Document ID: EPA-HQ-OPP-2006-0652-0002
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2006-08-09T04:00Z

Brian
sent
your
message
to
my
supervisor
Pauline
Wagner
who
has
forwarded
me
for
reply.

Seed
treatment
is
considered
a
food­
use
so
all
colorants
have
to
be
approved
by
EPA.

First
of
all
please
provide
me
with
the
list
of
all
colorant
for
which
you
want
exemptions
from
the
requirement
of
a
tolerance
or
you
say
approval.
Provide
me
with
chemistry
and
CAS
Reg.
Nos.
and
I
will
look
Agency's
data
base
to
check
if
any
of
them
are
on
our
approved
list.

Those
colorants
not
on
Agency's
approved
list
will
require
all
chemistry,
toxicological,
environmental,
ecological
and
exposure
data
and
a
Notice
of
Filing
for
all
colorants.
This
is
a
lengthy
process
and
I
will
explain
to
you
in
brief
so
provide
me
your
telephone
so
we
can
talk
.
FILE
NAME:
AD_
company.
wpt
(
1/
1/
2006)
(
xml)
Template
Number
AD20
ATTENTION:

All
commodity
terms
must
comply
with
the
Food
and
Feed
Commodity
Vocabulary
database
(
http://
www.
epa.
gov/
pesticides/
foodfeed/).

All
text
in
blue
font
(
instructions
for
preparing
the
document),
should
be
removed
prior
to
sending
the
document
to
the
Federal
Register
Staff.
Instructional
text
and
prompts
in
green
font
should
also
be
removed.

COMPANY
FEDERAL
REGISTER
DOCUMENT
SUBMISSION
TEMPLATE
(
1/
1/
2006)

EPA
Registration
Division
contact:
[
Pauline
Wagner:
(
703)
308­
6164]

TEMPLATE:

Syngenta
Crop
Protection,
Inc.

PP
EPA
has
received
a
pesticide
petition
(
PP)
from
Syngenta
Crop
Protection,
Inc.,
P.
O.
Box
18300,
Greensboro,
NC
27410
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
to
establish
an
exemption
from
the
requirement
of
a
tolerance
for
[
phosphoric
acid,
tris(
2­
ethyl
hexyl)
ester
as
an
adjuvant
when
used
in
pesticide
formulations
applied
to
growing
crops
which
contain
pinoxaden,
clodinafop­
propargyl
and
tralkoxydim]
in
or
on
the
raw
agricultural
commodities
[
wheat
and
barley].
EPA
has
determined
that
the
petition
contains
data
or
information
regarding
the
elements
set
forth
in
section
408(
d)(
2)
of
the
FFDCA;
however,
EPA
has
not
fully
evaluated
the
sufficiency
of
the
submitted
data
at
this
time
or
whether
the
data
supports
granting
of
the
petition.
Additional
data
may
be
needed
before
EPA
rules
on
the
petition.

A.
Residue
Chemistry
1.
Plant
metabolism.
[
NA­
Remove]

2.
Analytical
method.
[
NA­
Remove]

3.
Magnitude
of
residues.
[
NA­
Remove]

B.
Toxicological
Profile
1.
Acute
toxicity.
Tris(
2­
ethylhexyl)
phosphate
(
TEHP)
is
of
very
low
acute
toxicity
by
oral
and
dermal
routes
The
oral
LD50
in
rats
is
greater
than
36,800
mg/
kg
and
the
dermal
LD50
is
greater
than
20,000
mg/
kg.
The
inhalation
LC50
is
greater
than
0.45
mg/
l,
indicating
a
relatively
low
potential
for
acute
inhalation
hazard.
TEHP
is
classified
as
a
moderate
skin
irritant,
is
not
a
dermal
sensitizer
and
is
non­
irritating
to
the
eyes
of
rabbits.

