Document ID: EPA-HQ-OPP-2004-0032-0027
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2006-06-28T04:00Z

UNITED
STATES
ENVIRONMENTAL
PROTECTION
AGENCY
WASHINGTON,
D.
C.
20460
MEMORANDUM
December
22,
2005
Subject:
EPA
Id
#
097301.
Formetanate
hydrochloride.
December
2005
Revision
of
the
Toxicology
chapter
for
the
Registration
Eligibility
Document.

TXR
#
0053982
DP
Barcode
No.:
D324302
Submission
No.:
S517345
PC
Code:
097301
From:
John
Doherty
ReRegistration
Branch
III
Health
Effects
Division
7509C
To:
Danette
Drew
Risk
Assessor
ReRegistration
Branch
III
Health
Effects
Division
7509C
Through:
Catherine
Eiden
Branch
Senior
Scientist
ReRegistration
Branch
III
Health
Effects
Division
7509C
Attached
is
the
revised
Toxicology
Chapter
for
the
Registration
Eligibility
Document
for
formetanate
hydrochloride.
The
revisions
included
the
impact
of
the
comparative
cholinesterase
study
(
2005,
MRID
No.:
46618901)
on
the
selection
of
the
endpoints
and
uncertainty
factors
for
risk
assessments.
This
revision
replaces
the
original
Toxicology
Chapter
for
formetanate
dated
May
21,
2003.
OFFICE
OF
PREVENTION,
PESTICIDES,
AND
TOXIC
SUBSTANCES
1
CHEMICAL
NAME
Formetanate
PC
Code:
097301
Revised
(
December
2005)
Toxicology
Disciplinary
Chapter
for
the
Reregistration
Eligibility
Decision
Document
(
Replaces
the
May,
21,
2003
version)

Date
completed:

December
22,
2005
Prepared
by:
Health
Effects
Division
Office
of
Pesticide
Programs
U.
S.
Environmental
Protection
Agency
Arlington,
VA
22202
form:
FINAL
June
21,
2000
EPA
Reviewer:
John
Doherty
,
Date
Reregistration
Branch
III
(
7509C)
EPA
Secondary
Reviewer:
Catherine
Eiden
,
Date
Reregistration
Branch
III
(
7509C)

TABLE
OF
CONTENTS
1.0
HAZARD
CHARACTERIZATION....................................................................................
3
2.0
REQUIREMENTS
.............................................................................................................
4
3.0
DATA
GAP(
S)
...................................................................................................................
5
4.0
HAZARD
ASSESSMENT..................................................................................................
5
4.1
Acute
Toxicity
............................................................................................................
5
4.2
Subchronic
Toxicity....................................................................................................
6
4.3
Prenatal
Developmental
Toxicity.................................................................................
8
4.4
Reproductive
Toxicity...............................................................................................
10
4.5
Chronic
Toxicity
.......................................................................................................
11
4.6
Carcinogenicity.........................................................................................................
11
4.7
Mutagenicity.............................................................................................................
13
4.8
Neurotoxicity............................................................................................................
14
4.9
Metabolism...............................................................................................................
14
4.10
Special/
Other
Studies
(
optional
section)
....................................................................
16
5.0
TOXICITY
ENDPOINT
SELECTION.............................................................................
17
5.1
See
Section
9.2
for
Endpoint
Selection
Table.
........................................................
(
28)
5.2
Dermal
Absorption....................................................................................................
17
5.3
Classification
of
Carcinogenic
Potential.....................................................................
17
6.0
FQPA
CONSIDERATIONS
.............................................................................................
18
6.1
Special
Sensitivity
to
Infants
and
Children
.................................................................
18
6.2
Recommendation
for
a
Developmental
Neurotoxicity
Study......................................
18
6.3.
Database
Uncertainty
Factor............................................................................
.....
18
7.0
OTHER
ISSUES
(
optional
section)...................................................................................
19
8.0
REFERENCES.................................................................................................................
19
9.0
APPENDICES..................................................................................................................
23
9.1
Toxicity
Profile
Summary
Tables...............................................................................
23
9.1.1
Acute
Toxicity
Table........................................................................................
(
5)
9.1.2
Subchronic,
Chronic
and
Other
Toxicity
Tables.................................................
24
9.2
Summary
of
Toxicological
Dose
and
Endpoints.........................................................
28
Formetanate/
April/
2003
RED
Toxicology
Chapter
3
1.0
HAZARD
CHARACTERIZATION
Formetanate
hydrochloride
is
a
carbamate
insecticide
belonging
to
a
class
of
chemicals
that
inhibits
cholinesterase.
Exposure
to
formetanate
hydrochloride
resulted
in
decreased
plasma,
whole
blood
and/
or
brain
cholinesterase.
Cholinesterase
inhibition
appears
to
be
the
only
manifestation
of
exposure
in
the
variety
of
studies
run
to
support
registration.
The
clinical
signs
following
acute
and
chronic
exposure
to
formetanate
hydrochloride
in
rats
and
dogs
are
consistent
with
cholinesterase
inhibition.
A
special
study
conducted
to
compare
the
cholinesterase
inhibitory
effects
of
formetanate
in
11
day
old
pups
and
young
adults
demonstrated
that
when
benchmark
dose
statistical
analysis
was
conducted
the
pups
were
more
sensitive
than
the
adults.
A
the
lower
limit
of
the
benchmark
dose
from
this
study
based
on
inhibition
of
brain
acetylcholinesterase
was
selected
for
the
oral
and
inhalation
endpoints
for
formetanate.
In
subchronic
and
chronic
studies
in
rats,
there
were
body
weight
gain
decreases.
This
weight
loss
seen
in
some
studies
at
dose
levels
higher
than
dose
levels
showing
inhibition
of
cholinesterase
is
not
considered
a
specific
response
to
formetanate
exposure.
Formetanate
hydrochloride
did
not
result
in
developmental
toxicity
in
either
rats
or
rabbits
or
in
the
multi­
generation
reproduction
study.
There
were
no
indications
of
increased
neoplastic
tissue
in
either
the
rat
or
mouse
carcinogenicity
studies
and
there
were
no
concerns
for
mutagenicity
based
on
a
battery
of
mutagenicity
studies.
There
were
also
no
obvious
effects
on
the
immune
or
endocrine
systems.
The
metabolism
and
excretion
of
formetanate
as
well
as
the
identification
of
its
metabolites
in
rats
is
considered
characterized.
Formetanate/
April/
2003
RED
Toxicology
Chapter
4
2.0
REQUIREMENTS
The
requirements
(
CFR
158.340)
for
food
use
and
for
protection
of
applicators
for
formetanate
hydrochloride
are
in
Table
1.
Use
of
the
new
guideline
numbers
does
not
imply
that
the
new
(
1998)
guideline
protocols
were
used
to
meet
the
requirement.

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.........................................................
yes
yes
yes
yes
yes
yes
no
no
no
yes
no
yes
870.3100
Oral
Subchronic
(
rodent)..................................................
870.3150
Oral
Subchronic
(
nonrodent)............................................
870.3200
21­
Day
Dermal
.................................................................
870.3250
90­
Day
Dermal
.................................................................
870.3465
90­
Day
Inhalation
.............................................................
yes
yes
yes
no
yes
(
1)
(
2)
yes
­­
no
870.3700a
Developmental
Toxicity
(
rodent)......................................
870.3700b
Developmental
Toxicity
(
nonrodent)................................
870.3800
Reproduction.....................................................................
yes
yes
yes
yes
yes
yes
870.4100a
Chronic
Toxicity
(
rodent)
.................................................
870.4100b
Chronic
Toxicity
(
nonrodent)
...........................................
870.4200a
Oncogenicity
(
rat)
.............................................................
870.4200b
Oncogenicity
(
mouse)
.......................................................
870.4300
Chronic/
Oncogenicity.......................................................
yes
yes
yes
yes
yes
yes
yes
yes
yes
yes
870.5100
Mutagenicity 
Gene
Mutation
­
bacterial........................
870.5300
Mutagenicity 
Gene
Mutation
­
mammalian...................
870.5xxx
Mutagenicity 
Structural
Chromosomal
Aberrations
.....
870.5xxx
Mutagenicity 
Other
Genotoxic
Effects
..........................
yes
yes
yes
yes
yes
yes
yes
yes
870.6100a
Acute
Delayed
Neurotox.
(
hen)
........................................
870.6100b
90­
Day
Neurotoxicity
(
hen)..............................................
870.6200a
Acute
Neurotox.
Screening
Battery
(
rat)..........................
870.6200b
90
Day
Neuro.
Screening
Battery
(
rat).............................
870.6300
Develop.
Neuro.................................................................
no
no
yes
yes
(
3)
­
­
yes
yes
yes
870.7485
General
Metabolism..........................................................
870.7600
Dermal
Penetration
...........................................................
yes
no
yes
­­

Special
Studies
for
Ocular
Effects
Acute
Oral
(
rat).................................................................
Subchronic
Oral
(
rat)........................................................
Six­
month
Oral
(
dog)........................................................
no
no
no
­­
­­
­­

(
1).
The
rat
subchronic
study
was
determined
to
be
unacceptable
but
there
is
an
acceptable
chronic
study
and
an
acceptable
subchronic
neurotoxicity
study
so
that
an
additional
Subchronic
rat
study
is
not
required.
(
2).
There
is
no
acceptable
subchronic
dog
study
but
there
is
an
acceptable
chronic
dog
study
so
that
no
additional
subchronic
dog
study
is
required.
Formetanate/
April/
2003
RED
Toxicology
Chapter
5
(
3).
The
HIARC
determined
that
a
guideline
developmental
toxicity
study
is
not
required
for
formetanate
hydrochloride.
However,
the
HIARC
recommended
that
a
special
study
following
the
exposure
protocol
for
the
developmental
neurotoxicity
study
be
but
only
comparative
susceptibility
to
cholinesterase
inhibition
between
the
neonatal
rats
and
the
adults
be
assessed.
This
study
(
2005,
MRID
No.:
46618901)
was
submitted
and
reviewed
(
Fall,
2005).

3.0
DATA
GAP(
S)

The
acute
toxicity
data
base
is
currently
supported
by
older
IBT
studies.
Replacement
studies
for
the
following
acute
toxicity
studies
are
required.

870.1100.
Acute
oral
toxicity
870.1200.
Acute
dermal
toxicity
870.1300.
Acute
inhalation
toxicity
870.2500.
Primary
dermal
irritation
The
following
study
is
also
required:

870.3465.
28
day
inhalation
toxicity
study.
The
protocol
for
this
study
should
also
be
submitted
to
OPP
for
review
prior
to
initiating
this
study.
This
study
will
require
preliminary
work
to
determine
the
optimum
time
following
removal
from
inhalation
exposure
and
blood
sampling
in
order
to
assure
maximum
inhibition
of
cholinesterase.

4.0
HAZARD
ASSESSMENT
4.1
Acute
Toxicity
Adequacy
of
data
base
for
acute
toxicity:
The
data
base
for
acute
toxicity
consists
of
studies
conducted
by
the
IBT
Company
and
are
considered
INVALID
and
will
need
replacement.
Formetanate
is
a
carbamate
inhibitor
of
cholinesterase
and
the
onset
of
typical
cholinesterase
inhibition
clinical
signs
is
rapid
and
transient.
The
acute
toxicity
data
(
including
the
results
of
the
IBT
studies)
on
the
formetanate
Technical
is
summarized
below
in
Table
2.

Table
2.
Acute
Toxicity
Data
on
formetanate.

