Document ID: EPA-HQ-OPP-2004-0411-0008
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2004-12-21T05:00Z

OFFICE
OF
PREVENTION,
PESTICIDES,
AND
TOXIC
SUBSTANCES
UNITED
STATES
ENVIRONMENTAL
PROTECTION
AGENCY
WASHINGTON,
D.
C.
20460
TXR
No.:
0052862
MEMORANDUM
DATE:
September
17,
2004
SUBJECT:
AMETRYN:
Report
of
the
Cancer
Assessment
Review
Committee
PC
Code:
080801
FROM:
Jessica
Kidwell,
Executive
Secretary
Cancer
Assessment
Review
Committee
Health
Effects
Division
(
7509C)

TO:
John
Doherty,
Toxicologist
(
RRB3)
William
Donovan,
Risk
Assessor
(
RRB3)
Health
Effects
Division
(
7509C)

Mark
Howard,
CRM
Reregistration
Branch
3
Special
Review
and
Reregistration
Division
(
7508C)

The
Cancer
Assessment
Review
Committee
met
on
July
21,
2004
to
evaluate
the
carcinogenic
potential
of
Ametryn.
Attached
please
find
the
Final
Cancer
Assessment
Document.

cc:
J.
Pletcher
Y.
Woo
CANCER
ASSESSMENT
DOCUMENT
EVALUATION
OF
THE
CARCINOGENIC
POTENTIAL
OF
AMETRYN
PC
Code
080801
FINAL
REPORT
September
17,
2004
CANCER
ASSESSMENT
REVIEW
COMMITTEE
HEALTH
EFFECTS
DIVISION
OFFICE
OF
PESTICIDE
PROGRAMS
AMETRYN
CANCER
ASSESSMENT
DOCUMENT
FINAL
iii
DATA
PRESENTATION:
John
Doherty,
Toxicologist
DOCUMENT
PREPARATION:
Jessica
Kidwell,
Executive
Secretary
COMMITTEE
MEMBERS
IN
ATTENDANCE:
(
Signature
indicates
concurrence
with
the
assessment
unless
otherwise
stated).

Karl
Baetcke
Lori
Brunsman,
Statistician
William
Burnam,
Chair
Marion
Copley
Vicki
Dellarco
Abdallah
Khasawinah
Nancy
McCarroll
Esther
Rinde
Jess
Rowland
Linda
Taylor
NON­
COMMITTEE
MEMBERS
IN
ATTENDANCE:
(
Signature
indicates
concurrence
with
the
pathology
report
and
statistical
analysis
of
data,
respectively)
AMETRYN
CANCER
ASSESSMENT
DOCUMENT
FINAL
iv
John
Pletcher,
Consulting
Pathologist
OTHER
ATTENDEES:
Karlyn
Bailey
(
HED/
RAB2),
Kelly
Schumacher
(
HED/
RAB2),
Gerome
Burke
(
HED/
RAB3),
Zaida
Tigueroa
(
HED/
RAB2),
Bridgett
Bobowiec
(
HED/
SIMB),
Kimberly
Kosick
(
HED/
RAB2)

TABLE
OF
CONTENTS
EXECUTIVE
SUMMARY
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1
I.
INTRODUCTION
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3
II.
BACKGROUND
INFORMATION
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3
III.
EVALUATION
OF
CARCINOGENICITY
STUDIES
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3
1.
Combined
Chronic
Toxicity/
Carcinogenicity
Study
with
Ametryn
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3
2.
Carcinogenicity
Study
in
Mice
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15
IV.
TOXICOLOGY
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16
1.
Metabolism
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16
2.
Mutagenicity
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16
3.
Structure­
Activity
Relationship
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16
4.
Subchronic
and
Chronic
Toxicity
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17
5.
Mode
of
Action
Studies
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19
V.
COMMITTEE'S
ASSESSMENT
OF
THE
WEIGHT­
OF­
THE­
EVIDENCE
.
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.
.
20
1.
Carcinogenicity
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20
2.
Mutagenicity
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20
3.
Structure
Activity
Relationship
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20
4.
Mode
of
Action
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20
VI.
CLASSIFICATION
OF
CARCINOGENIC
POTENTIAL
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21
VII.
QUANTIFICATION
OF
CARCINOGENIC
POTENTIAL
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21
VIII
BIBLIOGRAPHY
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21
AMETRYN
CANCER
ASSESSMENT
DOCUMENT
FINAL
v
AMETRYN
CANCER
ASSESSMENT
DOCUMENT
FINAL
1
EXECUTIVE
SUMMARY
On
July
21,
2004,
the
Cancer
Assessment
Review
Committee
of
the
Health
Effects
Division
of
the
Office
of
Pesticide
Programs
met
to
evaluate
the
carcinogenic
potential
of
Ametryn.

John
Doherty
of
Reregistration
Branch
3
presented
the
chronic
toxicity/
carcinogenicity
studies
in
Sprague­
Dawley
rats
and
HAM/
ICE
Swiss
mice.
In
the
rat
carcinogenicity
study,
ametryn
was
administered
in
the
diet
to
groups
of
Sprague­
Dawley
rats
(
70/
sex/
dose)
at
dose
levels
of
0,
50,
500,
or
5000/
4000/
2000
ppm
(
0,
2,
20.9,
145.3
mg/
kg/
day
for
males;
0,
2.5,
26.2,
176.1
mg/
kg/
day
for
females)
for
104
weeks.
The
high
dose
group
rats
received
5000­
ppm
that
was
reduced
to
4000
ppm
after
141
days
and
further
reduced
to
2000
ppm
after
239
days
because
of
reductions
in
weight
gain.
In
the
mouse
study,
ametryn
was
administered
in
the
diet
to
groups
of
HAM/
ICE
Swiss
mice
(
60/
sex/
dose)
at
dose
levels
of
0,
10,
1000
or
2000
ppm
ametryn
for
a
period
of
102
weeks.
These
doses
corresponded
to
approximately
0,
1.5,
150
and
300
mg/
kg/
day.

The
CARC
concluded
the
following:

Rat

The
CARC
considered
dosing
at
the
high
dose
in
male
and
female
rats
to
be
excessive
and
not
adequate
for
the
assessment
of
carcinogenicity.
The
tumor
findings
at
the
high
dose
cannot
be
interpreted
because
the
animals
were
compromised
due
to
large
decreases
in
body
weight/
body
weight
gain
during
the
first
8
months
of
the
study.
Consequently,
although
statistical
analyses
were
performed,
the
tumor
data
in
rats
were
not
discussed
at
this
meeting.
In
addition,
the
500
ppm
dose
group
was
not
considered
adequate
for
assessment
of
carcinogenicity
since
this
was
the
NOAEL
for
the
study,
no
tumors
were
seen
at
this
dose,
and
the
dose
spread
(
500
ppm

5000
(
10­
fold)/
4000
(
8­
fold)/
2000
ppm
(
4­
fold)
was
considered
to
be
too
large.

