Document ID: EPA-HQ-OPP-2005-0181-0021
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2006-03-22T05:00Z

UNITED
STATES
ENVIRONMENTAL
PROTECTION
AGENCY
WASHINGTON,
D.
C.
20460
OFFICE
OF
PREVENTION,
PESTICIDES
AND
TOXIC
SUBSTANCES
MEMORANDUM
DATE:
November
14,
2005
SUBJECT:
Para­
tertiary
amylphenol
(
4­
t­
amylphenol)
and
its
sodium
and
potassium
salts:
EPA
Response
to
Public
Comments
on
AD's
Risk
Assessment.
Chemical
Nos.
064101,
064111,
064112.
Case
No.
3016.
DP
Barcode:
321344
FROM:
Deborah
Smegal,
MPH,
Toxicologist/
Risk
Assessor
David
C.
Bays
Antimicrobials
Division
(
7510C)

THRU:
Norm
Cook,
Chief
Risk
Assessment
and
Science
Support
Branch
Antimicrobials
Division
(
7510C)

TO:
Killian
Swift,
Risk
Manager
Reviewer
Team
36,
Reregistration
Antimicrobials
Division
(
7510C)

The
following
comments
are
submitted
on
behalf
of
Clariant
Corporation,
the
sole
registrant
for
technical
para­
tertiary
amylphenol
(
PTAP).

Comment:
EPAs
review
of
existing
literature
should
include
the
large
existing
database
on
para­
substituted
mono
alkylphenols
Comments
of
Clariant
Corporation
Para­
tertiary
Amyphenol
Risk
Assessment
EPA
Docket
ID
Number
2005­
0181
Page
2
of
14
The
para
substituted
mono
alkylphenols
class
of
chemicals,
i.
e.,
nonylphenol
(
NPh),
octylphenol
(
OPh),
and
para
tert­
butyl
phenol
has
been
the
subject
of
many
recent
reviews
and
studies
under
a
number
of
EPA
and
international
programs.
These
data
should
be
used
in
EPA's
evaluations
of
the
toxicology
and
environmental
database,
gap
analysis
as
well
as
in
its
toxicology
endpoint
selections.

EPA's
assessment
of
estrogenic
potential
cites
several
screening
studies
as
a
basis
for
heightened
concern
for
reproductive
and
developmental
effects.
Data
generated
on
similar
alkylphenols,
the
recent
Nonylphenol
and
Octylphenol
multigeneration
studies
and
the
conclusions,
general
principles,
and
strategy
laid
out
in
the
Endocrine
Disruptor
Screening
Program
(
EDSP)
were
not
considered
in
the
assessment.

A
large
number
of
studies
have
been
published
on
alkylphenols
in
the
last
5
to
10
years.
While
many
of
these
studies
focus
on
the
octyl­
and
nonylphenols,
a
number
of
studies
have
included
longer
and
shorter
chain
para­
substituted
mono
alkylphenols
including
tert­
amyl
phenol.
Results
of
in
vitro
and
other
screening
studies
have
indicated
that
many
alkylphenols
can
interact
with
the
estrogen
receptor
and
therefore
have
the
potential
to
cause
endocrine
disrupting
effects.
Many
of
the
studies
conclude
that
the
alkylphenols
interact
with
the
estrogen
receptor
only
at
very
high
doses.
The
potency
of
the
alkyl
phenols
is
estimated
to
be
several
orders
of
magnitude
less
than
17­
 ­
estradiol.
Relative
potency
among
the
alkylphenols
is
estimated
to
be
nonylphenol
>
octylphenol
>
tert­
amylphenol
with
NPh
and
OPh
estimated
to
be
1000­
10,000
fold
less
potent
than
17­
 ­
estradiol,
and
tert­
amylphenol
estimated
to
be
100,000
fold
less
potent
than
17­
 ­
estradiol.

These
screening
studies
were
followed
up
with
in
vivo
studies.
NIEHS
conducted
a
3­
generation
rat
feeding
study
with
nonylphenol.
NPh
was
administered
in
the
diet
at
concentrations
of
0,
200,
650,
and
2000
ppm
to
groups
of
Sprague­
Dawley
rats
over
three
generations.
Effects
observed
at
higher
doses
in
females,
were
consistent
with
NPhs
known
weak
estrogenic
action.
However,
no
effect
fertility
or
reproductive
performance
was
observed
at
any
of
the
doses
tested.
The
NIEHS
study
found
no
consistent
effect
on
fertility
from
all
levels
of
exposure
to
nonylphenol.
Consistent
with
exposure
to
very
high
doses
of
nonylphenol,
the
study
found
effects
including
male
and
female
reproductive
changes
in
rats
at
doses
of
650
ppm
and
above,
based
on
decreased
epididymal
sperm
density
and
testicular
spermatid
head
counts
in
males
(
F2
generation
only),
and
increased
estrous
cycle
length
and
decreased
ovarian
weights
observed
in
females.
However,
these
changes
in
reproductive
parameters
were
not
linked
to
alterations
in
fertility.
(
Since
the
effects
on
sperm
were
observed
in
only
one
generation
and
were
not
associated
with
adverse
effects,
the
study's
author
questioned
whether
this
represents
random
chance,
or
real
biological
effects.)
There
were
no
adverse
reproductive
effects
at
doses
of
200
ppm,
which
translates
to
a
No
Observable
Effect
Level
(
NOEL)
for
reproductive
toxicity
of
15
mg/
kg/
day.
This
NOEL
for
rats
is
several
multiples
of
10
higher
than
an
estimated,
maximal
daily
human
intake
of
NPh.
In
addition,
there
were
no
adverse
effects
on
fertility
at
doses
of
2000
ppm,
which
means
the
No
Observable
Adverse
Effects
Level
(
NOAEL)
is
greater
than
150
milligrams
of
nonylphenol
per
kilogram
of
body
weight
in
rats.
(
NTP
Report
#
RACB94021)

RTI
conducted
a
rat
2­
generation
study
on
octylphenol
(
870.3800
with
additions).
Dietary
exposure
to
octylphenol
for
two
generations
one
litter
per
generation,
at
0,
0.2,
20,
200
and
2000
ppm,
resulted
in:
decreased
body
weights
and
weight
gains
at
2000
ppm,
offspring
toxicity
(
reduced
body
weight
during
lactation
at
2000
ppm,
delayed
vaginal
opening
and
preputial
Comments
of
Clariant
Corporation
Para­
tertiary
Amyphenol
Risk
Assessment
EPA
Docket
ID
Number
2005­
0181
Page
3
of
14
separation
at
2000
ppm,
which
was
considered
related
to
body
weight
decreases,
no
effects
on
reproductive
parameters
or
developmental
effects
were
observed.
(
Two­
Generation
Reproductive
Toxicity
Evaluation
of
Para­
tert
Octylphenol
Administered
in
the
Feed
to
CD
(
Sprague­
Dawley
Rats)
RTI
Project
No.:
65C­
6569­
200.
The
study
results
are
expected
to
be
published
in
an
upcoming
edition
of
Regulatory
Toxicology
and
Pharmacology.
The
results
also
were
reported
at
a
recent
Society
of
Toxicologists
(
SOT)
meeting
in
Washington,
DC.
A
copy
of
the
abstract
may
be
found
at:
http://
www.
aperc.
org/
docs/
abstract­
sd.
pdf.