Guideline
No.
Study
Type
MRID
#(
s)
Results
Toxicity
Category
81­
1
Acute
Oral
00077666
LD50
=
26.4
±
3.4
mg/
kg
_
14.8
±
2.6
mg/
kg
_
I*

81­
2
Acute
Dermal
00077666
LD50
>
10.2
gm/
kg
III*
Formetanate/
April/
2003
RED
Toxicology
Chapter
6
81­
3
Acute
Inhalation
00776668
LC50
=
0.29
mg/
L
II*

81­
4
Primary
Eye
Irritation
41208501
Non­
irritating
IV
81­
5
Primary
Skin
Irritation
00077666
PIS
=
3.9/
8.0
III*

81­
6
Dermal
Sensitization
42089802
00077728
Sensitizer
(
guinea
pig/
Buehler
test)
Sensitizer
(
human)*

*
IBT
study
and
needs
replacement
(
except
for
the
dermal
sensitization
study
with
humans).

4.2
Subchronic
Toxicity
Adequacy
of
data
base
for
subchronic
toxicity:
The
data
base
for
subchronic
toxicity
is
considered
complete
except
for
the
need
for
a
subchronic
inhalation
toxicity
study.

870.3100
90­
Day
Oral
Toxicity
­
Rat
Executive
Summary:
In
this
subchronic
feeding
study
(
1992,
MRID
No.:
42664401
and
42664402),
four
groups
of
20
male
Sprague
­
Dawley
strain
rats
were
dosed
as
control
1,
10,
20
or
50
ppm
of
formetanate
hydrochloride
(
purity
91%,
batch
#
CR
19558/
01/
821004)
in
their
diets
for
90
days.
These
dose
levels
corresponded
to
0,
0.07,
0.69,
1.43
or
3.48
mg/
kg/
day.
A
primary
purpose
of
this
study
was
to
determine
the
NOAEL
and
LOAEL
for
inhibition
of
plasma,
blood
and
brain
cholinesterase
(
ChE)
and
assessments
were
made
at
pretest
day
­
1
and
at
weeks
7
and
13.
Females
were
not
tested.
Systemic
Effects.
There
were
no
definite
systemic
effects
and
a
possible
effect
of
body
weight
gain
noted
between
weeks
7
and
13
was
obscured
since
half
of
the
rats
were
sacrificed
at
7
weeks.
Cholinesterase
Data.
Pretest
ChE
showed
moderate
variation
among
the
four
groups
with
the
standard
deviation
was
as
high
as
17%
for
whole
blood
and
20%
for
plasma
ChE.
Group
differences
in
whole
blood
and
plasma
ChE
did
not
reach
statistical
significance
for
the
50
ppm
dose
group
although
there
were
apparent
decreases
of
11%
and
4%
for
whole
blood
ChE
and
5%
and
no
decrease
for
plasma
ChE
at
weeks
7
or
13
respectively.
Brain
ChE
data
demonstrated
standard
deviations
of
8
to
9%
at
weeks
7
and
13.
At
week
7,
there
was
5%,
8%,
7%
and
10%
apparent
decrease
and
at
week
13
there
was
7%,
5%,
6%
and
9%
apparent
decrease
for
the
1,
10
,
20
and
50
ppm
dose
groups
respectively.
Since
there
was
no
dose
response
with
respect
to
the
apparent
decrease
in
brain
AChE
and
since
neither
the
plasma
or
blood
ChE
was
definitely
inhibited
at
these
dose
levels,
there
is
insufficient
justification
to
conclude
that
there
was
actually
inhibition
of
brain
AChE
in
this
study.
A
subsequent
subchronic
neurotoxicity
screen
study
(
MRID
No.:
45314202)
conducted
at
higher
doses
did
not
demonstrate
any
consistent
inhibition
of
brain
AChE
in
the
cortex,
hippocampus
or
cerebellum)
and
thus
did
not
verify
the
possible
indication
of
inhibition
of
brain
ChE
in
this
study.
This
study
is
classified
as
UNACCEPTABLE/
Non­
Guideline
and
does
not
satisfy
the
requirement
for
a
subchronic
oral
toxicity
study
in
rats.
The
study
was
not
considered
to
have
established
definite
NOAEL
and
LOAELs
for
inhibition
of
plasma,
whole
blood
or
brain
AChE.
Males
only
were
tested.

Note.
A
series
870.6200
subchronic
neurotoxicity
study
with
formetanate
addressed
the
cholinesterase
inhibition
issues
and
therefore
another
study
is
not
required.

870.3100
90­
Day
Oral
Toxicity
­
Mouse
An
acceptable
mouse
carcinogenicity
study
is
available
and
a
subchronic
study
with
formetanate
is
not
needed.
Formetanate/
April/
2003
RED
Toxicology
Chapter
7
870.3150
90­
Day
Oral
Toxicity
­
Dog
There
is
an
acceptable
chronic
feeding
study
with
formetanate
and
a
subchronic
study
is
not
needed.

870.3200
21/
28­
Day
Dermal
Toxicity
 
Rat
Non­
Guideline
­
Special
Single
Dose
Dermal
Toxicity
Study
In
a
special
study
(
2000,
MRID
No.:
45311901)
conducted
especially
to
determine
if
a
previous
study
(
MRID
No.:
44948501)
assessed
the
blood
for
cholinesterase
at
an
appropriate
time
following
dermal
application
of
the
carbamate
insecticide
formetanate
hydrochloride,
four
groups
of
ten/
sex
Sprague­
Dawley
strain
rats
were
dermally
dosed
with
0,
10,
20
or
500
mg/
kg
formetanate
hydrochloride
(
92.5%
purity)
in
deionized
water
and
a
fifth
group
was
dosed
with
500
mg/
kg
in
1%
methyl
cellulose
suspension.
The
test
material
was
kept
in
contact
with
the
skin
for
six
hours.
Blood
samples
from
the
lateral
tail
vein
were
taken
from
two
sets
of
five
rats/
sex
for
whole
blood
cholinesterase
assessment.
The
first
set
was
assessed
at
hours
4
and
5
during
exposure
and
at
hours
0.5
and
19
during
the
post
exposure
period.
The
second
set
was
assessed
at
hour
6
during
exposure
and
at
hours
1,
2
and
3
during
the
post
exposure
period.
Systemic
Effects.
There
were
no
deaths
and
only
one
rat
(
500
mg/
kg
in
methyl
cellulose)
displayed
salivation,
a
sign
expected
for
a
cholinesterase
inhibitor.
Cholinesterase
Inhibition.
At
20
mg/
kg
whole
blood
cholinesterase
was
consistently
decreased
12
to
18%
(
not
statistically
significant)
for
the
males
at
the
1,
2,
and
3
hour
post
exposure
assessments.
At
500
mg/
kg
in
deionized
water,
male
blood
cholinesterase
was
decreased
13
to
56%
for
the
intervals
at
6
hours
during
dosing
and
0.5.
1,
2
and
3
hours
during
the
post
exposure
period.
Female
blood
cholinesterase
was
also
decreased
23
to
36%
at
this
level
at
0.5
and
1
hour
during
the
post
exposure
period.
Whole
blood
cholinesterase
data
indicated
a
return
to
control
levels
for
the
20
mg/
kg
group
males
and
all
of
the
500
mg/
kg
dose
group
males
and
females
by
the
19th
hour
of
the
post
exposure
period.
The
time
to
peak
effect
was
demonstrated
to
be
from
0.5
hours
to
3
hours
after
removal.
Since
the
previous
21­
day
dermal
study
(
MRID
No.:
44948501)
assessed
for
cholinesterase
one
hour
post
exposure,
the
assessment
time
is
considered
appropriate
for
that
study.
The
LOAEL
is
20
mg/
kg
based
on
consistent
decrease
of
whole
blood
cholinesterase
in
males
of
12
to
18%.
The
NOAEL
is
10
mg/
kg.
20
mg/
kg
may
also
be
considered
a
threshold
effect
level
since
statistical
differences
were
not
attained.
Classification:
This
study
is
classified
as
ACCEPTABLE/
Non­
Guideline.
The
study
satisfies
the
intent
of
its
original
objective.

870­
3200.
Subchronic
Dermal
Toxicity.
(
Supporting
study)
In
a
subchronic
dermal
toxicity
study
(
1999,
MRID
No.:
44948501)
conducted
according
to
the
series
870.3200
guidelines,
formetanate
hydrochloride
(
92.7%
w/
w
a.
i.)
was
administered
to
two
sets
of
four
groups
of
Sprague­
Dawley
strain
rats
10/
sex/
dose
in
methylcellulose
(
1
%
w/
v)
at
dose
levels
of
0,
10,
15
or
20
mg/
kg/
day.
The
first
set
was
the
main
group.
The
second
set
was
a
satellite
group
that
was
assessed
for
neurotoxicity
(
Functional
Observational
Battery,
FOB,
at
pretest
and
weekly
during
testing,
motor
activity
at
the
end
of
treatment)
and
cholinesterase
(
at
day
20)
and
starting
one
hour
after
removal
of
the
test
material.
The
test
material
was
applied
as
a
semi
occluded
dermal
application
for
six
hours
duration
at
least
5
days
per
week
for
a
total
of
15
to
16
applications
in
three
weeks.
Systemic
Toxicity.
Treatment
had
no
adverse
effects
on
survival,
mean
body
weight,
body
weight
Formetanate/
April/
2003
RED
Toxicology
Chapter
8
gain,
food
consumption,
clinical
signs
of
toxicity,
hematology
and
clinical
chemistry
parameters,
FOB
parameters,
motor
activity,
as
well
as
systemic
gross
and
histopathology.
No
treatment­
related
gross
or
histopathological
lesions
of
the
skin
were
observed
at
any
dose
level.
The
FOB
and
motor
activity
assessments
were,
however,
considered
compromised
since
there
was
no
demonstration
that
the
assessment
times
were
optimal
for
effects
from
a
carbamate.
The
NOAEL
was
20
mg/
kg/
day
(
highest
dose
tested)
for
systemic
toxicity;
a
LOAEL
was
not
established.
Cholinesterase
Assessments.
Assessment
of
whole
blood,
plasma
and
brain
cholinesterase
was
considered
confounded
and
unacceptable
because
critical
information
on
the
time
of
assay
relative
to
drawing
the
blood
and
dilution
of
the
blood
were
not
presented
and
because
there
were
no
supporting
time
course
data
to
verify
that
the
blood
was
sampled
at
the
time
for
optimal
assessment
for
potential
inhibition.
Whole
blood
cholinesterase
in
males
at
20
mg/
kg/
day
(­
7%)
and
in
females
at
15
mg/
kg/
day
(­
9%)
showed
statistically
significant
(
p<
0.05)
decreases.
These
decreases,
however,
were
determined
not
to
be
of
toxicological
significance
since:
1)
the
magnitude
of
the
decrease
was
minimal;
2)
there
was
no
dose­
response
in
females;
and
3)
no
plasma
or
brain
cholinesterase
decrease
was
seen
in
either
sex
at
any
dose.
No
NOAEL
or
LOAEL
is
being
assigned
by
HED
for
cholinesterase
data
for
this
study
until
submission
and
review
of
the
additional
data
requested
by
the
Agency
as
detailed
in
Attachment
1.
Classification:
Classification
of
this
21­
day
dermal
toxicity
study
is
PENDING
upon
submission
and
successful
review
of
additional
data.

870.3465
90­
Day
Inhalation
 
Rat
There
is
no
subchronic
inhalation
toxicity
study
with
formetanate
currently
available
and
a
study
is
being
requested.

4.3
Prenatal
Developmental
Toxicity
Adequacy
of
data
base
for
Prenatal
Developmental
Toxicity:
The
data
base
for
prenatal
developmental
toxicity
is
considered
complete.
No
additional
studies
are
required
at
this
time.
The
rat
(
1985,
MRID
No.:
00151570)
and
rabbit
(
1985,
MRID
No.:
00151571)
developmental
toxicity
studies
clearly
showed
maternal
toxicity
at
dose
levels
lower
than
dose
levels
showing
any
indications
of
fetal
toxicity
or
developmental
effects.