The
high­
dose
males
weighed
29­
38%
less
than
controls
when
fed
5000
ppm
from
day
1­
140,
except
for
day
21
when
they
weighed
48%
less
than
controls.
They
weighed
23­
28%
less
than
controls
when
fed
the
4000­
ppm
diet
from
day
140­
239
and
the
2000­
ppm
diet
for
the
remainder
of
the
first
year
(
day
239­
364),
and
18­
23%
less
than
controls
during
the
second
year
of
the
study.
The
males
gained
38%
less
weight
than
controls
when
fed
the
5000­
ppm
diet,
20%
less
when
fed
the
4000
ppm
diet,
and
29%
more
than
controls
when
fed
the
2000
ppm
diet
for
the
remainder
of
the
first
year.
Although
high­
dose
males
gained
two
times
more
weight
than
controls
during
the
second
year,
the
resulting
overall
weight
gain
was
22%
below
that
of
controls.

High­
dose
females
weighed
20­
26%
less
than
controls
when
fed
the
5000
ppm
diet,
24­
AMETRYN
CANCER
ASSESSMENT
DOCUMENT
FINAL
2
34%
less
than
controls
when
fed
the
4000
ppm
diet
and
the
2000­
ppm
diet
for
the
remainder
of
the
first
year,
and
25­
28%
less
than
controls
during
the
second
year
of
the
study.
High­
dose
females
gained
40%
less
weight
than
controls
when
fed
the
5000­
ppm
diet,
57%
less
when
fed
the
4000­
ppm
diet,
and
15%
more
weight
than
controls
when
fed
the
2000­
ppm
diet
for
the
remainder
of
the
first
year
of
the
study.
High­
dose
females
gained
51%
less
weight
than
controls
during
the
second
year,
resulting
in
an
overall
weight
gain
37%
less
than
that
of
controls.

Mouse

No
treatment­
related
tumors
were
seen
in
male
or
female
mice.

The
CARC
concluded
that
dosing
at
the
high
dose
in
both
male
and
female
mice
was
adequate
and
not
excessive.
Although
the
high
dose
of
2000
ppm
(
300
mg/
kg/
day)
in
the
definitive
mouse
study
did
not
result
in
systemic
toxicity,
the
mouse
28­
day
range
finding
study
demonstrated
body
weight
gain
decreases
at
1000
(

12%
in
males
and

17%
in
females)
and
3000
(

24%
in
males
and

46%
in
females)
ppm
which
justified
selection
of
2000
ppm
as
the
high
dose
for
the
definitive
cancer
study
with
mice.

There
is
no
mutagenicity
concern
with
ametryn.

Atrazine
is
a
triazine
herbicide.
The
chlorotriazine
pesticides
have
been
shown
to
increase
mammary
gland
tumors
in
female
rats.
Because
ametryn
is
not
a
chlorotriazine,
SAR
does
not
provide
support
for
carcinogenic
potential.

No
specific
mode
of
action
studies
were
submitted
with
ametryn.

In
accordance
with
the
EPA
Draft
Guidelines
for
Carcinogen
Risk
Assessment
(
July,
1999),
the
Committee
classified
ametryn
into
the
category
"
Data
Are
Inadequate
for
An
Assessment
of
Human
Carcinogenic
Potential".
The
carcinogenicity
study
in
the
rats
is
unacceptable
because
the
high
dose
was
considered
to
be
excessive
in
both
sexes.
The
animals
in
the
high
dose
group
were
compromised
due
to
large
decreases
in
body
weight/
body
weight
gain
which
render
the
neoplastic
findings
in
this
group
uninterpretable.
In
addition,
the
500
ppm
dose
group
was
not
considered
adequate
for
assessment
of
carcinogenicity
since
this
was
the
NOAEL
for
the
study,
no
tumors
were
seen
at
this
dose,
and
the
dose
spread
(
500
ppm

5000
(
10­
fold)/
4000
(
8­
fold)/
2000
ppm
(
4­
fold)
was
too
large.
The
CARC
requested
that
the
carcinogenicity
study
in
rats
be
repeated
at
a
dose
that
was
adequate
to
assess
carcinogenicity.
Quantification
of
carcinogenic
potential
is
not
applicable.
AMETRYN
CANCER
ASSESSMENT
DOCUMENT
FINAL
3
I.
INTRODUCTION
On
July
21,
2004,
the
Cancer
Assessment
Review
Committee
of
the
Health
Effects
Division
of
the
Office
of
Pesticide
Programs
met
to
evaluate
the
carcinogenic
potential
of
Ametryn.

II.
BACKGROUND
INFORMATION
Chemical
common
name:
Ametryn
Type
of
pesticide:
triazine
herbicide
PC
Code:
080801
CAS
Number:
834­
12­
8
Chemical
name:
2­
ethylamino­
4­
isopropylamino­
6­
methylthio­
s­
triazine.
Structure:

III.
EVALUATION
OF
CARCINOGENICITY
STUDIES
1.
Combined
Chronic
Toxicity/
Carcinogenicity
Study
with
Ametryn
References:
Hazelette,
J.
and
J.
Green
(
1987)
Ametryn:
Combined
chronic
toxicity/
oncogenicity
study
in
rats.
CIBA­
GEIGY
Corporation,
Research
Department,
Pharmaceutical
Division,
Summit,
New
Jersey.
Laboratory
Report
No.
842119.
August
24,
1987.
MRID
40349906.
Unpublished.

Hazelette,
J.
and
J.
Green
(
1987)
Ametryn:
Supplement
to
combined
chronic
toxicity/
oncogenicity
study
in
rats.
CIBA­
GEIGY
Corporation,
Research
Department,
Pharmaceutical
Division,
Summit,
New
Jersey.
Laboratory
Report
No.
842119.
August
24,
1987.
MRID
41184201.
Unpublished.

Tai,
C.
1987.
Ametryn:
4­
week
range­
finding
study
in
rats.
CIBY­
GEIGY
Corporation,
Pharmaceuticals
Division,
Summit,
NJ.
Laboratory
Report
No.
842084.
August,
11,
1987.
MRID
40382001.
Unpublished.
AMETRYN
CANCER
ASSESSMENT
DOCUMENT
FINAL
4
A.
Experimental
Design
In
a
combined
chronic
toxicity/
carcinogenicity
study
(
1987,
MRID
40349906),
Ametryn
(
98.6%
a.
i.,
FL
840991)
was
administered
to
groups
of
70
Sprague­
Dawley
[
Crl:
COBS
®
CD
®
(
SD)
BR]
rats
per
sex
at
concentrations
of
0,
50,
or
500
ppm
for
104
weeks.
Groups
of
70
rats
per
sex
received
5000­
ppm
that
was
reduced
to
4000
ppm
after
141
days
and
further
reduced
to
2000
ppm
after
239
days
because
of
reductions
in
weight
gain.
Ten
rats/
sex/
group
were
sacrificed
after
52
weeks
for
interim
evaluation,
and
ten
rats/
sex
in
the
control
and
high
dose
groups
were
dosed
for
52
weeks
followed
by
control
diet
for
4
weeks
to
assess
recovery,
and
sacrificed
at
56­
weeks
(
recovery
group).

B.
Discussion
of
Survival
and
Tumor
Data
[
Note:
Although
statistical
analyses
were
performed
and
are
presented
in
this
document,
the
results
were
not
discussed
at
the
CARC
meeting.]

Survival
Analyses
The
statistical
evaluation
of
mortality
indicated
a
statistically
significant
decreasing
trend
with
increasing
doses
of
Ametryn
in
both
male
and
female
rats
(
Memo,
J.
Kidwell,
6/
30/
04,
TXR
No.
0052655)
.
See
Table
1
for
male
mortality
test
results
and
Table
2
for
female
mortality
test
results
showing
the
increase
in
survival
in
the
groups
dosed
with
ametryn.