A
combined
Repeat
Dose
Reproductive/
Developmental
Toxicity
Screening
Test
(
OECD
TG
422)
was
completed
on
para
tert­
butylphenol.
Male
rats
were
dosed
for
44
days,
and
females
were
dosed
14­
days
prior
to
mating
to
day
4
of
lactation
with
20,
60
or
200
mg/
kg/
day
pTBP
by
gavage.
No
treatment
related
toxic
effects
on
pregnant
and
lactating
females
or
their
offspring
were
seen.

The
EDSP
describes
a
tiered
testing
approach
for
the
evaluation
of
endocrine
disrupting
potential.
Tier
1
recommends
in
vitro
or
low
animal
use
screening
studies
similar
to
the
literature
studies
cited
for
PTAP.
The
purpose
of
the
Tier
1
studies
is
largely
to
provide
fast,
inexpensive,
low
or
no
animal
use
studies
that
serve
as
a
screen
to
identify
compounds
that
should
be
tested
in
more
robust
studies.
The
EDSP
recognizes
that
the
tier
1
screening
studies
are
likely
to
result
in
false
positive
results.
Furthermore,
the
screening
studies
cited
for
PTAP
have
not
been
validated,
and
during
validation
testing,
many
of
the
results
have
not
been
able
to
be
reproduced,
nor
have
the
methods
yielded
consistent
results.
Positive
results
in
Tier
1
studies
should
be
confirmed
with
more
robust
in
vivo
studies.

The
EDSP's
"
weight­
of­
evidence"
approach
makes
explicit
the
assumption
that
results
of
some
assays/
tests,
in
some
taxa,
at
some
level
of
severity,
are
intrinsically
"
worth"
more
than
others
and
should,
therefore,
carry
more
weight
in
decisions
following
Tier
1
and
Tier
2.
For
example,
positive
results
showing
reproducible,
high
levels
of
effects
at
low
doses
(
near
the
doses
produced
by
environmental
or
human
exposures)
are
likely
of
greater
weight
than
weak
effects
observed
only
at
very
high,
perhaps
excessively
toxic,
levels
of
exposure.

Using
the
weight
of
evidence
approach,
tert­
amylphenol
has
been
shown
to
have
potential
to
interact
with
the
estrogen
receptor
in
screening
studies
at
relatively
high
doses.
In
the
rat
gavage
developmental
toxicity
study,
maternal
toxicity
(
mucoid/
soft
stools,
urine
stains
rales,
hair
loss,
salivation)
was
observed
at
200
and
500
mg/
kg/
day.
No
adverse
maternal
effects
were
observed
at
50
mg/
kg/
day.
Fetal
effects
(
skeletal
abnormalities,
decreased
body
weight
gain)
were
observed
at
500
mg/
kg/
day.
No
effects
were
observed
at
200
mg/
kg/
day.
A
number
of
screening
studies
have
shown
that
both
NPh
and
OPh
are
likely
to
be
at
least
10
to
100
fold
more
potent
in
interacting
with
the
estrogen
receptor
than
tert­
amyl
phenol.
Since
multi
generation
studies
with
both
NPh
and
OPh
did
not
demonstrate
adverse
developmental
or
reproductive
effects
at
environmentally
relevant
concentrations,
and
since
both
NPh
and
OPh
were
estimated
to
be
10­
100
times
more
potent
in
interacting
with
the
estrogen
receptor,
and
given
the
lack
of
effects
seen
in
the
reproductive/
developmental
screening
study
with
pTBP
and
in
the
oral
developmental
study
or
subchronic
dermal
study
with
PTAP,
and
low
anticipated
exposures
outlined
in
the
dietary,
occupational
and
residential
assessments
heightened
concern
for
endocrine
disrupting
effects
does
not
appear
to
be
warranted.

For
additional
details
concerning
the
many
pertinent
studies
on
NPh
and
OPh,
see,
for
example:
Van
Miller,
J.
P.,
and
Staples,
C.
A.
(
2005).
Review
of
the
potential
environmental
and
human
Comments
of
Clariant
Corporation
Para­
tertiary
Amyphenol
Risk
Assessment
EPA
Docket
ID
Number
2005­
0181
Page
4
of
14
health­
related
hazards
and
risks
from
long­
term
exposure
to
p­
tert­
octylphenol.
Human
and
Ecological
Risk
Assessment,
11,
319­
351;
Tyl,
R.
W.,
Myers,
C.
B.,
and
Marr,
M.
C.
(
2004,
February
12).
Three­
Generation,
Endpoint­
Specific
Evaluation
of
para­
Nonylphenol
(
NP;
CAS
RN
84852­
15­
3)
Toxicity
in
Rats.
Unpublished
Report
65C­
07946­
000.
RTI
International,
Center
for
Life
Sciences
and
Toxicology,
Health
Science
Group,
Research
Triangle
Park,
NC,
USA;
Chapin,
R.
E.,
Delaney,
J.,
Wang,
Y.,
Lanning,
L.,
Davis,
B.,
Collins,
B.,
Mintz,
N.,
and
Wolfe,
G.
(
1999).
The
Effects
of
4­
Nonylphenol
in
Rats:
A
Multigeneration
Reproduction
Study.
Toxicological
Sciences,
52,
80­
91;
Latendresse,
J.
R.,
Weis,
C.
C.,
Mellick,
P.
W.,
Newbold,
R.
R.,
and
Delclos,
K.
B.
(
2004).
A
Five
Generation
Reproductive
Toxicity
Assessment
of
p­
Nonylphenol
(
NP)
In
CD
Sprague­
Dawley
Rats.
Toxicologist,
1066,
219;
Nagao,
T.,
Wada,
K.,
Marumo,
H.,
Yoshimura,
S.,
and
Ono,
H.
(
2001).
Reproductive
Effects
of
Nonylphenol
in
Rats
after
Gavage
Administration:
A
Two­
Generation
Study.
Reproductive
Toxicology,
15,
293­
315;
Odum,
J.,
and
Ashby,
J.
(
2000).
Neonatal
Exposure
of
Male
Rats
to
Nonylphenol
Has
No
Effect
on
the
Reproductive
Tract.
Toxicological
Sciences,
56,
400­
404;
Odum,
J.,
Pyrah,
I.
T.
G.,
Soames,
A.
R.,
Foster,
J.
R.,
Van
Miller,
J.
P.,
Joiner,
R.
L.,
and
Ashby,
J.
(
1999).
Effects
of
p­
Nonylphenol
(
NP)
and
Diethylstilboestrol
(
DES)
on
the
Alderly
Park
(
Alpk)
Rat:
Comparison
of
Mammary
Gland
and
Uterus
Sensitivity
Following
Oral
Gavage
or
Implanted
Mini­
pumps.
Journal
of
Applied
Toxicology,
19,
367­
378.
9
Odum,
J.,
Pyrah,
I.
T.
G.,
Foster,
J.
R.,
Van
Miller,
J.
P.,
Joiner,
R.
L.,
and
Ashby,
J.
(
1999).
Comparative
Activities
of
p­
Nonylphenol
and
Diethylstilbestrol
in
Noble
Rat
Mammary
Gland
and
Uterotrophic
Assays.
Regulatory
Toxicology
and
Pharmacology,
29,
184­
195.
10
Cunny,
H.
C.,
Mayes,
B.
A.,
Rosica,
K.
A.,
Trutter,
J.
A.,
and
Van
Miller,
J.
P.
(
1997).
Subchronic
Toxicity
(
90­
Day)
Study
with
para­
Nonylphenol
in
Rats.
Regulatory
Toxicology
and
Pharmacology,
26,
172­
178.