870.3700a
Prenatal
Developmental
Toxicity
Study
­
Rat
Rat
Study
(
As
revised
in
March
2002).
Formetanate
­
HCl
(
in
distilled
water)
was
dosed
to
four
groups
of
22
pregnant
rat
dams
(
Sprague­
Dawley
CD,
SPF)
were
dosed
as
0,
1,
3,
or
5
mg/
kg/
day
on
days
6
through
15
of
gestation
in
a
developmental
toxicity
study
(
1985,
MRID
No.:
00151570
or
40151570)
and
on
day
20
of
gestation
they
were
sacrificed
and
their
uterine
contents
examined.
Maternal
Toxicity.
The
only
effect
definitely
attributed
to
treatment
was
decreased
body
weight
gain
(
up
to
17%)
in
both
the
3
and
5
mg/
kg/
day
dose
groups.
However,
there
was
also
one
episode
of
salivation
and
tremors
in
two
dams
in
the
group
dosed
with
3
mg/
kg/
day.
The
LOAEL
for
maternal
toxicity
is
3
mg/
kg/
day
based
mainly
on
body
weight
decrease.
The
NOAEL
is
1
mg/
kg/
day.
Developmental
Toxicity.
There
were
no
indications
of
treatment
related
developmental
toxicity.
Formetanate/
April/
2003
RED
Toxicology
Chapter
9
The
LOAEL
is
>
5
mg/
kg/
day.
The
NOAEL
is
>
5
mg/
kg/
day.
This
study
is
classified
as
ACCEPTABLE/
Guideline
and
satisfies
the
requirement
for
a
series
83­
3
developmental
toxicity
study
in
rats.

870.3700b
Prenatal
Developmental
Toxicity
Study
­
Rabbit
Rabbit
Study
(
As
revised
March
2002).
Formetanate
­
HCl
(
96%
purity
in
)
was
administered
in
this
developmental
toxicity
study
(
1985,
MRID
No.:
00151571)
to
four
groups
of
14
or
15
pregnant
rabbits
(
New
Zealand
White)
at
dose
levels
of
0,
5,
15
or
30
mg/
kg/
day)
on
days
6
through
19
of
gestation
and
on
day
29
of
gestation
were
sacrificed
and
their
uterine
contents
were
examined.
Maternal
Toxicity.
The
15
mg/
kg/
day
dose
group
was
associated
with
both
decreases
in
body
weight
(­
6%,
p
<
0.01
at
day
29)
and
the
presence
of
ataxia
(
3
does
affected).
The
30
mg/
kg/
day
dose
group
had
decreased
weight
gain
for
the
days
6
to
10
intervals
and
also
had
ataxia
(
all
does)
as
well
as
other
signs
of
cholinergic
intoxication
(
i.
e
prostration,
pupillary
constriction,
increased
respiratory
rate,
muscle
tremors,
hyperactivity
and
salivation)
and
there
was
one
death
in
this
group.
The
maternal
toxicity
LOAEL
is
15
mg/
kg/
day
based
on
body
weight
decrease
and
ataxia.
The
NOAEL
is
5
mg/
kg/
day.
Developmental
Toxicity.
There
were
no
indications
of
treatment
related
effects
on
fetal
abnormalities
or
malformations
with
respect
to
increased
incidence
in
fetuses
or
litters.
The
NOAEL
and
LOAEL
for
developmental
effects
is
30
mg/
kg/
day.
This
study
is
classified
as
Acceptable/
Non­
Guideline.
This
study
satisfies
the
series
83­
3
requirement
for
a
developmental
toxicity
study
in
rabbits.
A
study
deficiency
that
precludes
classifying
this
study
as
Guideline
is
that
there
were
only
12
to
13
does
delivering
fetuses
and
not
20
does
with
implantation
sites.

4.4
Reproductive
Toxicity
4.
Reproductive
Toxicity
Study
Conclusions
Adequacy
of
data
base
for
Reproductive
Toxicity:
The
data
base
for
reproductive
toxicity
is
considered
complete.
No
additional
studies
are
required
at
this
time.
In
the
rat
multi
generation
reproduction
study
(
1987,
MRID
No.:
40411801,
­
02
and
­
03),
the
LOAEL
(
22.75
mg/
kg/
day)
and
NOAEL
(
4.5
mg/
kg/
day)
for
both
parental
and
developmental
toxicity
was
the
same.
There
was
decreased
pup
weight
at
birth
for
the
F2a
( 
10%,
p
<
0.05)
and
F2b
( 
8%,
p
<
0.05)
in
the
high
dose
group
(
22.75
mg/
kg/
day.)
There
was
also
an
indication
of
a
decrease
in
the
viability
index
in
the
high
dose
group
since
the
lowest
percentage
for
survival
was
always
found
in
the
high
dose
group
for
the
F2a
(
83%
and
74%
for
day
4
and
day
21)
and
F2b
(
86%
and
64%
for
day
4
and
day
21)
compared
to
all
other
groups
for
F2a
(
89%
to
90%
for
day
4
and
78%
to
87%
for
day
21)
and
F2b
(
87%
to
90%
for
day
4
and
73%
to
84%
for
Formetanate/
April/
2003
RED
Toxicology
Chapter
10
day
21).
The
difference
in
viability
in
the
group
dosed
with
22.75
mg/
kg/
day
is
small
but
may
still
be
real.

870.3800
Reproduction
and
Fertility
Effects
­
Rat
Reproductive
Toxicity
Study
In
this
multi
generation
reproduction
study
(
1987,
MRID
Nos.:
40411801,
­
02
and
­
03)
an
initial
set
(
Fo)
of
four
groups
of
30/
sex
Charles
River
derived
CD
strain
rats
were
continuously
dosed
as
either
control,
10,
50
or
250
ppm
formetanate
hydrochloride
(
batch
#
234206716)
for
10
weeks
and
then
were
mated
to
produce
an
F1
generation.
An
additional
set
of
30/
sex
per
group
were
selected
from
the
F1
generation
to
produce
the
F2a
and
F2b
litters.
These
dose
levels
corresponded
to
approximately
0.9,
4.5
or
22.75
mg/
kg/
day
for
the
10,
50
or
250
ppm
dose
group.
Parental
Toxicity.
Maternal
body
weight
gains
were
considered
slightly
decreased
for
the
F1
( 
7%),
F2a
and
( 
13%,
p
<
0.05))
but
not
the
F2b
generation.
Reproductive
performance
was
not
considered
affected
in
either
sex.
There
were
also
decreases
in
water
intake
(~
10%)
in
the
high
dose
group.
The
Fo
generation
was
determined
to
have
a
22%
decrease
(
p
<
0.05)
in
both
whole
blood
ChE
and
brain
AChE.
Other
apparent
decreases
in
ChE
were
noted
but
did
not
attain
statistical
significance
and
the
F1
generation
did
not
show
decreases
in
brain
AChE.
The
parental
LOAEL
is
22.75
mg/
kg/
day
based
on
slight
decreases
in
body
weight
and
apparent
inhibition
of
whole
blood
and
brain
ChE.
The
NOAEL
is
4.5
mg/
kg/
day.
Developmental
Toxicity.
Responses
to
treatment
were
noted
in
the
250
ppm
dose
group.
Mean
pup
bodyweight
was
decreased
in
the
F2a
( 
9.5%,
p
<
0.05)
and
F2b
( 
8%,
p
<
0.05)
litters.
There
were
also
indications
of
decreases
in
the
viability
index
on
lactation
day
21
with
the
F2a
groups
having
a
viability
indices
of
87%,
78%,
82%
and
74%
and
the
F2b
groups
having
viability
indices
of
84%,
75%,
76%
and
64%
for
the
control,
10,
50
and
250
ppm
dose
groups
respectively.
Thus,
the
viability
index
was
lowest
in
the
high
dose
group
for
both
the
F2a
and
F2b
generations
indicating
an
effect
of
treatment.
The
LOAEL
for
developmental
toxicity
is
22.75
mg/
kg/
day
based
on
decreased
pup
weight
and
viability
index.
The
NOAEL
is
4.5
mg/
kg/
day.
This
study
is
classified
as
ACCEPTABLE/
Guideline
and
satisfies
the
requirement
for
a
series
83­
4
reproduction
study
in
rats.

4.5
Chronic
Toxicity
Adequacy
of
data
base
for
chronic
toxicity:
The
data
base
for
chronic
toxicity
is
considered
complete.
No
additional
studies
are
required
at
this
time.

870.4100a
(
870.4300)
Chronic
Toxicity
 
Rat
See
under
combined
chronic
feeding/
carcinogenicity
study
below.

870.4100b
Chronic
Toxicity
­
Dog
Executive
Summary:
In
this
chronic
feeding
study
(
1986,
MRID
#
00164341)
four
groups
of
6/
sex
beagle
dogs
were
dosed
as
control,
10,
50
or
250
ppm
of
formetanate
hydrochloride
(
95.7%,
lot
#
BX234206716)
in
their
diets
for
52
weeks.
These
doses
corresponded
to
mean
values
of
0,
0.37
(
for
both
sexes),
1.74
for
males
Formetanate/
April/
2003
RED
Toxicology
Chapter
11
and
1.78
for
females
and
8.45
for
males
and
9.20
for
females
mg/
kg/
day.
The
dogs
were
periodically
assessed
for
plasma
and
whole
blood
cholinesterase
(
ChE)
and
for
brain
acetylcholinesterase
AChE)
at
study
termination.
Systemic
Toxicity.
Clinical
signs
believed
to
be
related
to
cholinesterase
inhibition
were
noted
at
50
ppm
but
were
more
frequent
at
250
ppm.
These
included
excessive
salivation,
wheezing
labored
breathing,
trembling,
vomiting,
coughing,
and
abnormal
quietness.
There
was
no
effect
on
body
weight.
The
systemic
LOAEL
is
1.74
mg/
kg/
day
based
on
clinical
signs.
The
systemic
NOAEL
is
0.37
mg/
kg/
day.
Cholinesterase
Effects.
Plasma
ChE
( 
21%
to
25%
in
males,
p
<
0.05
to
0.01)
and
whole
blood
ChE
( 
17%
to
24%,
p
<
0.05
in
males)
was
noted
to
be
inhibited
at
weeks
13,
26
and
50.
Decreases
in
plasma
ChE
in
females
reached
statistical
significance
at
week
13
only
( 
15%,
p
<
0.05).
At
250
ppm,
plasma
ChE
was
further
decreased
(
38
to
45%
in
males
and
37
to
42%
in
females,
all
p
<
0.01)
and
whole
blood
ChE
was
decreased
(
34
to
45%
in
males
and
47
to
54%,
all
p
<
0.01).
Brain
AChE
was
statistically
significantly
decreased
in
the
250
ppm
dose
group
for
males
only
(
21%,
p
<
0.01).
The
LOAEL
for
plasma
and
whole
blood
ChE
inhibition
is
1.74
mg/
kg/
day.
The
NOAEL
is
0.37
mg/
kg/
day.
The
LOAEL
for
brain
AChE
inhibition
is
8.45
mg/
kg/
day.
The
NOAEL
is
1.74
mg/
kg/
day.
This
study
is
classified
as
ACCEPTABLE/
Guideline
and
satisfies
the
requirement
for
a
chronic
feeding
study
in
dogs.

4.6
Carcinogenicity
Adequacy
of
data
base
for
Carcinogenicity:
The
data
base
for
carcinogenicity
is
considered
complete.
There
was
no
indication
of
a
carcinogenic
effect
is
rats
or
mice.
No
additional
studies
are
required
at
this
time.

