Document ID: EPA-HQ-OPP-2005-0181-0015
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:
September
29,
2005
SUBJECT:
Para­
tertiary
amylphenol
(
4­
t­
amylphenol)
and
its
sodium
and
potassium
salts
Evaluation
of
Toxicology
Database
for
the
Reregistration
Eligibility
Decision
Document
Disciplinary
Chapter.
Chemical
Nos.
064101,
064111,
064112.
Case
No.
3016.
DP
Barcode:
D316279
FROM:
Myron
Ottley,
Ph.
D.,
Toxicologist
And
Deborah
Smegal,
MPH
Toxicologist
Antimicrobials
Division
(
7510C)

TO:
Killian
Swift,
Risk
Manager
Reviewer
Team
36,
Reregistration
Antimicrobials
Division
(
7510C)
4­
Tert­
Amylphenol
and
Salts
RED
Toxicology
Chapter
AV­
11
1
TABLE
OF
CONTENTS
1.0
BACKGROUND...................................................................................................................................................
3
2.0
HAZARD
CHARACTERIZATION..................................................................................................................
3
3.0
REQUIREMENTS...............................................................................................................................................
4
4.0
DATA
GAP(
S).......................................................................................................................................................
5
5.0
HAZARD
ASSESSMENT...................................................................................................................................
5
5.1
Acute
Toxicity.....................................................................................................................................................
5
5.2
Subchronic
Toxicity..........................................................................................................................................
6
5.3
Developmental
Toxicity
....................................................................................................................................
7
5.4
Reproductive
Toxicity
.......................................................................................................................................
8
5.5
Chronic
Toxicity................................................................................................................................................
8
5.6
Carcinogenicity
.................................................................................................................................................
8
5.7
Mutagenicity......................................................................................................................................................
9
5.8
Neurotoxicity
...................................................................................................................................................
10
5.9
Metabolism......................................................................................................................................................
10
5.10
Special/
Other
Studies......................................................................................................................................
10
6.0
TOXICITY
ENDPOINT
SELECTION...........................................................................................................
11
6.1
ACUTE
DIETARY
(
Acute
Reference
Dose).................................................................................................
11
6.2.
CHRONIC
DIETARY
(
Chronic
Reference
Dose)
General
Population.....................................................
13
6.3.
INCIDENTAL
ORAL
EXPOSURE...............................................................................................................
13
6.4
OCCUPATIONAL
/
RESIDENTIAL
EXPOSURE.....................................................................................
14
6.5
Margins
of
Exposure......................................................................................................................................
17
6.6
Recommendation
for
Aggregate
Exposure
Risk
Assessments....................................................................
18
6.7
Classification
of
Carcinogenic
Potential
......................................................................................................
18
7.0
FQPA
CONSIDERATIONS
.............................................................................................................................
18
7.1
Adequacy
of
the
Data
Base
............................................................................................................................
18
7.2
Neurotoxicity
Data..........................................................................................................................................
18
7.3.
Developmental
&
Reproductive
Toxicity.......................................................................................................
18
7.4
Determination
of
Susceptibility
.....................................................................................................................
19
7.5
Determination
of
the
Need
for
Developmental
Neurotoxicity
Study..........................................................
19
4­
Tert­
Amylphenol
and
Salts
RED
Toxicology
Chapter
AV­
11
2
7.6.
Database
Uncertainty
Factor.........................................................................................................................
19
8.0
OTHER
ISSUES.................................................................................................................................................
19
9.0
REFERENCES
...................................................................................................................................................
20
10.0
APPENDICES.....................................................................................................................................................
21
10.1
Toxicity
Profile
Summary
Tables..................................................................................................................
21
4­
Tert­
Amylphenol
and
Salts
RED
Toxicology
Chapter
AV­
11
3
1.0
BACKGROUND
4­
tertiary­
amylphenol
(
C5H11C6H4OH,
PC
code
64101)
is
a
white
to
pale
yellow
flaky
substance
soluble
only
in
alcohols
and
ethers
while
its
sodium
and
potassium
salts
(
C5H11C6H4Na+
and
C5H11C6H4K+,
PC
codes
64111
and
64112,
respectively)
are
soluble
in
water.
4­
tert­
amylphenol
and
its
salts
are
active
ingredients
in
pesticides,
including
bacteriostats,
microbicides,
microbistats,
nematicides,
fumigants,
and
bacteriocides
used
in
manufacturing,
reformulating,
and
repackaging
facilities.
It
is
also
used
in
wood
protection
and
adhesive
coatings,
human
bedding
and
clothing,
diapers,
laundry
equipment,
and
air
treatment
systems.

4­
tert­
Amylphenol
and
its
salts
are
applied
in
the
following
food
uses,
which
may
result
in
indirect
food
contact:
commercial
egg
washing,
handling,
hatchery,
and
processing
facilities;
milking
equipment;
farm
and
agricultural
equipment
and
structures/
premises;
mushroom
house
equipment
and
houses;
canneries
and
frozen
food
plants;
feed
mills
and
stores;
meat
processing
plants;
beverage
processing
plants;
eating
establishment
surfaces,
equipment,
and
utensils;
food
storage
and
distribution
equipment
and
utensils;
and
food
dispensing
equipment.

4­
tert­
Amylphenol
is
used
in
the
following
public
and
private
facilities:
indoor
and
outdoor
use
on
domestic
dwelling
and
its
contents;
recreation
areas;
transit
vehicles,
including
ships,
railway
cars,
aircrafts,
automobiles,
and
taxis;
hospitals;
veterinary
facilities;
barbers
and
beauty
shops;
morgues,
mortuaries,
and
funeral
equipment
and
premises;
solid
waste
sites
and
containers;
and
bathroom
premises.

2.0
HAZARD
CHARACTERIZATION
The
toxicology
database
for
4­
t­
amylphenol,
in
terms
of
guideline
studies,
is
largely
incomplete.
Studies
from
the
open
literature
provide
limited
information,
and
more
data
are
needed
to
put
together
a
complete
profile.

4­
t­
Amylphenol
is
a
primary
dermal
irritant
(
Category
I)
and
is
in
Category
III
for
acute
oral
toxicity
based
on
guideline
studies.
It
also
appears
to
be
an
eye
irritant
(
Category
I),
and
may
be
in
Category
III
for
acute
dermal
toxicity
according
to
data
from
the
open
literature.
However,
acceptable
guideline
acute
studies
are
not
available
for
dermal,
inhalation,
primary
eye
irritation
or
dermal
sensitization,
and
the
literature
data
protocols
were
inadequate.
In
short­
term
studies,
4­
t­
amylphenol
produced
clinical
signs
along
with
decreased
food
consumption
and
body
weight
in
a
developmental
toxicity
study,
but
no
systemic
effects
in
a
13­
week
dermal
study.
The
structural
abnormalities
and
developmental
delays
that
occurred
in
the
developmental
study,
occurred
at
higher
dose
levels
than
the
maternal
effects,
suggesting
that
increased
quantitative
susceptibility
concerns
are
not
warranted;
however,
the
minimal
maternal
effects
(
reversible
clinical
signs)
seen
in
the
presence
of
the
developmental
effects
increases
concern
for
qualitative
susceptibility.
Neither
a
developmental
study
in
rabbits
nor
a
reproduction
study
was
available
to
provide
confirmation.
4­
Tert­
Amylphenol
and
Salts
RED
Toxicology
Chapter
AV­
11
4
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".
When
taken
with
the
lack
of
available
developmental
and
reproductive
toxicity
data,
concerns
for
FQPA
issues
are
heightened.