2.
Genotoxicty.
TEHP
has
been
tested
in
a
number
of
well
conducted
in
vivo
and
in
vitro
mutagenicity
assays.
In
vitro
assays
included
Ames
assay,
mammalian
cell
mutation/
cytogenetics,
cytogenicity
and
sister
chromatid
exchange.
Concentrations
ranged
from
63.5
microliters/
liter
(
limit
of
solubility)
to
251
micrograms/
milliliter.
All
assay
results
were
negative
with
or
without
S9
activation.
In
vivo
assays
included
bone
marrow
micronucleus,
cytogenicity,
and
UDS
assay.
Doses
administered
ranged
from
500
mg/
kg
to
2000
mg/
kg
(
both
gavage
and
IP)
and
all
results
were
negative.
Therefore,
TEHP
shows
no
potential
for
genotoxicity
in
a
wide
array
of
in
vitro
and
in
vivo
assays.
3
3.
Reproductive
and
developmental
toxicity.
No
reproductive
toxicity
studies
or
developmental
toxicity
studies
are
available
for
TEHP.
However,
a
significant
number
of
reproductive
and
developmental
toxicity
studies
are
available
on
closely­
related
structures
and
a
likely
metabolite
of
TEHP,
2­
ethylhexanol.
In
a
reproduction
study
in
rats
triethyl
phosphate
(
CAS
No.
78­
40­
0)
had
a
NOAEL
was
335
mg/
kg/
d;
decreased
litter
size
was
noted
at
670
mg/
kg.
Small
numbers
of
animals
were
tested;
maternal
toxicity
was
not
clearly
defined.
There
were
no
effects
on
testis
histopathology.
In
a
developmental
study
in
rats
the
NOAEL
was
greater
than
625
mg/
kg/
d
(
no
effects);
the
maternal
NOAEL
was
125
mg/
kg
bw/
day.
Reduced
body
weight
gain,
food
intake
and
feces
excretion
at
noted
at
625
mg/
kg/
d.

In
a
reproduction
study
in
rats
dibutyl
hydrogen
phosphate
(
CAS
No.
107­
66­
4)
had
a
NOAEL
greater
than
1000
mg/
kg/
d.
No
reproduction
effects
were
noted.
Parental
NOAEL
was
30
mg/
kg/
d;
reduced
food
consumption,
red
urine,
histopathology
changes
in
the
stomach
and
the
bladder
were
seen
at
100
mg/
kg/
d
and
higher.
Deaths
occurred
at
1000
mg/
kg/
d.
The
pup
NOAEL
was
300
mg/
kg/
d;
there
was
reduced
viability
at
1000
mg/
kg/
d.
In
a
rat
developmental
study
in
rats
the
NOAEL
was
300
mg/
kg.
The
pup
NOAEL
in
the
rat
reproduction
study,
based
on
reduced
viability
was
established
at
1000
mg/
kg/
d.
No
guideline
developmental
toxicity
studies
exist
with
this
compound.

Tributyl
phosphate
(
CAS
No.
126­
73­
8)
had
a
NOAEL
greater
than
225
mg/
kg/
d
in
a
rat
reproduction
study.
There
were
no
reproductive
effects
noted.
The
maternal
NOAEL
was
greater
than
15
mg/
kg/
d
(
decreased
BW
gain
15,
52
and
225
mgk/
g/
d).
The
pup
NOAEL
was
also
greater
than
15
mg/
kg/
d
(
reduced
pup
weights).
Tributyl
phosphate
was
tested
in
developmental
studies
in
rats
and
rabbits.
The
rat
NOAEL
was
250
mg/
kg/
d
(
increase
in
short
ribs
at
500
mg/
kg/
d).
The
maternal
NOAEL
was
62.5
mg/
kg/
d
(
Reduced
body
weight
gain,
food
consumption,
salivation).
In
the
Rabbit
the
NOAEL
was
greater
than
400
mg/
kg/
d,
and
the
maternal
NOAEL
was
150
mg/
kg/
d
(
Reduced
body
weight
gain,
deaths
at
400
mg/
kg/
d).