EPA
Response:

The
Agency's
risk
assessment
and
Reregistration
Eligibility
Decision
(
RED)
are
focused
on
4­
tamylphenol
to
ensure
this
registered
pesticide
meets
the
FIFRA
and
FQPA
standards.
The
Agency
has
identified
potential
concerns
and
data
gaps,
especially
for
endocrine
effects
and
their
impact
on
reproductive
effects
for
4­
t­
amylphenol.
Available
data
suggest
that
4­
t­
amylphenol
has
endocrine
disrupter
capabilities
(
uterotrophic
and
estrogenic
effects)
and
increased
bilirubin
production
in
babies.
In
addition,
this
chemical
is
listed
on
a
European
list
of
"
Chemicals
purported
to
be
endocrine
disruptors"
(
IEH
2005).
When
the
appropriate
screening
and/
or
testing
protocols
being
considered
under
the
Agency's
Endocrine
Disruptor
Screening
Program
(
EDSP)
have
been
developed,
4­
t­
amylphenol
and
its
potassium
and
sodium
salts
may
be
subjected
to
additional
screening
and/
or
testing
to
better
characterize
effects
related
to
endocrine
disruption.

The
Agency
has
agreed
to
place
the
request
for
the
2­
generation
reproduction
study
in
reserve,
pending
the
outcome
of
a
90­
day
rat
oral
toxicity
study
with
modifications
to
address
endocrine
effects
and
neurotoxicity.
The
Agency
plans
to
re­
evaluate
the
need
for
the
reproduction
study
based
on
these
results
and
any
additional
information
that
may
become
available.
Comments
of
Clariant
Corporation
Para­
tertiary
Amyphenol
Risk
Assessment
EPA
Docket
ID
Number
2005­
0181
Page
5
of
14
The
argument
the
registrant
is
making
contains
an
aspect
of
extrapolating
across
chemicals,
which
can
be
addressed
based
on
in
vitro
data
(
humans
and
fish),
and
in
vivo
fish
(
below).
But
in
trying
to
assess
what
occurs
in
vivo,
there
are
additional
complications
due
to
chemical
kinetics
and
metabolism.
Then,
in
this
exercise
there
are
added
complications
when
making
comparisons
across
species.
Below
the
Agency
tries
to
present
information
about
extrapolations
across
chemicals,
and
species,
and
levels
of
biological
organization.

The
Agency
agrees
that
the
registrant's
argument
seems
pretty
logical
about
looking
at
nonylphenol
and
octylphenol
when
assessing
4­
t­
amylphenol.
1)
The
Agency
is
not
trying
to
argue
that
there
is
a
mode
of
action
difference;
all
the
assumptions
are
that
alkylphenols
are
working
through
the
estrogen
receptor
(
ER)
when
assessing
potential
for
reproductive
effects.
2)
Starting
with
the
in
vitro
data
(
See
attached
Table
I
=
(
potencies
relative
to
Estradiol);
or
Table
II
=
IC50
or
EC50)
for
a
series
of
relevant
alkylphenols
(
APs).
Comparing
the
effect
of
carbon
alkyl
chain
length
on
receptor
affinity
shows
that,
in
general,
nonyl­
(
C9)
and
octyl­
(
C8)
phenols
bind
the
ER
with
about
an
order
of
magnitude
greater
potency
than
do
the
shorter
chains
amyl
(
C5)
or
butyl
(
C4)
phenols,
with
C5
and
C4
about
equal.
This
general
trend
holds
for
both
the
rainbow
trout
ER
(
rtER),
and
human
ER
(
hER),
[
interestingly
the
affinity
relative
to
estradiol
is
about
10X
greater
for
APs
at
the
hER
than
the
fish
ER.]

3)
You
can
also
compare
the
next
higher
level
of
biological
organization,
the
gene
activation
assays.
We
list
several
because
no
one
assay
has
the
complete
set
of
data
across
all
chemicals
we
want
to
compare.
Assays
included
=
human
ER
yeast
reporter
gene
assay
(
Table
II­
last
column);
human
ER
in
2
different
cell
lines;
and
trout
[
vitellogenin
(
VTG)
liver
slice
assay]
(
Table
I
or
II).
First
recognize
that
there
are
greater
differences
in
just
estradiol
affinity
between
the
different
hER
driven
assays,
than
between
hER
and
fish
ER.
In
particular,
the
T47D
cells
are
really
sensitive
to
estradiol
10­
12
M
while
other
assays
are
typically
sensitive
at
10­
8
M
whether
fish
or
human.
So,
maybe
it's
better
to
just
look
at
rank
order
of
potency
for
what
we
want
to
do
here.
Using
this
rough
metric,
t­
octylphenol
appears
most
potent,
with
nonyl­
somewhat
less
potent.
If
you
look
at
the
YES,
n­
amyl
is
more
potent
than
t­
amyl,
with
both
more
potent
than
C4.
So,
shorter
chains
are
less
potent.
Potency
for
the
series
generally
peaks
around
octyl,
so
the
registrant's
reference
to
octyl
data
is
logical.
Figure
1
shows
graphs
of
fish
VTG
induction
vs.
T47D
response
­
(
sometimes
easier
to
see
a
picture).
Same
story
though,
response
can
be
equal
to
that
induced
by
estradiol,
just
at
a
higher
concentration.
But
you
can't
use
the
absolute
numbers
from
in
vitro
to
predict
in
vivo
response.
In
the
Agency's
experience
with
over
50
chemicals
run
in
both
binding
and
slice
assays,
the
chemical
concentration
needed
for
gene
activation
is
always
less
than
what
was
needed
to
see
binding.
Same
holds
true
then
when
you
go
to
in
vivo,
at
least
for
fish,
the
concentration
(
for
continous
aqueous
exposure
at
least)
is
lower
than
needed
for
either
in
vitro
model.
Comments
of
Clariant
Corporation
Para­
tertiary
Amyphenol
Risk
Assessment
EPA
Docket
ID
Number
2005­
0181
Page
6
of
14
4)
in
vivo
 