The
statistical
evaluation
of
mortality
was
based
upon
the
Thomas,
Breslow
and
Gart
computer
program.

Tumor
Analyses
Males
Testicular
Interstitial
Cell
Tumors
(
benign):
Male
rats
had
a
significant
increasing
trend
in
benign
interstitial
cell
tumors
of
the
testes
at
p<
0.01.
However,
no
significant
differences
in
the
pair­
wise
comparisons
of
the
dosed
groups
with
the
controls
were
seen
for
benign
interstitial
cell
tumors
of
the
testes
(
Table
3).

Epididymides
(
Mesothelioma):
Male
rats
had
a
significant
increasing
trend
in
benign
mesotheliomas
of
the
epididymides
at
p<
0.05.
However,
no
significant
differences
in
the
pairwise
comparisons
of
the
dosed
groups
with
the
controls
were
seen
for
benign
mesotheliomas
of
the
epididymides
(
Table
4).

Thyroid
Follicular
Cell
Tumors:
There
were
no
significant
trends
or
pair­
wise
comparisons
of
AMETRYN
CANCER
ASSESSMENT
DOCUMENT
FINAL
5
the
dosed
groups
with
the
controls
for
thyroid
follicular
cell
adenomas
for
male
rats.
Male
rats
had
a
significant
increasing
trend
in
thyroid
follicular
cell
adenocarcinomas
at
p<
0.01,
and
a
significant
pair­
wise
comparison
of
the
5000/
4000/
2000
ppm
dose
group
with
the
control
for
this
tumor
at
p<
0.05.
There
was
a
significant
increasing
trend
in
combined
thyroid
follicular
cell
adenomas
and/
or
adenocarcinomas
at
p<
0.01.
No
significant
differences
in
the
pair­
wise
comparisons
of
the
dosed
groups
with
the
controls
were
seen
for
combined
thyroid
tumors
(
Table
5).

Females
Liver
Tumors:
Female
rats
had
a
significant
increasing
trend
in
liver
adenomas
at
p<
0.05,
however,
no
significant
differences
in
the
pair­
wise
comparisons
were
seen.
There
were
no
significant
trends
or
pair­
wise
comparisons
of
the
dosed
groups
with
the
controls
for
liver
carcinomas
in
female
rats.
There
was
a
significant
increasing
trend
in
combined
liver
adenomas
and/
or
carcinomas
in
female
rats
at
p<
0.05,
however,
there
was
no
significant
pair­
wise
comparisons
of
the
dosed
groups
with
the
controls
(
Table
6).

Mammary
Gland
Tumors:
Female
rats
had
a
significant
increasing
trend
in
mammary
gland
adenomas
at
p<
0.05,
however
no
significant
differences
in
the
pair­
wise
comparisons
were
noted
for
this
tumor.
There
were
significant
increasing
trends,
and
significant
differences
in
the
pairwise
comparisons
of
the
5000/
4000/
2000
ppm
dose
group
with
the
controls,
for
mammary
gland
adenocarcinomas
and
combined
adenomas
and/
or
adenocarcinomas,
all
at
p<
0.05
(
Table
7).

The
statistical
analyses
of
the
male
and
female
rats
were
based
upon
Peto's
prevalence
test
due
to
significant
differential
mortality
among
the
dose
groups
in
both
sexes
(
Memo,
J.
Kidwell,
6/
30/
04,
TXR
No.
0052655).
AMETRYN
CANCER
ASSESSMENT
DOCUMENT
FINAL
6
Table
1.
Ametryn
­
Sprague­
Dawley
Rat
Study
Male
Mortality
Rates+
and
Cox
or
Generalized
K/
W
Test
Results
Weeks
Dose
(
ppm)
1­
26
27­
52
53
i
53­
56
56r
57­
78
79­
106f
Total
0
1/
90
1/
89
10/
88
1/
78
9/
77
5/
68
33/
63
41/
71**
n
(
58)

50
0/
80
3/
80
10/
77
1/
67
­­
7/
66
21/
59
32/
70
(
46)

500
0/
80
1/
80
10/
79
0/
69
­­
10/
69
23/
59
34/
70
(
49)

5000/
4000/
2000
0/
90
0/
90
10/
90
0/
80
10/
80
3/
70
11/
67
14/
70**
n
(
20)

+
Number
of
animals
that
died
during
interval/
Number
of
animals
alive
at
the
beginning
of
the
interval.
iInterim
sacrifice
at
week
53.
rRecovery
group
sacrifice
at
week
56.
fFinal
sacrifice
at
week
106.
nNegative
trend
or
negative
change
from
control.
(
)
Percent.

Note:
Time
intervals
were
selected
for
display
purposes
only.
Significance
of
trend
denoted
at
control.
Significance
of
pair­
wise
comparison
with
control
denoted
at
dose
level.
If
*,
then
p
<
0.05.
If
**,
then
p
<
0.01.
AMETRYN
CANCER
ASSESSMENT
DOCUMENT
FINAL
7
Table
2.
Ametryn
­
Sprague­
Dawley
Rat
Study
Female
Mortality
Rates+
and
Cox
or
Generalized
K/
W
Test
Results
Weeks
Dose
(
ppm)
1­
26
27­
52
53
i
53­
56
56r
57­
78
79­
106f
Total
0
0/
90
2/
90
10/
88
1/
78
9/
77
10/
68
27/
58
40/
71**
n
(
56)

50
0/
80
1/
80
10/
79
0/
69
­­
5/
69
33/
64
39/
70
(
56)

500
0/
80
2/
80
10/
78
0/
68
­­
8/
68
32/
60
42/
70
(
60)

5000/
4000/
2000
1/
90
3/
89
10/
86
1/
76
9/
75
1/
66
17/
65
23/
71**
n
(
32)

+
Number
of
animals
that
died
during
interval/
Number
of
animals
alive
at
the
beginning
of
the
interval.
iInterim
sacrifice
at
week
53.
rRecovery
group
sacrifice
at
week
56.
fFinal
sacrifice
at
week
106.
nNegative
trend
or
negative
change
from
control.
(
)
Percent
Note:
Time
intervals
were
selected
for
display
purposes
only.
Significance
of
trend
denoted
at
control.
Significance
of
pair­
wise
comparison
with
control
denoted
at
dose
level.
If
*,
then
p
<
0.05.
If
**,
then
p
<
0.01.
AMETRYN
CANCER
ASSESSMENT
DOCUMENT
FINAL
8
Table
3.
Ametryn
­
Sprague­
Dawley
Rat
Study:
Male
Testes
Tumor
Rates+
and
Peto's
Prevalence
Test
Results
Dose
(
ppm)
0
50
500
5000/
4000/
2000
Benign
Interstitial
Cell
Tumors
(%)

p
=
3a/
49
(
6)

0.0033**
0/
51
(
0)

0.9455n
3/
48
(
6)

0.4548
9/
62
(
15)

0.0557
Interstitial
cell
hyperplasia(
a)
2/
70
4/
70
5/
70
12/
70**

+
Number
of
tumor
bearing
animals/
Number
of
animals
examined,
excluding
those
that
died
before
observation
of
the
first
tumor.
aFirst
benign
interstitial
cell
tumor
observed
at
week
94,
dose
0
ppm.
nNegative
change
from
control
(
a)
The
non­
neoplastic
condition
is
included
to
verify
that
the
testis
is
affected
by
ametryn.