Tris
(
2­
butoxyethyl)
phosphate
(
CAS
No.
78­
51­
3)
was
tested
in
a
rat
developmental
study
and
had
a
NOAEL
greater
than
1500
mg/
kg/
d.
No
effects
were
seen
in
this
study.

In
addition
to
the
previous
comparisons,
the
presumed
2­
ethylhexanol
metabolite
of
TEHP
has
been
well
studied.
2­
Ethylhexanol
is
currently
exempt
from
tolerances
for
pre­
harvest
uses
in
40CFR
Part
180.
Study
data
with
2­
ethylhexanol
indicate
low
potential
for
developmental
toxicity,
seen
only
at
high
doses
in
presence
of
maternal
toxicity,
as
described
below.
4
In
a
developmental
toxicity
study
in
rats,
2­
ethylhexanol
was
administered
from
days
6­
15
of
gestation
by
oral
gavage
at
dose
levels
of
0,
130,
650
and
1300
mg/
kg/
day.
The
following
effects
were
reported:
at
130
mg/
kg
there
were
no
effects
(
This
dose
was
considered
a
maternal
and
developmental
NOAEL).
At
the
650
mg/
kg
dose,
there
was
maternal
toxicity
+
?
fetal
wt
and
increased
skeletal
variations/
delays
in
ossification,
while
at
1300
mg/
kg:
there
was
severe
maternal
toxicity
(
BW,
FC,
deaths)
+
fetotoxicity
+
dilated
renal
pelvis,
hydroureter,
skeletal
malformations.

Thus,
significant
developmental
effects
were
only
seen
at
a
dose
level
that
was
severely
maternally
toxic,
and
slight
effects
that
reflect
delayed
development
were
seen
in
the
presence
of
less
significant
maternal
toxicity
at
the
LOAEL
of
650
mg/
kg/
day.
2­
Ethylhexanol
did
not
show
a
significant
potential
for
developmental
toxicity.

Results
of
a
dermal
developmental
toxicity
study
in
rats
with
2­
ethylhexanol
were
consistent
with
this
observation.
No
teratogenic
effects
were
observed
up
to
the
highest
dose
tested,
despite
maternal
toxicity
(
decreased
bodyweight
gain)
at
3
ml/
kg/
day
(~
3000
mg/
kg/
day).
In
an
inhalation
developmental
toxicity
study,
groups
of
Sprague­
Dawley
rats
were
exposed
for
7
hours
per
day
on
gestation
days
1­
19
to
2­
ethylhexanol
at
the
highest
concentration
that
could
be
generated
as
a
vapor.
2­
Ethylhexanol
reduced
maternal
feed
intake,
but
did
not
produce
any
malformations.

The
potential
for
developmental
toxicity
of
2­
ethylhexanol
has
also
been
studied
in
mice,
because
a
well­
studied
peroxisome
proliferator,
di(
2­
ethylhexyl)
phthalate
(
DEHP),
has
been
shown
to
produce
developmental
effects
in
this
species.
Very
early
work
on
2­
ethylhexanol
had
indicated
that
it
was
a
peroxisome
proliferator,
along
with
DEHP.
However,
more
modern
techniques
and
a
greater
understanding
of
the
sequence
of
events
that
lead
to
"
peroxisome
proliferation",
namely
activation
of
the
peroxisome­
proliferator
activating
receptor
alpha
(
PPAR
),
call
into
question
whether
2­
ethylhexanol
was
truly
a
peroxisome
proliferator
by
today's
standards
in
these
older
studies.
In
fact,
tests
on
parameters
more
closely
related
to
PPAR
activation
clearly
showed
that
2­
ethylhexanol
did
not
produce
any
effects
associated
with
peroxisome
proliferation,
whereas
DEHP
and
a
phthalate­
containing
metabolite
did.
Consistent
with
this,
no
liver
histopathology
consistent
with
peroxisome
proliferation
was
reported
in
the
subchronic
or
chronic
rat
and
mouse
studies
conducted
on
TEHP.

