Document ID: EPA-HQ-OPP-2004-0303-0007
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2004-09-10T04:00Z

HALOHYDANTOINS
Toxicology
Chapter
TABLE
OF
CONTENTS
1.0
HAZARD
CHARACTERIZATION
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3
2.0
REQUIREMENTS
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5
3.0
DATA
GAPS
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6
4.0
HAZARD
ASSESSMENT
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6
4.1
Acute
Toxicity
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6
4.2
Subchronic
Toxicity
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7
4.3
Prenatal
Developmental
Toxicity
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4.4
Reproductive
Toxicity
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12
4.5
Chronic
Toxicity
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14
4.6
Carcinogenicity
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17
4.7
Mutagenicity
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18
4.8
Neurotoxicity
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26
4.9
Metabolism.
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27
5.0
TOXICITY
ENDPOINT
SELECTION
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27
5.1
See
Section
9.2
for
Endpoint
Selection
Table.
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27
5.2
Dermal
Absorption
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27
5.3
Classification
of
Carcinogenic
Potential
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27
6.0
FQPA
CONSIDERATIONS
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27
6.1
Special
Sensitivity
to
Infants
and
Children
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27
6.2
Recommendation
for
a
Developmental
Neurotoxicity
Study
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27
7.0
ENDOCRINE
DISRUPTION
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28
8.0
OTHER
ISSUES
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28
9.0
REFERENCES
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29
10.0
APPENDICES
10.1
Toxicity
Profile
Summary
Tables
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32
10.1.1
Acute
Toxicity
Table
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10.1.2
Subchronic,
Chronic
and
Other
Toxicity
Tables
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32
10.2
Summary
of
Toxicological
Dose
and
Endpoints
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38
Page
3
of
41
1.0
HAZARD
CHARACTERIZATION
The
hydantoins
are
a
group
of
chemicals
composed
of
several
halogenated
and
nonhalogenated
compounds.
This
group
of
chemicals
includes
the
following:
1­
Bromo­
3­
chloro­
5,5­
dimethylhydantoin,
1.3­
Dibromo­
5,5­
dimethylhydantoin,
1,3­
Dichloro­
5,5­
dimethylhydantoin,
1,3­
Dichloro­
5­
ethyl­
5­
methylhydantoin,
1,3­
bis(
hydroxymethyl)­
5,5­
dimethylhydantoin,
and
1­
hydroxymethyl)­
5,5­
dimethylhydantoin.
In
addition
to
these
four
hydantoins,
the
Agency
determined
that
the
5,5­
Dimethylhydantoin
and
5,5­
Ethylmethylhydantoin
metabolites
of
the
halogenated
hydantoins
are
appropriate
test
substances
for
assessing
the
toxicity
of
the
hydantoins.
However,
since
the
hydroxymethylhydantoins
as
mentioned
above
have
the
potential
for
release
of
formaldehyde,
the
risks
associated
with
this
release
need
to
be
assessed.
The
Agency
has
determined
that
the
risks
from
exposure
to
formaldehyde
via
the
hydroxymethylhydantoins
will
be
addressed
when
the
active
ingredient
formaldehyde
is
assessed
for
reregistration
eligibility.
Therefore,
this
reregistration
eligibility
decision
(
RED)
document
assesses
the
eligibility
of
the
halogenated
hydantoins
and
their
metabolites
for
reregistration.

These
antimicrobial
chemicals
are
registered
for
use
in
indoor
food,
indoor
non­
food,
indoor
residential,
aquatic
non­
food
residential,
aquatic
food,
aquatic
non­
food,
and
aquatic
non­
food
industrial
sites
for
control
of
bacteria,
fungi,
and
algal
slimes.

The
acute
toxicity
of
dimethylhydantoin
is
low
by
the
oral
and
dermal
routes
of
exposure
(
Toxicity
categories
III
and
IV,
respectively).
Acute
lethality
by
the
inhalation
route
is
more
significant
(
Toxicity
category
II).
The
dimethylhydantoins
are
significant
eye
and
skin
irritants
(
Toxicity
category
I
and
II,
respectively).
Positive
dermal
sensitization
has
also
been
observed.

Non­
acute
toxicity
testing
of
dimethylhydantoins
(
including
subchronic,
developmental,
reproductive,
and
chronic
toxicity
testing)
all
show
the
presence
of
non­
specific
toxicity
only
at
relatively
high
doses
of
the
test
chemical.
Developmental
and
reproductive
toxicity
data
demonstrate
no
increase
in
susceptibility
to
the
toxic
effects
of
dimethylhydantoin
with
the
exception
of
one
study,
where
fetal
and
litter
effects
(
increased
incidence
of
27th
presacral
vertebrae)
in
rabbits
were
observed
at
a
lower
dose
level
than
that
which
resulted
in
maternal
toxicity
(
decreased
body
weight
and
food
consumption
during
the
dosing
period)
following
treatment.
In
a
prenatal
developmental
toxicity
study
conducted
in
rabbits
with
ethylmethylhydantoin,
there
was
no
increased
susceptibility
of
the
fetuses
observed.

Chronic
toxicity
testing
of
dimethylhydantoins
in
rats
showed
a
decrement
in
body
weight
and
body
weight
gain
in
females
and
increased
mortality,
particularly
in
females.
Males
showed
increased
incidences
of
hyperplasia
of
submandibular
lymph
nodes
and
testicular
fibrinoid
vascular
degeneration
in
early
decedents.
Both
sexes
showed
increased
mammary
galactoceles
in
early
decedents
and
enlarged
pituitary
glands.
In
two
chronic
toxicity
studies
conducted
in
dogs,
dimethylhydantoin
produced
slight
(
enlarged
pituitary
glands)
to
no
toxicity
at
or
above
the
limit
dose
of
1000
mg/
kg/
day.
Page
4
of
41
Cancer
studies
in
rats
and
mice
indicated
no
systemic
effects
other
than
decreased
body
weight
and
body
weight
gains
in
females
(
rats)
and
males
(
mice)
and
increased
hyperplasia
of
submandibular
lymph
nodes
in
males
(
rats).
No
evidence
of
tumorigenicity
of
the
test
material
was
reported.
5,5­
dimethylhydantoin
is
classified
as
`
not
likely'
to
be
a
carcinogen
based
upon
the
negative
evidence
for
carcinogenicity
in
both
the
rat
and
mouse
studies
as
well
as
the
negative
evidence
of
mutagenicity.

The
data
on
mutagenicity
of
dimethylhydantoins
shows,
in
large
part,
negative
responses
in
the
studies
conducted.
Literature
reports
indicate
a
positive
effect
for
2
in
vitro
mammalian
cytogenetic
assays
in
Chinese
Hamster
Ovary
cells.

Available
metabolism
data
indicate
that
the
dimethylhydantoins
are
excreted
unchanged
in
the
rat.
However,
it
is
known
that
methylhydantoins
are
formaldehyde
releasers.
Therefore,
any
risk
assessment
involving
dietary
or
non­
dietary
exposure
to
the
methylhydantoins
will
also
involve
calculating
risk
from
formaldehyde
exposure.

On
July
25,
2000
,
the
Health
Effects
Division
(
HED)
Hazard
Identification
Assessment
Review
Committee
(
HIARC)
reviewed
the
recommendations
of
the
toxicology
reviewer
for
5,5­
dimethylhydantoin
(
a
chemical
representative
of
hydantoin
toxicity)
with
regard
to
the
acute
and
chronic
Reference
Doses
(
RfDs)
and
the
toxicological
endpoint
selection
for
use
as
appropriate
in
occupational/
residential
exposure
risk
assessments.
The
potential
for
increased
susceptibility
of
infants
and
children
from
exposure
to
this
hydantoin
was
also
evaluated
as
required
by
the
Food
Quality
Protection
Act
(
FQPA)
of
1996.
Endpoints
were
established
for
the
Halohydantoinss
and
a
report
issued.
A
summary
of
the
endpoints
selected
is
provided
at
the
end
of
this
chapter.
Page
5
of
41
2.0
TOXICOLOGY
DATA
REQUIREMENTS
The
requirements
(
CFR
158.340)
for
the
registered
uses
for
the
Halohydantoinss
are
in
Table
1.
Use
of
the
new
guideline
numbers
does
not
imply
that
the
new
(
1998)
guideline
protocols
were
used.

Table
1.
Toxicity
Data
Requirements
for
Halohydantoinss
Test
Technical
Required
Satisfied
870.1100Acute
Oral
Toxicity
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870.1200Acute
Dermal
Toxicity
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870.1300Acute
Inhalation
Toxicity
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870.2400
Primary
Eye
Irritation
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870.2500
Primary
Dermal
Irritation
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870.2600
Dermal
Sensitization
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yes
yes
yes
yes
yes
yes
yes
yes
yes
yes
yes
yes
870.3100
Oral
Subchronic
(
rodent)
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870.3150
Oral
Subchronic
(
nonrodent)
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870.3250
90­
Day
Dermal
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870.3465
90­
Day
Inhalation
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.
yes
yes
yes
yes
yes
no
yes
no
870.3700
Developmental
Toxicity
(
rodent)
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.
870.3700
Developmental
Toxicity
(
nonrodent)
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870.3800Reproduction
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yes
yes
yes
yes
yes
yes
870.4100Chronic
Toxicity
(
rodent)
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870.4100Chronic
Toxicity
(
nonrodent)
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870.4200
Oncogenicity
(
rat)
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870.4200
Oncogenicity
(
mouse)
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yes
yes
yes
yes
yes1
yes
yes
yes
870.5100Mutagenicity
C
Gene
Mutation
­
bacterial
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.
.
870.5375Mutagenicity
C
Structural
Chromosomal
Aberrations
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870.5550Mutagenicity
C
Other
Genotoxic
Effects
.
.
.
.
yes
yes
yes
yes
yes
yes
870.6100
Acute
Delayed
Neurotox.
(
hen)
.
.
.
.
.
.
.
.
.
.
870.6300
Developmental
Neurotoxicity
.
.
.
.
.
.
.
.
.
.
.
.
no
no
­­

870.7485
General
Metabolism
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
yes
yes
1Satisfied
by
chronic/
oncogenicity
study
Page
6
of
41
3.0
DATA
GAPS
A
90­
day
inhalation
toxicity
study
in
rats
is
required
because
of
the
concerns
for
inhalation
exposure
to
formaldehyde
as
a
result
of
the
degradation
of
hydroxymethyl­
5,5­
dimethylhydantoin
and
1,3­
bis(
hydroxymethyl­
5,5­
dimethylhydantoin)
into
free
formaldehyde
and
dimethylhydantoin.
Data
on
the
inhalation
toxicity
of
formaldehyde
are
also
relevant
for
assessing
risks
posed
by
inhalation
5,5­
DMH.
The
Agency
for
Toxic
Substances
and
Disease
Registry
has
recently
published
a
Toxicology
Profile
for
Formaldehyde
(
July,
1999).
Minimal
Risk
Levels
(
MRLs)
have
been
developed
for
inhalation
exposure
to
formaldehyde.
Acute,
Intermediate,
and
Chronic
MRLs
of
0.04
ppm,
0.03
ppm,
and
0.008
ppm
have
been
selected
for
formaldehyde
based
on
human
data
(
acute
and
chronic
MRLs)
or
animal
data
(
intermediate).
These
can
be
used
in
assessing
risk
from
inhalation
exposure
to
formaldehyde
as
a
result
of
its
formation
from
breakdown
of
dimethylhydantoins.