Note:
Interim
sacrifice
and
recovery
animals
are
not
included
in
these
analyses.
There
were
no
tumors
observed
in
any
interim
sacrifice
animals.

Significance
of
trend
denoted
at
control.
Significance
of
pair­
wise
comparison
with
control
denoted
at
dose
level.
If
*,
then
p
<
0.05.
If
**,
then
p
<
0.01.

The
study
report
referenced
a
single
study
for
historical
control
information
which
indicated
that
the
frequency
was
8.8%.
Historical
control
information
from
the
Charles
River
Company
Bulletin
(
March,
2001
for
the
Sprague­
Dawley
Crl:
COBS
®
CD
®
(
SD)
BR
strain
rat)
indicated
that
the
range
was
from
1.43
to
7.14%
for
23
studies.
Thus,
the
incidence
of
testicular
interstitial
cell
tumors
at
the
high
dose
is
in
excess
of
the
historical
control
range.

Table
3
also
shows
that
at
the
highest
dose
there
is
an
increase
in
interstitial
hyperplasia,
a
possibly
preneoplastic
lesion.
AMETRYN
CANCER
ASSESSMENT
DOCUMENT
FINAL
9
Table
4.
Ametryn
­
Sprague­
Dawley
Rat
Study:
Male
Epididymides
Tumor
Rates+
and
Peto's
Prevalence
Test
Results
Dose
(
ppm)
0
50
500
5000/
4000/
2000
Benign
Mesothelioma
(%)

p
=
0/
20
(
0)

0.0155*
0/
28
(
0)

 
0/
25
(
0)

 
3a/
46
(
7)

0.1230
+
Number
of
tumor
bearing
animals/
Number
of
animals
examined,
excluding
those
that
died
before
observation
of
the
first
tumor.

aFirst
mesothelioma
tumor
observed
at
week
105,
dose
5000/
4000/
2000
ppm.

Note:
Interim
sacrifice
and
recovery
animals
are
not
included
in
these
analyses.
There
were
no
tumors
observed
in
any
interim
sacrifice
animals.

Significance
of
trend
denoted
at
control.
Significance
of
pair­
wise
comparison
with
control
denoted
at
dose
level.
If
*,
then
p
<
0.05.
If
**,
then
p
<
0.01.

Mesothelioma
in
the
epididymidis
was
not
reported
in
either
the
single
study
for
historical
control
data
provided
with
the
study
report
or
in
the
historical
control
database
for
the
Charles
River
Laboratory,
meaning
this
tumor
type
is
rare.
There
were
no
non­
neoplastic
or
pre­
neoplastic
lesions
in
the
epididymides.
AMETRYN
CANCER
ASSESSMENT
DOCUMENT
FINAL
10
Table
5.
Ametryn
­
Sprague­
Dawley
Rat
Study:
Male
Thyroid
Follicular
Cell
Tumor
Rates+
and
Peto's
Prevalence
Test
Results
Dose
(
ppm)
0
50
500
5000/
4000/
2000
Adenomas
(%)

p
=
6/
65
(
9)

0.1454
0/
62
(
0)

0.9945n
2/
62
(
3)

0.9226n
6a/
68
(
9)

0.6689
Adenocarcinomas
(%)

p
=
0/
51
(
0)

0.0009**
0/
52
(
0)

­­
0/
49
(
0)

­­
4b/
63
(
6)

0.0259*

Combined
(%)

p
=
6/
65
(
9)

0.0068**
0/
62
(
0)

0.9945n
2/
62
(
3)

0.9226n
10/
68
(
15)

0.2629
Follicular
hypertrophy
0/
70
0/
70
0/
70
1/
70
+
Number
of
tumor
bearing
animals/
Number
of
animals
examined,
excluding
those
that
died
before
observation
of
the
first
tumor.

aFirst
adenoma
observed
at
week
74,
dose
5000/
4000/
2000
ppm
(
excluding
interim
sacrifice
and
recovery
animals).
bFirst
adenocarcinoma
observed
at
week
93,
dose
5000/
4000/
2000
ppm.
nNegative
change
from
control
Note:
Interim
sacrifice
and
recovery
animals
are
not
included
in
these
analyses.
One
interim
sacrifice
animal
in
dose
group
50
ppm
had
a
thyroid
follicular
cell
adenoma
at
week
52.
One
recovery
group
animal
in
dose
group
5000/
4000/
2000
ppm
had
a
thyroid
follicular
cell
adenoma
at
week
57.

Significance
of
trend
denoted
at
control.
Significance
of
pair­
wise
comparison
with
control
denoted
at
dose
level.
If
*,
then
p
<
0.05.
If
**,
then
p
<
0.01.

The
historical
control
data
from
a
single
study
provided
by
Ciba­
Geigy
reports
an
incidence
of
only
1.3%,
whereas
the
Charles
River
historical
control
database
reports
a
range
of
incidence
of
0.87
to
3.85%,
meaning
the
incidence
in
this
study
with
ametryn
exceeds
the
historical
control
range.
There
was
no
indication
of
increased
thyroid
follicular
cell
hyperplasia
or
hypertrophy
that
may
have
preceded
the
neoplastic
lesions.
AMETRYN
CANCER
ASSESSMENT
DOCUMENT
FINAL
11
Table
6.
Ametryn
­
Sprague­
Dawley
Rat
Study:
Female
Liver
Tumor
Rates+
and
Peto's
Prevalence
Test
Results
Dose
(
ppm)
0
50
500
5000/
4000/
2000
Adenomas
(%)

p
=
1/
64
(
2)

0.0312*
0/
67
(
0)

0.8413n
2a/
65
(
3)

0.2932
4/
66
(
6)

0.1828
Carcinomas
(%)

p
=
0/
21
(
0)

0.2776
0/
21
(
0)

­­
1b/
19
(
5)

0.1466
1/
38
(
3)

0.2286
Combined
(%)

p
=
1/
64
(
2)

0.0236*
0/
67
(
0)

0.8413n
3/
65
(
5)

0.1579
5/
66
(
8)

0.1209
Hepatocellular
Alteration
Hyperplasia
20/
90
18/
90
24/
90
21/
90
28/
90
21/
90
59/
90**
36/
90**

+
Number
of
tumor
bearing
animals/
Number
of
animals
examined,
excluding
those
that
died
before
observation
of
the
first
tumor.

aFirst
adenoma
observed
at
week
70,
dose
500
ppm
(
excluding
recovery
animal).
bFirst
carcinoma
observed
at
week
105,
dose
500
ppm.
nNegative
change
from
control.

Note:
Interim
sacrifice
and
recovery
animals
are
not
included
in
these
analyses.
One
recovery
group
animal
in
dose
group
0
ppm
had
an
adenoma
at
week
56.

Significance
of
trend
denoted
at
control.
Significance
of
pair­
wise
comparison
with
control
denoted
at
dose
level.
If
*,
then
p
<
0.05.
If
**,
then
p
<
0.01.