No
dermal
penetration
studies
were
available
for
4­
t­
amylphenol,
and
an
extrapolation
between
the
91­
dermal
study
and
the
oral
developmental
study
does
not
seem
possible,
for
the
purposes
of
estimating
dermal
absorption.

4­
t­
Amylphenol
was
negative
for
carcinogenicity
in
a
subchronic
skin
painting
study
from
the
open
literature.
However,
guideline
studies
for
carcinogenicity
are
not
available.
All
mutagenicity
tests
were
negative.

3.0
REQUIREMENTS
The
toxicity
data
requirements
for
indirect
food
uses
of
4­
t­
amylphenol
and
its
salts,
and
additional
studies
requested
by
Agency's
ADTC
committee
(
2005)
are
indicated
in
Table
1.

Table
1.

Technical
Test
Required
Satisfied
870.1100
Acute
Oral
Toxicity
........................................................
870.1200
Acute
Dermal
Toxicity....................................................
870.1300
Acute
Inhalation
Toxicity................................................
870.2400
Primary
Eye
Irritation
.....................................................
870.2500
Primary
Dermal
Irritation
...............................................
870.2600
Dermal
Sensitization.......................................................
870.6100
Acute
Delayed
Neurotox.
(
Hen)
.....................................
870.6200a
Acute
Neurotox.
Screening
Battery
(
Rat).......................
Y
Y
Y
Y
Y
Y
N
N
Y
N
N
N
Y
N
870.3100
Oral
Subchronic
(
Rodent)...............................................
870.3150
Oral
Subchronic
(
Non­
Rodent)
......................................
870.3200
21­
Day
Dermal
...............................................................
870.3250
90­
Day
Dermal
...............................................................
870.3465
90­
Day
Inhalation
...........................................................
Y
N
N
Y
Y
(
28
days)
(
a)
N
N
Y
N
870.3700a
Developmental
Toxicity
(
rodent)....................................
870.3700b
Developmental
Toxicity(
non­
rodent)
............................
870.3800
Reproduction...................................................................
Y
Y
(
b)

Y
©
Y
N
N
870.4100a
Chronic
Toxicity
(
Rodent)
..............................................
870.4100b
Chronic
Toxicity
(
Non­
rodent).......................................
870.4200a
Oncogenicity
(
Rat)..........................................................
870.4200b
Oncogenicity
(
Mouse)
....................................................
870.4300
Chronic/
Oncogenicity.....................................................
N
N
N
N
N
N
N
N
N
N
870.5100
Mutagenicity
C
Gene
Mutation
­
bacterial.......................
870.5300
Mutagenicity
C
Gene
Mutation
­
mammalian..................
Y
Y
Y
Y
4­
Tert­
Amylphenol
and
Salts
RED
Toxicology
Chapter
AV­
11
5
Technical
Test
Required
Satisfied
870.5395
Mutagenicity
C
Mammalian
erythrocyte
micronucleus
..
870.5xxx
Mutagenicity
C
Other
Genotoxic
Effects
.........................
Y
N
Y
N
870.6100
90­
Day
Neurotoxicity
(
hen)............................................
870.6200b
90
Day
Neuro.
Screening
Battery
(
Rat)
.........................
870.6300
Develop.
Neuro...............................................................
N
N
N
870.7485
General
Metabolism........................................................
870.7600
Dermal
Penetration
.........................................................
N
N
870.7200
Companion
Animal
Safety..............................................
N
Special
Studies
for
Ocular
Effects......................................................
Acute
Oral
(
Rat)
.............................................................
Subchronic
Oral
(
Rat).....................................................
Six­
month
Oral
(
Dog).....................................................
N
Y
­
Yes;
N
 
no
(
a)
Requested
by
the
ADTC
(
2005)
because
4­
t­
amylphenol
is
an
air
deodorizer,
and
thus
the
committee
was
concerned
about
the
hazard
associated
with
inhalation
exposure.
(
b)
Requested
by
the
ADTC
(
2005)
because
the
rat
developmental
toxicity
study
showed
qualitative
evidence
of
increased
susceptibility.
©
Requested
by
the
ADTC
(
2005)
because
available
data
suggest
the
potential
for
endocrine
disruptor
capabilities.

4.0
DATA
GAP(
S)

There
are
several
data
gaps
for
4­
t­
amylphenol.
The
existing
acute
toxicity
data
are
unacceptable
and
four
acute
toxicity
studies
using
the
technical
grade
active
ingredient
must
be
conducted.
In
addition,
the
use
sites
for
this
chemical
involve
indirect
food
contact.
Therefore,
a
90
day
rat
oral
toxicity
study
must
be
submitted
to
support
this
use.
In
addition,
the
ADTC
(
2005)
identified
potential
qualitative
susceptibility
concerns
in
the
existing
rat
developmental
study,
and
thus
requested
a
developmental
toxicity
study
in
another
species
(
rabbits).
In
addition,
because
of
the
potential
concerns
for
endocrine
disruption
of
4­
t­
amylphenol
in
the
literature,
the
ADTC
(
2005)
requested
a
reproduction
toxicity
study
be
submitted.
Because
4­
t­
amylphenol
is
an
air
deodorizer,
the
ADTC
(
2005)
was
concerned
about
the
hazard
associated
with
inhalation
exposure,
and
thus
requested
a
repeat
28­
day
inhalation
study.

5.0
HAZARD
ASSESSMENT
The
acid
p­
t­
amylphenol
(
PTAP)
is
the
active
ingredient
and
the
salt
products
(
potassium
and
sodium)
are
the
end
use
formulations.
There
is
no
technical
grade
active
PTAP
salt.

5.1
Acute
Toxicity
Adequacy
of
data
base
for
acute
toxicity:
4­
t­
Amylphenol
is
a
primary
dermal
irritant
4­
Tert­
Amylphenol
and
Salts
RED
Toxicology
Chapter
AV­
11
6
(
Category
I)
and
is
in
Category
III
for
acute
oral
toxicity
based
on
guideline
studies.
It
also
appears
to
be
an
eye
irritant
(
Category
I),
and
may
be
in
Category
III
for
acute
dermal
toxicity
according
to
data
from
the
open
literature.
However,
acceptable
guideline
acute
studies
are
not
available
for
dermal,
inhalation,
primary
eye
irritation
or
dermal
sensitization,
and
the
literature
data
protocols
were
inadequate.
The
additional
studies
required
are
listed
in
Table
1
and
in
Section
3,
Data
Gaps.

Guideline
No./
Study
Type
MRID
No.
Results
Toxicity
Category
870.1100
Acute
oral
toxicity
46616601
LD50
>
2000
mg/
kg
for
males
and
females
III
870.1200
Acute
dermal
toxicity
NA
[
]

870.1300
Acute
inhalation
toxicity
NA
[
]

870.2400
Acute
eye
irritation
NA
No
adequate
acute
toxicity
studies
were
provided
or
identified
in
the
open
literature.

[
]

870.2500
Acute
dermal
irritation
46616602
Corrosive
following
4
hour
application;
scar
tissue
noted
14
days
after
treatment
I
870.2600
Skin
sensitization
NA
NA=
Not
available
5.2
Subchronic
Toxicity
Adequacy
of
data
base
for
subchronic
toxicity:
A
subchronic
oral
rodent
toxicity
test
is
required
for
the
indirect
food
uses
of
4­
tert­
amylphenol.