4.0
HAZARD
ASSESSMENT
4.1
Acute
Toxicity
Adequacy
of
data
base
for
acute
toxicity:
The
data
base
for
acute
toxicity
is
considered
complete.
No
additional
studies
are
required
at
this
time.

The
acute
toxicity
data
on
technical
Halohydantoins
is
summarized
below
in
Table
2.

Table
2.
Acute
Toxicity
Profile
for
the
Halohydantoins
Guideline
No./
Study
Type
MRID
No.
(
TRID
No.)
Results
Toxicity
Category
5,5­
Dimethylhydantoin
870.1100
Acute
oral
(
gastric
intubation)
toxicity
(
limit
test)­
Mouse
45738401
LD50
(
combined)
>
5,000
mg/
kg
IV
1­
Bromo­
3­
chloro­
5,5­
dimethylhydantoin
870.1100
Acute
oral
toxicity­
Rat
93074006,
00128244
(
4226­
010­
01)
LD50(
males)
=
1,350
mg/
kg
LD50(
females)
=
1,520
mg/
kg
LD50(
combined)
=
1,390
mg/
kg
III
870.1100
Acute
oral
toxicity­
Rat
93077008,
00147325
(
4600­
950­
21)
LD50(
males)
=
1,037
mg/
kg
LD50(
females)
=
860
mg/
kg
LD50(
combined)
=
929
mg/
kg
III
870.1300
Acute
inhalation
toxicity­
Rat
43654101
LC50(
males)
=
0.157
mg/
L
LC50(
females)
=
0.213
mg/
L
LC50(
combined)
=
0.168
mg/
L
II
Page
7
of
41
870.2500
Acute
dermal
irritation­
Rabbit
93074011,
93075014,
00128242
(
4225­
014­
10)
severe
skin
irritant
I
870.2500
Acute
dermal
irritation­
Rabbit
93077009,
00147326
(
4600­
950­
22)
severe
skin
irritant
I
870.2600
Skin
sensitization­
Guinea
pig
41670001
positive
sensitizer
N/
A
1,3­
Dibromo­
5,5­
dimethylhydantoin
870.1100
Acute
oral
toxicity­
Rat
93076011,
00137105
(
4334­
012­
01)
LD50
=
760
mg/
kg
III
870.1200
Acute
dermal
toxicity­
Rabbit
93076025,
00137110
(
4334­
012­
07)
LD50
cannot
be
ascertained
(
study
is
classified
as
Unacceptable/
non­
guideline
­­

870.2500
Acute
dermal
irritation­
Rabbit
93076017,
00137109
(
4334­
012­
05)
severe
skin
irritant
I
1,3­
Dichloro­
5,5­
dimethylhydantoin
870.1200
Acute
dermal
toxicity­
Rabbit
93076013,
00084176
(
2402­
448­
05)
LD50
>
20,000
mg/
kg
IV
870.2500
Acute
dermal
irritation­
Rabbit
93076017,
00137109
(
2402­
448­
01)
severe
skin
irritant
I
4.2
Subchronic
Toxicity
Adequacy
of
data
base
for
subchronic
toxicity:
The
data
base
for
subchronic
toxicity
of
Halohydantoins
is
complete.

870.3100
90­
Day
Oral
Toxicity
­
Rat
Executive
Summary:
In
a
subchronic
toxicity
study
(
MRID
42009201),
Dimethylhydantoin
(>
99.5%
a.
i.)
was
administered
orally
by
gavage
to
15
Crl:
CDBR
(
Sprague­
Dawley)
rats/
sex
at
dose
levels
of
0,
100,
300,
or
1000
mg/
kg/
day,
5
days/
week
for
13
weeks.

There
were
neither
treatment­
related
deaths
not
treatment­
related
clinical
signs
of
toxicity
in
any
animal.
No
biologically
significant
effects
were
seen
on
body
weight,
body
weight
gain,
or
food
consumption
in
either
sex.
Hematology
and
clinical
chemistry
analyses
revealed
no
significant
differences
from
controls;
urinalysis
was
not
performed.
Page
8
of
41
Statistically
significant
decrements
in
absolute
and
relative­
to­
body
liver
weights
were
reported
for
high­
dose
males,
but
the
decrement
in
liver­
relative­
to­
brain
weight
was
not
statistically
significant
nor
were
the
differences
considered
toxicologically
significant
in
the
absence
of
histopathological
or
clinical
chemistry
correlates
indicative
of
toxicity.
A
16%
(
p<
0.05)
increase
in
absolute
liver
weight
in
the
high­
dose
female
group
and
increases
relative­
to­
body
weight
in
the
high­
dose
and
mid­
dose
females
were
not
considered
toxicologically
significant
in
the
absence
of
significantly
increased
relative­
to­
body
or
brain
weight
or
histopathological
or
clinical
chemistry
correlates.
The
8.7%
(
p<
0.05)
increase
in
kidney
weight
of
the
high­
dose
female
group
was
considered
toxicologically
insignificant
in
the
absence
of
increased
relative­
to­
body
or
brain
weight
and
the
absence
of
clinical
chemistry
or
histopathological
findings.
The
higher
mean
kidney
weight
was
likely
related
to
the
higher
body
weight
of
this
group.
There
were
no
treatment­
related
gross
or
microscopic
lesions
in
any
examined
tissue.
Since
the
highest
dose
and
evaluation
of
higher
doses
was
not
necessary.

No
treatment­
related
neoplastic
findings
were
reported.

The
Subchronic
Toxicity
NOAEL
is
greater
than
or
equal
to
1000
mg/
kg/
day
(
highest
dose
tested).
The
LOAEL
is
greater
than
1000
mg/
kg/
day
(
not
established).

This
subchronic
toxicity
study
is
classified
as
Acceptable­
guideline
as
it
satisfies
the
guideline
requirement
for
a
subchronic
oral
study
[
OPPTS
870.3100
(
§
82­
1)]
in
rats
870.3100
28­
Day
Oral
Toxicity
­
Mouse
Executive
Summary:
The
test
compound,
Dimethylhydantoin[
100%
a.
i.],
was
offered
on
a
continuous
basis
in
the
diet
to
four
(
4)
groups
of
5
animal/
sex
of
Charles
River
CD­
1
mice
for
a
period
of
4
weeks
[
MRID
45738402].
Dose
levels
of
0,
1000
[
males:
177,
females:
289
mg/
kg/
day],
5,000
[
males:
945,
females:
1231
mg/
kg/
day],
10,000
[
males:
1612,
females:
2866
mg/
kg/
day]
and
50,000
[
males:
10,057,
females:
14,972
mg/
kg/
day]
ppm
were
selected
for
the
study.
All
mice
were
observed
twice
daily
for
mortality
and
signs
of
over
toxicity.
Detailed
physical
examinations,
individual
body
weights
and
food
consumption
were
recorded
weekly.
Clinical
pathology
parameters
were
evaluated
at
study
termination.
Complete
gross
necropsy
examinations
were
performed
at
the
scheduled
sacrifice
and
selected
organs
were
weighed.
A
microscopic
examination
was
conducted
on
selected
tissues
from
all
animals.

No
compound­
related
effect
was
apparent
at
any
dose
level
on
survival,
clinical
observations,
body
weight
data,
food
consumption,
hematology
parameters
organ
weight,
or
macroscopic
or
microscopic
findings.
Mean
serum
alkaline
phosphatase
in
the
female
50,000
ppm
group
was
significantly
increased
(
60%,
p<
0.05)
when
compared
to
the
control
group.
No
other
differences
in
serum
chemistry
parameters
were
apparent
between
the
control
and
treated
groups.

The
Subchronic
Toxicity
NOAEL
is
greater
than
or
equal
to
50,000
ppm
[
males:
10,057,
females:
14972
mg/
kg/
day]
(
highest
dose
tested).
The
LOAEL
is
greater
than
50,000
ppm
[
males:
10,057,
females:
14,972
mg/
kg/
day]
(
not
established).
Page
9
of
41
870.3150
90­
Day
Oral
Toxicity
­
Dog
No
study
is
available.
However,
a
chronic
toxicity
study
is
available
in
the
dog.

870.3200
21/
28­
Day
Dermal
Toxicity
B
Rat
No
study
is
available.
However,
a
90­
day
dermal
toxicity
study
is
available.

870.3250
90­
Day
Dermal
Toxicity
B
Rat
Executive
Summary:
In
a
90­
day
subchronic
toxicity
study
(
MRID
#
43173901),
male
and
female
CD
rats
were
treated
with
5,5­
dimethylhydantoin
(
DMH)
by
dermal
occlusion
at
doses
of
0,
39,
130,
or
390
mg/
kg/
day
for
6
hours/
day,
5
days/
week
for
13
weeks.