The
historical
control
incidence
for
liver
adenomas
from
the
single
study
provided
by
Ciba­
Geigy
was
3.8%
and
the
historical
control
range
for
adenomas
in
the
liver
of
females
was
0.77
to
13.33%
from
the
Charles
River
database.
The
incidence
of
liver
adenomas
at
the
high
dose
is
within
historical
control
range.
Table
6
also
shows
increases
in
hepatocellular
alterations
and
hyperplasia,
possibly
pre­
neoplastic
lesions,
which
also
demonstrate
that
the
liver
is
a
target
AMETRYN
CANCER
ASSESSMENT
DOCUMENT
FINAL
12
organ.

Table
7.
Ametryn
­
Sprague­
Dawley
Rat
Study:
Female
Mammary
Gland
Tumor
Rates+
and
Peto's
Prevalence
Test
Results
Dose
(
ppm)
0
50
500
5000/
4000/
2000
Adenomas
(%)

p
=
0/
90
(
0)

0.0458*
2/
79
(
3)

0.1053
0/
79
(
0)

­­
3a/
86
(
3)

0.0534
Adenocarcinomas
(%)

p
=
12/
90
(
13)

0.0438*
14/
79
(
18)

0.3186
17/
79
(
22)

0.1299
24b/
86
(
28)

0.0342*

Combined
(%)

p
=
12/
90
(
13)

0.0303*
15c/
79
(
19)

0.2532
17/
79
(
22)

0.1299
25d/
86
(
29)

0.0210*

+
Number
of
tumor
bearing
animals/
Number
of
animals
examined,
excluding
those
that
died
before
week
42.
aFirst
adenoma
observed
at
week
91,
dose
5000/
4000/
2000
ppm.
bFirst
adenocarcinoma
observed
at
week
42,
dose
5000/
4000/
2000
ppm.
cOne
animal
in
the
50
ppm
dose
group
had
both
an
adenoma
and
adenocarcinoma.
dTwo
animals
in
the
5000/
4000/
2000
ppm
dose
group
had
both
an
adenoma
and
adenocarcinoma.

Note:
Interim
sacrifice
and
recovery
animals
are
included
in
these
analyses.

Significance
of
trend
denoted
at
control.
Significance
of
pair­
wise
comparison
with
control
denoted
at
dose
level.
If
*,
then
p
<
0.05.
If
**,
then
p
<
0.01.

The
incidence
in
the
single
study
provided
by
Ciba­
Geigy
was
only
8.8%,
but
it
was
not
specified
if
this
was
for
adenoma
or
adenocarcinoma.
The
Charles
River
data
information
bulletin
indicates
that
there
were
1.67%
to
32%
incidence
of
adenoma
and
8.57%
to
58.33%
adenocarcinoma
in
their
historical
control
database.
Thus,
the
incidence
of
both
adenoma
and
carcinoma
in
the
study
with
ametryn
is
within
the
historical
control
range.
There
were
no
non­
neoplastic
conditions
in
the
mammary
gland
to
indicate
preneoplastic
conditions.

c.
Non­
neoplastic
Lesions
Non­
neoplastic
lesions
considered
noteworthy
are
summarized
in
Table
8.
AMETRYN
CANCER
ASSESSMENT
DOCUMENT
FINAL
13
TABLE
8.
Notable
microscopic
lesions
in
male
and
female
rats
fed
ametryn
for
1
year
and
2
years
Organ/
Lesion
Dietary
concentration
0
50
500
5000/
4000/
2000a
Males
 
1
year
Pancreas
[
No.
animals
examined]
Acinar
cell
metaplasia
[
11]
0
[
10]
0
[
10]
0
[
10]
1
Testes
[
No.
animals
examined]
Interstitial
cell
hyperplasia
[
11]
0
[
10]
0
[
10]
0
[
10]
2
Males
­
1
year
+
recovery
Testes
[
No.
animals
examined]
Interstitial
cell
hyperplasia
[
9]
0
 
 
[
10]
1
Males
 
2
years
Kidney
(
pelvis)
[
No.
animals
examined]
Mineralization
­
concretions
[
70]
10
[
70]
13
[
70]
16
[
70]
25**

Liver
[
No.
animals
examined]
Hepatocellular
hyperplasia
[
70]
22
[
70]
15
[
70]
24
[
70]
34*

Pancreas
[
No.
animals
examined]
Acinar
cell
metaplasia
[
68]
0
[
70]
0
[
70]
1
[
70]
3
Pituitary
[
No.
animals
examined]
Hyperplasia
[
70]
13
[
63]
13
[
69]
5
[
70]
26*

Testes
[
No.
animals
examined]
Interstitial
cell
hyperplasia
[
70]
2
[
70]
4
[
70]
5
[
70]
12**

Females
 
1
year
Liver
[
No.
animals
examined]
Hepatocellular
alterations
[
10]
1
[
10]
5
[
10]
4
[
11]
7*

Pancreas
[
No.
animals
examined]
Acinar
cell
metaplasia
[
10]
0
[
10]
0
[
10]
0
[
11]
2
Females
 
1
year
+
recovery
Liver
[
No.
animals
examined]
Hepatocellular
alterations
[
10]
0
 
 
[
9]
3
Females
 
2
years
Liver
[
No.
animals
examined]
Hepatocellular
alterations
Hepatocellular
hyperplasia
[
70]
19
18
[
70]
19
21
[
70]
24
21
[
70]
49**
36**

Pancreas
[
No.
animals
examined]
Acinar
cell
metaplasia
[
70]
0
[
69]
0
[
70]
1
[
70]
4
Data
taken
from
pages
3572­
3617,
MRID
40349906.
aThe
dietary
concentration
was
reduced
to
4000
ppm
on
1/
22/
85
(
Day
141)
and
to
2000
ppm
on
4/
30/
85
(
Day
239)
(
see
footnote,
page
202).
*
p

0.05,
**
p

0.01,
statistically
significant,
treated
groups
compared
with
the
control
group.
AMETRYN
CANCER
ASSESSMENT
DOCUMENT
FINAL
14
D.
Adequacy
of
the
Dosing
for
Assessment
of
Carcinogenicity
The
CARC
considered
dosing
at
the
high
dose
in
male
and
female
rats
to
be
excessive
and
not
adequate
for
the
assessment
of
carcinogenicity.
They
concluded
that
the
tumor
findings
at
the
high
dose
cannot
be
interpreted
because
the
animals
were
compromised
due
to
large
decreases
in
body
weight/
body
weight
gain
during
the
first
8
months
of
the
study.
In
addition,
the
500
ppm
dose
group
was
not
considered
adequate
for
assessment
of
carcinogenicity
since
this
was
the
NOAEL
for
the
study,
no
tumors
were
seen
at
this
dose,
and
the
dose
spread
(
500
ppm

5000
(
10­
fold)/
4000
(
8­
fold)/
2000
ppm
(
4­
fold)
was
too
large.
The
high
dose
group
was
initially
started
at
5000
ppm
and
dosed
at
this
level
for
141
days
before
being
reduced
to
4000
ppm
and
it
was
later
reduced
to
2000
ppm
on
day
239.
High­
dose
male
and
female
rats
weighed
significantly
(
p

0.01)
less
than
controls
throughout
the
entire
study
starting
with
day
7.
The
NOAEL
and
LOAEL
for
this
study
was
500
ppm
and
5000/
4000/
2000
ppm,
respectively.
The
high­
dose
males
weighed
29­
38%
less
than
controls
when
fed
5000
ppm
from
day
1­
140,
except
for
day
21
when
they
weighed
48%
less
than
controls.
They
weighed
23­
28%
less
than
controls
when
fed
the
4000­
ppm
diet
from
day
140­
239
and
the
2000­
ppm
diet
for
the
remainder
of
the
first
year
(
day
239­
364),
and
18­
23%
less
than
controls
during
the
second
year
of
the
study.
The
males
gained
38%
less
weight
than
controls
when
fed
the
5000­
ppm
diet,
20%
less
when
fed
the
4000
ppm
diet,
and
29%
more
than
controls
when
fed
the
2000
ppm
diet
for
the
remainder
of
the
first
year.
High­
dose
males
gained
two
times
more
weight
than
controls
during
the
second
year
resulting
in
an
overall
weight
gain
22%
below
that
of
controls.

