel, D. (2005) Acute Dermal Toxicity Study in Rats - Limit Test: GF-1478.
Project Number: 17047, 050208, P322/DOW. Unpublished study prepared by
Product Safety Laboratories. 27 p.
Merkel, D. (2005) Primary Eye Irritation Study in Rabbits: Dinocap II. Project
Number: 17044, 050200, P324/DOW. Unpublished study prepared by Product
Safety Laboratories. 27 p.
Merkel, D. (2005) Primary Eye Irritation Study in Rabbits: GF-1478. Project
Number: 050210, 17048, P324/DOW. Unpublished study prepared by Product
Safety Laboratories. 32 p.
Merkel, D. (2005) Primary Skin Irritation Study in Rabbits: Dinocap II. Project
Number: 050199, 17045, P326/DOW. Unpublished study prepared by Product
Safety Laboratories. 28 p.
Merkel, D. (2005) Primary Skin Irritation Study in Rabbits: GF-1478. Project
Number: 17049, 050209, P326/DOW. Unpublished study prepared by Product
Safety Laboratories. 30 p.
Woolhiser, M.; Wiescinski, C. (2005) Dinocap II (DE-126): Local Lymph Node
Assay in Balb/cAnNCrl Mice. Project Number: 041 156. Unpublished study
prepared by Dow Chemical Co. 27 p
Woolhiser, M.; Wiescinski, C. (2005) GE-1478: Local Lymph Node Assay in
Balb/cAnNCrl Mice. Project Number: 051057. Unpublished study prepared by
Dow Chemical Co. 25 p.
Thomas, J.; Yano, B.; Dryzga, M. (2005) Dinocap II (DE-126): 28-Day Dietary
Toxicity Study in CD-I Mice. Project Number: 041161. Unpublished study
prepared by Dow Chemical Co. 193 p.
Johnson, K.; Andrus, A. (2005) Dinocap II (DE-126): 90-Day Dietary Toxicity
Study in CRL: CD (SD) IGS BRRats. Project Number: 041157. Unpublished
study prepared by Dow Chemical Co. 447 p.
Stebbins, K.; Brooks, K.; Lacher, J. (2005) Dinocap II (DE-126): 90-Day
17
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MRID
Citation
DietaryToxicity Study in Beagle Dogs with a Dinocap Comparative Control and a
1-Year Dinocap II Satellite Group-Interim Report. Project Number: 041148.
Unpublished study prepared by Dow AgroSciences LLC. 415 p
47289130
Stebbins, K.; Brooks, K.; Lacher, J. (2006) Dinocap II (DE-126): 90-Day
Dietary Toxicity Study in Beagle Dogs with a Dinocap Comparative Control and a
1-Year Dinocap II Satellite Group-Final Report. Project Number: 041148A.
Unpublished study prepared by Dow AgroSciences LLC. 133 p.
47289131
Stebbins, K.; Brooks, K.; Lacher, J. (2006) Supplemental Report for Study ID
041148 - Dinocap II (DE-126): 90-Day DietaryToxicity Study in Beagle Dogs
with a Dinocap Comparative Control and a 1-Year Dinocap II Satellite Group-
Interim Report. Project Number: 041148S. Unpublished study prepared by Dow
AgroSciences LLC. 14 p.
47289132
Carney, E.; Tornesi, B. (2005) Dinocap II (DE-126): Oral Gavage Developmental
Toxicity Study in CD-I Mice. Project Number: 040329. Unpublished study
prepared by Dow AgroSciences LLC. 264 p.
47289133
Carney, E.; Tornesi, B. (2005) Revised Report for: Teratogenicity of Selected
Dinocap Isomers in CRL:CD1 (ICR) Mice. Project Number: 051068. Unpublished
study prepared by Dow AgroSciences LLC. 211 p
47289134
Carney, E.; Tornesi, B. (2005) Dinocap II (DE-126): Oral Gavage Developmental
Toxicity Study in CD Rats. Project Number: 041128. Unpublished study prepared
by Dow AgroSciences LLC. 366 p.
47289136
Carney, E.; Tornesi, B. (2005) Dinocap II (DE-126): Oral Gavage Developmental
Toxicity Study in New Zealand White Rabbits. Project Number: 041127.
Unpublished study prepared by Dow AgroSciences LLC. 356 p.
47289137
Mecchi, M. (2005) Salmonella escherichia coli; Mammalian Microsome Reverse
Mutation Assay Preincubation Method with a Confirmatory Assay with Dinocap
II (DE-126): Final Report. Project Number: 6736/148, 26949/0/42203CD.
Unpublished study prepared by Covance Laboratories Inc. 35 p.
47289138
Seidel, S.; Schisler, M.; Kleinert, K. (2005) Evaluation of Dinocap II (DE-126) in
the Chinese Hamster Ovary Cell / Hypoxanthine-Guanine-Phosphoribosyl
Transferase (Cho/HGPRT) Forward Mutation Assay. Project Number: 041160.
Unpublished study prepared by Dow AgroSciences LLC. 30 p.