fish
data,
which
is
the
data
the
Agency
referenced
from
the
literature,
it
really
seems
clear
that
there
is
a
response.
In
vivo
responses
to
octyl
and
nonyl
have
also
been
shown
in
fish,
where
it's
been
studied
a
lot.
So,
within
fish
the
data
seems
consistent
for
alkylphenols.
The
registrant
argues
the
same
is
true
within
mammals,
where
they
say
there
are
no
effects
for
NP
and
OP,
and
further
none
seen
for
t­
butyl,
so
why
should
they
do
more
on
PTAP.
However,
the
fish
effects
may
be
due
to
a
difference
of
exposure
and
the
kinetics
of
chemical
uptake
and
distribution
based
on
those
exposures.
These
alkylphenols
have
a
significantly
high
LogP
to
be
taken
up
very
efficiently
by
fish,
so
they
can
bioaccumulate
to
high
levels,
apparently
high
enough
to
produce
in
vivo
effects
(
e.
g.,
sex
reversal
in
medaka)
from
a
full
life
cycle
exposure.

Table
I.
Relative
binding
affinity
(
RBA)
in
rainbow
trout
cytosolic
estrogen
receptor
and
full
length
human
 ­
estrogen
receptor
binding
assays.
Relative
estrogenic
potency
(
REP)
in
rainbow
trout
vitellogenin
mRNA­
slice,
human
pS2
mRNA­
MCF­
7,
and
human
T47D­
KBluc
reporter
gene
activation
assays.

Estrogen
Receptor
Binding
Gene
Activation
Chemical
CAS
#
Trout
Cytosol
RBA
(%))
Human
Recomb.
RBA
(%)
Trout
VTG
REP
(%)
Human
pS2
REP
(%)
Human
T47D
REP
(%)
17­
 ­
Estradiol
50­
28­
2
100
100
100
100
100
p­
nonylphenol
84852­
15­
3
0.0460
nt
0.027
nt
0.00004
p­
tert­
octylphenol
140­
66­
9
0.0750
0.254
0.013
7.2
0.0071
p­
tert­
amylphenol
80­
46­
6
0.0040
nt
0.004
nt
nt
p­
tert­
butylphenol
98­
54­
4
0.0014
nt
nt
nt
nt
p­
n­
butylphenol
1638­
22­
8
0.0035
0.024
0.017
0.74
0.0003
Bold
=
p­
n­
Butylphenol
EC
50
value
used
in
REP
calculation
was
calculated
from
curves
that
only
achieved
25%
of
maximum
estradiol
response,
therefore
REP
value
is
overestimated.
nt=
not
tested
Comments
of
Clariant
Corporation
Para­
tertiary
Amyphenol
Risk
Assessment
EPA
Docket
ID
Number
2005­
0181
Page
7
of
14
Gene
Activation
p­
Nonylphenol
CTRL
1.0
×
103
1.0
×
104
1.0
×
105
1.0
×
106
1.0
×
107
1.0
×
108
E2
p­
Nonylphenol
­
10
­
9
­
8
­
7
­
6
­
5
­
4
­
3
­
2
Control
Log
Concentration
(
M)
Vtg
mRNA
(
copy
#/
400
ng
total
RNA)

CTRL
­
10
0
10
20
30
40
50
60
70
80
90
100
110
120
130
140
­
12
­
11
­
10
­
9
­
8
­
7
­
6
­
5
­
4
­
3
­
2
E2
p­
Nonylphenol
Log
Concentration
(
M)
Response
Relative
to
Maximum
E2
(%)
p­
Nonylphenol
CTRL
1.0
×
10
3
1.0
×
10
4
1.0
×
10
5
1.0
×
10
6
1.0
×
10
7
1.0
×
10
8
p­
tert­
Octylphenol
­
10
­
9
­
8
­
7
­
6
­
5
­
4
­
3
­
2
E2
p­
tert­
Octylphenol
Control
Log
Concentration
(
M)
Vtg
mRNA
(
copy
#/
400
ng
total
RNA)

CTRL
­
10
0
10
20
30
40
50
60
70
80
90
100
110
120
130
140
­
12
­
11
­
10
­
9
­
8
­
7
­
6
­
5
­
4
­
3
­
2
E2
p­
tert­
Octylphenol
Log
Concentration
(
M)
Response
Relative
to
Maximum
E2
(%)
p­
tert­
Octylphenol
CTRL
1.0
×
102
1.0
×
103
1.0
×
104
1.0
×
105
1.0
×
106
1.0
×
107
1.0
×
108
p­
tert­
Amylphenol
­
10
­
9
­
8
­
7
­
6
­
5
­
4
­
3
­
2
p­
tert­
Amylphenol
E2
Control
Log
Concentration
(
M)
Vtg
mRNA
(
copy
#/
400
ng
total
RNA)

CTRL
1.0
×
10
3
1.0
×
10
4
1.0
×
10
5
1.0
×
10
6
1.0
×
10
7
1.0
×
10
8
­
10
­
9
­
8
­
7
­
6
­
5
­
4
­
3
­
2
E2
p­
n­
Butylphenol
Control
p­
n­
Butylphenol
Log
Concentration
(
M)
Vtg
mRNA
(
copy
#/
400
ng
total
RNA)