870.4200a
Carcinogenicity
Study
­
rat
Executive
Summary:
In
this
combined
chronic
feeding
carcinogenicity
study
(
1988,
MRID
No.:
40640901),
four
groups
of
50
male
and
female
Sprague­
Dawley
strain
rats
were
dosed
as
control,
10,
50
or
250
ppm
of
formetanate
hydrochloride
(
95.4%,
batch
BX234206716)
in
their
diets
for
two
years
and
four
groups
of
20
per
sex
were
dosed
for
one
year
as
an
interim
sacrifice
group.
These
dose
levels
corresponded
to
mean
levels
of
0,
0.45,
2.3
or
12
mg/
kg/
day
in
males
and
0,
0.58,
2.9
or
15
mg/
kg/
day
in
females.
Whole
blood
and
plasma
cholinesterase
(
ChE)
assessments
were
made
at
1,
3,
6,
12,
18
and
24
months.
Brain
AChE
was
assessed
at
termination.
Systemic
Effects.
The
only
effect
noted
was
a
decrease
in
body
weight
and
gain
in
the
high
dose
group
In
males,
the
body
weight
was
5%,
6%
and
8%
(
p
<
0.05
or
0.01)
at
weeks
13,
51
and
79
and
this
corresponded
to
up
to
10%
decrease
in
body
weight
gain
in
the
main
group.
In
the
satellite
group,
maximum
weight
decrease
was
10%
(
p
<
0.001)
at
week
13
.
In
females,
maximum
decrease
in
weight
was
6%
at
week
51
and
this
corresponded
to
a
body
weight
gain
of
up
to
12%.
The
LOAEL
for
systemic
effects
is
250
ppm
(~
12
mg/
kg/
day
in
males)
based
on
decreased
body
weight.
The
NOAEL
is
50
ppm.
Cholinesterase
Data.
Whole
blood
ChE
was
statistically
inhibited
at
50
ppm
in
males
only
at
the
12th
month
assessment
(
16%,
p
,
0.01)
and
in
females
at
the
18th
month
(
15%,
p
<
0.05)
but
there
were
decreases
of
4
to
9%
for
males
at
the
other
intervals
and
8%
for
females.
Plasma
ChE
differences
did
not
reach
statistical
significance
in
either
males
or
females.
At
250
ppm,
whole
blood
ChE
was
statistically
significantly
(
p
0.05
to
0.001)
inhibited
at
all
but
one
assessment
time
and
in
males
the
decrease
was
from
Formetanate/
April/
2003
RED
Toxicology
Chapter
12
11%
(
at
month
1)
to
31%
(
at
month
24)
and
in
females
the
decrease
was
from
18%
(
at
month
1
and
month
24)
to
40%
(
at
month
12).
Plasma
ChE
was
only
occasionally
inhibited
in
males
(
i.
e.
at
month
12
­
37%,
and
at
month
18
­
48%,
both
p
<
0.05)
but
in
females
it
was
statistically
inhibited
at
most
assessment
times
with
inhibition
ranging
from
22
to
44%).
At
termination,
brain
AChE
for
males
was
10%
(
p
<
0.05),
24%
(
p
<
0.001)
and
44%
(
p
<
0.001)
decreased
for
the
10,
50
and
250
ppm
dose
groups
but
only
the
250
ppm
dose
group
females
attained
a
statistically
significant
decrease
(
32%,
p
<
0.001).
No
assignment
for
NOAEL
and
LOAELs
for
inhibition
of
whole
blood,
plasma
or
brain
ChE
is
being
made
for
this
study
since
the
NOAEL
and
LOAEL
for
these
parameters
will
be
set
based
on
the
weight
of
evidence
from
three
studies
that
assess
for
inhibition
by
formetanate
hydrochloride.
Carcinogenicity
Evaluation.
There
was
no
evidence
of
compound
related
increases
in
neoplasia
associated
with
formetanate
hydrochloride.
The
dose
levels
were
considered
adequate
for
carcinogenicity
evaluation
based
on
decreased
body
weight.
This
study
is
classified
as
ACCEPTABLE/
Guideline
and
satisfies
the
requirement
for
a
series
83­
5
combined
chronic
feeding
carcinogenicity
study
in
rats.
.

870.4200b
Carcinogenicity
(
feeding)
­
Mouse
Executive
Summary:
In
this
carcinogenicity
study
(
1988,
MRID
No.:
40707101)
in
mice,
four
groups
of
50/
sex
CD­
1
strain
mice
were
dosed
as
control,
10,
50
or
500
ppm
formetanate
hydrochloride
(
94.6%
to
95.7%,
batch
#
BX
234206716)
in
their
diets
for
95
weeks.
These
doses
corresponded
to
mean
doses
of
0,
1.4,
7,
and
70
mg/
kg/
day
in
males
and
0,
1.9,
9.3
and
98
mg/
kg/
day
in
females.
Systemic
effects.
The
only
systemic
effects
noted
were
decreased
body
weight
in
the
high
dose
group
females
(
7
to
9%,
p
=
0.05
to
0.001)
particularly
during
the
first
year
of
the
study.
Body
weight
gain
in
females
was
also
decreased
(
up
to
29%)
and
in
males
(
8%
for
weeks
0
to
51
and
14%
for
the
entire
study).
Actual
food
consumption
was
not
affected
but
food
conversion
was
decreased
in
females
especially
during
weeks
1
to
13.
No
effects
on
organ
weights
or
hematology
were
noted.
Clinical
chemistry,
cholinesterase
and
urinalysis
were
not
assessed.
Carcinogenicity
assessment.
The
decrease
in
body
weight
in
females
and
gain
in
both
sexes
provided
a
basis
for
adequacy
of
dosing.
In
addition,
the
dose
range
finding
study
determined
that
there
was
ChE
inhibition
at
500
ppm
or
the
highest
dose
tested.
There
were
no
increases
in
tumors
associated
with
dietary
formetanate
hydrochloride.
This
study
is
classified
as
ACCEPTABLE/
Guideline
and
satisfies
the
requirement
for
a
series
85­
2
carcinogenicity
study
in
mice.

4.7
Mutagenicity
Adequacy
of
data
base
for
Mutagenicity:
The
data
base
for
Mutagenicity
is
considered
adequate
based
on
post
1991
mutagenicity
guidelines.
There
is
no
concern
for
mutagenicity
at
this
time.

Gene
Mutation
Reverse
mutation
(
Ames
test)
Not
mutagenic
up
to
the
limit
dose
(
5000
µ
g/
plate)
and
to
cytotoxic
Formetanate/
April/
2003
RED
Toxicology
Chapter
13
Covance
Laboratories,
Study
No.
:
21810­
0­
409OECD,
January
3,
2001.
MRID
No.:
45314203.
concentrations
(>
3330
or
5000
µ
g/
plate
in
the
presence
or
absence
of
metabolic
activation.

Cytogenetics
Chromosome
aberration
­
human
Huntingdon
Research
Center,
Study
#
SHG209/
841181,
April
30,
1985.
MRID
No.:
00152837
Positive.
Very
significant
increase
in
chromosome
aberrations
in
human
lymphocytes
in
vitro
at
all
selected
doses
60
to
140
µ
g/
mL
without
metabolic
activation.
At
100
µ
g/
mL
the
mutagenic
potency
is
approximately
7
fold
greater
than
the
positive
control
EMS
on
a
molar
basis.

Mouse
lymphoma
gene
mutation
Inveresk
Research
International
Study
#
3016,
December
1,
1984
MRID
No.:
00149921
Positive.
Produces
increased
mutation
frequency
in
mouse
lymphoma
L5178Y
cells
at
40
to
890
µ
gms/
mL
in
the
presence
of
activation
and
at
20
to
80
µ
/
mL
without
activation.

Micronucleus
assay
­
mouse
Huntingdon
Research
Center,
Study
#
TOX
90494,
January
29,
1991
MRID
No.:
42664405.
Not
clastogenic
at
doses
2.3,
4.6
or
9.2
mg/
kg.

Mammalian
spermatogonial
chromosome
aberration
test.
BioScience,
Study
No.:
AA35XW.
109BTL,
January
25,
2001.
MRID
No.:
45416201.
No
evidence
of
chromosome
aberrations
at
doses
up
to
and
including
10
mg/
kg
in
this
in
vivo
study.

HGPRT
study
in
Chinese
hamster
Haskell
Laboratory,
Study
#
HL­
676­
82,
January
1,
1982.
MRID
No.:
40883201.
Negative
at
concentrations
that
are
cytotoxic
(
50%
cell
survival)
with
and
without
metabolic
activation.

Other
Genotoxicity
Unscheduled
DHA
synthesis.
Huntingdon
Research
Lab,
Study
#
85061,
October
23,
1985.
MRID
No.:
40883201.
Negative
in
Hela
cells
at
concentrations
ranging
from
30
to
61,440
µ
g/
mL.

The
mouse
lymphoma
and
in
vitro
chromosome
aberration
study
in
humans
are
both
positive
while
several
other
studies
are
considered
negative.
Formetanate
Formetanate/
April/
2003
RED
Toxicology
Chapter
14
hydrochloride
is
classified
as
a
Group
"
E"
carcinogen
(
no
evidence
of
carcinogenicity)
and
these
positive
studies
were
considered.
A
more
recent
bacterial
mutagenicity
study
was
negative.
There
are
no
other
new
mutagenicity/
genetic
toxicity
data
to
follow
up
on
the
apparent
positive
response
in
the
mouse
lymphoma
and
human
chromosome
aberration
studies.

4.8
Neurotoxicity
Adequacy
of
data
base
for
Neurotoxicity:
The
neurotoxicity
testing
is
considered
complete.

870.6100
Delayed
Neurotoxicity
Study
­
Hen
Study
is
not
required
for
formetanate.

870.6200
Acute
Neurotoxicity
Screening
Battery
Acute
Neurotoxicity.
In
this
acute
neurotoxicity
screening
battery
(
2000,
MRID
No.:
45314201),
formetanate
hydrochloride
(
92.8%
a.
i.,
Lot/
Batch#
F0880708)
was
administered
by
gavage
to
Crl:
CD[
SD]
IGS
BR
(
Sprague
Dawley,
CD)
rats
in
the
main
study
(
10/
sex/
group)
and
cholinesterase
phase
(
5/
sex/
group)
at
doses
of
0,
0.1,
1,
or
10
mg/
kg
in
a
volume
of
5
mL
(
deionized
water)/
kg.
All
main
study
rats
were
subjected
to
FOB
and
motor
activity
measurements
at
the
time
of
peak
effect
(
day
1,
30­
60
minutes
post­
dosing)
and
on
days
8
and
15.
Cholinesterase
phase
animals
were
subjected
to
cholinesterase
analysis
at
the
time
of
peak
effect.
Five
main
study
animals/
sex/
dose
were
subjected
to
perfusion
and
neuropathological
examination
upon
study
termination.
Systemic,
FOB
and
Motor
Activity
Effects.
Treatment
related
effects
were
noted
at
10
mg/
kg
at
the
time
of
peak
effect
only.
These
are
described
as
follows.
During
the
homecage
observations,
increased
(
p 
0.001
or
0.01)
incidences
of
slight
to
moderate
tremors
(
15/
20
vs
0/
20
in
controls)
were
reported.
The
following
effects
were
noted
in
the
open
field
observations
(
p 
0.05,
0.01,
or
0.001)
(
i)
slight
to
moderate
ataxic
gait
(
13/
20);
(
ii)
slight
to
extreme
gait
incapacity
(
15/
20);
(
iii)
slight
to
moderate
tremors
(
16/
20);
(
iv)
very
slight
to
slight
locomotor
activity
level
(
15/
20);
and
(
v)
severely
to
moderately
decreased
arousal
(
17/
20).
Decreased
rearing
was
observed
in
the
males
(
0.9
treated
vs.
10.1
controls)
and
females
(
2.0
treated
vs.
17.2
controls).
The
following
handling
observations
were
noted
(
p 
0.05,
0.01,
or
0.001):
(
i)
pinpoint
pupils
(
11/
20);
(
ii)
none
to
slight
response
to
toe
pinch
(
15/
20);
and
(
iii)
visual
placing
after
vibrissae
touch
(
12/
20).
Slight
to
moderate
salivation
was
noted
in
the
males
(
8/
10
vs.
0/
10
controls).
None
to
slight
response
to
tail
pinch
was
noted
in
both
sexes
(
18/
20
vs.
3/
20
controls).
During
observations
made
on
surface,
increased
(
p 
0.05)
incidences
of
reduced
(
2/
10)
and
increased
(
3/
10)
auricular
startle
responses
were
noted
in
the
males
(
vs.
0/
10
controls).
Quantitatively,
body
temperature
was
decreased
(
p 
0.001;
males:
34.78
°
C
treated
vs.
37.82
°
C
controls;
females
34.79
°
C
treated
vs.
38.42
°
C
controls).
Decreased
( 
21%,
p 
0.001)
forelimb
grip
strength
was
observed
in
the
males.
Decreased
(
p 
0.001)
motor
activity
was
observed
at
the
time
of
peak
effect
in
both
sexes
( 
61­
64%).
There
were
no
neuropathological
effects
and
brain
dimensions
were
not
affected.
The
LOAEL
for
systemic
effects
is
10
mg/
kg
based
on
multiple
FOB
findings
and
decreased
motor
activity.
The
NOAEL
for
systemic
effects
is
1
mg/
kg.
Formetanate/
April/
2003
RED
Toxicology
Chapter
15
Cholinesterase
Effects.
At
1
and
10
mg/
kg
on
day
1
(
30
to
60
minutes
post­
dosing),
whole
blood
and
plasma
cholinesterases
were
decreased
(
p 
0.05
or
0.01)
in
the
males
( 
33­
46%
and
 