No
statistically
significant
differences
in
group
mean
body
weight
or
cumulative
weight
gain
was
observed
at
any
dose
level
tested.
There
were
no
treatment­
related
effects
on
mortality,
skin
irritation,
or
clinical
signs
of
toxicity
in
males
or
females
at
any
dose
level
tested.
DMH
caused
no
significant
changes
in
hematology,
clinical
chemistry,
or
gross
and
microscopic
pathology
in
male
or
female
rats.
Absolute
weight
of
the
adrenal
gland
was
significantly
decreased
in
male
rats
at
the
39
and
390
mg/
kg/
day
dose
levels
(
12.5%
and
13.6%,
respectively).
Adrenal
to
body
weight
ratio
was
also
decreased
by
11.1%
in
female
rats
at
130
ppm.
The
differences
in
adrenal
weight
were
considered
unrelated
to
treatment
as
there
was
no
definitive
dose­
response
and
there
was
no
evidence
of
microscopic
lesions.

In
this
study
,
the
NOAEL
was
determined
to
be
390
mg/
kg/
day
(
the
highest
dose
tested),
and
the
LOAEL
is
greater
than
390
mg/
kg/
day
(
not
established).

This
study
is
classified
as
Acceptable­
Guideline
and
it
satisfies
the
guideline
requirements
for
a
subchronic
toxicity
study
[
OPPTS
870.3250
(
§
82­
1b)]
in
rats.
Higher
doses
of
DMH
were
not
possible
in
this
study;
thus,
although
a
limit
dose
was
not
tested,
the
study
is
considered
acceptable.

870.3465
90­
Day
Inhalation
B
Rat
This
study
is
required
to
assess
risks
from
formaldehyde
exposure,
but
will
be
assessed
in
the
RED
assessment
for
formaldehyde.
Page
10
of
41
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.

Developmental
toxicity
testing
in
the
rat
showed
no
increase
in
susceptibility
of
the
fetus
to
the
toxic
effects
of
DMH
because
maternal
toxicity
occurred
at
the
highest
dose
tested
in
the
absence
of
fetal
effects.
In
a
prenatal
developmental
study
in
rabbits,
there
is
quantitative
evidence
of
increased
susceptibility
for
this
species;
fetal
and
litter
effects
(
increased
incidence
of
27th
presacral
vertebrae)
occurred
at
a
lower
dose
level
than
that
for
maternal
toxicity
(
decreased
body
weight
and
food
consumption
during
the
dosing
period)
following
exposure
to
dimethylhydantoin.
However,
in
a
second
prenatal
developmental
toxicity
study
that
used
ethylmethylhydantoin
as
the
test
material,
rabbits
showed
no
increase
in
susceptibility
of
the
fetuses.

870.3700
Prenatal
Developmental
Toxicity
Study
­
Rat
Executive
Summary:
In
a
developmental
toxicity
study
(
MRID
#
42432701),
mated
female
CD
rats
were
administered
DMH
(
99.8%
a.
i.)
by
gavage
(
in
filtered
water)
at
dose
levels
of
0,
100,
300,
or
1000
mg/
kg/
day
on
gestation
days
6­
15,
inclusive.

There
were
no
treatment­
related
effects
on
mortality,
clinical
signs,
food
consumption,
gross
pathology
or
Caesarean
section
observations
in
dams
administered
DMH
at
any
dose
level
tested.
Maternal
toxicity
was
observed
at
1000
mg/
kg
and
consisted
of
a
transient
decrease
in
body
weight
gain
(
16%)
on
gestation
days
12­
15
for
this
dose
group.
The
maternal
toxicity
NOAEL
is
300
mg/
kg/
day
and
the
maternal
toxicity
LOAEL
is
1000
mg/
kg/
day
based
on
the
transient
decrease
in
body
weight
gain
during
gestation
days
9­
12.

No
statistically
significant
differences
were
observed
between
the
treated
and
control
groups
for
number
of
corpora
lutea/
doe,
implantations/
doe,
pre­
or
postimplantation
loss,
resorptions/
doe,
or
fetal
sex
ratios.

There
was
no
evidence
of
developmental
toxicity
in
fetuses
at
any
dose
level
tested;
external,
visceral
and
skeletal
malformations
occurred
at
similar
incidences
across
dose
groups
or
occurred
as
single,
sporadic
events.
Based
on
the
results
of
this
study,
the
developmental
toxicity
NOAEL
is
greater
than
or
equal
to
1000
mg/
kg/
day
(
highest
dose
tested),
and
the
developmental
toxicity
LOAEL
is
greater
than
1000
mg/
kg/
day
(
not
established).

This
study
is
classified
as
Acceptable­
Guideline
and
satisfies
the
guideline
requirements
for
a
developmental
toxicity
study
[
OPPTS
870.3700
(
§
83­
3)]
in
rats.

Executive
Summary:
In
a
developmental
toxicity
study
(
MRID
#
42413101),
groups
of
artificially
inseminated
New
Zealand
White
Rabbits
(
20/
dose)
were
administered
5,5­
dimethylhydantoin
(
DMH)
by
gavage
on
gestation
days
6
through
18
at
doses
of
0,
100,
500,
and
1000
mg/
kg/
day
in
a
dose
volume
of
5
ml/
kg.
Page
11
of
41
Maternal
toxicity
was
observed
at
the
1000
mg/
kg/
day
dose
level
as
decreased
body
weight
gain
and
decreased
food
consumption
during
the
dosing
period.
The
Maternal
Toxicity
NOAEL
is
500
mg/
kg/
day.
The
Maternal
Toxicity
LOAEL
is
1000
mg/
kg/
day
based
on
decreased
body
weight
and
food
consumption
during
the
dosing
period.

No
statistically
significant
differences
were
observed
between
the
treated
and
control
groups
for
number
of
corpora
lutea/
doe,
implantations/
doe,
pre­
or
postimplantation
loss,
resorptions/
doe,
or
fetal
sex
ratios.

Developmental
toxicity
was
observed
at
the
500
mg/
kg/
day
dose
level
as
an
increased
incidence
of
skeletal
variations
of
the
27th
presacral
vertebrae
(
fetal
incidence
of
39/
134,
42/
140,
82/
145,
and
91/
123;
litter
incidence
of
11/
16,
11/
18,
17/
19,
and
17/
17
respectively).
The
increased
incidence
at
500
mg/
kg/
day
exceeded
both
the
concurrent
and
historical
control
incidence.
The
Developmental
Toxicity
NOAEL
is
100
mg/
kg/
day
and
the
Developmental
toxicity
LOAEL
is
500
mg/
kg/
day
based
on
the
increased
incidence
of
27th
presacral
vertebrae.

This
study
is
classified
as
Acceptable­
Guideline
and
satisfies
the
guideline
[
870.3700;
(
§
83­
3)]
for
a
developmental
toxicity
study
in
the
rabbit.

870.3700
Prenatal
Developmental
Toxicity
Study
­
Rabbit
EXECUTIVE
SUMMARY:
In
a
developmental
toxicity
study
(
MRID
42205401),
20
presumed
pregnant
New
Zealand
rabbits
per
group
were
administered
5­
Ethyl­
5­
methylhydantoin
(
EMH)
(
99.5%
a.
i.;
Batch
No.:
II)
by
gavage
at
doses
of
0,
50,
125,
or
375
mg/
kg/
day
on
gestation
days
(
GD)
6­
18,
inclusive
(
phase
I).
When
no
toxicity
was
observed
at
the
highest
dose
tested,
an
additional
control
group
and
a
1000
mg/
kg/
day
group
were
evaluated
later
(
phase
II).
On
GD
29,
all
surviving
does
were
sacrificed
and
all
fetuses
were
weighed
and
examined
for
external
malformations
variations.
Each
fetus
was
examined
viscerally
by
gross
dissection
and
the
sex
determined.
The
gross
pathology
of
the
brain
of
each
fetus
was
examined.
All
carcasses
were
processed
for
skeletal
examination.

The
only
treatment­
related
clinical
sign
of
toxicity
among
surviving
animals
was
the
observation
of
small
amount
or
no
stool
in
16/
20
does
in
the
1000
mg/
kg/
day
group
vs
6/
20
in
the
concurrent
control
group.
A
high­
dose
doe
was
killed
on
GD
22
and
another
was
found
dead
on
GD
21
following
apparent
abortions
by
both
of
these
animals.
In
addition,
three
high­
dose
does
were
sacrificed
moribund,
one
each
on
GD
15,
16,
and
18,
after
the
observations
of
emaciation,
hypoactivity,
and/
or
prostration.
All
other
does
survived
to
terminal
sacrifice.
No
treatmentrelated
findings
were
observed
in
any
animal
at
necropsy.

No
effects
on
maternal
body
weights,
body
weight
gains,
or
food
consumption
were
observed
at
doses
of
375
mg/
kg/
day
and
lower.
In
the
high
dose
group,
lower
body
weight
gains
occurred
in
the
high­
dose
group
(
p

0.05
or
0.01)
during
the
intervals
of
GD
9­
12,
12­
15,
and
18­
21.
The
high­
dose
group
also
had
an
overall
decrease
in
the
rate
of
weight
gain
during
the
entire
dosing
interval
(­
183.3
gm
vs.
39.9
gm
in
the
control;
p

0.01)
and
during
the
entire
study
(
47.7
gm
vs.
274.3
gm
in
the
control;
p

0.05).
Page
12
of
41
Food
consumption
by
the
high­
dose
group
was
significantly
(
37­
63%
vs.
controls;
p

0.01)
during
the
intervals
of
GD
6­
9,
9­
12,
12­
15,
15­
18,
and
18­
21.
This
resulted
in
significantly
(
p

0.01)
lower
food
consumption
by
the
high
dose
group
during
the
entire
dosing
interval
and
overall
for
the
study
(
51%
and
24%
vs.
controls,
respectively).
Therefore,
the
Maternal
Toxicity
LOAEL
is
1000
mg/
kg/
day
based
on
mortality,
reduced
body
weights
gains
and
reduced
food
consumption.
The
Maternal
Toxicity
NOAEL
is
375
mg/
kg/
day.