870.3250
90­
Day
Dermal
Toxicity
B
Rat
Executive
Summary:
In
a
subchronic
dermal
toxicity
study
(
MRID
42470301),
Nipacide
Amylphenol
(
Amenphenol,
Batch
No.
L18K)
was
administered
to
the
clipped
skin
of
Sprague
Dawley
Crl:
CD
BR
VAF/
Plus
rats
(
10
males
and
10
females/
group)
at
dose
levels
of
0,
2.5,
10
and
25
mg/
kg,
6
hr/
day,
five
days/
week
for
13
weeks.
The
test
substance
was
dissolved
in
a
50%
v/
v
solution
of
ethanol
(
200
proof)
in
distilled
water;
all
doses
were
administered
at
a
constant
volume
of
6.0
ml/
kg.

No
treatment­
related
deaths
or
clinical
signs
were
observed.

Dermal
irritation
was
not
observed
in
controls
or
at
2.5
mg/
kg/
day.
At
10
and
25
4­
Tert­
Amylphenol
and
Salts
RED
Toxicology
Chapter
AV­
11
7
mg/
kg/
day,
both
sexes
exhibited
dose­
related
dermal
irritation,
such
as
erythema
and
desquamation
which
progressed
to
eschar
formation
with
subsequent
eschar
exfoliation.
The
incidence
and
severity
of
the
dermal
irritation
were
increased
in
the
25
mg/
kg/
day
group
where
the
eschar
formation
progressed
to
cover
50
­
75%
of
the
application
site
in
two
males
and
five
females.
Ulcerations
were
also
observed
within
the
exposure
site
of
three
males
and
five
females
in
the
25
mg/
kg/
day
group.
Eschar
formation
in
the
10
mg/
kg/
day
group
progressed
to
cover
10
­
25
of
the
application
site
in
one
male
and
three
females.

No
biologically
significant
changes
in
body
weight
or
body
weight
gain
were
observed
at
any
dose
level.
No
biologically
significant
changes
in
food
consumption
were
observed.
A
transient
increase
(
p<
0.05)
in
food
consumption
was
noted
during
study
days
8
­
15,
but
was
small
(+
8%),
and
not
accompanied
by
a
corresponding
change
in
body
weight.

No
treatment­
related
ocular
effects
were
noted
in
test
animals.

Hematological
parameters
showed
no
biologically
significant
changes
due
to
the
test
substance.
Clinical
chemistry
parameters
were
affected
significantly
by
treatment
to
the
test
substance
Organ
weights
were
not
affected
by
treatment
to
the
test
substance.
No
other
gross
pathological
findings
were
made.
Histopathological
observations
were
limited
to
the
treated
skin
of
rats
in
the
10
and
25
mg/
kg/
day
groups.
These
changes
included
minimal
to
marked
acanthosis,
minimal
to
mild
chronic
or
acute
dermatitis,
inflammatory
exudate
on
the
epidermal
surface
and
occasional
ulcers.
The
incidence
and
severity
of
the
dermal
changes
were
dose
dependent.

The
systemic
NOAEL
is
25
mg/
kg/
day.
The
LOAEL
has
not
been
established.

The
dermal
NOAEL
is
2.5
mg/
kg/
day.
The
LOAEL
is
10
mg/
kg/
day
based
on
histopathological
changes,
dermal
irritation
characterized
by
erythema,
desquamation,
eschar
formation
and
subsequent
eschar
exfoliation..

5.3
Developmental
Toxicity
Adequacy
of
data
base
for
developmental
toxicity:
The
data
base
for
developmental
toxicity
is
adequate
only
for
non­
food
uses
of
amylphenol.
Additional
data
are
required
for
indirect
or
direct
food
uses.

The
one
study
provided,
a
prenatal
developmental
toxicity
study
in
rats,
indicated
a
lower
NOAEL
and
LOAEL
for
maternal
toxicity
(
i.
e.,
50
and
200
mg/
kg­
day)
than
for
developmental
toxicity
(
i.
e.,
200
and
500
mg/
kg­
day),
and
the
developmental
effects
were
not
frankly
teratogenic.
Thus,
there
is
no
indication
that
the
fetus
is
more
susceptible
than
the
pregnant
female.
4­
Tert­
Amylphenol
and
Salts
RED
Toxicology
Chapter
AV­
11
8
870.3700a
Prenatal
Developmental
Toxicity
Study
­
Rat
Executive
Summary
:
In
a
developmental
toxicity
study
(
MRID
41920002)
Nipacide
Amylphenol
(
a.
i.
not
specified;
Batch
L18K)
was
administered
by
gavage
to
pregnant
Sprague­
Dawley
rats
(
25/
dose)
from
gestation
days
(
GD)
6
to
GD
15
at
dose
levels
of
0,
50,
200,
and
500
mg/
kg/
day.
Animals
were
sacrificed
on
GD
20,
and
dams
and
litters
were
examined
for
signs
of
toxicity.

Maternal
toxicity,
observed
at
200
and
500
mg/
kg/
day
was
manifested
as
increased
incidences
of
clinical
signs
(
mucoid/
soft
stools,
urine
stains
rales,
hair
loss,
salivation).
Decreased
body
weight
(
p<
0.05,
p<
0.01)
and
decreased
body
weight
gain
of
10
­
50%
(
p<
0.05,
p<
0.01)
were
observed
at
several
periods
during
gestation
in
the
200
and
500
mg/
kg/
day
groups,
respectively.
Similarly,
mean
food
consumption
was
decreased
9
­
58%
respectively
during
gestation
at
200
and
500
mg/
kg/
day.

No
adverse
maternal
effects
were
observed
at
50
mg/
kg/
day.

The
maternal
NOAEL
is
50
mg/
kg/
day,
and
the
LOAEL
is
200
mg/
kg/
day,
based
on
clinical
signs,
decreases
in
body
weight
and
body
weight
gain,
and
decreases
in
food
consumption.

Effects
in
the
conceptus
observed
at
500
mg/
kg/
day
were
decreased
fetal
body
weight
(­
5.6%,
p<
0.05,
measured
as
fetal
weight/
litter)
and
an
increased
incidence
of
bent
ribs
(
p<
0.05).

No
adverse
developmental
effects
were
observed
at
50
or
200
mg/
kg/
day.

The
developmental
NOAEL
is
200
mg/
kg/
day,
and
the
LOAEL
is
500
mg/
kg/
day,
based
on
an
decreased
fetal
body
weight
and
an
increased
incidence
of
bent
ribs.

5.4
Reproductive
Toxicity
Adequacy
of
data
base
for
reproductive
toxicity:
The
data
base
for
reproductive
toxicity
is
inadequate
for
indirect
or
direct
food
uses
of
amylphenol.
To
support
those
uses
of
amylphenol,
a
reproductive
toxicity
test
must
be
submitted.

5.5
Chronic
Toxicity
Adequacy
of
data
base
for
chronic
toxicity.
The
data
base
for
chronic
toxicity
is
adequate
for
indirect
food
uses
of
amylphenol.

5.6
Carcinogenicity
Adequacy
of
data
base
for
carcinogenicity:
The
data
base
for
carcinogenicity
is
adequate
4­
Tert­
Amylphenol
and
Salts
RED
Toxicology
Chapter
AV­
11
9
for
indirect
food
uses
of
amylphenol.