27­
58%,
respectively).
Whole
blood
and
plasma
cholinesterases
were
decreased
(
p 
0.05
or
0.01)
in
the
10
mg/
kg
females
( 
43
and
68%,
respectively).
Cerebral
cortex,
hippocampus,
and
cerebellum
cholinesterases
were
decreased
(
p 
0.05
or
0.01)
at
the
1
( 
34­
45%)
and
10
( 
65­
76%)
mg/
kg
dose
levels.
The
LOAEL
is
1
mg/
kg
for
whole
blood,
plasma
and
brain
cholinesterase.
The
NOAEL
is
0.1
mg/
kg/
day.
This
study
is
classified
as
acceptable/
guideline.
The
study
satisfies
the
guideline
requirement
for
a
series
870.6200
acute
neurotoxicity
screen
study.

870.6200
Subchronic
Neurotoxicity
Screening
Battery
Subchronic
Neurotoxicity.
In
this
subchronic
neurotoxicity
screening
battery
(
MRID
45314202),
formetanate
(
92.8%
a.
i.,
Lot/
Batch#
F0880708)
was
administered
via
the
diet
for
up
to
13
weeks
to
Crl:
CD[
SD]
IGS
BR
(
Sprague
Dawley,
CD)
rats
(
10/
sex/
dose
in
the
main
study
group
and
10
/
sex/
dose
in
the
cholinesterase
phase
group)
at
doses
of
0,
10,
50,
or
300
ppm
(
equivalent
to
[
M/
F]
0/
0,
0.6/
0.7,
3.0/
3.5,
and
18.4/
20.9
mg/
kg/
day).
All
main
study
animals
were
subjected
to
FOB
and
motor
activity
measurements
at
weeks
4,
8,
and
13.
Five
cholinesterase
phase
animals/
sex/
dose
were
subjected
to
cholinesterase
determination
prior
to
sacrifice
at
weeks
5
and
9.
Five
main
study
animals/
sex/
dose
were
subjected
to
cholinesterase
activity
determination,
perfusion,
and
neuropathological
examination
upon
study
termination.
Systemic
Effects.
No
animals
died
during
the
study.
Clinical
signs,
FOB
parameters,
motor
activity,
gross
pathology,
neuropathology,
and
brain
weights
were
unaffected
by
the
test
substance.
At
300
ppm,
body
weights
were
decreased
(
p 
0.01)
throughout
the
study
in
the
females
( 
10­
13%).
Overall
body
weight
gains
were
decreased
in
both
sexes
( 
15­
25%).

Decreased
(
p 
0.01
or
0.05)
food
consumption
was
noted
in
the
males
( 
9%)
and
females
( 
18%)

during
days
1­
8.
In
addition,
food
consumption
was
decreased
(
p 
0.01
or
0.05)
in
the
females
during
days
22­
29
( 
9%)
and
71­
92
( 
12%).
The
systemic
LOAEL
is
300
ppm
(
equivalent
to
18.4
mg/
kg
in
males
and
20.9
mg/
kg
in
females)
based
on
decreased
body
weights
and
body
weight
gains
in
both
sexes
and
decreased
food
consumption
in
the
females.
The
NOAEL
for
this
study
is
50
ppm
(
equivalent
to
3.0
mg/
kg
in
males
and
3.5
mg/
kg
in
females).
Cholinesterase
Effects.
No
effects
on
whole
blood,
plasma
and
brain
cholinesterase
were
noted
at
any
assay
interval
except
that
decreased
(
p 
0.05)
hippocampus
cholinesterase
was
noted
in
the
females
at
week
9
only
( 
19%).
Since
no
effect
was
noted
in
the
hippocampus
at
termination,
this
finding
is
not
considered
related
to
treatment.
The
whole
blood,
plasma,
and
brain
cholinesterase
LOAEL
was
not
observed.
The
whole
blood,
plasma,
and
brain
cholinesterase
NOAEL
was
300
ppm
(
equivalent
to
18.4
mg/
kg
in
males
and
20.9
mg/
kg
in
females).
This
study
is
classified
as
acceptable/
guideline
and
satisfies
the
requirement
for
a
subchronic
neurotoxicity
screen
study
(
82­
7a)
in
rats.

870.6300
Developmental
Neurotoxicity
Study
(
Comparative
Cholinesterase
Inhibition
only).

This
series
of
non­
guideline
studies
was
undertaken
to
evaluate
any
differences
between
neonatal
and
adult
rats
with
regard
to
acetylcholinesterase
(
AChE)
inhibition.
In
this
series
of
non
Formetanate/
April/
2003
RED
Toxicology
Chapter
16
guideline
cholinesterase
inhibition
studies
(
2005,
MRID
46618901),
formetanate
HCL
(
97.8%
a.
i.;
Lot
#:
930904)
in
deionized
water
was
administered
once
via
gavage
(
5
mL/
kg)
to
5
adult
and
5
PND
11
Sprague
Dawley
rats/
sex/
sacrifice
time
at
doses
of
0
or
5.0
mg/
kg
to
determine
the
time
of
peak
cholinesterase
inhibition.
Erythrocyte
and
brain
AChE
was
determined
at
0.25,
0.5,
1,
4,
8,
and
24
hours.
In
the
definitive
dose
response
studies,
formetanate
HCL
was
administered
once
via
gavage
to
10
adult
and
10
PND
11
rats/
sex/
dose
at
doses
of
0,
0.6,
1.5,
or
3.0
mg/
kg.
Erythrocyte
and
brain
AChE
was
determined
at
0.5
hours
post­
dosing
(
estimated
time
of
peakeffect
in
all
groups.
AChE
was
assessed
at
26
°
C
rather
than
at
37
°
C
to
minimize
reversal
of
inhibition
by
the
carbamate
inhibitor.
Clinical
signs.
There
were
no
treatment­
related
effects
on
mortality
or
clinical
signs.
RBC
ACHE.
RBC
AChE
inhibition
data
did
not
exhibit
informative
time
response
curves
in
pups
or
adults
in
that
the
apparent
inhibitory
effects
lacked
dose
responses.
The
apparent
peak
inhibition
(
p<=
0.05)
occurred
at
15
minutes
post­
dosing
in
the
male
pups
and
at
30
minutes
in
the
female
pups.
Recovery
occurred
between
8
and
24
hours
post­
dosing.
In
the
adults,
decreases
in
RBC
AChE
were
similar
to
those
in
the
pups.
Comparative
dose
response
studies
at
30
minutes
post
dosing
showed
decreased
(
p<=
0.01)
RBC
AChE
in
all
dose
groups
in
the
pups
of
both
sexes
(
decr.
21­
30%)
and
in
the
3
mg/
kg
adult
males
(
decr.
29%).
Overall,
the
RBC
AChE
data
were
of
limited
value
and
no
reliable
or
definite
indication
that
the
pups
were
more
sensitive
than
the
adults
was
established.
.
Brain
AChE.
Brain
AChE
in
pups
was
decreased
in
both
sexes
beginning
at
15
minutes
and
continuing
through
8
hours
post­
dosing,
with
recovery
evident
at
24
hours.
In
the
adults,
brain
AChE
was
decreased
in
both
sexes
beginning
at
15
minutes
and
continuing
through
4
hours
post­
dosing.
At
8
hours
post­
dose,
recovery
was
marginal
in
the
males
and
was
evident
in
the
females.
Comparative
dose
response
studies
conducted
at
30
minutes
post
dosing
revealed
dosedependently
decreased
(
p<=
0.05)
brain
cholinesterase
activity
at
all
doses
in
both
sexes
of
pups
(
decr.
34­
74%)
and
adults
(
decr.
16­
50%).
The
LOAEL
for
brain
AChE
inhibition
is
<
0.6
mg/
kg.
The
NOAEL
was
not
established.
Separate
benchmark
dose
analysis1
demonstrated
that
the
BMDL10
for
female
pup
brain
AChE
inhibition
was
0.065
mg/
kg.
The
BMD
analysis
of
the
brain
AChE
data
indicated
that
both
male
and
female
pups
had
lower
BMDs
than
the
adults
indicating
that
the
pups
were
more
sensitive
than
the
adults
to
the
inhibitory
effects
of
formetanate
HCl.
These
studies
are
classified
as
acceptable/
non­
guideline
and
although
the
data
with
RBC
AChE
was
of
limited
value,
the
data
with
brain
AChE
achieved
the
objectives
of
the
study.

4.9
Metabolism
Adequacy
of
data
base
for
metabolism:
The
data
base
for
metabolism
is
considered
to
1
Refer
to
memo
entitled
"
Benchmark
dose
analysis
of
cholinesterase
levels
from
the
oral
gavage
acute
relative
sensitivity
toxicity
study
with
formetanate
HCl
in
neonatal
and
adult
rats"
from
P.
Villanueva
and
A.
Lowit,
dated
December
15,
2005,
TXR
No.:
0053699).
Formetanate/
April/
2003
RED
Toxicology
Chapter
17
be
complete.
No
additional
studies
are
required
at
this
time.

870.7485
Metabolism
­
Rat
Executive
Summary.
In
this
series
of
studies
(
all
1993,
MRIDs
42684601,
42684602,
42684603
and
42684604
and
the
supplement
MRID
42909701)
the
disposition
of
(
14C)­
formetanate
was
investigated
in
the
Sprague­
Dawley
rat
at
single
and
repeated
(
14days)
low
dose
of
0.1
mg/
kg
and
a
higher
dose
of
10
mg/
kg.
Absorption
of
formetanate
was
rapid
at
all
dose
levels.
Greater
than
90%
of
the
dose
was
recovered
in
the
urine
within
24
hours
and
less
than
10%
was
recovered
in
the
feces.
Intravenous
dosing,
repeated
oral
dosing
or
a
high
dose
had
no
significant
effects
on
the
disposition
of
formetanate.
Terminal
disposition
of
radioactivity
demonstrated
the
highest
levels
in
liver,
gastro­
intestinal
tract,
adrenals,
fat,
residual
carcass
and
eyes.
In
most
cases
these
organs
had
levels
near
the
lower
limit
of
detection.
At
the
low
dose,
the
major
metabolites
were
identified
as
conjugates
of
3­
formanidophenol,
3­
acetamidophenol
and
3­
dimethylaminomethylene­
aminophenol.
At
the
high
dose,
there
appeared
to
be
alteration
in
the
metabolic
profile.
A
conjugate
of
3­
aminophenol
was
identified
as
a
major
metabolite,
This
series
of
studies
is
classified
as
ACCEPTABLE/
Guideline
and
satisfies
the
guideline
requirement
for
a
series
85­
1.
General
metabolism
study
in
rats.

4.10
Special/
Other
Studies
Certain
special
studies
to
assess
for
the
time
to
peak
effect
for
cholinesterase
inhibition
were
noted
above.