No
statistically
significant
differences
were
observed
between
the
treated
and
control
groups
for
number
of
corpora
lutea/
doe,
implantations/
doe,
pre­
or
postimplantation
loss,
resorptions/
doe,
or
fetal
sex
ratios.

Body
weights
of
the
high­
dose
female
fetuses
were
significantly
(
12%;
p

0.05)
less
than
the
concurrent
controls.
Body
weights
of
the
high­
dose
male
fetuses
were
not
statistically
different
from
the
concurrent
controls;
however,
the
mean
weight
of
the
treated
group
was
also
12%
vs.
the
control
level.
No
dose­
or
treatment­
related
external,
visceral,
or
skeletal
malformations/
variations
were
observed
in
any
fetus.
Therefore,
the
Developmental
Toxicity
LOAEL
is
1000
mg/
kg/
day
based
on
decreased
fetal
body
weights
and
the
Developmental
Toxicity
NOAEL
is
375
mg/
kg/
day.

This
study
is
classified
as
Acceptable/
guideline
and
satisfies
the
guideline
requirements
for
a
developmental
toxicity
study
(
§
83­
3)
in
rabbits.

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

No
increased
susceptibility
was
observed
in
the
reproduction
studies.

870.3800
Reproduction
and
Fertility
Effects
­
Rat
Executive
Summary:
In
a
two­
generation
reproduction
study
(
MRID
42462502),
groups
of
28
male
and
28
female
F0
and
F1
rats
were
administered
5,5­
dimetylhydantoin
(
0,
2000,
6000
or
20000
ppm)
in
their
diets
for
10
weeks
before
mating
and
during
mating,
gestation,
and
lactation.
Calculated
doses
were
136
and
127,
408
and
379,
and
1396
and
1322
mg/
kg/
day,
respectively,
for
F0
and
F1
males
(
premating/
postmating
periods)
and
176
and
158,
516
and
475,
and
1775
and
1602
mg/
kg/
day,
respectively
for
F0
and
F1
females
(
premating
periods
only).

There
was
no
evidence
that
dietary
administration
of
5,5­
dimethylhydantoin
resulted
in
treatmentrelated
effects
on
mortality,
clinical
signs
of
toxicity,
gross
lesions,
or
microscopic
lesions
in
Fo
or
F1
adult
rats
of
either
sex.
Body
weights
and
body
weight
gain
were
significantly
increased
in
Fo
males
fed
20,000
ppm
of
the
test
material
during
the
mating
and
postmating
periods.
The
increased
body
weight
is
not
considered
to
be
a
toxic
response,
because
food
consumption
was
Page
13
of
41
also
significantly
increased
during
the
same
period.
There
were
no
treatment­
related
effects
on
body
weight
or
body
weight
gain
in
F0
and
F1
females
during
the
premating
period.
Body
weights
and
body
weight
gain
in
F0
and
F1
females
during
gestation
and
lactation
were
similar
to
their
corresponding
controls
except
for
a
significantly
elevated
body
weight
gain
(
213%)
during
lactation
of
F0
females
receiving
20,000
ppm
of
DMH.
There
was
a
nonsignificant
increase
(
122%)
in
body
weight
gain
during
lactation
of
the
F1
females
receiving
20,000
ppm
of
DMH.
The
increased
body
weight
gain
is
not
considered
to
be
a
toxic
effect.
The
parental/
systemic
toxicity
NOAEL
is
equal
to
or
greater
than
the
highest
dose
tested,
20,000
ppm
(
1322
and
1602
mg/
kg/
day,
respectively)
for
male
and
female
rats.
The
parental/
systemic
toxicity
LOAEL
cannot
be
established
(
greater
than
20,000
ppm)
because
of
the
absence
of
toxicity
at
any
dose
tested.
In
addition,
the
lack
of
toxicity
at
doses
greater
than
the
limit
dose
of
1000
mg/
kg/
day,
suggests
that
the
test
material
has
low
systemic
toxicity.

The
indices
(
mating,
fertility,
and
fecundity)
of
reproductive
performance
in
F0
and
F1
animals
were
similar
to
those
of
their
corresponding
controls;
no
treatment­
related
effects
were
observed
on
the
indices
of
reproductive
performance
as
well
as
litter
size,
pup
viability,
pup
survival
or
sex
ratio.
The
NOAEL
for
reproductive
toxicity
is
equal
to
or
greater
than
20,000
ppm
(
1322
and
1602
mg/
kg/
day
for
males
and
females,
respectively)
and
the
corresponding
reproductive
toxicity
LOAEL
is
greater
than
20,000
ppm
(
not
established).

Growth
of
F1
and
F2
pups
was
reduced
as
indicated
by
lower
body
weights
(
7
to
8%;
males
and
females
combined)
and
body
weight
gain
(
7
to13%)
between
day
7
of
lactation
and
weaning
in
high­
dose
(
20,000
ppm)
pups
compared
with
the
controls.
Body
weights
were
still
significantly
lower
on
day
28
in
F1
and
F2
females
weanlings
compared
with
controls.
However,
these
effects
may
be
explained
as
a
transient
rejection
of
the
treated
diets
by
the
pups
since
the
decreased
body
weight
and
body
weight
gain
were
seen
only
during
a
two
week
period
that
coincides
with
the
period
in
time
that
the
pups
begin
eating
solid
food.
In
the
absence
of
any
other
reproductive
effect,
the
fact
that
the
body
weight
effects
were
not
observed
at
birth
or
during
the
first
week
after
birth
rules
out
any
relationship
to
reproduction.
The
opinion
of
the
study
authors
is
supported
by
US
EPA
Guideline
for
Reproductive
Toxicity
Risk
Assessment
(
61
Fed.
Reg.
56273­
56322,
October
31,
1996)
that
do
not
list
isolated
changes
in
growth
during
the
latter
stages
of
lactation
as
adverse
reproductive
findings.
Therefore,
the
NOAEL
for
offspring
toxicity
is
equal
to
or
greater
than
20,000
ppm
(
1322
and
1602
mg/
kg/
day
for
males
and
females,
respectively)
and
the
corresponding
offspring
toxicity
LOAEL
is
greater
than
20,000
ppm
(
not
established).

This
study
is
classified
as
Acceptable­
Guideline
and
it
satisfies
the
guideline
requirements
for
for
a
two­
generation
reproductive
toxicity
study
[
870.3800
(
§
83­
4]
in
rats.
Page
14
of
41
4.5
Chronic
Toxicity
Adequacy
of
data
base
for
chronic
toxicity:
The
data
base
for
chronic
toxicity
is
considered
complete.

The
combined
chronic/
carcinogenicity
studies
in
rat
showed
a
decrement
in
body
weight
and
body
weight
gain
in
females
and
increased
mortality,
particularly
in
females.
Males
showed
increased
incidences
of
hyperplasia
of
submandibular
lymph
nodes,
and
testicular
fibroid
vascular
degeneration
in
early
decedents.
Both
sexes
showed
increased
mammary
galactoceles
in
early
decedents
and
enlarged
pituitary
glands.
In
two
chronic
toxicity
studies
conducted
in
dogs,
dimethylhydantoin
produced
slight
(
hypertrophy
in
the
adrenal
cortex
of
male
dogs
upon
microscopic
examination)
to
no
toxicity
at
or
above
the
limit
dose
of
1000
mg/
kg/
day.

870.4100a
(
870.4300)
Chronic
Toxicity
B
Rat
Executive
Summary:
In
a
chronic
toxicity/
carcinogenicity
study
(
MRID
#
43397702),
5,5­
dimethylhydantoin
(
DMH)
was
administered
in
the
diet
to
groups
of
60
CD
rats/
sex/
dose
for
104
weeks
at
dietary
levels
of
0
(
first
control),
100,
300,
1000,
or
0
(
second
control)
mg/
kg/
day.
These
dosage
levels
correspond
to
dietary
concentrations
of
DMH
over
the
course
of
the
study
that
ranged
from
1080­
26794
ppm
(
males)
and
from
945­
20890
(
females).
[
Note:
5,5­
dimethylhydantoin
is
the
organic
moiety
of
1­
bromo­
3­
chloro­
5,5­
dimethylhydantoin.
The
Agency
agreed
that
toxicology
studies
on
the
technical
should
be
performed
on
the
organic
moiety.]

In
both
sexes
at
the
highest
dose
tested,
there
was
no
evidence
of
compound
related
effects
on
clinical
signs,
mortality,
food
consumption
and
organ
weights,
or
on
clinical
pathology.
At
the
highest
dose
level,
statistically
significant
(
p<
0.01
for
the
first
control
and
p<
0.05
for
the
second
control
groups)
treatment­
related
effects
on
body
weight
and
body
weight
gain
were
observed
in
females
only
at
weeks
90,
92,
and
96.
During
weeks
90
to
96
of
the
study,
body
weights
were
14­
15%
lower
than
control
1
and
9%
lower
than
control
2
and
the
body
weight
gains
were
23­
24%
lower
than
the
control
1
and
16%
lower
than
control
2.
There
were
statistically
significant
increased
incidences
of
hyperplasia
of
submandibular
lymph
nodes
[
5/
19
(
26%)
vs.
0/
31
to
1/
33
(
0­
3%)
of
both
controls]
at
week
104
(
p,
0.05
and
p<
0.01
for
the
controls
1
and
2,
respectively)
in
the
high
dose
males
only.
This
increased
incidence
was
considered
to
be
related
to
the
administration
of
the
DMH.

The
Chronic
Toxicity
NOAEL
is
300
mg/
kg/
day.
The
LOAEL
is
1000
mg/
kg/
day,
based
on
decreases
in
body
weight
and
body
weight
gain
in
females
and
hyperplasia
of
submandibular
lymph
nodes
in
males.