5.7
Mutagenicity
Adequacy
of
data
base
for
mutagenicity:
The
data
base
for
mutagenicity
is
considered
adequate
based
on
EPA
=

s
1991
mutagenicity
guidelines
and
indicates
that
p­
tert­
amylphenol
is
not
mutagenic
or
genotoxic.
In
a
submitted
bacterial
study
(
MRID
No.
414384­
01)
and
a
study
identified
in
the
published
literature
(
Zeiger
et
al.
1988),
p­
tert­
amylphenol
was
not
mutagenic
to
the
bacteria
in
the
presence
or
absence
of
mammalian
metabolic
activation.
An
assay
using
cultured
mouse
lymphoma
cells
also
proved
negative
(
MRID
No.
415727­
01).
Finally,
a
mouse
micronucleus
test
using
male
and
female
CD­
1
mice
also
was
negative
(
MRID
No.
417108).

Gene
Mutation
Guideline
870.5265,
870.5100,
The
Salmonella
typhimurium
reverse
mutation
assay
MRID
No.
414384­
01
Classification:
Acceptable
Nipacide
PTAP
(>
98.5%
a.
i.)
was
tested
for
its
ability
to
induce
reverse
mutations
in
selected
Salmonella
typhimurium
strains.
Five
dose
levels
were
tested
both
with
and
without
metabolic
activation:
1,
3.2,
10,
31.6,
and
100
Fg/
plate.
Results
were
negative
at
all
doses,
with
and
without
activation.
At
100
Fg/
plate,
inhibition
of
growth,
observed
as
thinning
of
the
background
lawn
of
non­
revertant
cells
and
reduction
in
revertant
colony
numbers,
occurred
in
all
strains
following
exposure.
There
was
no
indication
of
a
mutagenic
response
in
any
strain
at
any
dose
level
with
or
without
S9
activation.

Guideline
870.5300,
In
vitro
mammalian
cell
gene
mutation
test
MRID
No.
415727­
01
Classification:
Acceptable
Technical
Nipacide
PTAP
was
tested
in
the
mouse
lymphoma
cell
mutation
system,
both
with
and
without
metabolic
activation,
at
the
following
dose
levels:
non­
activated
conditions
­
5,
10,
20,
30,
and
40
Fg/
ml;
activated
conditions
­
2,
4,
6,
8,
and
10
Fg/
ml.
The
few
positive
results
in
single
cultures
were
inconsistent
and
not
related
to
dose.
Historical
control
data
provided
in
showed
that
mutation
frequencies
of
the
controls
in
this
study
were
slightly
lower
than
the
historical
controls,
indicating
that
the
mutation
frequencies
in
the
controls
of
this
experiment
were
more
similar
to
historical
controls.
Thus,
the
results
are
negative
for
gene
mutations
under
the
conditions
of
the
study.

Cytogenetics
Guideline
870.5395,
Mammalian
erythrocyte
micronucleus
test
Nipacide
PTAP
was
tested
in
a
micronucleus
test
in
male
and
female
CD­
1
mice
at
the
following
dose
levels:
62.5
(
M),
250
(
M+
F),
1000
(
M+
F),
and
4000
mg/
kg
(
F).
There
was
no
4­
Tert­
Amylphenol
and
Salts
RED
Toxicology
Chapter
AV­
11
10
MRID
No.
41710801
Classification:
Acceptable
evidence
that
Nipacide
induced
chromosomal
or
other
damage
leading
to
micronucleus
formation
in
polychromatic
erythrocytes.
Although
inadequate
in
demonstrating
any
interaction
in
target
cells,
the
negative
results
are
acceptable
for
reregistration
purposes.

Other
Genotoxicity
No
studies
in
this
category
5.8
Neurotoxicity
Adequacy
of
data
base
for
Neurotoxicity:
These
studies
are
not
required
at
this
time.

5.9
Metabolism
Adequacy
of
data
base
for
metabolism:
These
studies
are
not
required
at
this
time.

5.10
Special/
Other
Studies
5.10.1
Skin
Sensitization
and
Depigmentation
P­
tert­
amylphenol
has
been
reported
to
be
a
skin
sensitizer
and
depigmenting
agent
(
BIBRA
Working
Group,
1990).
Stevenson
(
1984),
however,
reported
p­
tert­
amylphenol
to
have
a
A
low
depigmenting
potential
@

because
none
of
129
men
who
had
been
exposed
to
the
compound
during
its
manufacture
exhibited
depigmentation.

5.10.2
Endocrine
Disruption
4­
t­
Amylphenol
is
listed
on
a
European
list
of
"
Chemicals
purported
to
be
endocrine
disruptors"
(
IEH
2005).

Soto
et
al.
(
1995)
have
found
p­
tert­
amylphenol
to
be
estrogenic
in
the
E­
SCREEN
assay,
which
assesses
the
estrogenicity
of
a
compound
by
measuring
its
proliferative
effect
on
estrogensensitive
cells.
The
cell
number
achieved
by
similar
inocula
of
MCF­
7
cells
(
estrogen­
sensitive
human
breast
cancer
cells)
in
the
absence
of
estrogens
(
negative
control)
and
in
the
presence
of
17 ­
estradiol
(
positive
control)
is
compared
with
the
number
of
cells
achieved
with
a
range
of
concentrations
of
the
test
chemical.
For
4­
tert­
pentylphenol,
a
concentration
of
10
FM
was
the
lowest
concentration
needed
for
maximal
cell
yield.
For
the
positive
control
17 ­
estradiol,
the
lowest
concentration
needed
was
30
pM.
The
relative
proliferative
effect
(
RPE)
is
calculated
as
100
x
(
PE­
1)
of
the
test
compound
divided
by
(
PE­
1)
of
17 ­
estradiol.
A
value
of
100
indicates
that
the
compound
tested
is
a
full
agonist
of
the
estradiol;
a
value
of
0
indicates
that
the
4­
Tert­
Amylphenol
and
Salts
RED
Toxicology
Chapter
AV­
11
11
compound
lacks
estroenicity
at
the
doses
tested.
Intermediate
values
suggest
that
the
compound
is
a
partial
agonist
of
17 ­
estradiol.
For
4­
tert­
pentylphenol,
and
RPE
of
105
was
estimated.

Routledge
and
Sumpter
(
1997)
demonstrated
estrogenic
activity
of
4­
tert­
amylphenol
using
an
estrogen­
inducible
strain
of
yeast
(
Saccharomyces
cerevisiae)
that
expresses
the
human
estrogen
receptor.
Using
the
natural
estrogen
17 ­
estradiol
for
comparison,
the
data
indicated
that
both
the
position
(
para
>
meta
>
ortho)
and
branching
(
tertiary
>
secondary
=
normal)
of
the
alkyl
group
affect
estrogenicity.
In
this
assay,
4­
tert­
amylphenol
was
found
to
be
100,000­
fold
less
potent
than17 ­
estradiol.

Reference
Model
Estrogenic
LOEC*
(
log
M)
IC50
(
M)
Relative
Binding
Affinity
(
RBA)
(%)
Relative
Potency
(%)
Comments
Blair
2000
Rat
uterine
ER
competitive
binding
1.6x10­
4
0.0005
Miller
2001
Yeast
recombinant
Human
ER 
transcriptional
activation
1/
200000
of
E2
PTAP
IC50/
E2
IC50
Schultz
2000
Yeast
recombinant
Human
ER 
transcriptional
activation
4.8x10­
6
0.0008
~
70%
of
max
E2
*
LOEC=
lowest
observed
effects
concentration
E2=
17 ­
estradiol
6.0
TOXICITY
ENDPOINT
SELECTION
6.1
ACUTE
DIETARY
(
Acute
Reference
Dose)

6.1.1.
Acute
RfD
Subpopulation:
Females
13+

Study
Selected:
Developmental
Toxicity
B
Rat
'
83­
3a
MRID
No.:
41920002
Executive
Summary
:
In
a
developmental
toxicity
study
(
MRID
41920002)
Nipacide
Amylphenol
(
a.
i.
not
specified;
Batch
L18K)
was
administered
by
gavage
to
pregnant
Sprague­
Dawley
rats
(
25/
dose)
from
gestation
days
(
GD)
6
to
GD
15
at
dose
levels
of
0,
50,
200,
and
500
mg/
kg/
day.
Animals
were
sacrificed
on
GD
20,
and
dams
and
litters
were
examined
for
signs
of
toxicity.