CTR
L
­
10
0
10
20
30
40
50
60
70
80
90
100
110
120
130
140
­
12
­
11
­
10
­
9
­
8
­
7
­
6
­
5
­
4
­
3
­
2
p­
n­
Butylphenol
E2
p­
n­
Butylphenol
Log
Concentration
(
M)
Response
Relative
to
Maximum
E2
(%)
Rainbow
Trout
VTG
mRNA
Human
T47D­
KBluc
Reporter
Gene
Comments
of
Clariant
Corporation
Para­
tertiary
Amyphenol
Risk
Assessment
EPA
Docket
ID
Number
2005­
0181
Page
8
of
14
Comment:
A
tiered
testing
strategy
should
be
used
to
fill
data
gaps
and
prevent
duplicative
studies
In
the
toxicology
endpoint
selection
document
EPA
requests
a
90­
oral
toxicity
study
with
modifications
to
assess
endocrine
disruptor
effects
and
uterotropic
effects,
a
second
developmental
study
and
a
reproductive
study
based
on
the
in
vitro
screening
studies.
In
some
cases,
the
same
test
procedure
is
being
duplicated
in
two
or
more
species
(
e.
g.,
developmental
dosing
studies
in
rats
and
rabbits).
In
other
places,
EPA
is
proposing
to
conditionally
require
a
second
species
because
the
data
will
provide
"
some
assurance"
that
EPA
is
not
basing
its
assessment
on
a
single
species
that
may
be
highly
sensitive.
However,
"
some
assurance"
is
not
a
sufficient
rationale
for
requiring
testing
of
another
species.
EPA
should
not
require
testing
on
additional
animals
when
the
value
of
the
testing
requirement
has
not
been
established
through
tiered
testing
and
full
assessment
of
the
available
database
on
PTAP
and
structurally
similar
compounds.

Any
concerns
regarding
potential
endocrine
disruptor
effects
and
uterotropic
effects
can
likely
be
resolved
by
the
results
of
the
90­
day
oral
study
if
the
protocol
is
modified
as
requested
by
the
ADTC.
Accordingly,
any
requirement
for
additional
developmental
and
reproductive
studies
should
be
held
in
reserve
pending
completion
and
review
of
the
new
90­
day
oral
study
being
requested.
Any
requirement
to
perform
either
the
additional
developmental
or
a
2­
generation
reproductive
study
prior
to
receipt
of
the
90­
day
study,
risks
unnecessarily
increasing
the
number
of
animals
tested
and
providing
little
or
no
useful
additional
information
that
would
affect
the
overall
risk
assessment.

EPA
Response:
The
Agency's
Registration
Eligibility
Decision
(
RED)
Document
agrees
that
a
tiered
testing
approach
is
acceptable,
and
that
the
developmental
and
reproductive
studies
are
held
in
reserve
pending
the
completion
of
the
modified
90­
day
oral
study.
The
Agency
originally
requested
the
rabbit
developmental
study
because
the
rat
prenatal
developmental
study
showed
qualitative
evidence
of
increased
susceptibility
[
i.
e.,
fetal
effects
(
skeletal
abnormalities,
decreased
body
weight
gain)
were
considered
to
be
more
severe
than
the
maternal
toxicity
(
reversible
clinical
signs)
observed
at
the
same
dose
level].
However,
since
the
Agency
retained
the
FQPA
factor
of
10X,
and
the
risks
did
not
exceed
the
Agency's
level
of
concern
for
most
uses
(
and
all
risks
of
concern
were
mitigated),
the
Agency
believes
it
is
appropriate
to
hold
the
rabbit
developmental
study
in
reserve
pending
the
outcome
of
the
90­
day
rat
modified
toxicity
study
that
will
evaluate
endocrine
effects
and
uterotropic
effects.

Comment:
EPAs
test
requirements
need
to
incorporate
the
best
available
science
in
terms
of
determining
the
need
for
testing
as
well
as
appropriate
test
methods
if
testing
is
needed.

As
mentioned
above,
a
tiered
testing
strategy
and
weight
of
evidence
approach
to
testing
requirements
has
not
been
applied.
The
EDSP
is
currently
evaluating
and
validating
the
models
available
to
study
potential
endocrine
disrupting
effects.
Clariant
is
willing
to
work
with
EPA
to
ensure
that
these
principles
are
incorporated
into
the
design
of
the
90­
day
oral
study.
Comments
of
Clariant
Corporation
Para­
tertiary
Amyphenol
Risk
Assessment
EPA
Docket
ID
Number
2005­
0181
Page
9
of
14
EPA
Response:
The
Agency's
Registration
Eligibility
Decision
(
RED)
Document
agrees
that
a
tiered
testing
approach
is
acceptable,
and
that
the
developmental
and
reproductive
studies
are
held
in
reserve
pending
the
completion
of
the
modified
90­
day
oral
study.
In
addition,
4­
t­
amylphenol
and
its
potassium
and
sodium
salts
may
be
subjected
to
additional
screening
and/
or
testing
to
better
characterize
effects
related
to
endocrine
disruption
following
validation
of
test
models
by
EDSP.

Comment:
PTAP
does
not
meet
the
criteria
for
additional
developmental
or
reproductive
toxicity
testing
as
described
in
the
Draft
158
w
testing
requirements.

Testing
in
two
species
if
one
of
two
conditions
is
met.

a.
Significant
exposure
to
females
of
childbearing
age
may
reasonably
be
expected.
In
EPA's
current
dietary
risk
assessment,
a
conservative
target
MOE
of
3000
was
chosen.
EPA's
dietary
risk
assessment
concluded
that
none
of
the
exposure
scenarios
approach
the
target
MOE.
b.
Significant
developmental
toxicity
is
observed
after
testing
in
the
first
species.
Significant
developmental
effects
were
not
observed
in
the
rat
developmental
study.

EPA
Response:
These
studies
were
not
requested
based
on
the
Draft
158W
testing
requirements.
The
risk
assessment
was
revised
to
more
clearly
state
the
reasons
for
the
requested
studies.
As
noted
previously,
the
Agency's
Antimicrobials
Division
Toxicity
Endpoint
Selection
Committee
(
ADTC)
originally
requested
the
rabbit
developmental
study
because
the
rat
prenatal
developmental
study
showed
qualitative
evidence
of
increased
susceptibility
[
i.
e.,
fetal
effects
(
skeletal
abnormalities,
decreased
body
weight
gain)
were
considered
to
be
more
severe
than
the
maternal
toxicity
(
reversible
clinical
signs)
observed
at
the
same
dose
level].
The
ADTC
requested
the
reproduction
study
because
of
concerns
in
the
literature
of
possible
endocrine
effects.
However,
since
the
Agency
retained
the
FQPA
factor
of
10X,
and
the
risks
did
not
exceed
the
Agency's
level
of
concern
for
most
uses
(
and
all
risks
of
concern
were
mitigated),
the
Agency
believes
it
is
appropriate
to
hold
the
reproduction
and
rabbit
developmental
study
in
reserve
pending
the
outcome
of
the
90­
day
rat
modified
toxicity
study
that
will
evaluate
endocrine
effects
and
uterotropic
effects.