There
were
no
increases
in
tumor
incidences
for
the
DMH
treated
groups
when
compared
to
the
control
group.
This
study
is
classified
as
Acceptable­
guideline
and
satisfies
the
guideline
requirement
for
a
chronic
toxicity/
carcinogenicity
study
(
870.4300
§
83­
5)
in
rats.
Page
15
of
41
Executive
Summary:
In
a
chronic/
oncogenicity
toxicity
study
(
MRID
44095901),
dimethylhydantoin
(
DMH)
(
97.3%,
97.1%
and
93.5%
a.
i.
for
lot
#
6,
#
2412­
67­
D1,
and
#
2412­
67­
D2,
respectively)
was
administered
to
80
Crl:
CDBR
rats/
sex/
dose
in
the
diet
at
dose
levels
of
0,
100,
300,
or
1000
mg/
kg/
day
for
104­
105
weeks.
The
same
doses
of
DMH
were
given
to
20
rats/
sex/
dose
in
a
52­
week
interim
study.
The
concentration
of
DMH
in
the
diets
was
adjusted
weekly
according
to
body
weight
and
food
consumption
measurements
to
achieve
the
target
doses.

No
treatment­
related
statistically
significant
increases
in
the
incidences
of
any
lesion
were
seen
at
the
termination
of
this
105­
week
study.
However,
the
animals
that
died
during
the
study
tended
to
die
earlier
at
the
high
dose.
Mortality
during
treatment
weeks
52­
79
was
11%
in
control
males
and
15%
in
high
dose
males;
7%
in
control
females,
and
27%
(
p

0.001)
in
high
dose
females.
Significantly
increased
incidences
of
enlarged
pituitary
glands
were
found
in
high
dose
early
decedent
males
(
control,
20%;
high
dose,
38%,
p

0.05)
and
females
(
control,
33%;
high
dose,
61%,
p

0.05).
Pituitary
pars
distalis
adenomas
were
the
most
common
cause
of
early
deaths
in
the
study
and
contributed
to
the
increased
mortality
seen
during
weeks
52­
79
at
the
high
dose.
Increased
incidences
of
mammary
galactoceles
occurred
in
high
dose
early
decedent
females
(
control,
31%;
high
dose,
59%,
p

0.01).
The
incidence
of
testicular
fibrinoid
vascular
degenerations
was
increased
in
high
dose
males
(
control,
13%;
high
dose,
8%,
p

0.01).
The
incidence
of
iliac
lymph
node
lymphangiectasia
was
increased
in
high
dose
males
(
control,
13%;
high
dose,
26%)
and
females
(
control,
1%;
high
dose,
9%).
The
number
of
times
that
dried
yellow
matting
in
the
urogenital
area
was
observed
over
the
24­
month
treatment
period
increased
about
3­
fold
in
high
dose
males
and
females
compared
to
controls.
Urine
volume
roughly
doubled
in
high
dose
males
and
females,
and
specific
gravity
decreased
during
week
77.
Kidney
tubule
dilation
was
increased
in
high
dose
males
at
52
weeks
(
control,
65%;
high
dose,
100%,
p

0.01).
Lung
mineralization
at
52
weeks
was
increased
in
males
at
1000
mg/
kg/
day
(
68%,
p

0.05)
compared
to
the
controls
(
30%).
The
mean
absolute
brain
weight
was
slightly
decreased
in
high
dose
males
(
4%,
p

0.05)
compared
to
the
controls
at
52
weeks.

The
Chronic
Toxicity
NOAEL
is
320
mg/
kg/
day.
The
LOAEL
is
1000
mg/
kg/
day,
based
on
enlarged
pituitary
glands
in
decedents
of
both
sexes,
increased
mortality
occurring
early
in
(
especially)
females,
increased
mammary
galactoceles
in
early
decedents
of
both
sexes
and
testicular
fibroid
vascular
degeneration
in
early
decedent
males.

At
the
doses
tested,
there
was
not
a
treatment
related
increase
in
tumor
incidence
after
105
weeks
of
treatment
with
DMH.
The
increase
at
52
weeks
in
the
incidences
of
pituitary
adenomas
in
the
pars
distalis
in
high
dose
females
(
control,
10%;
high
dose,
50%,
p

0.01)
and
males
(
control,
10%;
high
dose,
32%,
N.
S.)
was
not
dose­
related.
There
were
no
differences
in
pituitary
adenoma
incidences
between
control
and
high
dose
groups
by
the
end
of
the
105­
week
study.
The
high
dose
of
1000
mg/
kg/
day
meets
the
limit
dose
requirement
for
non­
toxic
agents.

This
study
is
classified
as
Acceptable­
Guideline,
and
does
satisfy
the
guideline
requirements
for
a
chronic/
carcinogenicity
study
[
OPPTS
870.4300
(
§
83­
5)]
in
rats.
Page
16
of
41
870.4100b
Chronic
Toxicity
­
Dog
EXECUTIVE
SUMMARY:

In
a
chronic
toxicity
study
in
dogs
(
MRID
No.
43813301),
5,5­
dimethylhydantoin
(
97.4%
a.
i.)
was
administered
to
32
beagle
dogs
(
4/
sex/
dose)
by
capsule
at
dose
levels
of
0,
250,
500,
or
1000
mg/
kg/
day
for
52
weeks
(
capsules
given
7
days/
week).

There
were
no
treatment­
related
effects
on
mortality,
clinical
signs,
body
weight,
body
weight
changes,
food
consumption,
hematology,
clinical
chemistry,
urinalysis,
organ
weights,
organ/
body
weight
or
organ/
brain
weight
ratios,
ophthalmological
parameters,
or
gross
or
microscopic
results
from
histologic
examination
of
selected
tissues.
The
LOAEL
is
greater
than
1000
mg/
kg/
day
(
HDT),
based
on
the
lack
of
any
observable
toxic
effects.
The
NOAEL
is
greater
than
or
equal
to
1000
mg/
kg/
day.

This
chronic
toxicity
study
in
the
dog
is
classified
as
Acceptable­
guideline
and
does
satisfy
the
guideline
requirement
(
870.4100)
for
a
chronic
oral
study
in
the
dog.

EXECUTIVE
SUMMARY:

In
this
chronic
(
one­
year)
toxicity
study
(
MRID
No.
43553101),
purebred
beagle
dogs,
4/
sex/
group,
were
administered
5,5­
dimethylhydantoin
(
98.9%
a.
i.)
in
the
diet
att
levels
of
0,
4000,
12000,
or
40000
ppm
(
corresponding
to
measured
dose
levels
of
0,
120,
342,
or
1506
mg/
kg
body
wt./
day
for
males
and
0,
121,
414,
and
1352
mg/
kg
body
wt/
day
for
females,
respectively).

All
animals
survived
to
scheduled
sacrifice.
At
all
doses
tested,
5,5­
dimethylhydantoin
had
no
effect
on
body
weight
compared
with
control
values
at
any
time
period.
Statistically
significant
increases
in
the
absolute
weight
of
the
adrenals
and
adrenal
/
body
weight
and
adrenal
brain
weigh
ratios
were
observed
in
the
Group
IV
(
40000
ppm)
males;
no
other
statistically
significant
effects
on
organ
weight
or
organ
to
body
or
brain
weight
ratios
were
observed.
Increases
in
food
consumption
during
the
latter
half
of
the
study
(
weeks
26­
52)
by
Group
IV
(
40000
ppm)
males
most
likely
resulted
from
inaccurate
measurements
due
to
digging
in
the
food
hoppers
by
two
of
the
four
dogs
in
this
group;
decreases
in
food
consumption
by
females
in
all
dose
groups
was
neither
dose­
nor
time­
related
and
are
not
considered
to
be
related
to
treatment
with
5,5­
diethyl
hydantoin.
Neither
the
apparent
increases
or
decreases
in
food
consumption
were
reflected
by
corresponding
changes
in
body
weight.
5,5­
dimethylhydantoin,
at
all
dose
levels
tested,
had
no
statistically
significant
effect
on
any
of
the
hematology,
clinical
chemistry,
or
urinalysis
parameters
examined
for
either
males
or
females.
Treatment­
related
clinical
observations
included
discolored
feces
and
oily
coat
in
both
males
and
females,
with
the
latter
observation
most
prevalent
in
males.
Primarily
in
the
mid­
(
Group
III;
12000
ppm)
and
high­
(
Group
IV;
40000
ppm)
dose
groups,
gross
necropsy
revealed
treatment­
related
effects
on
the
ear
(
nodule,
scab,
red
color),
lymph
nodes
(
enlarged),
skin
(
alopecia,
red
color),
and
spleen
(
red
foci).
Microscopic
histopathology
revealed
hypertrophy
of
the
adrenal
cortex
in
all
four
males
in
the
high­
dose
group
(
Group
IV;
40000
ppm).
This
microscopic
finding
correlates
with
the
increased
weight
of
adrenals
and
Page
17
of
41
adrenal
weight
to
body
and
brain
weight
ratios
found
in
this
same
treatment
group.
This
finding
was
not
observed
in
males
or
females
in
the
control
group
or
mid­
(
Group
III;
12000
ppm)
or
low­
(
Group
II;
4000
ppm)
dose
treatment
groups.
The
NOAEL
is
12000
ppm
(
342
mg/
kg/
day)
and
the
LOAEL
is
40000
ppm
(
1506
mg/
kg/
day),
based
on
enlarged
adrenal
glands
in
male
dogs,
shown
by
microscopic
examination
to
exhibit
hypertrophy
in
the
adrenal
cortex.

4.6
Carcinogenicity
Adequacy
of
data
base
for
Carcinogenicity:
The
data
base
for
carcinogenicity
is
considered
complete.
No
additional
studies
are
required
at
this
time.

In
carcinogenicity
testing
of
rats
and
mice
there
is
some
evidence
of
target
organ
toxicity,
but
no
evidence
of
positive
tumorigenicity
for
the
test
material.

870.4200a
Carcinogenicity
Study
­
rat
See
chronic
toxicity/
carcinogenicity
studies
above
(
MRID
#
43397702
and
44095901).