Maternal
toxicity,
observed
at
200
and
500
mg/
kg/
day
was
manifested
as
increased
incidences
of
clinical
signs
(
mucoid/
soft
stools,
urine
stains
rales,
hair
loss,
salivation).
4­
Tert­
Amylphenol
and
Salts
RED
Toxicology
Chapter
AV­
11
12
Decreased
body
weight
(
p<
0.05,
p<
0.01)
and
decreased
body
weight
gain
of
10
­
50%
(
p<
0.05,
p<
0.01)
were
observed
at
several
periods
during
gestation
in
the
200
and
500
mg/
kg/
day
groups,
respectively.
Similarly,
mean
food
consumption
was
decreased
9
­
58%
respectively
during
gestation
at
200
and
500
mg/
kg/
day.

No
adverse
maternal
effects
were
observed
at
50
mg/
kg/
day.

The
maternal
NOAEL
is
50
mg/
kg/
day,
and
the
LOAEL
is
200
mg/
kg/
day,
based
on
clinical
signs,
decreases
in
body
weight
and
body
weight
gain,
and
decreases
in
food
consumption.

Effects
in
the
conceptus
observed
at
500
mg/
kg/
day
were
decreased
fetal
body
weight
(­
5.6%,
p<
0.05,
measured
as
fetal
weight/
litter)
and
an
increased
incidence
of
bent
ribs
(
p<
0.05).

No
adverse
developmental
effects
were
observed
at
50
or
200
mg/
kg/
day.

The
developmental
NOAEL
is
200
mg/
kg/
day,
and
the
LOAEL
is
500
mg/
kg/
day,
based
on
an
decreased
fetal
body
weight
and
an
increased
incidence
of
bent
ribs.

Dose
Selected
for
Risk
Assessment:
200
mg/
kg/
day
based
on
skeletal
effects
and
decreased
fetal
body
weight
gain
observed
at
the
LOAEL
of
500
mg/
kg/
day
Comments
about
Study/
Endpoint
Uncertainty
Factor:
The
effects
observed
at
the
developmental
LOAEL,
skeletal
abnormalities,
can
occur
in
the
conceptus
following
a
single
exposure
to
pregnant
females.

This
risk
assessment
IS
required.

Acute
RfD
=
200
mg/
kg/
day
(
NOAEL)
=
0.67
mg/
kg/
day
300
(
UF)

6.1.2.
Acute
RfD
(
General
Population
including
Infants
and
children)

Study
Selected
:
None
Guideline
#:
'
83­
3
MRID
No.:
None
Dose
Selected
for
Risk
Assessment:
None
Comments
about
Study/
Endpoint
Uncertainty
Factor:
A
study
appropriate
for
this
endpoint
was
not
identified.

This
risk
assessment
is
NOT
required.
4­
Tert­
Amylphenol
and
Salts
RED
Toxicology
Chapter
AV­
11
13
6.2.
CHRONIC
DIETARY
(
Chronic
Reference
Dose)
General
Population
Study
Selected:
Developmental
Toxicity
B
Rat
'
83­
3a
MRID
No.:
41920002
Executive
Summary:
See
Acute
Dietary,
Females
13+

Uncertainty
Factor:
300
(
10
x
for
inter­
species
variation,
10x
for
intra­
species
extrapolation,
3x
for
database
inadequacies).

Dose
Selected
for
Risk
Assessment:
50
mg/
kg/
day
based
on
clinical
signs,
decreases
in
body
weight
and
body
weight
gain,
decreased
food
consumption
at
the
LOAEL
of
200
mg/
kg/
day.

Comments
about
Study/
Endpoint
Uncertainty
Factor:
This
study
represents
the
best
available
data
to
assess
chronic
toxicity.

Chronic
RfD
=
50
mg/
kg/
day
(
NOAEL)
=
0.17
mg/
kg/
day
300
(
UF)

Comments
about
Study/
Endpoint
Uncertainty
Factor:
The
ADTC
concluded
this
study
can
be
used
to
establish
a
chronic
RfD
because
it
is
the
best
oral
study
available.
An
extra
uncertainty
factor
to
compensate
for
the
lack
of
a
chronic
study
was
deemed
necessary.

6.3.
INCIDENTAL
ORAL
EXPOSURE
6.3.1.
Short­
Term
Study
Selected:
Developmental
Toxicity
­
Rats
Guideline#:'
82­
3
MRID
No.:
41920002
Executive
Summary:
See
Acute
RfD,
Females
13+

Dose
Selected
for
Risk
Assessment:
50
mg/
kg/
day
based
on
clinical
signs,
decreases
in
body
weight
and
body
weight
gain,
decreased
food
consumption
at
the
LOAEL
of
200
mg/
kg/
day.

Comments
about
Study/
Endpoint:
The
maternal
toxicity
seen
at
the
LOAEL
can
be
attributed
to
short­
term
exposure.
4­
Tert­
Amylphenol
and
Salts
RED
Toxicology
Chapter
AV­
11
14
This
risk
assessment
is
required.

6.3.2.
Intermediate­
Term
Study
Selected:
Developmental
Toxicity
­
Rats
Guideline#:'
82­
3
MRID
No.:
41920002
Executive
Summary:
See
Acute
RfD,
Females
13+

Dose
Selected
for
Risk
Assessment:
50
mg/
kg/
day
based
on
clinical
signs,
decreases
in
body
weight
and
body
weight
gain,
decreased
food
consumption
at
the
LOAEL
of
200
mg/
kg/
day.

Comments
about
Study/
Endpoint:
The
maternal
toxicity
seen
at
the
LOAEL
can
be
attributed
to
short­
term
exposure.

This
risk
assessment
is
required.

6.4
OCCUPATIONAL
/
RESIDENTIAL
EXPOSURE
6.4.1.
DERMAL
ABSORPTION
Study
Selected:
None
Guideline
#:
'
85­
2
MRID
No.:
None
Executive
Summary:
None.
An
appropriate
study
was
not
available
Dermal
Absorption
Factor:
100%

Comments
about
Dermal
Absorption
Factor:
Since
a
dermal
absorption
study
was
not
available,
a
dermal
absorption
factor
of
100%
is
assumed.

6.4.2.
SHORT­
TERM
DERMAL
(
1
­
30
days)

Study
Selected:
Dermal
Subchronic
Toxicity
­
Rats
Guideline#:'
82­
3
MRID
No.:
42470301
Executive
Summary:
In
a
subchronic
dermal
toxicity
study
(
MRID
42470301),
4­
Tert­
Amylphenol
and
Salts
RED
Toxicology
Chapter
AV­
11
15
Nipacide
Amylphenol
(
Amenphenol,
Batch
No.
L18K)
was
administered
to
the
clipped
skin
of
Sprague
Dawley
Crl:
CD
BR
VAF/
Plus
rats
(
10
males
and
10
females/
group)
at
dose
levels
of
0,
2.5,
10
and
25
mg/
kg,
6
hr/
day,
five
days/
week
for
13
weeks.
The
test
substance
was
dissolved
in
a
50%
v/
v
solution
of
ethanol
(
200
proof)
in
distilled
water;
all
doses
were
administered
at
a
constant
volume
of
6.0
ml/
kg.