47289139
Charles, G.; Schisler, M.; Kleinert, K. (2005) Evaluation of Dinocap II (DE-126)
in an in vitro Chromosomal Aberration Assay Utilizing Rat Lymphocytes. Project
Number: 041159. Unpublished study prepared by Dow AgroSciences LLC. 35 p.
(001-260). Unpublished study prepared by Biosafety Research Center. 90 p.
47289140
Charles, G.; Grundy, J.; Schisler, M. (2005) Evaluation of Dinocap II (DE-126) in
the Mouse Bone Marrow Micronucleus Test. Project Number: 041163.
Unpublished study prepared by Dow AgroSciences LLC. 51 p.
47289141
Porter, D. (1996) Identification of 2,4-Dinitro-6-(l-Methylheptyl)Phenyl
Crotonate Metabolites in Rat and Mouse Urine. Project Number: 95R/0064,
95P/064. Unpublished study prepared by Rohm and Haas Co. 94 p.
47289142
Honeycutt, R.; Gartska, T. (1976) The Identification of Metabolites of 2,4-
Dinitro-6-(2-Octyl) Phenyl Crotonate in Rat Urine and Feces. Project Number:
3423/76/29. Unpublished study prepared by Rohm and Haas Co. 134 p.
47304900
Dow Agrosciences LLC (2007) Submission of Product Chemistry, Residue, and
Toxicity Data in Support of the Application for Registration of Meptyldinocap
and the Petition for Tolerance of Meptyldinocap for Use on Grapes. Transmittal of
18
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MRID
47304901
47304902
47304903
47304904
47304905
47304906
47304907
47602200
47602201
47663000
47663001
Citation
7 Studies.
Nelson, R. (2007) Product Chemistry Data Requirements for Import Tolerance for
Meptyldinocap. Project Number: NAFST/07/150. Unpublished study prepared by
Dow Agrosciences LLC and Dow Chemical Co., and Huntingdon Life Sciences,
Ltd. 333 p.
Feilden, A.; Howie, D. (1999) To Determine the Magnitude of Residues of
Dinocap During the Twenty Eight Days Following the Final Application in the
Raw Agricultural and Processed Commodity of Wine Grapes Resulting from
Sequential Directed Application of Karathane LC or Karathane FN57 in Germany
and Northern France. Project Number: RAS/17, RAS/17/980214, ER/72/1/LC.
Unpublished study prepared by Huntingdon Life Sciences, Ltd. 274 p.
Lees, M. (1998) To Determine the Magnitude of Residues of Dinocap During the
Twenty Eight Days Following the Final Application in the Raw and Processed
Agricultural Commodity of Grapes Resulting from Sequential Directed
Application of Karathane LC in Germany. Project Number: R/H/204,
R/H/204/973651. Unpublished study prepared by Huntingdon Life Sciences, Ltd.
250 p.
Class, T. (2002) Dinocap: Assessment and Validation of the Multi-Residue
Enforcement Method DFG S19 (Extended Revision) for the Determination of
Dinocap in Plant Material. Project Number: 021219, P/649/G, P/B/649G.
Unpublished study prepared by PTRL Europe Gmbh. 57 p.
Honeycutt, R.; Garstka, T. (1976) The Decline of Karathane Residues in Squash.
Project Number: 3423/776/3. Unpublished study prepared by Rohm & Haas Co.
127 p.
Brooks, K.; Golden, R. (2005) GF-1478: Acute Oral Toxicity Screening Studies in
F344 and CD (SD) Rats. Project Number: 050413, DR/0395/1 562/0 10.
Unpublished study prepared by Dow Chemical Co., 12 p.
Rogers, J.; Carver, B.; Gray, L.; et al. (1987) The Developmental Toxicity of
Dinocap in the Mouse is not Due to Two Isomers of the Major Active Ingredients.
Project Number: 87RJ/2742. Unpublished study prepared by EPA / RTP. 15 p.
Dow Agrosciences Lie. (2008) Submission of Residue Data in Support of the
Petition for Tolerance of Meptyldinocap for Use on Grape, Grape Juice and Wine.
Transmittal of 1 Study.
Jones, G. (2006) Residues of Dinocap or DE-126 in Wine Grapes at Intervals and
Harvest Following Multiple Applications of GF-1344 or GF-1478, Southern
Europe-2005. Project Number: GHE/P/11347, AF/8928/DE, 10001049.
Unpublished study prepared by Agrisearch UK, Ltd. 145 p.
Dow Agrosciences, LLC. (2009) Submission of Residue Data in Support of the
Petition for Tolerance of Meptyldinocap for Use on Apples and Grapes.
Transmittal of 1 Study.
Foster, D. (2002) Dinocap Method Validation: DNOPC and DNOP Validation of
Methodology for the Determination of DNOPC and DNOP in Apples and Grapes
Using LC-MS/MS (Replacement Study for MRID 47289107). Project Number:
GH/C/5503, DOS/220/DOS/220/0229, DOS/220/022962. Unpublished study
prepared by Huntingdon Life Sciences, Ltd. 76 p.
19
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