870.4200b
Carcinogenicity
(
feeding)
­
Mouse
EXECUTIVE
SUMMARY:
(
MRID
#
43397701)
DMH
was
administered
in
the
diets
of
CD­
1
mice
at
dietary
concentrations
of
0,
400,
1850,
or
8500
ppm
(
target
doses
of
0,
100,
300,
or
1000
mg/
kg/
day)
for
78
weeks.
At
the
highest
dose
tested,
there
was
no
evidence
of
carcinogenicity,
nor
were
there
compound
related
clinical
signs,
effects
on
mortality
or
on
clinical
pathology.
In
males
at
the
highest
dose
level,
there
was
a
statistically
significant
(
4­
9%)
decrease
in
the
mean
absolute
body
weight
and
in
mean
body
weight
gain
(
19
and
28%,
respectively,
when
compared
to
controls
1
and
2)
which
persisted
from
week
16
of
the
study.
Based
on
the
decreases
in
body
weight
and
body
weight
gain
in
males,
the
NOAEL
is
300
mg/
kg
and
the
LOAEL
is
1000
mg/
kg.
No
signs
of
toxicity
were
reported
in
females.

The
study
satisfies
the
guideline
requirements
for
a
mouse
oncogenicity
study
as
set
forth
in
Subdivision
F,
Guideline
83­
2
(
870.4200).

EXECUTIVE
SUMMARY:
In
a
mouse
oncogenicity
study
(
MRID
4463901),
DMH
(
97.1­
97.3%
a.
i.)
was
administered
to
CD­
1
mice
(
80/
sex/
group)
for
18
months
at
0,
100,
320,
or
1000
mg/
kg/
day.
No
significant
differences
were
observed
in
survival
rates
in
male
or
female
mice
in
any
of
the
treated
groups
throughout
the
study
when
compared
to
the
respective
control
groups.
Overall
body
weight
gains,
leukocyte
differential
counts,
absolute
and
relative
organ
weights,
gross
necropsy,
as
well
as
microscopic
findings
for
both
sexes
at
all
doses
were
unaffected
by
treatment
with
DMH.
Page
18
of
41
Negligible
systemic
toxicity
was
characterized
by
statistically
significant
decreases
in
mean
body
weights
in
males
receiving
the
1,000
or
320
mg/
kg/
day
diets
(

3­
5%;
p<
0.05
or
0.01)
and
increases
in
mean
feed
consumption
by
the
high­
dose
animals
(

3.8­
9.8%;
p<
0.05
or
0.01).
The
biological
significance
of
these
small,
but
statistically
significant
differences
in
mean
body
weights
and
feed
consumption
is
unknown.

The
Systemic
Toxicity
NOAEL
is
greater
than
or
equal
to
1000
mg/
kg/
day
(
highest
dose
tested)
and
the
Systemic
Toxicity
LOAEL
is
greater
than
1000
mg/
kg/
day
(
not
established).

Under
the
conditions
of
this
study,
there
was
no
evidence
of
carcinogenic
potential
in
mice
following
treatment
with
DMH
and
the
dosing
was
considered
adequate
because
the
highest
dose
of
1000
mg/
kg/
day
represents
a
"
limit
dose."

This
study
is
classified
as
Acceptable­
Guideline
and
does
satisfy
the
guideline
requirements
for
a
carcinogenicity
study
[
OPPTS
870.4200
(
§
83­
2b)]
in
mice.

4.7
Mutagenicity
Adequacy
of
data
base
for
Mutagenicity:
The
data
base
for
Mutagenicity
is
considered
(
in)
adequate
based
on
pre
1991
mutagenicity
guidelines.
A
battery
of
mutagenicity
assays
were
performed;
including
reverse
mutation,
mammalian
cell
gene
mutation,
chromosome
aberration
and
unscheduled
DNA
damage.
In
most
assays
no
mutagenicity
was
observed;
however,
two
in
vitro
mammalian
cytogenetics
assays
in
Chinese
Hamster
Ovary
cells
indicated
positive
results.

Substance:
Dimethylhydantoin
Salmonella
Reverse
Gene
Mutation
Assay
In
an
Ames
Salmonella
assay
(
MRID
No.
164036,
Accession
number
265457),
5,5­
dimethylhydantoin
(
DHM)
was
tested
in
S.
tyhimurium
strains
TA1535,
TA
100,
TA1538,
TA98
and
TA1537
in
the
absence
and
presence
of
S9
metabolic
activation
at
concentrations
of
100,
500,
2500,
5000,
and
10,000

g/
plate.
There
was
neither
a
cytotoxic
nor
a
mutagenic
response
in
this
assay
at
any
dose
level
tested
in
the
absence
or
presence
of
metabolic
activation.

Substance:
Ethylmethylhydantoin
Salmonella
Reverse
Gene
Mutation
Assay
EXECUTIVE
SUMMARY:
In
a
reverse
gene
mutation
assay
in
bacteria
(
MRID
No.
137095,
TRID
No.
433401118),
S.
typhimurium
strains:
TA98,
TA100,
TA1535,
TA1537
and
TA1538
were
exposed
to
Ethylmethylhydantoin
(
Test
Article
447:
34­
4)
(
purity
not
provided)
in
water
at
concentrations
of
67,
333,
1667,
3333
and
6666
µ
g/
plate
in
the
presence
and
absence
of
mammalian
metabolic
activation
(
S9­
mix).
All
platings
were
in
triplicate.
The
S9­
fraction
was
obtained
from
Aroclor
1254
induced
male
Sprague­
Dawley
rat
liver.
Page
19
of
41
Ethylmethylhydantoin
was
tested
up
to
a
limit
concentration
of
6666
µ
g/
plate.
In
a
preliminary
cytotoxicity
assay
with
TA100
in
the
absence
of
S9­
mix,
no
cytotoxicity
(
as
determined
by
a
reduction
in
the
number
of
revertants
per
plate
or
by
a
thinning
or
absence
of
the
background
lawn
of
bacteria)
was
seen
at
concentrations
ranging
from
1.0
to
3333
µ
g/
plate.
In
the
mutagenicity
assay,
Ethylmethylhydantoin
did
not
affect
the
background
lawn
of
bacteria
or
increase
the
number
of
revertants
over
solvent
control
values
in
any
tester
strain
at
any
concentration,
with
or
without
S9­
mix.
The
solvent
and
positive
control
values
were
appropriate
for
each
of
the
five
tester
strains.
In
this
study,
there
was
no
evidence
of
induced
mutant
colonies
over
background.

This
study
is
classified
as
Acceptable/
nonguideline.
It
satisfies
the
requirement
for
FIFRA
Test
Guideline
§
84­
2
for
in
vitro
mutagenicity
(
bacterial
reverse
gene
mutation)
data
with
the
exception
that
no
confirmatory
assay
was
conducted.
In
the
absence
of
any
evidence
of
an
increase
in
the
number
of
revertants
per
plate
over
solvent
control
values
in
any
strain
at
any
concentration
up
to
10,000
µ
g/
plate,
and
with
acceptable
control
values,
this
omission
does
not
make
the
study
unacceptable.

Substance:
Dimethylhydantoin
Salmonella
typhimurium
Reverse
Mutation
Assay
EXECUTIVE
SUMMARY:
In
a
reverse
gene
mutation
assay
in
bacteria
(
MRID
No.
137100,
TRID
433401124),
S.
typhimurium
strains
TA98,
TA100,
TA1535,
TA1537
and
TA1538
were
exposed
to
Test
Article
447:
34­
2,
Dimethylhydantoin
(
purity
not
provided)
in
water
at
concentrations
of
100,
500,
2500,
5000
and
10,000
µ
g/
plate
in
the
presence
and
absence
of
mammalian
metabolic
activation
(
S9­
mix).
All
platings
were
in
triplicate.
The
S9­
fraction
was
obtained
from
Aroclor
1254
induced
male
Sprague­
Dawley
rat
liver.

DMH
was
tested
up
to
a
limit
concentration
of
10,000

g/
plate.
In
a
preliminary
cytotoxicity
assay
with
TA100
in
the
absence
of
S9­
mix,
no
cytotoxicity
(
as
determined
by
a
reduction
in
the
number
of
revertants
per
plate
or
by
a
thinning
or
absence
of
the
background
lawn
of
bacteria)
was
seen
at
concentrations
ranging
from
2.9
to
10,000
µ
g/
plate.
In
the
mutagenicity
assay,
DMH
did
not
affect
the
background
lawn
of
bacteria
or
increase
the
number
of
revertants
over
solvent
control
values
in
any
tester
strain
at
any
concentration,
with
or
without
S9­
mix.
The
solvent
and
positive
control
values
were
appropriate
for
each
of
the
five
tester
strains.
In
this
study,
there
was
no
evidence
of
induced
mutant
colonies
over
background.

This
study
is
classified
as
Acceptable/
nonguideline.
It
satisfies
the
requirement
for
FIFRA
Test
Guideline
§
84­
2
for
in
vitro
mutagenicity
(
bacterial
reverse
gene
mutation)
data
with
the
exception
that
no
confirmatory
assay
was
conducted.
In
the
absence
of
any
evidence
of
an
increase
in
the
number
of
revertants
per
plate
over
solvent
control
values
in
any
strain
at
any
concentration
up
to
10,000
µ
g/
plate,
and
with
acceptable
control
values,
this
omission
does
not
make
the
study
unacceptable.
Page
20
of
41
Substance:
5­
Ethyl,
5­
methylhydantoin
Mammalian
cells
in
Culture
Gene
Mutation
Assay
in
L5178Y
+/­
Mouse
Lymphoma
Cells
EXECUTIVE
SUMMARY:
In
a
mammalian
cell
gene
mutation
assay,
L5178Y
TK+/­
mouse
lymphoma
cells
(
MRID
No.
137089,
TRID
No.
433401121)
cultured
in
vitro
were
exposed
to
Ethylmethylhydantoin
(
purity
not
provided)
in
F
0
P
medium
(
Fisher's
media
for
leukemic
cells
of
mice
with
0.1%
Pluronic)
at
concentrations
of
751,
1001,
1335,
1780,
2373,
3164,
4219,
5000,
5625,
7500
µ
g/
mL
in
the
absence
of
mammalian
metabolic
activation
(
S9­
mix)
and
at
concentrations
of
563,
751,
1001,
1780,
2373,
3164,
4219,
5625,
7500,
10,000
µ
g/
mL
in
the
presence
of
S9­
mix.
The
S9­
fraction
was
obtained
from
Aroclor
induced
rat
liver.