No
treatment­
related
deaths
or
clinical
signs
were
observed.

Dermal
irritation
was
not
observed
in
controls
or
at
2.5
mg/
kg/
day.
At
10
and
25
mg/
kg/
day,
both
sexes
exhibited
dose­
related
dermal
irritation,
such
as
erythema
and
desquamation
which
progressed
to
eschar
formation
with
subsequent
eschar
exfoliation.
The
incidence
and
severity
of
the
dermal
irritation
were
increased
in
the
25
mg/
kg/
day
group
where
the
eschar
formation
progressed
to
cover
50
­
75%
of
the
application
site
in
two
males
and
five
females.
Ulcerations
were
also
observed
within
the
exposure
site
of
three
males
and
five
females
in
the
25
mg/
kg/
day
group.
Eschar
formation
in
the
10
mg/
kg/
day
group
progressed
to
cover
10
 
25%
of
the
application
site
in
one
male
and
three
females.

No
biologically
significant
changes
in
body
weight
or
body
weight
gain
were
observed
at
any
dose
level.
No
biologically
significant
changes
in
food
consumption
were
observed.
A
transient
increase
(
p<
0.05)
in
food
consumption
was
noted
during
study
days
8
­
15,
but
was
small
(+
8%),
and
not
accompanied
by
a
corresponding
change
in
body
weight.

No
treatment­
related
ocular
effects
were
noted
in
test
animals.

Hematological
parameters
showed
no
biologically
significant
changes
due
to
the
test
substance.
Clinical
chemistry
parameters
were
affected
significantly
by
treatment
to
the
test
substance
Organ
weights
were
not
affected
by
treatment
to
the
test
substance.
No
other
gross
pathological
findings
were
made.
Histopathological
observations
were
limited
to
the
treated
skin
of
rats
in
the
10
and
25
mg/
kg/
day
groups.
These
changes
included
minimal
to
marked
acanthosis,
minimal
to
mild
chronic
or
acute
dermatitis,
inflammatory
exudate
on
the
epidermal
surface
and
occasional
ulcers.
The
incidence
and
severity
of
the
dermal
changes
were
dose
dependent.
4­
Tert­
Amylphenol
and
Salts
RED
Toxicology
Chapter
AV­
11
16
The
systemic
NOAEL
is
25
mg/
kg/
day.
The
LOAEL
has
not
been
established.

The
dermal
NOAEL
is
2.5
mg/
kg/
day.
The
LOAEL
is
10
mg/
kg/
day
based
on
histopathological
changes,
dermal
irritation
characterized
by
erythema,
desquamation,
eschar
formation
and
subsequent
eschar
exfoliation..

Dose
Selected
for
Risk
Assessment:
25
mg/
kg/
day,
which
is
the
systemic
NOAEL
and
the
highest
dose
level
tested.

Comments
about
Study/
Endpoint:
None.

This
risk
assessment
is
required.

6.4.3.
INTERMEDIATE­
TERM
DERMAL
(
One
month
to
Several
Months)

Study
Selected:
Subchronic
Dermal
­
Rats
Guideline#:
'
82­
3
MRID
No.:
42470301
Executive
Summary:
See
Short­
Term
Dermal.

Dose
Selected
for
Risk
Assessment:
25
mg/
kg/
day,
which
is
the
systemic
NOAEL
and
the
highest
dose
level
tested.

Comments
about
Study/
Endpoint:
None.

This
risk
assessment
is
required.

6.4.4.
LONG­
TERM
DERMAL
(
Several
Months
to
Lifetime)

Study
Selected:
Subchronic
Dermal
­
Rats
Guideline#:
'
82­
3
MRID
No.:
42470301
Executive
Summary:
See
Short­
Term
Dermal.

Dose
Selected
for
Risk
Assessment:
25
mg/
kg/
day,
which
is
the
systemic
NOAEL
and
the
highest
dose
level
tested.

Comments
about
Study/
Endpoint:
None.

This
risk
assessment
is
required.
4­
Tert­
Amylphenol
and
Salts
RED
Toxicology
Chapter
AV­
11
17
6.4.5.
INHALATION
(
All
Durations).

Study
Selected:
Developmental
Toxicity
­
Rats
Guideline#:'
82­
3
MRID
No.:
41920002
Executive
Summary:
See
Acute
RfD,
Females
13+

Dose
Selected
for
Risk
Assessment:
50
mg/
kg/
day
based
on
clinical
signs,
decreases
in
body
weight
and
body
weight
gain,
decreased
food
consumption
at
the
LOAEL
of
200
mg/
kg/
day.

Comments
about
Study/
Endpoint:
The
maternal
toxicity
seen
at
the
LOAEL
can
be
attributed
to
short­
term
exposure.

This
risk
assessment
is
required.

6.5
Margins
of
Exposure
Acute
and
chronic
dietary:
10x
interspecies
extrapolation,
10x
intraspecies
variation,
10x
FQPA
safety
factor,
3x
database
uncertainty
factor.

Incidental
oral:
Target
MOE=
3000
(
10x
interspecies
extrapolation,
10x
intraspecies
variation,
10x
FQPA
safety
factor,
3x
database
uncertainty
factor).

Short­
and
Intermediate
Term
Dermal
Residential:
Target
MOE=
1000
(
10x
interspecies
extrapolation,
10x
intraspecies
variation,
10x
FQPA
safety
factor)
Short­
and
Intermediate
Term
Dermal
Occupational:
Target
MOE=
1000
(
10x
interspecies
extrapolation,
10x
intraspecies
variation)

Long­
Term
Dermal
Residential:
Target
MOE=
3000
(
10x
interspecies
extrapolation,
10x
intraspecies
variation,
10x
FQPA
safety
factor,
and
3X
for
subchronic
to
chronic
exposure)
Long­
Term
Dermal
Occupational:
Target
MOE=
300
(
10x
interspecies
extrapolation,
10x
intraspecies
variation
and
3X
for
subchronic
to
chronic
exposure)

Inhalation
Residential:
Target
MOE=
3000
(
10x
interspecies
extrapolation,
10x
intraspecies
variation,
10x
FQPA
safety
factor,
3x
database
uncertainty
factor)
4­
Tert­
Amylphenol
and
Salts
RED
Toxicology
Chapter
AV­
11
18
Inhalation
Occupational:
Target
MOE=
300
(
10x
interspecies
extrapolation,
10x
intraspecies
variation,
3x
database
uncertainty
factor)

6.6
Recommendation
for
Aggregate
Exposure
Risk
Assessments
Food
and
water
exposures
of
amylphenol
should
be
aggregated.
An
acute
aggregate
assessment
is
required
for
Females
13+;
however
it
is
NOT
required
for
the
General
Population
including
Infants
and
Children
because
there
is
no
dietary
endpoint
identified.

Residential
exposures
of
amylphenol
resulting
in
incidental
oral
and
inhalation
exposures
should
be
aggregated
with
average
food
exposures.
However,
this
aggregation
should
take
into
consideration
the
different
uncertainty
factors
applied
to
the
various
endpoints.
Dermal
exposures
are
not
aggregated
with
the
other
scenarios
based
on
the
use
of
a
different
study
and
endpoint
for
dermal
risk
assessments.