In
order
to
evaluate
the
relative
roles
of
2­
ethylhexanol
and
mono(
2­
ethylhexyl)
phthalate
(
MEHP)
(
the
two
major
metabolites
of
DEHP
in
mice)
in
developmental
toxicity
of
DEHP,
the
NTP
conducted
dietary
developmental
toxicity
studies
with
DEHP,
MEHP
and
2­
ethylhexanol
at
equimolar
dose
levels
(
NTP,
1991).
No
developmental
or
maternal
effects
were
produced
by
2­
ethylhexanol
in
mice
at
up
to
191
mg/
kg/
day,
which
was
equimolar
with
dose
levels
of
DEHP
and
MEHP
that
caused
maternal
and
developmental
effects.
NTP
concluded
from
this
study
that
the
developmental
effects
of
DEHP
arise
from
MEHP,
and
not
2­
ethylhexanol.

In
summary,
the
potential
of
TEHP
to
cause
reproductive
or
developmental
effects
is
clearly
5
quite
low
and
is
sufficiently
understood
based
on
studies
with
its
major
metabolite
(
2­
ethylhexanol)
and
closely­
related
alkyl
phosphates.
All
of
these
related
compounds
show
minimal
to
no
potential
to
produce
reproductive
or
developmental
effects
in
the
absence
of
maternal
toxicity,
and
were
tested
up
to
very
high
dose
levels.
The
relatively
high
acute
oral
toxicity
(
LD50)
value
and
subchronic
NOAEL
values
for
TEHP
also
suggest
that
it
possesses
less
potential
for
general
toxicity
than
the
lower
molecular
weight
alkyl
phosphate
compounds,
which
would
probably
extend
to
reproductive
and
developmental
NOAEL
values
as
well.
In
addition
the
subchronic
and
chronic
testing
of
TEHP
has
shown
no
effects
on
target
organs
that
would
signal
concern
about
developmental
or
reproductive
toxicity,
such
as
the
testis,
ovaries,
or
uterus.
Therefore,
additional
testing
of
TEHP
in
reproductive
and
developmental
toxicity
studies
should
not
be
required
for
the
purposes
of
this
determination
of
TEHP
as
a
low­
toxicity
(
Tier
1)
inert.

There
is
a
consistent
lack
of
reproductive
and
developmental
toxicity
with
this
class
of
compounds,
except
for
certain
compounds
where
some
developmental
toxicity
was
observed
at
maternally
toxic
doses,
and
this
provides
a
strong
weight­
of­
evidence
that
reproductive/
developmental
toxicity
is
not
a
concern
with
TEHP.

4.
Subchronic
toxicity.
In
a
14­
day
range­
finding
study,
groups
of
5
male
and
5
female
rats
and
mice
were
administered
0,
375,
750,
3000,
or
6000
mg/
kg
bw/
day
of
TEHP
by
gavage
in
corn
oil.
No
deaths
were
observed
in
either
rats
or
mice.
Body
weights
were
lower
than
control
in
male
rats
at
greater
than
or
equal
to
1500
mg/
kg
bw/
day,
and
in
female
rats
at
equal
to
or
greater
than
3000
mg/
kg
bw/
day.
There
were
no
effects
on
body
weight
in
mice
up
to
the
highest
dose
tested
(
6000
mg/
kg
bw/
day.
In
a
90­
day
rat
study,
Fischer­
344
rats
were
dosed
with
0,
250,
500,
1000,
2000
or
4000
mg/
kg
bw/
day
of
TEHP
by
gavage,
5
days
a
week
for
13
weeks..
Body
weight
gain
was
reduced
by
5%
at
the
top
dose,
but
this
minimal
effect
was
not
considered
biologically
significant.
There
were
no
deaths,
no
signs
of
toxicity
and
no
adverse
effects
upon
histopathological
examination.
The
NOAEL
was
2860
mg/
kg/
day,
the
highest
dose
tested
(
4000
mg/
kg/
day
administered
5
of
7
days
in
a
week).
Groups
of
B6C3F1
mice
were
dosed
with
0,
500,
1000,
2000,
4000
or
8000
mg/
kg
bw/
day
by
gavage,
5
days
a
week
for
13
weeks.
Body
weight
gain
was
reduced
by
7%
and
5%
at
the
top
dose
in
males
and
females
respectively,
but
this
effect
was
not
considered
biologically
significant.
There
were
no
deaths,
no
signs
of
toxicity
and
no
adverse
effects
upon
histopathological
examination.
The
NOAEL
was
5710
mg/
kg/
day,
the
highest
dose
tested
(
8000
mg/
kg/
day,
administered
5
days
a
week.)