Ethylmethylhydantoin
was
tested
up
to
limit
concentrations
of
7500
µ
g/
mL
in
the
absence
of
S9­
mix
and
of
10,000
µ
g/
mL
in
the
presence
of
S9­
mix.
In
the
preliminary
cytotoxicity
assay,
concentration
of
ethylmethylhydantoin
ranging
from
0.01
to
5000
µ
g/
mL
were
tested.
In
the
absence
of
S9­
mix,
no
cytotoxicity
was
seen
at
any
concentration
with
suspension
growth
ranging
from
92%
to
104%
of
the
solvent
control
with
no
dose
relationship.
In
the
presence
of
S9­
mix,
the
suspension
growth
ranged
from
62%
to
98%
of
the
solvent
control,
but
again
with
no
dose
relationship
(
the
62%
value
was
seen
at
the
lowest
concentration
tested
while
the
value
at
the
highest
concentration
tested
was
97%).
In
the
mutagenicity
assay,
suspension
growth,
measured
following
the
expression
period,
ranged
from
93%
to
109%
of
the
solvent
control
in
the
absence
of
S9­
mix
(
discounting
a
value
of
38%
at
1001
µ
g/
mL,
the
next
to
lowest
dose
tested)
and
from
94%
to
118%
of
the
solvent
control
in
the
presence
of
S9­
mix.
The
mutant
frequencies
in
cultures
treated
with
the
test
article
in
the
absence
of
S9­
mix
ranged
from
0.3
to
0.4
mutants
per
104
surviving
cells
in
a
non
dose­
dependent
manner
compared
to
the
solvent
control
value
of
0.3
mutants
per
104
surviving
cells.
The
mutant
frequencies
in
cultures
treated
with
ethylmethylhydantoin
in
the
presence
of
S9­
mix
ranged
from
0.9
to
1.6
mutants
per
104
surviving
cells
in
a
non
dose­
dependent
manner
compared
to
the
solvent
control
value
of
1.3
mutants
per
104
surviving
cells.
The
solvent
and
positive
controls
induced
the
appropriate
response.
In
this
study,
there
was
no
evidence
of
induced
mutant
colonies
over
background.

This
study
is
classified
as
Acceptable/
nonguideline.
It
satisfies
the
requirement
for
FIFRA
Test
Guideline
§
84­
2
for
in
vitro
mutagenicity
(
mammalian
forward
gene
mutation)
data
with
the
exception
that
no
confirmatory
assay
was
conducted.
This
omission
did
not
render
the
study
unacceptable
because
no
hint
of
an
increase
in
mutant
frequency
was
seen
at
any
test
material
concentration
up
to
10,000
µ
g/
mL,
and
the
solvent
and
positive
control
data
were
acceptable.

Substance:
Dimethylhydantoin
Mammalian
Cells
in
Cullture
Gene
Mutation
Assay
in
L5178Y
+/­
Mouse
Lyphoma
Cells
EXECUTIVE
SUMMARY:
In
a
mammalian
cell
gene
mutation
assay,
L5178Y
TK+/­
mouse
lymphoma
cells
(
MRID
No.
132165,
TRID
No.
433401127)
cultured
in
vitro
were
exposed
to
Dimethylhydantoin
(
purity
not
provided)
in
F
0
P
medium
(
Fisher's
media
for
leukemic
cells
of
mice
with
0.1%
Pluronic)
at
concentrations
of
563,
1001,
1335,
1780,
2373,
3164,
4219,
5625,
7500,
Page
21
of
41
10,000
diethel­
hydantoin

/
mL
in
the
absence
of
mammalian
metabolic
activation
(
S9­
mix)
and
at
concen­
trations
of
751,
1001,
1335,
1780,
2373,
3164,
4219,
5625,
7500,
10,000

g/
mL
in
the
presence
of
S9­
mix.
The
S9­
fraction
was
obtained
from
Aroclor
induced
rat
liver.

Dimethylhydantoin
was
tested
up
to
a
limit
concentration
of
10,000

g/
mL
in
the
absence
of
any
significant
cytotoxicity.
No
cytotoxicity
was
seen
at
concentrations
up
to
5000

g/
mL,
with
or
without
S9­
mix,
in
the
preliminary
cytotoxicity
test.
In
the
mutagenicity
assay,
suspension
growth
(
measured
following
the
expression
period)
without
S9­
mix
was
at
least
90%
of
the
solvent
control
value
at
all
concentrations
except
10,000

g/
mL
where
the
suspension
growth
was
75%
of
the
solvent
control.
In
the
presence
of
S9­
mix,
the
suspension
growth
was
at
least
93%
of
the
solvent
control
value
at
all
tested
concentrations.
The
concurrent
solvent
controls
for
the
nonactivated
part
of
the
study
were
lost
due
to
contamination;
therefore,
the
historical
solvent
control
value
obtained
from
170
previous
tests
in
the
absence
of
S9­
mix
was
used
for
comparative
calculations
(
0.46
mutants
per
104
surviving
cells
with
a
standard
deviation
of
0.19).
The
mutant
frequencies
in
cultures
treated
with
Dimethylhydantoin
in
the
absence
of
S9­
mix
ranged
from
0.4
to
0.7
mutants
per
104
surviving
cells
in
a
non
dose­
dependent
manner.
The
mutant
frequency
of
the
concurrent
solvent
control
in
the
presence
of
S9­
mix
was
0.8
mutants
per
104
surviving
cells
compared
to
a
range
of
mutant
frequencies
in
dimethylhydantoin
treated
cultures
ranging
from
0.4
to
0.9
mutants
per
104
surviving
cells
in
a
non
dose­
dependent
manner.
The
positive
controls
induced
the
appropriate
response.
In
this
study,
there
was
no
evidence
of
induced
mutant
colonies
over
background.

This
study
is
classified
as
Acceptable/
nonguideline.
It
satisfies
the
requirement
for
FIFRA
Test
Guideline
§
84­
2
for
in
vitro
mutagenicity
(
mammalian
forward
gene
mutation)
data
with
the
exception
that
no
confirmatory
assay
was
conducted.
This
omission
did
not
render
the
study
unacceptable
because
no
hint
of
an
increase
in
mutant
frequency
was
seen
at
any
test
material
concentration
up
to
10,000

g/
mL
with
or
without
S9­
mix,
and
the
solvent
and
positive
control
data
were
acceptable.

Substance:
5,5­
Dimethylhydantoin
In
Vitro
Mammalian
Cytogenics
Assay
in
CHO
Cells
EXECUTIVE
SUMMARY:
In
a
mammalian
cell
cytogenetics
assay
(
MRID
No.
164037,
TRID
No.
265457),
CHO
cell
cultures
were
exposed
to
5,5­
dimethylhydantoin
at
concentrations
of
200
to
2000
µ
g/
ml.

In
this
study,
there
was
no
evidence
of
structural
chromosomal
aberration
induction
over
background.

This
study,
therefore,
is
classified
as
Acceptable/
guideline.
It
satisfies
the
requirement
for
FIFRA
Test
Guideline
§
84­
2
for
in
vitro
cytogenetic
mutagenicity
data.
Page
22
of
41
Substance:
1,3­
Dichloro­
5,5­
ethylmethylhydantoin
In
Vitro
Mammalian
Cytogenetics
Assay
in
CHO
Cells
(
MRID
40348201)

In
a
mammalian
cell
cytogenetics
assay
(
MRID
40348201),
CHO
cell
cultures
were
exposed
to
1,3­
Dichloro­
5,5­
ethylmethylhydantoin
[
purity
not
provided]
dissolved
in
McCoy's
5A
medium
at
concentrations
of
60,
30,
15,
and
8
µ
g/
ml
for
22
hours
without
metabolic
activation
(
S9­
mix)
and
at
concentrations
of
120,
60,
30,
and
15
µ
g/
ml
for
16
and
22
hours
with
S9­
mix.
The
S9­
fraction
was
obtained
from
Arochlor­
1254
induced
male
Sprague­
Dawley
rat
liver.

1,3­
Dichloro­
5,5­
ethylmethylhydantoin
was
tested
up
to
cytotoxic
concentrations.
A
preliminary
cytotoxicity
test
was
performed
over
the
dose
range
0.02
to
200
µ
g/
ml;
treatment
was
for
6
hours
without
activation
and
for
2
hours
with
activation.
1,3­
Dichloro­
5,5­
ethylmethylhydantoin
reduced
cell
growth
in
a
dose­
dependent
manner
without
metabolic
activation;
with
activation,

only
the
highest
dose
reduced
cell
growth.
Metaphase
cells
were
rare
or
absent
at
200
µ
g/
ml
with
and
without
metabolic
activation.

In
the
cytogenetic
assay,
200
cells/
dose/
treatment
time/
activation
condition
were
scored
for
structural
chromosomal
aberrations.
Significant
increase
in
the
percentage
of
cells
with
structural
chromosomal
aberrations
(
mainly
chromatid
and
chromosome
breaks
and
dicentrics)
was
seen
at
the
highest
dose
tested
without
S9­
mix;
the
percentage
of
cells
with
structural
chromosomal
aberrations,
excluding
gaps,
reached
9.5%
at
60
µ
g/
ml.
This
result
meets
the
testing
laboratory's
criterion
for
a
"
suspect"
positive.
The
frequency
of
cells
with
structural
chromosome
aberrations
was
significantly
increased
in
cultures
treated
with
120
and
60
µ
g/
ml
for
16
hours
with
S9­
mix,
and
at
all
dose
levels
in
cultures
treated
for
22
hours
with
S9­
mix.
Positive
and
solvent
control
values
were
appropriate
throughout
the
study.
There
was
evidence
of
structural
chromosomal
aberration
induction
greater
than
background.