6.7
Classification
of
Carcinogenic
Potential
Amylphenol
has
not
been
assigned
a
cancer
classification.
4­
t­
Amylphenol
was
negative
for
carcinogenicity
in
a
subchronic
skin
painting
study
from
the
open
literature.
However,
guideline
studies
for
carcinogenicity
are
not
available.
All
mutagenicity
tests
were
negative.

7.0
FQPA
CONSIDERATIONS
7.1
Adequacy
of
the
Data
Base
The
toxicology
data
base
is
not
complete
with
respect
to
assessing
the
increased
susceptibility
to
infants
and
children
as
required
by
FQPA
for
Amylphenol.
An
acceptable
rat
developmental
study
is
available,
but
a
guideline
study
in
the
rabbit
is
not
available,
nor
is
a
guideline
reproduction
study.

7.2
Neurotoxicity
Data
There
are
currently
no
guideline
neurotoxicity
studies
available
for
4­
t­
amylphenol.

7.3.
Developmental
&
Reproductive
Toxicity
7.3.1.
Developmental
Toxicity:

An
executive
summary
for
a
prenatal
developmental
study
is
provided
under
Acute
Dietary,
Females
13+.
This
study
showed
no
quantitative
evidence
of
increased
susceptibility
(
i.
e.,
developmental
NOAELs/
LOAELs
were
the
higher
than
those
for
4­
Tert­
Amylphenol
and
Salts
RED
Toxicology
Chapter
AV­
11
19
maternal
effects).
However,
there
was
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).

7.3.2.
Reproductive
Toxicity:

A
two­
generation
reproduction
study
in
rats
is
not
available
for
Amylphenol.

7.4
Determination
of
Susceptibility
Quantitative
evidence
of
increased
susceptibility
was
not
demonstrated
in
the
rat
developmental
study;
however,
a
possible
increase
in
qualitative
susceptibility
was
demonstrated
in
this
study.
In
addition,
there
is
an
absence
of
developmental
toxicity
data
in
the
rat,
and
an
absence
of
reproductive
toxicity
data.

In
the
open
literature
(
Yamasaki
et
al.
2003),
an
increase
in
non­
pregnant
uterine
weight
was
observed
in
rats
following
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
t­
amylphenol
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
Amylphenol.

The
ADTC
has
determined
that
the
FQPA
Safety
Factor
should
be
Ten
(
10).

7.5
Determination
of
the
Need
for
Developmental
Neurotoxicity
Study
The
ADTC
committee
has
not
identified
a
basis
for
requesting
a
developmental
neurotoxicity
study
at
this
time.
However,
the
Committee
is
recommending
that
when
the
90­
day
rat
subchronic
study
is
conducted,
the
protocol
be
modified
to
assess
endocrine
disruptor
effects
and
uterotropic
effects.
Protocols
are
available
from
HED.

7.6.
Database
Uncertainty
Factor
The
ADTC
has
assessed
an
additional
Uncertainty
Factor
of
10
at
this
time,
due
to
the
number
and
significance
of
the
data
gaps.

8.0
OTHER
ISSUES
There
are
no
outstanding
issues
at
this
time.
4­
Tert­
Amylphenol
and
Salts
RED
Toxicology
Chapter
AV­
11
20
9.0
REFERENCES
MRID
No.
41438401
May,
K.
1990.
Nipacide
PTAP
(
para­
tertiary
amylphenol):
Assessment
of
Mutagenic
Potential
in
Histidine
Auxotrophs
of
Salmonella
typhimurium.
Prepared
by
Life
Science
Research
Ltd.,
Suffolk,
UK.
Study
No.
90/
0109.
Submitted
by
Nipa
Laboratories,
Inc.,
Wilmington,
DE.

MRID
No.
41572701
Lloyd,
J.
M.
1990.
Investigation
of
Mutagenic
Activity
in
the
TK+/­
Mouse
Lymphoma
Cell
Mutation
System.
Prepared
by
Life
Science
Research
Ltd.,
Suffolk,
UK.
Study
No.
90/
NLL034/
0395.
Submitted
by
Nipa
Laboratories,
Inc.,
Wilmington,
DE.

MRID
No.
41710801
Edwards,
C.
N.
1990.
Assessment
of
Clastogenic
Action
on
Bone
Marrow
Erythrocytes
in
the
Micronucleus
Test.
Prepared
by
Life
Science
Research
Ltd.,
Suffolk,
UK.
Study
No.
90/
NLL033/
0533.
Submitted
by
Nipa
Laboratories,
Inc.,
Wilmington,
DE.

MRID
No.
41920002.
Siglin,
J.
C.
1991.
Nipacide
PTAP,
Teratology
Study
in
Rats.
Prepared
by
Springborn
Laboratories,
Inc.,
Spencerville,
OH.
Study
No.
3227.3.
Submitted
by
Nipa
Laboratories,
Inc.,
Wilmington,
DE.

MRID
42470301
Siglin
1992.
Ninety­
One
Day
Dermal
Toxicity
Study
in
Rats
with
Nipacide
PTAP.
Springborn
Laboratories.

MRID
No.
46616601.
Tuffnell,
P.
P.
Phenol,
4­(
1,1­
dimethylpropyl)­
Acute
Oral
Toxicity
in
the
Rat.
Safepharm
Laboratories
Ltd.,
Derby
U.
K.,
Laboratory
Test
No.
47/
2097.
July
23,
1992.
Unpublished.

MRID
No.
46616602.
Tuffnell,
P.
P.
Phenol,
4­(
1,1­
dimethylpropyl)­
Acute
Dermal
Irritation
Test
in
the
Rabbit.
Safepharm
Laboratories
Ltd.,
Derby
U.
K.,
Laboratory
Test
No.
47/
2098.
July
25,
1992.
Unpublished.

Antimicrobials
Toxicology
Endpoint
Selection
Committee
(
ADTC).
2005.
4­
t­
Amylphenol.
Report
of
the
Antimicrobials
Toxicology
Endpoint
Selection
Committee.
From
Myron
Ottley
and
Tim
McMahon
to
Mark
Hartman.
July
12,
2005.

BIBRA,
Working
Group
(
1990):
Para­
tertiary­
Amylphenol.
Toxicity
Profile
BIBRA
Toxicology
International.
3
pp.

Blair,
R.
M.,
Fang,
H.,
Branham,
W.,
Hass,
B.,
Dial,
S.,
Moland,
C.,
Tong,
W.,
Shi,
L.,
Perkins,
R.,
and
D.
Sheehan.
(
2000).
The
estrogen
receptor
relative
binding
affinities
of
188
4­
Tert­
Amylphenol
and
Salts
RED
Toxicology
Chapter
AV­
11
21
natural
and
xenochemicals:
structural
diversity
of
ligands.
Toxicol
Sci.
54,
138­
153.

Miller,
D.,
Wheals,
B.,
Beresford,
N.,
Sumpter,
J.
(
2001).
Estrogenic
activity
of
phenolic
additives
determined
by
an
in
vitro
yeast
assay.
Environ
Health
Perspect.
109,
133­
138.

Routledge,
E.
J.
and
Sumpter,
J.
P.
(
1997)
Structural
features
of
alkylphenolic
chemicals
associated
with
estrogenic
activity.
J.
Biol.
Chem.
272(
6):
3280­
3288.