Comment:
PTAP
does
not
meet
the
criteria
for
a
2­
generation
reproductive
study
laid
out
in
the
draft
158w
guideline.

A
2­
generation
test
is
required
if:

Adverse
effects
on
organs
of
the
reproductive
system
are
observed
in
90­
day
or
other
studies
or
if
developmental
toxicity
is
demonstrated
in
available
data.
In
the
90­
day
dermal
toxicity
no
systemic
toxicity
was
observed
at
the
highest
dose
tested,
25
mg/
kg/
day.
In
the
rat
developmental
toxicity
study
fetal
effects
were
limited
to
Comments
of
Clariant
Corporation
Para­
tertiary
Amyphenol
Risk
Assessment
EPA
Docket
ID
Number
2005­
0181
Page
10
of
14
skeletal
abnormalities
and
decreased
body
weight
gain
at
500
mg/
kg/
day.
In
this
study
maternal
toxicity
was
observed
at
200
and
500
mg/
kg/
day.

EPA
Response:
The
reproduction
study
was
not
requested
based
on
the
Draft
158W
testing
requirements.
The
risk
assessment
was
revised
to
more
clearly
state
the
reasons
for
the
requested
studies.
Available
data
suggest
that
4­
t­
amylphenol
has
endocrine
disrupter
capabilities
(
uterotrophic
and
estrogenic
effects)
and
increased
bilirubin
production
in
babies.
Specifically,
in
the
open
literature
(
Yamasaki
et
al.
2003),
an
increase
in
non­
pregnant
uterine
weight
was
observed
in
rats
following
4­
t­
amylphenol
exposure.
Another
study
(
Soto
et
al.
1995)
suggested
that
4­
t­
amylphenol
may
have
estrogenic
effect.
Wysowski
et
at.
(
1978)
reported
elevated
blood
levels
of
bilirubin
in
children
exposed
to
4­
tampyphenol
and
other
phenols
in
disinfectant.
These
studies,
while
not
indicative,
are
suggestive
of
a
basis
for
increased
concern
for
reproductive
and/
or
developmental
effects
due
to
exposure
to
4­
t­
amylphenol.
Also
see
EPA
response
to
above
comment.

Comment:
The
requested
ecotoxicity
tests
may
be
of
little
or
no
practical
value.

The
environmental
assessment
cites
a
number
of
ecotoxicity
and
environmental
studies
on
PTAP,
but
fails
to
cite
the
significant
number
of
studies
and
environmental
assessments
on
similar
para
substituted
mono
alkylphenols.
EPA
states
that
since
there
are
no
outdoor
uses
of
PTAP,
significant
exposure
is
unlikely
to
occur.
Despite
the
availability
of
literature
data
on
PTAP
and
structurally
similar
substances,
and
the
fact
that
there
are
no
outdoor
uses
for
PTAP,
EPA
has
requested
an
acute
ecotoxicity
battery.
(
See,
for
example,
the
recently
published
manuscript
in
the
Human
and
Ecological
Risk
Assessment
journal
(
Staples,
C.,
Mihaich,
E.,
Carbone,
J.,
Woodburn,
K.,
and
Klecka,
G.
(
2004).
A
Weight
of
Evidence
Analysis
of
the
Chronic
Ecotoxicity
of
Nonylphenol
Ethoxylates,
Nonylphenol
Ether
Carboxylates,
and
Nonylphenol.
Human
and
Ecological
Risk
Assessment,
10,
999­
1017)
which
provided
a
weight
of
evidence
hazard
assessment
using
a
robust
statistical
technique
known
as
Species
Sensitivities
Distribution
(
SSD).
About
90
chronic
toxicity
values
from
high
quality
peer­
reviewed
studies
were
evaluated.
Using
the
SSD
analysis
for
nonylphenol
(
NP)
the
authors
calculated
a
chronic
safe
level
of
5.7
ug/
L,
which
supports
the
draft
US
EPA
criteria
for
NP
of
5.9
ug/
L.)

Given
the
limited
exposure
and
EPA's
conclusion
that
an
environmental
risk
assessment
was
unnecessary,
new
studies
are
of
little
or
no
practical
value.
Requiring
such
tests
places
unnecessary
burdens
on
registrants,
misallocates
scientific
expertise
and
technical
resources
that
could
be
more
productively
used
for
other
purposes,
leads
to
unnecessary
animal
testing,
and
is
directly
contrary
to
EPA's
stated
goals
of
increasing
the
quality
of
the
data
and
the
efficiency
of
the
registration
program.
A
study
should
not
be
required
unless
it
can
clearly
be
linked
to
a
registration
decision.

EPA
Response:
The
Agency
requires
that
all
registrants
complete
a
core
group
of
four
ecological
effects
studies
to
get
a
baseline
on
the
toxicity
of
antimicrobial
pesticides.
These
studies
are
rarely
waived,
even
for
indoor
use
pesticides,
because
the
Agency
needs
this
information
to
ensure
that
the
toxicity
of
the
chemical
is
well
defined
in
case
there
are
ecotoxicity
concerns
in
the
future.
The
registrant
mentions
several
literature
studies
that
give
an
indication
of
the
ecotoxicity
of
this
chemical.
As
stated
in
the
risk
assessment,
the
Comments
of
Clariant
Corporation
Para­
tertiary
Amyphenol
Risk
Assessment
EPA
Docket
ID
Number
2005­
0181
Page
11
of
14
studies
from
the
literature
do
not
meet
Agency
standards
and
therefore
cannot
be
used
in
a
risk
assessment.
The
registrant
mentions
a
Species
Sensitivities
Distribution
(
SSD)
technique,
a
statistical
methodology,
that
has
been
used
in
the
literature
to
provide
a
weight
of
evidence
hazard
assessment
for
these
types
of
chemicals.
The
technique
may
be
of
academic
interest,
but
has
not
been
proven
to
be
a
valid
method
for
assessing
the
ecotoxicty
of
chemical
pesticides.
The
fact
that
the
registrant
sees
little
or
no
practical
value
in
doing
these
studies
is
not
a
valid
reason
for
waiving
them.
Therefore,
the
registrant
will
have
to
complete
the
required
ecotoxicity
studies.

Comment:
Adequate
Margins
of
Exposure
exist
for
inhalation,
and
a
28­
day
inhalation
study
should
not
be
required.