5.0
TOXICITY
ENDPOINT
SELECTION
5.1
See
Section
9.2
for
Endpoint
Selection
Table.

Dose­
response
modeling
is
preferred
over
the
use
of
NOAEL/
LOAELs
since
NOAELs
and
LOAELs
do
not
necessarily
reflect
the
relationship
between
dose
and
response
for
a
given
chemical,
but
instead
reflect
dose
selection
(
USEPA,
2000).
In
order
to
evaluate
the
appropriate
point
of
departure
(
PoD)
for
ChE
inhibition,
EPA
performed
a
benchmark
dose
(
BMD)
analysis
(
TXR
No.
0053699)
of
the
ChE
inhibition
data
from
the
comparative
ChE
study
(
2005,
MRID
No.:
46618901)
with
formetanate
in
the
rat
were
analyzed.

The
estimated
dose
at
which
10%
ChE
is
observed
(
BMD10)
and
the
lower
95%
confidence
intervals
(
BMDL10)
were
estimated
by
fitting
the
ChE
data
to
an
exponential
dose­
response
model
using
generalized
nonlinear
least
squares.
The
BMD10
was
selected
because
it
is
generally
at
or
near
the
limit
of
sensitivity
for
discerning
a
statistically
significant
decrease
in
ChE
activity
across
the
blood
and
brain
compartments
and
is
a
response
level
close
to
the
background
ChE.
The
exponential
model
was
used
in
the
Preliminary
OP
Cumulative
Risk
Assessment
(
USEPA,
2001)
to
determine
relative
potency
factors
and
points
of
departure.
The
exponential
model
and
statistical
methods
used
to
calculated
the
BMD10s
and
BMDL10s
have
been
supported
Formetanate/
April/
2003
RED
Toxicology
Chapter
18
by
the
FIFRA
Science
Advisory
Panel
(
FIFRA,
2002)
for
analysis
of
ChE
inhibition
data
similar
to
that
of
OPs
and
N­
methyl
carbamates,
including
formetanate.
Technical
description
of
the
statistical
methods
can
be
found
in
the
cumulative
hazard
assessment
of
the
Preliminary
OP
Cumulative
Risk
Assessment
(
USEPA,
2001).
Model
fits
and
model
parameters
specific
to
this
analysis
can
be
found
in
the
TXR
No.:
0053699
(
memo
from
P.
Villanueva
and
A.
Lowit
dated
December
15,
2005).
The
exponential
model
used
here
can
be
downloaded
by
the
public
at
http://
www.
epa.
gov/
pesticides/
cumulative/
EPA_
approach_
methods.
htm.

For
formetanate
endpoint
selection,
the
BMDL10
from
female
pup
brain
AChE
inhibition
data
from
the
comparative
ChE
study
was
selected
for
establishing
the
acute
oral
and
chronic
RfD
and
the
endpoints
for
short,
intermediate
and
long­
term
oral
and
inhalation
risk
assessments.
This
selection
is
justified
because
the
BMDL10
will
protect
against
toxicity
occurring
at
higher
doses
and
for
longer
exposures.
In
the
case
of
formetanate
hydrochloride
which
inhibits
brain
cholinesterase
at
all
dose
levels
tested
in
the
comparative
ChE
study,
long
term
daily
exposures
are
considered
as
multiple
daily
exposures
with
each
causing
transient
inhibition
of
cholinesterase
with
resulting
potential
toxicity.
Carbamate
inhibitors
of
cholinesterase
represent
a
special
case
because
of
their
short
acting
effects
on
cholinesterase
associated
with
the
reversible
nature
of
the
interaction
between
the
chemical
and
the
enzyme.
On
the
other
hand,
organophosphates
form
irreversibly
inhibited
enzyme
with
more
enzyme
being
inhibited
over
time
as
more
phosphorylated
enzyme
is
formed.
Thus,
the
LOAEL
for
subchronic
and
chronic
studies
with
organophosphates
is
usually
lower
than
the
acute
LOAEL.
Current
HED
policy
is
to
use
the
same
endpoint
for
all
oral
exposures
when
the
acute
BMDL10
is
lower
than
the
subchronic
or
chronic
value
regardless
of
gavage
or
dietary
administration
unless
there
is
a
reasonable
basis
not
to.
In
the
case
of
formetanate
hydrochloride,
the
quick
acting
and
reversible
nature
of
carbamate
inhibition
is
considered
by
HED
as
justification
for
using
data
from
the
comparative
CHE
study
following
a
single
acute
dose
for
chronic
RfD.

5.2
Dermal
Absorption
870.7600
Dermal
Absorption
­
Rat
There
is
no
dermal
absorption
study
available.
No
dermal
absorption
factor
was
assigned
for
formetanate
since
a
dermal
toxicity
study
will
be
used
for
dermal
occupational
and
residential
risk
assessments.

5.3
Classification
of
Carcinogenic
Potential
5.3.1
Conclusions
Formetanate/
April/
2003
RED
Toxicology
Chapter
19
5.3.2
Classification
of
Carcinogenic
Potential
Formetanate
hydrochloride
was
classified
as
a
Group
"
E"
carcinogen
as
per
the
June
27,
1989
meeting
of
the
Health
Effects
Division
Reference
Dose/
Peer
Review
Committee.
Since
no
new
data
have
been
submitted,
there
is
no
current
need
to
initiate
a
reclassification
for
formetanate
hydrochloride.

5.3.3
Quantification
of
Carcinogenic
Potential
N/
A
6.0
FQPA
CONSIDERATIONS
6.1
Special
Sensitivity
to
Infants
and
Children
A.
Determination
of
Susceptibility
The
HIARC
originally
concluded
that
there
was
no
quantitative
or
qualitative
increase
in
susceptibility
in
either
the
rat
and
rabbit
developmental
toxicity
studies.
In
the
rat
multigeneration
reproduction
study,
there
was
no
indication
of
a
quantitative
susceptibility.
However,
there
was
a
slight
decrease
in
the
viability
index
(
survival
index
Post
Natal
Day
1
to
21)
in
F2a
and
F2b
generations
noted
at
the
same
dose
as
maternal
toxicity.
In
particular,
the
F2a
generation
had
87,
78,
82
and
74%
survival
on
lactation
day
21
for
the
control,
10,
50
and
250
ppm
dose
groups
respectively.
Similarly,
the
F2b
generation
had
84,
73,
76
and
64%
survival
indicating
that
the
lowest
survival
was
in
the
high
dose
group
in
both
generations.

Since
the
HIARC
report
was
completed
(
May21,
2003),
the
registrant
has
submitted
the
comparative
cholinesterase
study
(
2005,
MRID
No.:
46618901)
and
based
on
benchmark
dose
analysis,
this
study
demonstrated
that
the
pups
were
more
sensitive
than
adults
to
the
inhibitory
effects
of
formetanate.

B.
Degree
of
Concern
Analysis
and
Residual
Uncertainties
.
Although
some
indication
of
an
apparent
qualitative
susceptibility
was
seen
in
the
twogeneration
reproduction
study,
the
concern
for
postnatal
toxicity
based
on
this
parameter
is
low
and
indicates
no
residual
uncertainties.
For
example,
the
apparent
decrease
in
viability
index
is
seen
only
in
the
F2
generations
and
not
in
the
F1
generation;
there
was
maternal
toxicity
at
the
same
dose;
decreased
viability
was
also
seen
in
the
control,
low,
and
mid
dose
groups
that
was
only
a
little
less
than
in
the
high
dose
(
i.
e.
the
magnitude
of
the
effect
in
the
high
dose
is
small).
However,
the
comparative
cholinesterase
study
demonstrated
increased
susceptibility
of
the
pups
relative
to
the
adults
for
cholinesterase
inhibition.
This
differential
in
the
inhibition
of
cholinesterase
is
regarded
as
a
moderate
concern.

C.
Hazard­
based
Special
FQPA
Safety
Factors
Formetanate/
April/
2003
RED
Toxicology
Chapter
20
The
HIARC
originally
determined
that
the
hazard­
based
special
FQPA
safety
factor
can
be
removed
(
reduced
to
1X)
because
of
a
lack
of
concern
and
no
residual
uncertainties
for
pre­
and
post­
natal
toxicity.
However,
based
on
moderate
concerns
for
increased
susceptibility
as
noted
in
the
comparative
cholinesterase
study,
a
FQPA
safety
factor
of
3
X
is
considered
appropriate
and
should
be
applied
when
the
endpoint
for
risk
assessment
is
based
on
data
from
a
study
with
adult
test
animals.

6.2
Recommendation
for
a
Developmental
Neurotoxicity
Study
The
HIARC
concluded
that
there
is
not
a
concern
for
developmental
neurotoxicity
per
se
resulting
from
exposure
to
formetanate
hydrochloride.
Therefore,
a
series
870.6300
developmental
neurotoxicity
study
is
not
required.

However,
formetanate
hydrochloride
is
a
carbamate
insecticide
belonging
to
a
family
of
chemicals
that
are
inhibitors
of
cholinesterase.
Formetanate
hydrochloride
has
been
demonstrated
to
be
an
inhibitor
of
cholinesterase
and
at
higher
doses
to
demonstrate
signs
of
toxicity
related
to
cholinesterase
inhibition.
Thus,
based
on
structure
activity
relationships
and
the
demonstration
of
toxicity
related
to
cholinesterase
inhibition
there
is
a
concern
for
additional
testing
and
evaluating
the
susceptibility
of
newborns
to
cholinesterase
inhibition.
Therefore,
a
special
non­
guideline
study
that
follows
the
dosing
protocol
used
for
the
developmental
neurotoxicity
study
but
that
assesses
for
differential
cholinesterase
inhibition
of
the
neonatal
rat
pups
relative
to
the
adults
should
provide
the
relevant
information,
and
is
required.
This
special
study
(
2005,
MRID
No.:
46618901)
comparing
the
potential
for
formetanate
to
inhibit
plasma,
RBC
and
brain
cholinesterase
in
11
day
old
pups
and
adults
has
been
submitted
and
reviewed.
The
Executive
Summary
is
above.

6.3
Database
Uncertainty
Factor.

Since
the
comparative
cholinesterase
study
was
submitted,
the
toxicity
data
base
is
considered
complete
as
far
as
endpoints
for
risk
assessment
are
concerned
and
no
database
uncertainty
factor
is
needed.

7.0
OTHER
ISSUES
There
are
no
other
toxicity
issues
for
formetanate.

8.0
REFERENCES
in
MRID
order
00077666
Schoenig,
G.
(
1967)
Report
to
Morton
Chemical
Company:
Acute
Toxicity
Studies
on
EP­
332
HCl,
Formetanate/
April/
2003
RED
Toxicology
Chapter
21
Technical:
IBT
No.
A5341.
(
Unpublished
study
received
Sep
11,
1969
under
9G0746;
prepared
by
Industrial
Bio­
Test
Laboratories,
Inc.,
submitted
by
Morton
Chemical
Co.,
Woodstock,
Ill.;
CDL:
091289­
B)

00077668
Hathaway,
D.
(
1967)
Report
to
Morton
Chemical
Company:
Acute
Dust
Inhalation
Toxicity
of
EP­
332
HCl,
Technical:
IBT
No.
N5342.
(
Unpublished
study
received
Sep
11,
1969
under
9G0746;
prepared
by
Industrial
Bio­
Test
Laboratories,
Inc.,
submitted
by
Morton
Chemical
Co.,
Woodstock,
Ill.;
CDL:
091289­
D)

00077728
Palazzolo,
R.
J.
(
1967)
Report
to
Morton
Chemical
Company:
Human
Repeated
Insult
Patch
Test
on
EP­
332
HCl:
IBT
No.
E5343.
(
Unpublished
study
received
Apr
15,
1970
under
0F0961;
prepared
by
Industrial
Bio­
Test
Laboratories,
Inc.,
submitted
by
Nor­
Am
Agricultural
Products,
Inc.,
Naperville,
Ill.;
CDL:
091642­
J)

00148267
Loving,
J.;
Fitzpatrick,
K.
(
1982)
CHO/
HGPRT
Assay
for
Gene
Mutation:
Report
No.
676­
82.
Unpublished
report
prepared
by
Haskell
Laboratory.
15
p.