Schultz,
T.,
Sinks,
G.,
Cronin,
M.
(
2000)
Effect
of
substituent
size
and
dimensionality
on
potency
of
phenolic
xenoestrogens
evaluated
with
a
recombinant
yeast
assay.
Environ
Toxicol
Chem
19,
2637­
2642
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.

Stevenson,
C.
J.
(
1984):
Environmentally
induced
vitiligo
(
leukoderma)
from
depigmenting
agents
and
chemicals.
J.
Toxicol.
Cutaneous
Ocul.
Toxicol.
3(
3):
299­
308.

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.

Zeiger,
E.,
Anderson,
B.,
Haworth,
S.,
Lawlor,
T.,
and
Mortelmans,
K.
(
198):
Salmonella
mutagenicity
tests.
4.
results
from
the
testing
of
300
chemicals.
Environ.
Mol.
Mutagen
11:
1­
158.

10.0
APPENDICES
10.1
Toxicity
Profile
Summary
Tables
10.1.1
Acute
Toxicity
Table
Guideline
No./
Study
Type
MRID
No.
Results
Toxicity
Category
870.1100
Acute
oral
toxicity
46616601
LD50
>
2000
mg/
kg
for
males
and
females
III
870.1200
Acute
dermal
toxicity
NA
[
]

870.1300
Acute
inhalation
toxicity
NA
[
]
No
adequate
acute
toxicity
studies
were
provided
or
identified
in
the
open
literature.
4­
Tert­
Amylphenol
and
Salts
RED
Toxicology
Chapter
AV­
11
22
870.2400
Acute
eye
irritation
NA
[
]

870.2500
Acute
dermal
irritation
46616602
Corrosive
following
4
hour
application;
scar
tissue
noted
14
days
after
treatment
I
870.2600
Skin
sensitization
NA
NA=
Not
available
10.1.2
Subchronic,
Chronic
and
Other
Toxicity
Table
Guideline
No./
Study
Type
MRID
No.
(
year)/
Classification
/
Doses
Results
870.3250
90­
Day
dermal
toxicity
MRID
42470301
(
1993)
0,
2.5,
10,
25
mg/
kg/
day
not
acceptable,
no
systemic
toxicity
demonstrated
NOAEL
=
2.5
mg/
kg/
day
LOAEL
=
10
mg/
kg/
day
based
on
dermal
effects
870.3700a
Prenatal
developmental
in
rodents
41920002
(
1991)
Acceptable
0,
50,
200,
500
mg/
kg/
day
Maternal
NOAEL
=
50
mg/
kg/
day
LOAEL
=
200
mg/
kg/
day
based
on
clinical
signs
and
decreased
body
weight,
weight
gain,
and
food
consumption
Developmental
NOAEL
=
200
mg/
kg/
day
LOAEL
=
500
mg/
kg/
day
based
on
decreased
fetal
body
weight
and
increased
incidence
of
bent
ribs
Gene
Mutation
870.5265
Salmonella
typhimurium
reverse
mutation
assay
414384­
01
(
1990)
Acceptable
1,
3.2,
10,
31.6,
and
100
Fg/
plate
Negative,
with
or
without
activation
Gene
Mutation
870.5300
In
vitro
mammalian
cell
gene
mutation
test
415727­
01
(
1990)
Acceptable
non­
activated
conditions
­
5,
10,
20,
30,
and
40
Fg/
ml;
activated
conditions
­
2,
4,
6,
8,
and
10
Fg/
ml
Negative
with
and
without
metabolic
activation.
The
few
positive
results
in
control
plates
are
consistent
with
historical
control
data
for
the
laboratory
and
test
system.

Cytogenetics
870.5395
Mammalian
erythrocyte
micronucleus
test
417108
(
1990)
Acceptable
62.5
(
M),
250
(
M+
F),
1000
(
M+
F),
and
4000
mg/
kg
(
F)
Negative
4­
Tert­
Amylphenol
and
Salts
RED
Toxicology
Chapter
AV­
11
23
10.1.3
Toxicity
Endpoint
Selection
Table
Exposure
Scenario
Dose
Used
in
Risk
Assessment
(
mg/
kg/
day)
Target
MOE,
UF,
Special
FQPA
SF,
for
Risk
Assessment
Study
and
Toxicological
Effects
Acute
Dietary
Females
13+

b.
w.
=
60kg
NOAEL=
200
mg/
kg/
day
UF
=
3000
(
10x
interspecies
extrapolation,
10x
intra­
species
variation)
FQPA
SF=
10
DB
UF
=
3
Acute
PAD
=
0.067
mg/
kg/
day
Developmental
toxicity
study
in
the
rat
NOAEL
of
200
mg/
kg/
da,
based
on
skeletal
effects
and
decreased
fetal
body
weight
at
500
mg/
kg/
day
Chronic
Dietary
All
populations
b.
w.
=
70
kg
NOAEL
=
50
mg/
kg/
day
UF
=
3000
(
10x
interspecies
extrapolation,
10x
intra­
species
variation)
FQPA
SF=
10
DB
UF
=
3
Chronic
PAD
=
0.017
mg/
kg/
day
Developmental
toxicity
study
in
the
rat
NOAEL
of
50
mg/
kg/
day,
based
on
clinical
signs,
decreased
body
weight
and
body
weight
gain,
and
decreased
food
consumption
in
maternal
animals
at
200
mg/
kg/
day
Incidental
Oral
(
short
and
intermediate
term)
NOAEL
=
50
mg/
kg/
day
MOE
=
3000
(
10x
interspecies
extrapolation,
10x
intraspecies
variation,
10x
FQPA
,
3x
database
UF)
Developmental
toxicity
study
in
the
rat
NOAEL
of
50
mg/
kg/
day,
based
on
clinical
signs,
decreased
body
weight
and
body
weight
gain,
and
decreased
food
consumption
in
maternal
animals
at
200
mg/
kg/
day
Dermal
(
short
and
intermediate­
term)
(
occupational
and
residential)
NOAEL
=
25
mg/
kg/
day
(
HDT)
MOE
(
occupational)
=
100
MOE
(
residential)
=
1000
(
10x
interspecies
extrapolation,
10x
intraspecies
variation,
10x
FQPA)
Subchronic
dermal
toxicity
in
the
rat
No
systemic
effects
identified
up
to
and
including
the
high
dose
of
25
mg/
kg/
day
Dermal
(
long­
term)
(
occupational
and
residential)
NOAEL
=
25
mg/
kg/
day
(
HDT)
MOE
(
occupational)
=
300
MOE
(
residential)
=
3000
(
10x
interspecies
extrapolation,
10x
intraspecies
variation,
10x
FQPA,
3X
for
subchronic
to
chronic
duration)
Subchronic
dermal
toxicity
in
the
rat
No
systemic
effects
identified
up
to
and
including
the
high
dose
of
25
mg/
kg/
day
Inhalation
All
time
periods
(
occupational
and
residential)
NOAEL
=
50
mg/
kg/
day
MOE
(
occupational)
=
300
MOE
(
residential)
=
3000
(
10x
interspecies
extrapolation,
10x
intraspecies
variation,
10x
route
extrapolation,
3x
database
uncertainty)
Developmental
toxicity
study
in
the
rat
NOAEL
of
50
mg/
kg/
day,
based
on
clinical
signs,
decreased
body
weight
and
body
weight
gain,
and
decreased
food
consumption
in
maternal
animals
at
200
mg/
kg/
day
Cancer
No
cancer
data
available
for
4­
t
amylphenol