The
ADTC
states
"
inhalation
exposure
is
expected
from
use
as
an
air
sanitizer".
(
It
should
be
noted
that
while
there
are
uses
for
PTAP
in
air
deodorizers,
it
is
not
registered
for
use
as
an
air
sanitizer.)
Although
it
is
not
discussed
by
the
ADTC,
the
other
use
that
may
result
in
postapplication
inhalation
exposure
occurs
as
a
result
of
its
use
in
fogging
agricultural
premises.

All
residential
and
institutional
handler/
applicator
inhalation
exposures
are
considerably
greater
than
the
target
MOE.
Post­
application
exposure
in
residential
settings
is
also
considerably
greater
than
the
very
conservative
target
MOE.
The
only
calculated
postapplication
exposure
below
the
target
MOE
results
from
exposure
following
a
two­
hour
reentry
period
in
fogged
barns.
The
ventilation
rate
assumed
by
EPA
in
its
model
is
too
conservative
and
it
severely
overestimates
the
exposure
to
PTAP.

Model
takes
no
account
of
the
application
time
The
model
calculates
a
peak
concentration
(
total
mass
applied/
volume
of
building)
to
give
a
peak
concentration.
In
reality,
this
peak
concentration
will
not
be
achieved
because
the
fog
is
not
applied
instantaneously,
nor
will
instantaneous
mixing
occur.

Ventilation
rate
is
too
low
Barns
such
as
stables,
poultry
and
livestock
buildings
have
extensive
guidance
available
issued
by
various
state
agencies
on
the
need
for
correct
ventilation
to
maintain
animal
welfare
and
prevent
disease.
For
example,
the
according
to
the
Ontario
State
Department
of
Food
and
Rural
Affairs
(
http://
www.
omafra.
gov.
on.
ca/
english/
engineer/
facts/
96­
031.
htm)
a
minimum
ventilation
rate
of
1
air
change
per
house
(
ACH)
is
recommended
for
a
stable.
The
U.
S.
Humane
Society
(
http://
www.
eap.
mcgill.
ca/
LPAW_
1.
htm)
recommends
a
minimum
of
4
air
changes
per
hour
in
winter
and
40
air
changes
per
hour
in
summer
as
necessary
to
keep
the
air
in
swine
facilities
reasonably
clean
and
fresh.
These
rates
are
much
larger
than
the
default
hourly
air
exchange
rate
(
ACH)
of
0.18
used
by
the
Agency
in
the
calculation.
An
ACH
of
0.18
is
only
apt
to
be
found
in
the
highly
energy
efficient
new
homes.
Indeed,
the
EPA
exposure
factors
handbook
(
EPA,
1997)
recommends
values
of
0.45
ACH
as
the
central
tendency
and
0.18
ACH
as
the
conservative
defaults
for
residential
risk
assessment.
Using
a
more
realistic
ventilation
rate
of
1
ACH
results
in
a
MOE
of
>
1000,
above
the
Agency's
level
of
concern.
Comments
of
Clariant
Corporation
Para­
tertiary
Amyphenol
Risk
Assessment
EPA
Docket
ID
Number
2005­
0181
Page
12
of
14
Should
the
Agency
still
have
concerns
over
the
MOE
at
2­
hour
reentry,
Clariant
is
willing
to
work
with
the
Agency
to
modify
the
label
language
to
change
the
reentry
interval
or
make
other
modifications
to
alleviate
any
concerns.
If
the
inhalation
MOEs
are
all
above
the
target,
requiring
that
the
registrant
conduct
a
28­
day
day
inhalation
study
would
have
no
affect
on
the
risk
assessment,
and
this
requirement
should
be
eliminated.

EPA
Response:
The
ADTC
originally
requested
a
28­
day
rat
inhalation
study
for
hazard
considerations
because
4­
t­
amylphenol
is
an
air
deodorizer.
However,
the
Agency
does
not
believe
this
study
is
necessary
because
the
MOEs
are
sufficiently
high
for
this
use,
and
thus
not
of
concern.
The
Agency
revised
the
air
exchange
rate
(
ACH)
used
in
assessing
the
entry
into
a
building
after
a
fogging
application
(
details
are
presented
in
the
Occupational
and
Residential
Exposure
Assessment
for
t­
Tert­
Amylphenol
and
Salts.
S.
Mostaghimi
.
September
2005.
D316290).
The
revised
calculated
inhalation
MOEs
were
above
the
target
MOE
of
300
for
all
fogging
postapplication
scenarios,
and
thus
are
not
of
concern.

Comment:
EPA
appears
to
have
created
a
new
"
Indirect
Food
Use"
category.

Finally,
EPA
seems
to
have
created
a
new
"
indirect
food"
contact
category.
Historically,
the
Agency
has
made
a
distinction
between
food
uses
and
non­
food
indoor
uses.
For
most
non­
food
uses
(
wood
preservation
being
a
notable
exception)
the
toxicology
data
requirements
were
those
enunciated
in
the
1987
Antimicrobial
Data
Call­
In
(
AMDCI).
Specifically,
the
standard
AMDCI
tier
1
requirements
for
those
uses
have
been
exposure
data
plus
acute
toxicity
data,
mutagenic
data,
and
developmental
toxicity
(
one
species),
and
one
90­
day
subchronic
performed
using
the
route
of
most
likely
exposure
(
In
the
case
of
PTAP
the
principal
route
of
exposure
was
dermal.)
Food
contact
uses
typically
required
additional
data
including
developmental
toxicity
in
a
second
species,
reproductive
toxicity,
chronic
toxicity,
and
oncogenicity.
This
distinction
between
these
two
basic
categories
of
use
and
the
data
required
to
support
those
uses
have
continued
until
very
recently.
In
point
of
fact,
the
distinction
was
apparent
in
the
"
error
only"
drafts
that
were
provided
to
Clariant
for
comment
in
May
2005.
See,
for
example,
the
data
requirements
table
on
page
2
of
the
RED
Toxicology
Chapter
dated
May
21,
2005.
Requirements
for
a
developmental
toxicity
study
in
a
second
species,
a
reproduction
study,
chronic
toxicity
and
oncogenicity
data
are
all
data
requirements
that
typically
apply
only
to
food
contact
or
direct
food
uses.