A
dose
of
30­
45
mg/
kg
TEHP
was
applied
to
clipped
intact
skin
of
rabbits
once
a
day
for
either
10
or
20
days.
There
were
no
signs
of
systemic
toxicity.
In
a
3­
month
inhalation
study,
groups
of
dogs
(
2
per
sex)
were
exposed
whole
body
for
6
hours/
day,
5
days
per
week
to
60
exposures
of
0,
10.8,
24.4
or
85
mg/
m3
TEHP.
The
median
particle
size
of
the
aerosol
was
4.4
m
with
a
GSD
of
3.0.
No
animals
died
and
there
was
no
effect
on
body
weight,
a
limited
set
of
hematological
parameters
or
plasma
and
erythrocyte
cholinesterase
activities.
The
lungs
showed
mild,
chronic
parenchymal
inflammatory
changes.
The
performance
of
the
dogs
6
trained
in
conditional
avoidance
deteriorated
as
exposure
concentrations
increased.

In
a
companion
3­
month
inhalation
study,
groups
(
2
per
sex)
of
rhesus
monkeys
were
exposed
whole
body
for
6
hours/
day,
5
days
per
week
to
60
exposures
of
0,
10.8,
24.4
or
85
mg/
m3
TEHP.
The
median
particle
size
of
the
aerosol
was
4.4
m
with
a
GSD
of
3.0.
There
were
no
effects
of
compound
on
bodyweight,
hematological
parameters,
cholinesterase
(
plasma
and
erythrocyte),
organ
pathology
or
the
performance
of
animals
in
visual
discrimination
tests.

Groups
of
20
male
and
20
female
guinea
pigs
were
exposed
by
inhalation
to
0,
1.6
or
9.6
mg/
m3
TEHP
for
3
months
(
6
hours
per
day,
5
days
per
week).
Animals
were
administered
tetracycline
prophylactically
in
drinking
water.
The
high
dose
animals
showed
significantly
higher
body
weights
than
controls,
and
both
test
groups
showed
lower
kidney
to
body
weight
ratios.
There
was
no
effect
of
compound
on
erythrocyte
or
plasma
cholinesterase
or
on
organ
histopathology.
There
were
no
pathological
changes
to
nerve
myelin
sheaths.

5.
Chronic
toxicity.
In
a
US
National
Toxicology
Program
(
NTP)
study,
TEHP
was
administered
in
corn
oil
(
10
ml/
kg
body
weight)
by
gavage
5
days/
week
for
103
weeks
to
groups
of
50
male
and
50
female
F­
344/
N
rats
and
B6C3F1
mice.
The
doses
administered
were:

Fischer­
344
rats
B6C3F1
mice
Dose
Male
Female
Male
Female
Control
Vehicle
Vehicle
Vehicle
Vehicle
Low
Dose
2000
mg/
kg
1000
mg/
kg
500
mg/
kg
500
mg/
kg
High
Dose
4000
mg/
kg
2000
mg/
kg
1000
mg/
kg
1000
mg/
kg
The
animals
were
observed
twice
daily
and
body
weight
was
measured
weekly
for
the
first
13
weeks
and
once
every
4
weeks
thereafter.
Clinical
examinations
were
performed
once
every
4
weeks.
Necropsies
and
histopathological
examinations
were
performed
on
all
animals,
but
organ
weight
changes
were
not
reported.