High­
dose
females
weighed
20­
26%
less
than
controls
when
fed
the
5000
ppm
diet,
24­
34%
less
than
controls
when
fed
the
4000
ppm
diet
and
the
2000­
ppm
diet
for
the
remainder
of
the
first
year,
and
25­
28%
less
than
controls
during
the
second
year
of
the
study.
High­
dose
males
and
females
lost
weight
during
the
first
7
days
of
treatment.
High­
dose
females
gained
40%
less
weight
than
controls
when
fed
the
5000­
ppm
diet,
57%
less
when
fed
the
4000­
ppm
diet,
and
15%
more
weight
than
controls
when
fed
the
2000­
ppm
diet
for
the
remainder
of
the
first
year
of
the
study.
High­
dose
females
gained
51%
less
weight
than
controls
during
the
second
year,
resulting
in
an
overall
weight
gain
37%
less
than
that
of
controls.

Body
weights
of
high­
dose
males
and
females
at
the
end
of
the
recovery
period
showed
a
similar
difference
compared
with
the
controls
as
did
high­
dose
rats
continuing
treatment
during
the
same
period.
Low­
dose
male
and
female
rats
had
body
weights
similar
to
controls
throughout
the
study.
Mid­
dose
male
and
female
rats
had
body
weights
statistically
significantly
(
p

0.05)
lower
than
controls
during
a
few
weeks
during
the
study.
Mid­
dose
males
weighed
4­
7%
(
p

0.05
or

0.01)
less
than
controls
during
the
first
63
days
and
at
sporadic
time
points
after
day
63.
Middose
females
weighed
only
2­
4%
(
p

0.05
or

0.01)
less
than
controls
for
almost
all
weeks
during
the
first
91
days
of
the
study.

Other
indications
of
exposure
to
ametryn
noted
in
the
high
dose
group
included
hepatocellular
AMETRYN
CANCER
ASSESSMENT
DOCUMENT
FINAL
15
hyperplasia
in
both
males
and
females
and
hepatocellular
"
alterations"
in
females,
interstitial
cell
hyperplasia
in
the
testes,
acinar
cell
metaplasia
in
the
pancreas
and
mineralization
in
the
kidneys.

2.
Carcinogenicity
Study
in
Mice
Reference:
Burdock,
G.,
1981,
FINAL
REPORT.
102
week
Oncogenicity
Study
in
Mice.
Hazleton
Laboratories.
Virginia,
Study
No.:
483­
128,
March
20,
1981.
MRID
No.:
40349904.

A.
Experimental
Design
Four
groups
of
60/
sex
of
HAM/
ICE
Swiss,
Charles
River
CD­
1
strain
mice
were
dosed
as
either
0,
10,
1000
or
2000
ppm
ametryn
(
technical,
Batch
No.:
FL­
761356,
98.9%
purity)
for
a
period
of
102
weeks.
These
doses
corresponded
to
approximately
0,
1.5,
150
and
300
mg/
kg/
day
based
on
an
estimate
of
1
ppm
=
0.15
mg/
kg/
day.

B.
Discussion
of
Tumor
Data
The
CARC
concurred
that
there
were
no
compound
related
increases
in
neoplasms.

C.
Adequacy
of
Dosing
for
Assessment
of
Carcinogenicity
The
CARC
concluded
that
dosing
at
the
high
dose
in
both
male
and
female
mice
was
adequate
and
not
excessive.
Although
the
high
dose
of
2000
ppm
(
300
mg/
kg/
day)
in
the
definitive
mouse
study
did
not
result
in
systemic
toxicity,
the
mouse
28­
day
range
finding
study
demonstrated
body
weight
gain
decreases
at
1000
(

12%
in
males
and

17%
in
females)
and
3000
(

24%
in
males
and

46%
in
females)
ppm
which
justified
selection
of
2000
ppm
as
the
high
dose
for
the
definitive
cancer
study
with
mice.
AMETRYN
CANCER
ASSESSMENT
DOCUMENT
FINAL
16
IV.
TOXICOLOGY
1.
Metabolism
The
metabolism
of
ametryn
demonstrates
that
ametryn
is
rapidly
absorbed
and
excreted
with
distribution
but
little
tissue
retention
(
MRIDs
41463301,
41463302,
41463303,
92002042).
Most
ametryn
was
excreted
in
the
urine.
Some
thirteen
water
soluble
metabolites
were
found.

2.
Mutagenicity
The
mutagenicity
data
base
does
not
indicate
a
concern
for
mutagenicity/
genetic
toxicity.
As
per
memo
from
I.
Mauer
(
July
2,
2004),
there
are
acceptable
and
negative
mutagenicity
studies
(
Ames
test
in
Salmonella,
UDS
in
rat
hepatocyte,
and
mouse
micronucleus
tests).
A
forward
gene
mutation
assay
in
mammalian
cell
cultures
is
required
to
complete
the
current
requirement
for
mutagenicity/
genetic
toxicity
testing.

MRID
Type
of
Assay
Concentrations
Reported
Results
EPA
Classification
40995820
41189701
Ames
Assay
0,
20,
80,
320,
1280,
5120
ug/
0.1
mL
No
evidence
of
mutagenicity
in
Salmonella
strains
TA
98,
TA
100,
TA
1535,
and
TA
1537,
up
to
cytotoxicity.
Acceptable/
guideline
41067904
Unscheduled
DNA
Synthesis
in
rat
hepatocytes
1.
0.41
to
100
ug/
mL
2.
0.137
to
33.3
ug/
mL
Negative
for
increased
UDS
up
to
cytotoxicity
Acceptable/
guideline
41067903
Mouse
Micronucleus
Test
1.
800
mg/
kg;
harvest
at
16,
24,
48
hrs.
2.
200,
400,
800
mg/
kg;
harvest
at
24
hrs.
Negative.
for
increased
MPCEs
up
to
clinical
toxicity
(
death).
Acceptable/
guideline
3.
Structure­
Activity
Relationship
Ametryn
is
a
methylthio
triazine
herbicide.
HED
recently
completed
a
comprehensive
structure
activity
assessment
for
a
model
for
the
common
mechanism
of
action
for
triazine
compounds
such
as
atrazine
to
induce
mammary
gland
tumors.
Rather
than
attempt
to
write
a
synopsis
of
this
document
here,
the
interested
readers
can
refer
to
the
document
entitled
"
The
Grouping
of
a
Series
of
Triazine
Pesticides
Based
on
a
Common
Mechanism
of
Toxicity"
(
HED
Document,
March,
2002).
Atrazine
is
a
triazine
herbicide.
The
chlorotriazine
pesticides
have
been
shown
to
increase
mammary
gland
tumors
in
female
rats.
Because
ametryn
is
not
a
chlorotriazine,
SAR
does
not
provide
support
for
carcinogenic
potential.
AMETRYN
CANCER
ASSESSMENT
DOCUMENT
FINAL
17
4.
Subchronic
and
Chronic
Toxicity
a)
Subchronic
Toxicity
The
subchronic
toxicity
data
base
for
ametryn
rat
and
mouse
studies
is
considered
old
and
the
chronic
studies
replace
the
subchronic
studies
in
the
data
base.