The
July
12,
2005
draft
Dietary
Exposure
Assessments
indicates
that
general
agricultural
premise
use
"
would
be
an
indirect
food
use",
which
could
require
additional
data
including
"
livestock
and
poultry
metabolism
studies,
analytical
methods
for
livestock
and
poultry
tissues
and
residues
for
livestock
and
poultry.
(
As
it
typically
appears
on
most
labels
these
general
agricultural
premise
uses
involve
application
of
PTAP
to
hard
interior
surfaces
of
barns
and
poultry
houses
followed
by
potable
water
rinses
or
soap/
detergent
scrubbing.)
It
is
suggested
that
such
uses
could
represent
an
indirect
food
use
premised
on
an
assumption
that
residues
could
remain
on
the
hard
surface
following
rinsing
or
scrubbing
and
that
an
animal
in
the
barn
cribbing
on
the
wood
might
consume
that
residue,
which
could
eventually
find
its
way
into
food;
however,
the
argument
is
hypothetical
at
best.
Historically
both
FDA
and
EPA
have
viewed
these
as
non­
food
uses.
Comments
of
Clariant
Corporation
Para­
tertiary
Amyphenol
Risk
Assessment
EPA
Docket
ID
Number
2005­
0181
Page
13
of
14
End­
use
registrations
for
phenolic
compounds
typically
contain
two
or
three
different
phenolic
compounds
formulated
together,
as
you
have
probably
noted
in
reviewing
the
labels.
These
combinations
often
include
PTAP
combined
with
ortho­
benzyl­
para­
chlorophenol
(
BCP)
and/
or
ortho­
phenylphenol
(
OPP).
In
this
particular
instance
the
issue
of
how
to
handle
uses
such
as
the
agricultural
premises
was
addressed
in
the
BCP
RED.
The
RED
required
a
number
of
changes
to
the
label
directions
"
for
farm
premises
to
permit
their
classification
as
non­
food
use
products."
The
label
changes
required
to
enable
EPA
to
classify
these
uses
of
BCP
as
non­
food
uses
have
already
been
made
for
many
of
the
end­
use
PTAP
products
when
new
labels
were
submitted
to
comply
with
the
BCP
RED.
Clariant
believes
that
these
changes
are
appropriate
in
this
instance
also,
and
recommends
adoption
of
these
in
lieu
of
classifying
such
uses
as
food
contact
uses.
To
the
extent
that
the
Agency
believes
that
further
changes
in
the
labeling
may
be
necessary,
Clariant
would
be
willing
to
discuss
such
further
modifications.

As
you
know,
the
issues
related
to
so­
called
indirect
food
uses
apply
to
many
active
ingredients.
The
Biocides
Panel
of
the
American
Chemistry
Council
has
been
carrying
on
a
dialogue
with
AD
trying
to
resolve
these
issues
and
the
data
requirements.
Clariant
is
a
member
of
that
Panel,
and,
along
with
the
other
Panel
members,
it
is
committed
to
developing
whatever
data
may
eventually
be
required
to
support
the
continued
registration
of
these
uses.
This
includes
confirmatory
exposure
data
if
required.
Clariant
believes
further
that
imposition
of
these
data
requirements
on
PTAP
without
similarly
imposing
them
on
all
active
ingredients
registered
for
the
same
uses
would
create
an
unfair
playing
field.
If
appropriate,
these
data
requirements
can
be
included
in
the
Part
158
Subpart
W
when
the
regulations
are
finalized.
At
that
point
in
time,
the
Agency
may
choose
to
issue
a
DCI
requesting
these
data
from
all
registrants.
Until
then,
however,
it
is
appropriate
for
EPA
to
be
consistent
in
how
it
handles
similar
compounds
and
uses.

EPA
Response:
The
risk
assessment
was
revised
to
more
clearly
state
the
reasons
for
the
requested
studies.
Many
of
the
outstanding
toxicity
studies
were
requested
by
the
ADTC
for
specific
reasons
as
outlined
in
previous
responses
above.
The
Agency
has
agreed
to
a
tiered
toxicity
testing
approach
in
fulfilling
the
outstanding
data
requests.

As
noted
in
the
RED,
the
Agency
has
established
an
interim
two­
tiered
system
for
toxicology
testing
requirements.
Tier
I
toxicology
data
requirements
would
apply
to
all
indirect
food
additives
that
result
in
residue
concentrations
ranging
from
0­
200
ppb
which
applies
to
4­
t
amylphenol.
The
requirements
would
consist
of
an
acute
toxicity
testing
battery,
subchronic
toxicity
studies
in
the
rodent,
a
developmental
toxicity
study
in
the
rat,
and
a
mutagenicity
testing
battery.
The
developmental
toxicity
study
in
the
rat,
mutagenicity
testing
battery,
the
acute
oral
toxicity
and
the
acute
dermal
irritation
data
requirements
has
been
fulfilled
for
4­
t
amylphenol.
The
Agency
also
conducts
a
literature
search
and
can
also
conduct
a
Structural
Activity
Relationship
analysis
(
SAR)
if
appropriate.
The
Agency
also
will
hold
in
reserve
a
two­
generation
reproduction
toxicity
study
in
the
rat
and
a
subchronic
toxicity
studies
in
a
non­
rodent
which
would
become
data
requirements
if
warranted
by
the
Agency's
evaluation
of
the
Tier
1
data.
A
2­
generation
reproduction
study
and
a
subchronic
toxicity
study
in
a
non­
rodent
are
being
held
in
reserve
for
4­
t
amylphenol.
Comments
of
Clariant
Corporation
Para­
tertiary
Amyphenol
Risk
Assessment
EPA
Docket
ID
Number
2005­
0181
Page
14
of
14
Tier
II
studies
would
be
triggered
by
the
presence
of
significant
(
i.
e.
>
200ppb)
residues
in
food
or
evidence
of
significant
toxicity
from
the
Tier
I
data
set,
which
may
include
developmental
/
reproductive,
or
other
systemic
toxicity
such
as
presence
of
neoplastic
growth
or
significant
target
organ
toxicity.
In
such
cases,
chronic
toxicity
and
carcinogenicity
testing
would
be
required.

References:

IEH
(
2005)
Chemicals
Purported
to
be
Endocrine
Disrupters:
A
Compilation
of
Published
Lists
(
Web
Report
W20),
Leicester,
UK,
MRC
Institute
for
Environment
and
Health,
available
at
http://
www.
le.
ac.
uk/
ieh/

Soto,
et
al.
(
1995)
The
E­
SCREEN
assay
as
a
tool
to
identify
estrogens:
An
update
on
estrogenic
environmental
pollutants.
Environ.
Health
Perspect.
103
(
Suppl.
7):
113­
122.

Wysowski,
D.
K.
et
al.
(
1978)
Epidemic
neonatal
hyperbilirubinemia
and
use
of
a
phenolic
disinfectant
detergent.
Pediatrics
61:
165­
170.

Yamasaki,
K.,
et
al.
(
2003)
Immature
rat
uterotrophic
assay
of
18
chemicals
and
Hershberger
assay
of
30
chemicals.
Toxicology
183:
93­
115.