No
compound­
related
clinical
toxicity
was
observed
in
either
sex
of
either
species.
Decrease
in
body
weight,
compared
with
controls,
was
limited
to
male
rats
at
the
low
dose
(
11.5%)
and
the
high
dose
(
15.8%).
The
decreased
body
weight
did
not
affect
survival.

In
male
rats
the
incidence
of
pheochromocytomas
(
benign
tumors
of
the
adrenal
medulla)
of
the
adrenal
gland
increased
with
dose
and
two
(
4%)
were
malignant
in
the
high­
dose
group.
The
incidence
of
adrenal
pheochromocytomas
in
male
rats
was:
control
2/
50
(
4%),
low­
dose
9/
50
(
18%)
and
high­
dose
12/
50
(
24%).
In
two
previous
gavage
studies
in
the
same
laboratory,
7
the
incidence
of
pheochromocytomas
in
control
male
rats
was
24
and
26%.

In
female
mice
the
incidence
of
hepatocellular
carcinomas
was:
control
0/
48
(
0%),
low
dose
4/
50
(
8%)
and
high
dose
7/
50
(
14%).
The
incidence
of
hepatocellular
carcinomas
showed
a
dose­
related
increase
and
the
incidence
at
the
high­
dose
level
was
statistically
significant.

The
results
of
these
2­
year
gavage
studies
in
rats
and
mice
were
interpreted
by
NTP
as
showing
some
evidence
of
carcinogenicity
in
female
mice
based
on
the
increase
in
hepatocellular
carcinomas
and
equivocal
evidence
of
carcinogenicity
in
male
rats
based
on
the
increased
incidence
of
pheochromocytomas.
In
this
same
study,
TEHP
caused
a
dose­
related
increase
in
the
incidence
of
follicular
cell
hyperplasia
of
the
thyroid
in
male
and
female
B6C3F1
mice.
The
incidence
of
hyperplasia
was:
in
males,
control
0/
49
(
0%),
low
dose
12/
48
(
25%)
and
high
dose
24/
47
(
51%);
in
females,
control
1/
44
(
2%),
low
dose
13/
47
(
28%)
and
high
dose
12/
46
(
26%).
There
was
no
dose­
related
increase
in
thyroid
tumours.
The
LOAEL
for
thyroid
hyperplasia
was
357
mg/
kg
body
weight
per
day;
a
NOAEL
was
not
established.

Two
toxicology
reviews
have
commented
on
the
significance
of
the
NTP
data:
The
European
Centre
for
Ecotoxicology
and
Toxicology
of
Chemicals
(
ECETOC)
commented
that:

"
The
probability
is
high
that
the
adrenal
pheochromocytoma
effect
was
spurious.
The
only
other
statistically
significant
neoplastic
finding
was
hepatocellular
carcinoma
in
female
mice
and,
on
its
own,
this
is
insufficient
evidence
of
carcinogenicity.
Considering
the
high
dose
used,
the
low
incidence
rate
of
the
tumours,
the
lack
of
genotoxic
activity
and
the
inconsistency
of
tumour
development
between
sexes
and
species,
a
carcinogenic
action
in
man
would
be
highly
improbable
at
exposure
levels
which
do
not
produce
other
toxic
effects."

The
World
Health
Organization
(
WHO)
concluded
that:

"
Although
there
were
increases
in
adrenal
pheochromocytomas
in
both
dose
groups
of
male
rats
and
in
hepatocellular
carcinomas
in
female
mice
in
the
high­
dose
group,
these
results
are
not
considered
to
indicate
that
TEHP
presents
a
significant
carcinogenic
risk
to
humans.
Pheochromocytomas
show
a
variable
background
incidence
in
rats.
The
incidences
of
these
tumours
in
two
previous
National
Toxicology
Programme
(
NTP)
bioassays
were
equal
to
the
incidence
observed
in
the
TEHP
bioassay.
The
only
other
significant
neoplastic
finding
was
hepatocellular
carcinomas
in
the
high­
dose
group
of
female
mice.
Considering
the
low
incidence
of
this
tumour,
its
occurrence
in
only
one
sex
of
one
species,
the
lack
of
evidence
of
genetic
8
toxicity,
and
the
low
exposure
of
humans
to
TEHP,
it
is
unlikely
that
TEHP
poses
a
significant
carcinogenic
risk
to
humans."