28­
day
range­
finding
mouse:
In
a
28­
day
range­
finding
study
(
MRID
92002041),
mice
(
5/
sex/
group)
were
fed
ametryn
technical
at
dietary
dose
levels
of
0,
30,
100,
300,
600,
1000,
3000,
10,000,
and
30,000
ppm..
All
30,000
ppm
animals
died
by
the
end
of
week
3.
At
10,000
ppm
1
male
and
2
females
also
died.
At
3000
ppm
clinical
signs
(
hunched
posture,
labored
breathing
and
thin
appearance)
were
observed
in
one
of
five
females.
At
1000
and
3000
ppm
decreased
mean
body
weight
gain
was
observed
in
males
(

12%,

24%)
and
females
(

17%,


46%),
respectively.
The
NOEL
was
600
ppm,
with
minimal
effects
occurring
at
1000
and
marked
effects
occurring
at
3000
ppm.

b)
Chronic
Toxicity
Rat
In
a
combined
chronic
toxicity/
carcinogenicity
study
(
MRID
40349906),
Ametryn
(
98.6%
a.
i.,
FL
840991)
was
administered
in
the
feed
to
groups
of
70
Sprague­
Dawley
[
Crl:
COBS
®
CD
®
(
SD)
BR]
rats
per
sex
at
concentrations
of
0,
50,
or
500
ppm
for
104
weeks.
Groups
of
70
rats
per
sex
received
a
5000­
ppm
diet
that
was
reduced
to
4000
ppm
after
141
days
and
further
reduced
to
2000
ppm
after
239
days
because
of
extreme
reductions
in
weight
gain
at
the
higher
doses.
Ten
rats/
sex/
group
were
administered
the
same
diets
under
the
same
protocol
for
52
weeks
for
interim
evaluation,
and
ten
rats/
sex/
group
were
administered
the
control
and
the
high­
dose
diets
for
56
weeks
followed
by
control
diet
for
4
weeks
to
assess
recovery.

Survival
rates
for
high­
dose
male
and
female
rats
were
significantly
greater
than
those
of
controls;
80%
of
males
and
69%
of
females
in
the
high­
dose
group
were
alive
at
study
termination
compared
with
only
43%
and
44%
of
controls,
respectively.
The
only
treatment­
related
clinical
sign
was
loose
feces
observed
in
high­
dose
males
during
the
time
they
were
fed
the
5000­
ppm
diet.

High­
dose
male
and
female
rats
weighed
significantly
less
than
controls
throughout
the
study.
High­
dose
males
weighed
29­
48%
less
than
controls
when
fed
the
5000­
ppm
diet
and
18­
26%
less
when
fed
the
4000­
ppm
diet
followed
by
the
2000­
ppm
diet.
High­
dose
females
weighed
20­
34%
less
than
controls
regardless
of
the
concentration
of
test
material
in
the
diet.
High­
dose
males
and
females
lost
weight
during
the
first
week
of
treatment
and
gained
38%
and
40%
less
weight,
respectively,
when
fed
the
5000­
ppm
diet,
20%
and
57%
less
weight,
respectively,
when
fed
the
4000­
ppm
diet,
and
29%
and
15%
more
weight,
respectively,
when
fed
the
2000­
ppm
diet
AMETRYN
CANCER
ASSESSMENT
DOCUMENT
FINAL
18
for
the
remainder
of
the
first
year.
During
the
second
year,
high­
dose
males
gained
two
times
more
weight
than
controls
and
high­
dose
females
gained
51%
less
weight
than.
High­
dose
males
and
females
consumed
18­
41%
and
30­
45%
less
food
when
fed
the
5000­
ppm
diet,
12­
17%
and
18­
22%
less
when
fed
the
4000­
ppm
diet,
and
6­
14%
and
7­
12%
less
when
fed
the
2000­
ppm
diet
up
to
day
560
and
532,
respectively.
No
toxicologically
significant
effects
were
observed
on
body
weight
or
food
consumption
in
mid­
dose
males
and
females.
Food
efficiency
for
the
first
91
days
was
reduced
by
22%
and
17%
for
high­
dose
males
and
females,
respectively.
Water
consumption
was
inconsistent
during
the
study
and
showed
no
treatment­
related
effect.

No
toxicologically
significant
effects
were
observed
on
hematology
or
clinical
chemistry
parameters
except
for
elevated
alkaline
phosphatase
activity
(
68­
94%
increase)
in
high­
dose
females.
No
treatment­
related
effects
were
observed
on
urinalysis
parameters
in
male
or
female
rats.

Postmortem
examination
showed
no
treatment­
related
effect
on
organ
weights;
tissue
masses
in
the
testes
of
high­
dose
male
rats
and
the
skin
of
high­
dose
female
rats
probably
correlated
with
neoplastic
lesions.
Treatment­
related
microscopic
lesions
were
observed
in
the
testes,
pancreas,
renal
pelvis,
liver,
and
pituitary
in
high­
dose
males
and
liver
and
pancreas
in
high­
dose
females.
High­
dose
male
rats
had
significantly
increased
incidences
of
mineralization/
concretions
in
the
renal
pelvis
(
25/
70
vs
10/
70
for
controls),
pituitary
hyperplasia
(
26/
70
vs
13/
70
for
controls),
and
interstitial
cell
hyperplasia
in
the
testes
(
12/
70
vs
2/
70
for
controls).
High­
dose
male
and
female
rats
had
a
significant
increase
in
the
incidence
of
hepatocellular
hyperplasia
(
males:
34/
70
vs
22/
70;
females:
36/
70
vs
18/
70)
and
a
non­
significant
increase
in
the
incidence
of
acinar
cell
metaplasia
(
hepatocyte­
like
cells)
in
the
pancreas
(
3/
70
for
males,
4/
69
for
females
vs
0/
70
for
controls
in
both
sexes).
High­
dose
females
had
a
significantly
increased
incidence
of
hepatocellular
alterations
(
49/
70
vs
19/
70
for
controls).
Acinar
metaplasia
in
both
sexes,
interstitial
cell
hyperplasia
in
the
testes,
and
hepatocellular
alterations
in
females
were
observed
in
the
high­
dose
groups
after
only
1
year
of
treatment.
The
incidences
of
lesions
after
1
year
were
reduced
after
the
4­
week
recovery
period.