00149921
Brown,
A.;
McGregor,
D.;
Riach,
C.
(
1984)
Technical
Formetanate
Hydrochloride:
Mouse
Lymphoma
Mutation
Assay:
Report
No.
3018:
IRI
Project
No.
732428.
Unpublished
study
prepared
by
Inveresk
Research
International.
44
p.

00151570
Willoughby,
C.
R.,
E.
P.
Lambert
and
D.
J.
Wood.
Technical
Formetanate
­
HCl:
Effects
of
Oral
Administration
(
Gavage)
Upon
Pregnancy
Outcome
in
the
Rat
(
Teratology
Study).
Life
Science
Research,
Study
No.:
LSR
81/
SCE004/
318.
July
8.
1985.

00151571
F.
W.
Ross,
T.
J.
Wightman
and
D.
J.
Ford.
Technical
Formetanate­
HCl:
Effects
of
Oral
Administration
(
Gavage)
Upon
Pregnancy
in
the
Rabbit
(
Teratology
Study).
Life
Science
Research,
Study
No.:
LSR
84/
SCE002/
319,
June
27,
1985.

00152837
Allen,
J.;
Brooker,
P.;
Birt,
D.;
et
al.
(
1985)
Technical
Formetanate
Hydrochloride:
Metaphase
Chromosome
Analysis
of
Human
Lymphocytes
Cultured
in
vitro:
HRC
Report
No.
SHG
209/
841181.
Unpublished
FBC
Ltd.
Study
No.
Tox
84071
prepared
by
Huntingdon
Research
Centre
plc.
21
p.

00164341
F.
W.
Ross,
T.
J.
Wightman
and
D.
J.
Ford.
Technical
Formetanate­
HCl:
Effects
of
Oral
Administration
(
Gavage)
Upon
Pregnancy
in
the
Rabbit
(
Teratology
Study).
Life
Science
Research,
Study
No.:
LSR
84/
SCE002/
319,
June
27,
1985.

00164343
164343
Mallyon,
B.;
Dunn,
L.
(
1986)
Technical
Formetanate
Hydrochloride:
Combined
Chronic
Toxicity
and
Carcinogenicity
Study
in
the
Rat
(
Interim
Report
­
64
Weeks):
Proj.
ID
No.
TOX/
86/
197­
58.
86
p.

40151701
Willoughby,
C.;
Lambert,
E.;
Wilby,
O.
(
1987)
Technical
Formetanate­
HCL:
Effects
of
Oral
Administration
(
Gavage)
Upon
the
Pregnancy
in
the
Rat
(
Teratology
Study):
T70­
Supplement
To:
Supplementary
Report:
Re­
evaluation
of
Ossification
of
the
Hyoid
Bone:
Laboratory
Project
ID
No:
Sponsors
Study
No.
TOX
84092.
Unpublished.
Formetanate/
April/
2003
RED
Toxicology
Chapter
22
40411801
J.
M
Tesh,
E.
Lambert
and
J.
S.
L.
Fowler.
T83
technical
formetanate
hydrochloride:
The
reproductive
performance
of
rats
treated
continuously
through
two
successive
generations.
Life
Science
Research
Ltd.
,
Study
#
86/
SCE
0074777,
September
28,
1987.

40411802
Refer
to
40411801
40411803
Refer
to
40411801.

40640901
B.
A.
Mallyon.
T87
Formetanate:
Technical
formetanate
hydrochloride:
An
Evaluation
of
Dietary
Oncogenic
and
Chronic
Toxicity
Potential
in
the
Rat.
Schering
Agrochemicals,
Ltd,
Study
No.:
TOX
84083,
May
13,
1988.

40707101
Mallyon,
B.
A.
"
T85
Technical
formetanate
hydrochloride:
An
evaluation
of
dietary
potential
in
the
mouse."
Schering
Agrochemicals,
Ltd.
Study
No.:
TOX/
87/
197­
64,
June
24,
1988.

40883201
Allen,
J.;
Proudlock,
R.
(
1985)
T73
Technical
Formetanate
Hydrochloride:
Unscheduled
DNA
Repair
in
Cultured
Mammalian
Cells:
Laboratory
Project
ID:
TOX/
85/
197­
6.
Unpublished
study
prepared
by
Huntingdon
Research
Centre.
21
p.

40151701
Willoughby,
C.;
Lambert,
E.;
Wilby,
O.
(
1987)
Technical
Formetanate­
HCL:
Effects
of
Oral
Administration
(
Gavage)
Upon
the
Pregnancy
in
the
Rat
(
Teratology
Study):
T70­
Supplement
To:
Supplementary
Report:
Re­
evaluation
of
Ossification
of
the
Hyoid
Bone:
Laboratory
Project
ID
No:
Sponsors
Study
No.
TOX
84092.
Unpublished.

42664401
S..
Wason
and
M.
Crofts.
T97
Formetanate:
Technical
formetanate
hydrochloride:
Investigational
study
into
the
effects
on
acetylcholinesterase
in
the
rat
following
treatment
for
3
months.
Schering
Agrochemicals,
Ltd,
Study
No.:
TOX/
91/
197­
71;
RESID/
91/
102,
April
15,
1992.

41208501
Daamen,
P.
(
1989)
T92
Formtanate
HCL:
Assessment
of
Primary
Eye
Irritation/
Corrosion
by
Formetanate
x
HCL
Techn.
(
Carzon
SP)
in
the
Rabbit:
Project
ID:
TB
88
019.
Unpublished
study
prepared
by
Schering
AG.
17
p.

42089802
Daaman,
P.
(
1991)
Assessment
of
the
Skin
Sensitization
Potential
of
Formetanate
HCL
Techn.
(
Carzol
SP)
in
the
Guinea
Pig
(
Buehler
Test):
Lab
Project
Number:
1124/
1452:
88020.
Unpublished
study
prepared
by
RCC
Notox
B.
V.
16
p.

42664402.
S.
Wason
and
M.
Crofts.
T97A
Formetanate:
Determination
of
formetanate
hydrochloride
dietary
concentrations
for
a
90­
day
study
in
the
rat.
Schering
Agrochemicals,
Ltd,
Study
No.:
TOX/
91/
197­
71;
RESID/
91/
102,
May
13,
1992.

42664405
Proudlock,
R.;
et
al.
(
1991)
Mouse
Micronucleus
Test:
T95­­
Technical
Formetanate
Hydrochloride:
Lab
Project
Number:
020905:
TOX
90494.
Unpublished
study
prepared
by
Huntingdon
Research
Centre,
Ltd.
31
p.

42684601
O'Boyle,
F.
(
1993)
M­
18:
The
Distribution
and
Excretion
of
Radiolabelled
Residues
in
the
Rat
Following
Oral
Dosing
with
(
carbon
14)­
Formetanate
Hydrochloride
at
10
mg/
kg
Body
Weight:
Formetanate/
April/
2003
RED
Toxicology
Chapter
23
Lab
Project
Number:
TOX/
92/
197­
75:
TOX
91043A:
M­
18.
Unpublished
study
prepared
by
Schering
Agrochemicals
Ltd.
16
p.

42684602
Elson,
L.
(
1993)
M­
17:
The
Metabolism
of
Formetanate
HC1
in
the
Rat:
Lab
Project
Number:
SMS
437A/
921189:
TOX
91043:
TOX/
92/
197­
78.
Unpublished
study
prepared
by
Huntingdon
Research
Center,
Ltd.
65
p.

42684603
O'Boyle,
F.
(
1993)
M­
24:
The
Metabolism
of
Formetanate
Hydrochloride
in
the
Rat
Following
Oral
Dosing
at
10
mg/
kg
Body
Weight:
Lab
Project
Number:
TOX/
93/
197­
79:
TOX/
91330:
M­
24.
npublished
study
prepared
by
Schering
Agrochemicals
Ltd.
60
42684604
Girkin,
R.
(
1993)
M­
25:
The
Metabolism
of
Formetanate
Hydrochloride
in
the
Rat
Following
Dosing
with
(
carbon
14)­
Formetanate
Hydrochloride
at
0.1
mg/
kg
Body
Weight:
Lab
Project
Number:
SMS
437B/
930480:
TOX
91043:
M­
25.
Unpublished
study
prepared
by
Huntingdon
Research
Center,
Ltd.
49
p.

42909701
O'Boyle,
F.;
Elson,
L.;
Girkin,
R.
(
1993)
Supplement
1:
Metabolism
of
Formetanate
Hydrochloride
in
the
Rat:
Lab
Project
Number:
M­
18:
M­
17:
M­
24.
Unpublished
study
prepared
by
NOR­
AM
Chemical
Co.
34
p.

44948501
McAlinden,
D.
(
1999)
Rat
21­
Day
Dermal
Toxicity
Study
Formetanate
Hydrochloride:
Lab
Project
Number:
TOX
98178:
C004820:
TOX/
99/
197­
87.
Unpublished
study
prepared
by
Quintiles
England
Ltd.
384
p.

45311901
deSilva,
S.
D.
and
C.
McAlinden
"
Rat
Dermal
Time
to
Peak
Effect
Study
for
Acetyl
Cholinesterase
Inhibition
Formetanate
Hydrochloride".
Sequani
Limited,
UK,
Study
No.:
AGR0002,
October
10,
2000.
MRID
No.:
45311901.

45314201
Beyrouty,
P.
(
2000)
Rat
Acute
Oral
Neurotoxicity
Study:
Formetanate
Hydrochloride:
Lab
Project
Number:
97553:
TOX20009.
Unpublished
study
prepared
by
ClinTrials
BioResearch
Ltd.
519
p.

45314202
Beyrouty,
P.
(
2000)
Rat
13­
Week
Dietary
Neurotoxicity
Study:
Formetanate
Hydrochloride:
Lab
Project
Number:
97554:
TOX20010.
Unpublished
study
prepared
by
ClinTrials
BioResearch
Ltd.
526
p.

45314203
Mecchi,
M.
(
2001)
Salmonella­
Escherichia
coli/
Mammalian­
Microsome
Reverse
Mutation
Assay
with
a
Confirmatory
Assay
with
Formetanate­
HCl,
Technical
Grade:
Lab
Project
Number:
21810­
0­
409OECD.
Unpublished
study
prepared
by
Covance
Laboratories
Inc.
27
p.

45416201.
Gudi,
R.
and
Krsmanovic,
L.
(
2001)
Mammalian
spermatogonial
chromosome
aberration
test.
BioReliance,
9630
Medical
Center
Drive,
Rockville,
Maryland
20850.
Laboratory
Study
No.
AA35XW.
109.
BTL,
January
25,
2001.

46618901.
Barnett,
JF
(
2005)
Oral
(
Gavage)
Acute
Relative
Sensitivity
Study
of
Formetanate
HCL
in
Neonatal
and
Adult
Rats.
Charles
River
Laboratories,
Horsham
Pa.,
Study
No.:
WJ100007,
August
4,
2005.
MRID
No.:
46618901.
648
pages.
Formetanate/
April/
2003
RED
Toxicology
Chapter
24
Formetanate/
April/
2003
RED
Toxicology
Chapter
25
9.0APPENDICES
Tables
for
Use
in
Risk
Assessment
Formetanate/
April/
2003
RED
Toxicology
Chapter
26
9.1
Toxicity
Profile
Summary
Tables
9.1.1
Acute
Toxicity
Table
­
See
Section
4.1
9.1.2
Subchronic,
Chronic
and
Other
Toxicity
Tables
Guideline
No./
Study
Type
MRID
No.
(
year)/
Classification
/
Doses
Results
870.3100
90­
Day
oral
toxicity
rodents
42664401
(
1992).
Unacceptable/
Non­
Guideline.
0,
0.07,
0.69,
1.43
or
3.48
mg/
kg/
day
(
males
only).
NOAEL
and
LOAEL
not
established.
Refer
to
subchronic
neurotoxicity
study
below.