In
summary,
the
chronic
toxicity/
oncogenicity
studies
with
TEHP
in
rats
and
mice
demonstrate
very
limited
toxicity
at
relatively
high
dose
levels
(
up
to
4000mg/
kg/
day
in
the
rat
and
1000mg/
kg/
day
in
the
mouse),
reflecting
the
low
repeat
dose
toxicity
of
this
chemical
in
rodents.
In
male
and
female
mice,
the
lowest­
observed­
adverse­
effect
level
(
LOAEL)
for
thyroid
follicular
cell
hyperplasia
was
357
mg/
kg
bodyweight
per
day.
A
NOAEL
in
mice
was
not
established.
TEHP
is
not
considered
to
show
any
convincing
evidence
for
carcinogenic
potential.
This
position
is
in
agreement
with
the
conclusion
of
two
expert
reviews
of
the
database.

6.
Animal
metabolism.
In
an
inhalation
study
rats
received
a
single
20
minute
head­
only
exposure
to
aerosols
of
[
32P]­
TEHP
(
concentrations
0.72
and
0.91
mg/
L).
Animals
were
killed
after
5
min,
30
min,
1,
4,
17,
18,
24,
48
and
72
hours
(
1
animal
per
time­
point).
TEHP
and
its
metabolites
were
found
in
the
lungs
(
13%
after
5
mins.),
stomach
(
64%
after
1
hour),
brain
and
liver
(
9
and
16%
after
30
mins.).
Fecal
excretion
was
high,
urinary
excretion
was
low.
Partial
biotransformation
was
confirmed
but
the
metabolites
were
not
identified.
Regarding
metabolism
of
trialkyl
phosphate
esters,
the
following
statements
have
been
made
in
prior
reviews
(
American
Chemistry
Council
[
ACC]
and
Beratergremium
fur
Umweltrelevante
Altstoffe
[
BUA])
"
In
mammalian
metabolism,
the
phosphoric
acid
tri­
esters
are,
as
a
rule,
degraded
to
the
corresponding
di­
ester.
Only
a
small
amount
is
further
metabolized
to
the
monophosphates."
Therefore,
TEHP
is
assumed
to
be
hydrolysed
to
2­
ethylhexanol
(
CAS
104­
76­
7)
and
bis
(
2­
ethylhexyl)
hydrogen
phosphate
(
CAS
298­
07­
7).
No
confirmatory
data
exist,
but
this
pattern
would
be
consistent
with
other
compounds
containing
2­
ethylhexyl
ester
groups.

7.
Metabolite
toxicology.
[
NA­
Remove]

8.
Endocrine
disruption.
There
is
no
information
in
the
literature
to
suggest
that
TEHP
possesses
any
potential
for
endocrine
disruption.
Several
well
known
international
organizations
have
studied
the
toxicity
of
TEHP
in
the
literature,
analyzing
data
from
a
number
of
studies
that
utilized
a
many
different
test
systems
under
short,
intermediate
and
long
term
exposure,
with
no
suggestion
of
the
potential
for
endocrine
disruption
from
exposure
to
TEHP.
9
C.
Aggregate
Exposure
1.
Dietary
exposure.
Potential
dietary
exposure
will
be
limited,
given
the
proposed
exempted
use
will
only
be
on
wheat
and
barley
crops
in
conjunction
with
herbicide
applications
at
the
early
stage
of
crop
growth
for
wheat
and
barley,
well
before
seed
head
development.