The
lowest­
observed­
adverse­
effect
level
(
LOAEL)
for
ametryn
in
rats
is
5000/
4000/
2000
ppm
(
145.3
and
176.1
mg/
kg/
day
for
males
and
females,
respectively)
based
on
decreased
body
weight
and
weight
gain
in
both
sexes
and
histopathologic
lesions
in
the
kidney,
testes,
and
pituitary
in
male
rats
and
in
the
liver
and
pancreas
in
male
and
female
rats.
The
corresponding
no­
observed­
adverse­
effect
level
(
NOAEL)
is
500
ppm
(
20.9
and
26.2
mg/
kg/
day,
for
males
and
females,
respectively)
AMETRYN
CANCER
ASSESSMENT
DOCUMENT
FINAL
19
Mouse
In
a
mouse
carcinogenicity
study
(
1992,
MRID
No.:
40349904),
four
groups
of
60/
sex
mice
(
HAM/
ICE,
Swiss,
CD­
1)
were
dosed
as
0,
10,
1000
or
3000
ppm
of
ametryn
(
Batch
FL­
761356,
98.9%
purity)
for
a
scheduled
102
weeks.
These
dose
levels
correspond
to
0,
1.5,
150
and
300
mg/
kg/
day
based
on
a
conversion
factor
of
1
ppm
=
0.15
mg/
kg/
day.

There
were
no
systemic
effects
of
treatment
at
the
highest
dose
tested.
There
were
also
no
treatment
related
increases
in
neoplasms.
The
dose
levels
were,
however,
considered
adequate
because
the
dose
range
finding
study
(
1990,
MRID
#
92002041)
demonstrated
that
there
was
significant
weight
gain
decrease
at
1000
ppm
(
12
to
17%)
and
3000
ppm
(
24
to
46%).

This
study
is
classified
as
Acceptable/
Guideline
and
satisfies
the
guideline
(
870.4200)
requirement
for
a
carcinogenicity
study
in
mice.

5.
Mode
of
Action
Studies
There
were
no
data
submitted
on
the
possible
mode
of
action
of
ametryn.
AMETRYN
CANCER
ASSESSMENT
DOCUMENT
FINAL
20
V.
COMMITTEE'S
ASSESSMENT
OF
THE
WEIGHT­
OF­
THE­
EVIDENCE
1.
Carcinogenicity
Rat
The
CARC
considered
dosing
at
the
high
dose
in
male
and
female
rats
to
be
excessive
and
not
adequate
for
the
assessment
of
carcinogenicity.
They
concluded
that
the
tumor
findings
at
the
high
dose
cannot
be
interpreted
because
the
animals
were
compromised
due
to
large
decreases
in
body
weight/
body
weight
gain
during
the
first
8
months
of
the
study.
Consequently,
although
statistical
analyses
were
performed,
the
tumor
data
in
rats
were
not
discussed
at
this
meeting.
In
addition,
the
500
ppm
dose
group
was
not
considered
adequate
for
assessment
of
carcinogenicity
since
this
was
the
NOAEL
for
the
study,
no
tumors
were
seen
at
this
dose,
and
the
dose
spread
(
500
ppm

5000
(
10­
fold)/
4000
(
8­
fold)/
2000
ppm
(
4­
fold)
was
too
large.

Mouse
No
treatment­
related
tumors
were
seen
in
male
or
female
mice.

The
CARC
concluded
that
dosing
at
the
high
dose
in
both
male
and
female
mice
was
adequate
and
not
excessive.
Although
the
high
dose
of
2000
ppm
(
300
mg/
kg/
day)
in
the
definitive
mouse
study
did
not
result
in
systemic
toxicity,
the
mouse
28­
day
range
finding
study
(
MRID
92002041)
demonstrated
body
weight
gain
decreases
at
1000
(

12%
in
males
and

17%
in
females)
and
3000
(

24%
in
males
and

46%
in
females)
ppm
which
justified
selection
of
2000
ppm
as
the
high
dose
for
the
definitive
cancer
study
with
mice.

2.
Mutagenicity
There
is
no
mutagenicity
concern
with
ametryn.

3.
Structure
Activity
Relationship
Atrazine
is
a
triazine
herbicide.
The
chlorotriazine
pesticides
have
been
shown
to
increase
mammary
gland
tumors
in
female
rats.
Because
ametryn
is
not
a
chlorotriazine,
SAR
does
not
provide
support
for
carcinogenic
potential.

4.
Mode
of
Action
No
specific
mode
of
action
studies
were
submitted
with
ametryn.

VI.
CLASSIFICATION
OF
CARCINOGENIC
POTENTIAL
AMETRYN
CANCER
ASSESSMENT
DOCUMENT
FINAL
21
In
accordance
with
the
EPA
Draft
Guidelines
for
Carcinogen
Risk
Assessment
(
July,
1999),
the
Committee
classified
ametryn
into
the
category
"
Data
Are
Inadequate
for
An
Assessment
of
Human
Carcinogenic
Potential".
The
carcinogenicity
study
in
the
rats
is
unacceptable
because
the
high
dose
was
considered
to
be
excessive.
The
animals
in
the
high
dose
group
were
compromised
due
to
large
decreases
in
body
weight/
body
weight
gain
which
render
the
neoplastic
findings
in
this
group
uninterpretable.
In
addition,
the
500
ppm
dose
group
was
not
considered
adequate
for
assessment
of
carcinogenicity
since
this
was
the
NOAEL
for
the
study,
no
tumors
were
seen
at
this
dose,
and
the
dose
spread
(
500
ppm

5000
(
10­
fold)/
4000
(
8­
fold)/
2000
ppm
(
4­
fold)
was
too
large.
The
CARC
requested
that
the
carcinogenicity
study
in
rats
be
repeated
at
a
dose
that
was
adequate
to
assess
carcinogenicity.

Note:
A
few
members
of
the
CARC
felt
that
ametryn
should
be
classified
as
"
Suggestive
Evidence
of
Carcinogenicity,
but
not
sufficient
to
Assess
Human
Carcinogenic
Potential"
based
on
the
tumor
findings
in
male
and
female
rats
at
an
excessive
dose
(
based
only
on
body
weight
gain
decrements).
However,
there
was
no
systemic
toxicity
and
survival
was
significantly
increased
relative
to
concurrent
controls
in
both
males
and
females.

VII.
QUANTIFICATION
OF
CARCINOGENIC
POTENTIAL
Not
applicable.

VIII
BIBLIOGRAPHY
MRID
No.
Citation
40349904
Burdock,
G.,
1981,
Final
Report.
102
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Oncogenicity
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Hazleton
Laboratories.
Virginia,
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483­
128,
March
20,
1981.

40349906
Hazelette,
J.
and
J.
Green
(
1987)
Ametryn:
Combined
chronic
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oncogenicity
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CIBA­
GEIGY
Corporation,
Research
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Summit,
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August
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1987.
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40382001
Tai,
C.
1987.
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August,
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1987.
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40995820
Deparade,
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41067903
Hertner,
T.
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Structural
Chromosomal
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CANCER
ASSESSMENT
DOCUMENT
FINAL
22
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Mouse,
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GEIGY
Limited,
Basle
(
Switzerland),
February
20,
1989.
Laboratory
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881548.
Unpublished.

41067904
Hertner,
T.
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1989).
Ametryn
Technical:
Tests
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Other
Genotoxic
Effects;
Autoradiographic
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Rat
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Basle
(
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1989.
Laboratory
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41184201
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J.
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Green
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1987)
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combined
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CIBA­
GEIGY
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Research
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August
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41189701
Deparade,
E.
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1984)
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Technical:
Gene
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Geigy
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23
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40995829)

41463301
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Analysis,
Quantitation,
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Structure
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215
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41463302
Reynolds,
J.
(
1990)
Ametryn
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in
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41463303
Braun,
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1990)
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­­­­­­­­­­­
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­­­­­­­­­­­
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