870.3150
90­
Day
oral
toxicity
in
nonrodents
There
is
an
acceptable
chronic
feeding
study
that
supercedes
the
requirement
for
this
study.

870.3200
21/
28­
Day
dermal
toxicity
44948501
(
2000)
Acceptable/
Non­
Guideline.
0,
10,
20
or
500
mg/
kg
(
single
dose).

44948501
(
1999)
0,
10,
15
or
20
mg/
kg/
day.
NOAEL
=
10
mg/
kg/
day
LOAEL
=
20
mg/
kg/
day
based
on
consistent
decrease
in
whole
blood
cholinesterase
in
males
of
12­
18%.

No
NOAEL
and
LOAEL
assigned
for
this
study.

870.3250
90­
Day
dermal
toxicity
No
study
available
and
not
required.

870.3465
90­
Day
inhalation
toxicity
No
study
available
and
a
study
is
being
required.

870.3700a
Prenatal
developmental
in
00151570
(
1985).
Acceptable/
Guideline.
0,
1,
3,
or
5
mg/
kg/
day
Maternal
NOAEL
=
1
mg/
kg/
day
LOAEL
=
3
mg/
kg/
day
based
mainly
on
body
weight
decreases.
Formetanate/
April/
2003
RED
Toxicology
Chapter
27
Guideline
No./
Study
Type
MRID
No.
(
year)/
Classification
/
Doses
Results
rats
Developmental
NOAEL
>
5
mg/
kg/
day
(
no
effects
noted
a
the
HDT).

870.3700b
Prenatal
developmental
in
nonrodents
00151571
(
1985).
Acceptable/
Non­
Guideline.
0,
5,
15
or
30
mg/
kg/
day.
Maternal
NOAEL
=
5
mg/
kg/
day
LOAEL
=
15
mg/
kg/
day
based
on
body
weight
decrease
and
ataxia.
Developmental
NOAEL
>
30
mg/
kg/
day
(
no
effects
noted
a
the
HDT).

870.3800
Reproduction
and
fertility
effects
40411801,
­
02
and
­
03
(
1987).
Acceptable/
Guideline.
0,
0.9,
4.5
or
22.75
mg/
kg/
day.
Parental/
Systemic
NOAEL
=
4.5
mg/
kg/
day
LOAEL
=
22.75
mg/
kg/
day
based
on
decreases
in
body
weight
and
apparent
inhibition
of
whole
blood
cholinesterase.
Reproductive
NOAEL
>
22.75
mg/
kg/
day.
Offspring
NOAEL
=
4.5
mg/
kg/
day
LOAEL
=
22.75
mg/
kg/
day
based
on
decreased
pup
weight
and
viability
index.

870.4100a
Chronic
toxicity
rodents
See
combined
chronic
toxicity
and
carcinogenicity
study
below.

870.4100b
Chronic
toxicity
dogs
00164341
(
1986).
Acceptable/
Guideline.
0,
0.37­
both
sexes,
1.74_/
1.78_,
or
8.45_/
9.20_
mg/
kg/
day.
Systemic
toxicity:
NOAEL
=
0.37
mg/
kg/
day.
LOAEL
=
1.74
mg/
kg/
day
based
on
clinical
signs.
Cholinesterase
inhibition:
NOAEL
=
0.37
mg/
kg/
day.
LOAEL
=
1.74
mg/
kg/
day
based
on
plasma
and
whole
blood
inhibition.
LOAEL
=
8.45
mg/
kg/
day.

870.4200
Carcinogenicity
rats
40640901
(
1988).
Acceptable/
Guideline.
0,
0.45_/
0.58_,
2.3_/
2.9_
or
12_
/
15_
mg/
kg/
day.
Systemic
toxicity:
NOAEL
=
2.3
mg/
kg/
day
LOAEL
=
12
mg/
kg/
day
based
on
decreased
body
weight.
Cholinesterase
inhibition.
No
assignment
of
the
NOAEL
and
LOAEL
since
this
will
be
based
on
the
weight­
of­
evidence
from
all
studies
with
rats.

No
evidence
of
carcinogenicity.
Formetanate/
April/
2003
RED
Toxicology
Chapter
28
Guideline
No./
Study
Type
MRID
No.
(
year)/
Classification
/
Doses
Results
870.4300
Carcinogenicity
mice
40707101
(
1988).
Acceptable/
Guideline.
0,
1.4_/
1.9_,
7_/
9.3_
or
70_/
98_
mg/
kg/
day.
Systemic
effects:
NOAEL
=
7
mg/
kg/
day
LOAEL
=
70
mg/
kg/
day
based
on
decreased
body
weight.
No
evidence
of
carcinogenicity
870.6200a
Acute
neurotoxicity
screening
battery
45314201
(
2000)
Acceptable/
Guideline.
0,
0.1,
1
or
10
mg/
kg/
day.
Systemic
effects:
NOAEL
=
10
mg/
kg/
day
LOAEL
=
1
mg/
kg/
day
based
on
multiple
FOB
findings
and
decreased
motor
activity.
Cholinesterase
inhibition:
NOAEL
=
0.1
mg/
kg/
day
LOAEL
=
1
mg/
kg/
day
based
on
whole
blood,
plasma
and
brain
cholinesterase
inhibition.

870.6200b
Subchronic
neurotoxicity
screening
battery
45314202
(
2002)
Acceptable/
Guideline.
0,
0.6_/
0.7_,
3.0_/
3.5_
or
18.4_/
20.9_
mg/
kg/
day.
Systemic:
NOAEL
=
3
mg/
kg/
day
LOAEL
=
18.4
mg/
kg/
day
based
on
decreased
body
weight
gains
and
food
consumption.
Cholinesterase
inhibition:
NOAEL
>
18.4
mg/
kg/
day
in
males
and
20.9
mg/
kg/
day
in
females.

Special
Non­
Guideline
comparative
ChE
inhibition
study.
46618901
(
2005)
Acceptable/
Nonguideline
0,
0.6,
1.5
or
3
mg/
kg
for
definitive
study.
Systemic
NOAEL
>
3
mg/
kg.
Cholinesterase:
RBC
AChE:
poor
dose
responses
­
possible
inhibition
at
all
doses.
Brain
AChE:
Inhibition
at
all
doses
in
pups
and
adults.
LOAEL
=
0.6
mg/
kg.
NOAEL
­
not
established.
A
BMD
analysis
was
conducted
(
TXR
#
0053699,
memo
from
P.
Villanueva
and
A.
Lowit,
December
15,
2005)
and
the
BMDL10
of
0.065
mg/
kg
based
on
female
pup
brain
AChE
inhibition
data
was
established.

870.7485
Metabolism
and
pharmacokinetics
42684601,
42684602,
42684603,
42684604
and
42909701
The
absorption,
excretion,
distribution
and
characterization
of
the
metabolites
has
been
described.

870.7600
Dermal
No
study
available.
Formetanate/
April/
2003
RED
Toxicology
Chapter
29
Guideline
No./
Study
Type
MRID
No.
(
year)/
Classification
/
Doses
Results
penetration
Special
studies
No
special
studies
required
for
registration.
Formetanate/
April/
2003
RED
Toxicology
Chapter
30
Section
9.1.3
Toxicology
Endpoint
Selection
Table.

[
Revised
and
updated
from
the
original
Table
as
presented
in
the
May
21.
2003
HIARC
report
to
include
endpoints
selected
from
the
comparative
cholinesterase
study.]

Exposure
Scenario
Dose
UF
/
MOE
Hazard
Based
Special
FQPA
Safety
Factor
Endpoint
for
Risk
Assessment
Dietary
Risk
Assessments
Acute
Dietary
females
13­
50
years
of
age
Not
applicable;
the
endpoint
selected
for
the
general
population
(
see
below)
will
include
this
population
subgroup.

Acute
Dietary
general
population
BMDL
1
10
=
0.065
mg/
kg
UF
=
100
(
a)

aRfD
=
0.00065
mg/
kg
1
X
Acute
PAD
=
0.00065
mg/
kg.
BMDL10
for
female
pup
brain
AChE
in
the
Comparative
ChE
study.
No
FQPA
SF
is
needed
because
pup
data
are
used.

Chronic
Dietary
BMDL
1
10
=
0.065
mg/
kg
UF
=
100
(
a)

cRFD
=
0.00065
mg/
kg
1
X
Chronic
PAD
=
0.00065
mg/
kg.
BMDL10
for
female
pup
brain
AChE
in
the
Comparative
ChE
study.
No
FQPA
SF
is
needed
because
pup
data
are
used.

Incidental
Oral
Short
and
intermediate
terms
Not
applicable.
There
are
no
current
registrations
for
residential
uses.

Non­
Dietary
Risk
Assessments
(
b)

Dermal
­
Occupational
Short­
Term
(
1
­
30
days)
Dermal
NOAEL=
10
mg/
kg
MOE
=
100
(
a)
1
X
Special
single
dose
time
to
peak
effect
dermal
application
study
(
2000,
MRID
#
45311901).

LOAEL
=
20
mg/
kg
based
on
whole
Formetanate/
April/
2003
RED
Toxicology
Chapter
31
Exposure
Scenario
Dose
UF
/
MOE
Hazard
Based
Special
FQPA
Safety
Factor
Endpoint
for
Risk
Assessment
blood
cholinesterase
inhibition.

Dermal
­
Occupational
Intermediate­
Term
(
1
­
6
Months)
Dermal
NOAEL=
10
mg/
kg
MOE
­
100
(
a)
1
X
Special
single
dose
time
to
peak
effect
dermal
application
study
(
2000,
MRID
#
45311901).

LOAEL
=
20
mg/
kg
based
on
whole
blood
cholinesterase
inhibition.

Dermal
­
occupational
Long­
Term
(>
6
Months)
Dermal
NOAEL=
10
mg/
kg
MOE
=
100
(
a)
1
X
Special
single
dose
time
to
peak
effect
dermal
application
study
(
2000,
MRID
#
45311901).

LOAEL
=
20
mg/
kg
based
on
whole
blood
cholinesterase
inhibition.

Inhalation
(
c)
­
occupational
Short­
Term
(
1
­
30
days)
Oral
NOAEL
=
0.1
mg/
kg
MOE
=
100
(
a)
1
X
Acute
Neurotoxicity
Screen
(
2000,
MRID
#
45314201)

LOAEL
=
1
mg/
kg
based
on
plasma,
whole
blood
and
brain
cholinesterase
inhibition.

Inhalation
(
c)­
occupational
Intermediate­
Term
(
1
­
6
Months)
Oral
NOAEL
=
0.1
mg/
kg
MOE
=
100(
a)
1
X
Acute
Neurotoxicity
Screen
(
2000,
MRID
#
45314201)

LOAEL
=
1
mg/
kg
based
on
plasma,
whole
blood
and
brain
cholinesterase
inhibition.

Inhalation
(
c)
­
occupational
Long­
Term
(>
6
Months)
Oral
NOAEL
=
0.1
mg/
kg
MOE
=
100(
a)
1
X
Acute
Neurotoxicity
Screen
(
2000,
MRID
#
45314201)

LOAEL
=
1
mg/
kg
based
on
plasma,
whole
blood
and
brain
cholinesterase
inhibition.

Cancer
Classification:
"
Not
likely".
Q1*
=
N/
A
(
a)
Based
on
10X
for
interspecies
extrapolation
and
10X
for
intraspecies
variability
(
b)
There
are
no
registered
residential
uses
of
formetanate
HCl.
Endpoints
were
selected
for
occupational
exposure
only.
(
c)
Absorption
via
the
inhalation
route
is
presumed
to
be
equivalent
to
oral
absorption.
Formetanate/
April/
2003
RED
Toxicology
Chapter
32