i.
Food.
Given
the
favorable
safety
profile
for
TEHP,
coupled
with
the
timing
of
application
to
growing
crops
for
herbicide
formulations
that
contain
TEHP
that
minimizes
potential
for
residues,
it
can
be
concluded
there
will
be
minimal
to
no
exposure
to
TEHP
in
food.
In
addition,
2
ethylhexanol,
a
likely
metabolite
of
TEHP,
is
currently
exempt
from
the
requirement
of
a
tolerance
for
use
as
an
inert
in
pesticide
formulations
applied
to
growing
crops
and
for
post­
harvest
use
on
raw
agricultural
food
commodities
under
40CFR
Part
180.910
and
180.912.

ii.
Drinking
water.
The
solubility
of
TEHP
is
extremely
low
(
2mg/
liter),
which
makes
the
compound
virtually
insoluble,
and
the
octanol/
water
partition
coefficient
of
4.2
indicates
that
TEHP
will
bind
strongly
to
soil
and
suggests
the
compound
is
largely
immobile.
There
has
been
some
water
monitoring
in
rivers
in
Europe
in
which
very
small
amounts
of
TEHP
have
been
detected.
These
detections
were
believed
to
be
due
to
point
source
discharges
from
production
operations,
and
not
as
a
result
of
leaching
or
runoff.
Because
of
these
factors,
it
is
highly
unlikely
that
TEHP
will
migrate
to
ground
or
surface
water
used
as
drinking
water.

2.
Non­
dietary
exposure.
TEHP
has
been
used
as
a
flame
retardant
for
many
years.
There
have
been
no
other
uses
identified.
The
low
vapor
pressure
would
suggest
that
it
is
unlikely
to
reach
the
atmosphere.
The
photolytic
half­
life
has
been
modeled
to
be
about
1.3
hours,
which
is
relatively
rapid.
Further,
the
solubility
is
very
low
and
as
noted
above
the
available
data
suggests
the
compound
is
largely
immobile.
Therefore,
it
is
concluded
that
non­
dietary
exposure
to
TEHP
as
a
result
of
applications
to
growing
crops
is
expected
to
be
minimal.

D.
Cumulative
Effects
TEHP
does
not
display
toxicity
concerns
as
a
result
of
an
evaluation
of
a
multitude
of
different
tests
on
mammalian
systems.
Based
on
these
data
there
does
not
appear
to
be
any
evidence
for
a
"
common
mechanism"
of
toxicity
with
other
substances.
10
E.
Safety
Determination
1.
U.
S.
population.
The
toxicology
data
base
is
sufficient
to
make
a
safety
determination
for
use
of
TEHP
as
an
inert
in
pesticide
formulations.
TEHP
has
a
very
low
acute
toxicity,
is
non­
genotoxic,
and
has
low
potential
for
developmental
or
reproductive
effects
based
on
lack
of
effects
in
structurally
similar
compounds
as
well
as
it's
major
metabolite,
2­
ethylhexanol.
Further
TEHP
has
low
subchronic/
chronic
toxicity
based
on
a
number
of
well
conducted
studies,
and
is
unlikely
to
be
carcinogenic
to
humans.
Therefore,
there
is
a
reasonable
certainty
that
no
harm
will
result
to
the
general
population,
including
children
and
infants,
and
TEHP
can
be
used
safely
in
pesticide
formulations
used
on
wheat
and
barley.

2.
Infants
and
children.
There
are
no
indications
in
the
available
published
literature
that
infants
and
children
are
more
susceptible
to
toxicity
from
exposure
to
TEHP
than
are
adults.
Several
international
organizations
have
evaluated
TEHP's
toxicity
and
no
concerns
have
been
raised.
Therefore
there
is
a
reasonable
certainty
that
no
harm
to
infants
and
children
will
result
from
TEHP.

F.
International
Tolerances
No
tolerances
or
exemptions
for
tolerance
for
TEHP
have
been
previously
requested
by
Syngenta
Crop
Protection,
Inc.
A
maximum
residue
level
(
MRL)
for
TEHP
has
not
been
established
by
the
Codex
Alimentarus
Commission.

BILLLING
CODE
6560­
50­
S