This
study
is
classified
as
Acceptable/
guideline.
It
satisfies
the
requirement
for
FIFRA
Test
Guideline
§
84­
2
for
in
vitro
cytogenetic
mutagenicity
data.

Substance:
Ethylmethylhydantoin
In
Vitro
Mammalian
Cytogenics
Assay
in
CHO
Cells
EXECUTIVE
SUMMARY:
In
a
mammalian
cell
cytogenetics
assay
(
MRID
No.
137096,
TRID
No.
433401119),
CHO
cell
cultures
were
exposed
to
Ethylmethylhydantoin
[
purity
not
provided]
at
concentrations
of
10,204.08,
7653.06,
and
5739.80
µ
g/
ml
for
4
hours
with
and
without
metabolic
activation
(
S9­
mix).
The
S9­
fraction
was
obtained
from
livers
of
Aroclor
1242/
1254­
induced
Sprague­
Dawley
rats
of
unspecified
sex.

Ethylmethylhydantoin
was
tested
up
to
the
maximum
soluble
dose.
A
preliminary
cytotoxicity
test
was
performed
using
seven
doses
ranging
from
10.204.08
down
to
10.36
µ
g/
ml.
Ethylmethyhydantoin
did
not
cause
dose
dependent
reduction
in
cell
growth
with
or
without
Page
23
of
41
metabolic
activation.
At
the
highest
dose,
relative
cloning
efficiency
was
88.78%
without
activation
and
113.71%
with
activation.

In
the
cytogenetic
assay,
50
cells/
dose/
treatment
time/
activation
condition
were
scored
for
visible
structural
and
numerical
frequency
of
chromosomal
aberrations.
A
two­
fold
or
greater
increase
in
the
percentage
of
cells
with
structural
chromosomal
aberrations,
excluding
gaps,
was
seen
at
two
nonconsecutive
doses
in
cultures
treated
with
S9­
mix.
No
dose
response
was
evident.
Results
from
the
treatment
without
S9­
mix
were
negative
at
all
doses.
Chromosome
numbers
were
recorded
but
no
increase
in
polyploid
cells
was
observed
in
treated
or
in
positive
control
cultures.
Positive
and
solvent
control
values
were
appropriate
throughout
the
study.
There
was
evidence
of
structural
chromosomal
aberration
induction
over
background
in
the
presence
of
metabolic
activation.

This
study
is
classified
as
Acceptable/
guideline.
It
satisfies
the
requirement
for
FIFRA
Test
Guideline
§
84­
2
for
in
vitro
cytogenetic
mutagenicity
data.

Substance:
5,5­
Dimethylhydantoin
In
Vitro
Mammalian
Cytogenics
Assay
in
CHO
Cells
EXECUTIVE
SUMMARY:
In
a
mammalian
cell
cytogenetics
assay
(
MRID
No.
137101,
TRID
No.
433401125),
CHO
cell
cultures
were
exposed
to
dimethylhydantoin
[
purity
not
provided]
in
the
absence
of
metabolic
activation
at
concentrations
of
20,000,
15,000,
and
11,250
µ
g/
ml
and
in
the
presence
of
metabolic
activation
at
concentrations
of
15,000,
11,250
and
8457.5
µ
g/
ml.
All
exposures
were
for
4
hours.
The
S9­
fraction
used
for
metabolic
activation
was
obtained
from
livers
of
Aroclor
1242/
1254­
induced
Sprague­
Dawley
rats
of
unspecified
sex.

Dimethylhydantoin
was
tested
up
to
the
maximum
soluble
dose.
A
preliminary
cytotoxicity
test
was
performed
using
nine
doses
ranging
from
10,000
down
to
0.99
µ
g/
ml.
Dimethylhydantoin
did
not
cause
dose
dependent
reduction
in
cell
growth
with
or
without
metabolic
activation.
At
the
highest
dose,
relative
cloning
efficiency
was
81.82%
without
activation
and
88.89%
with
activation.

In
the
cytogenetic
assay,
50
cells/
dose/
treatment
time/
activation
condition
were
scored
for
structural
and
numerical
chromosomal
aberrations.
A
two­
fold
or
greater
increase
in
the
percentage
of
cells
with
structural
chromosomal
aberrations,
excluding
gaps,
was
not
seen
at
any
dose
in
cultures
treated
with
or
without
S9­
mix.
Chromosome
numbers
were
recorded
but
no
increase
in
polyploid
cells
was
observed
in
treated
or
in
positive
control
cultures.
Positive
and
solvent
control
values
were
appropriate
throughout
the
study.
There
was
no
evidence
of
structural
chromosomal
aberration
induction
over
background.

This
study
is
classified
as
Acceptable/
guideline.
It
satisfies
the
guideline
requirement
for
an
in
vitro
cytogenetic
mutagenicity
assay
(
§
84­
2).
Page
24
of
41
Substance:
5,5­
Dimethylhydantoin
In
Vitro
Mammalian
Cytogenics
Assay
in
CHO
Cells
EXECUTIVE
SUMMARY:
In
a
mammalian
cell
cytogenetics
assay
(
MRID
No.
N/
A,
TRID
No.
470264004),
CHO
cell
cultures
were
exposed
to
5,5­
dimethylhydantoin
in
sterile
distilled
water
at
concentrations
of
800,
400
and
80
µ
g/
ml
for
20
hours
without
metabolic
activation
or
for
2
hours
with
metabolic
activation.
The
S9
fraction
was
obtained
from
Arochlor
1254­
induced
male
CD
rat
livers.

5,5­
dimethylhydantoin
was
tested
up
to
the
maximum
soluble
dose.
A
preliminary
cytotoxicity
test
was
performed
with
seven
doses
from
12.5
to
800
µ
g/
ml.
No
dose
related
effect
on
mitotic
index
was
observed
in
the
presence
or
the
absence
of
metabolic
activation.

In
the
cytogenetic
assay,
100
cells/
dose/
activation
condition
were
scored
for
structural
chromosomal
aberrations.
Statistically
significant
increase
in
the
percentage
of
cells
with
structural
chromosomal
aberrations
was
not
seen,
including
or
excluding
gaps,
at
any
dose
in
the
presence
or
absence
of
metabolic
activation.
Positive
and
solvent
control
values
showed
the
appropriate
results.

throughout
the
study.
In
this
study,
there
was
no
evidence
of
structural
chromosomal
aberration
induction
over
background.

This
study,
therefore,
is
classified
as
Acceptable/
guideline.
It
satisfies
the
requirement
for
FIFRA
Test
Guideline
§
84­
2
for
in
vitro
cytogenetic
mutagenicity
data.

Substance:
5,5­
Dimethylhydantoin
Unscheduled
DNA
Synthesis
in
Mamalian
Cells
in
Culture
EXECUTIVE
SUMMARY:
In
an
unscheduled
DNA
synthesis
(
UDS)
assay
in
HeLa
S3
cells
(
MRID
No.
N/
A,
TRID
No.
470264005),
cell
cultures
were
exposed
in
two
duplicate
experiments
to
twelve
concentrations
of
5,5­
dimethylhydantoin
ranging
[
purity
not
available]
from
10
to
20,480
µ
g/
ml.
The
test
material
was
dissolved
in
distilled
water
and
cells
were
exposed
for
180
minutes.
Autoradiography
was
used
to
detect
UDS.

No
cytotoxicity
assessment
was
made
but
5,5­
dimethylhydantoin
was
tested
to
the
maximum
soluble
dose.
Positive
and
solvent
control
produced
the
appropriate
results.
In
one
experiment,
one
relatively
low
dose
of
5,5­
dimethylhydantoin
produced
a
statistically
significant
increase
in
net
nuclear
grain
count.
No
increase
was
seen,
however,
at
higher
doses
in
that
experiment
and
the
increase
was
not
reproduced
in
the
second
experiment.
Therefore,
the
reproducibility
criterion
for
a
positive
response
was
not
met.
No
positive
UDS
response
to
5,5­
dimethylhydantoin
was
seen
in
the
assay.
Page
25
of
41
This
study
is
classified
as
Acceptable/
guideline.
It
satisfies
the
requirements
for
FIFRA
Test
Guideline
§
84­
2
for
other
genotoxic
mutagenicity
data.

Substance:
5,5­
Dimethylhydantoin
Unscheduled
DNA
Synthesis
in
Mamalian
Cells
in
Culture
EXECUTIVE
SUMMARY:
In
an
unscheduled
DNA
synthesis
(
UDS)
assay
in
primary
rat
hepatocytes
(
MRID
No.
164038,
Accession
No.
265457),
cell
cultures
were
exposed
to
5,5­
dimethylhydantoin
ranging
[
purity
not
available]
from
100
to
10,000
µ
g/
ml.

No
positive
UDS
response
to
5,5­
dimethylhydantoin
was
seen
in
the
assay.

This
study
is
classified
as
Acceptable/
guideline.
It
satisfies
the
requirements
for
FIFRA
Test
Guideline
§
84­
2
for
other
genotoxic
mutagenicity
data.

Substance:
Ethylmethylhydantoin
Unscheduled
DNA
Synthesis
in
Mammalian
Cells
in
Culture
EXECUTIVE
SUMMARY:
In
an
unscheduled
DNA
synthesis
(
UDS)
assay
in
rat
primary
hepatocytes
(
MRID
No.
137097,
TRID
No.
433401120),
cultures
of
primary
hepatocytes
from
adult
male
Sprague­
Dawley
rats
were
exposed
to
Ethylmethylhydantoin
at
concentrations
of
15,
10,
5,
1,
0.5
and
0.1
mg/
mL,
selected
on
the
basis
of
a
preliminary
cytotoxicity
test.
The
test
material
was
delivered
in
culture
medium
and
cells
were
exposed
for
18
hours.
The
autoradiographic
technique
was
used
to
detect
UDS.

Viability
as
assessed
by
trypan
blue
exclusion
was
used
as
the
measure
of
cytotoxicity.
Cytotoxicity
relative
to
the
solvent
control
was
almost
95%
at
the
highest
dose,
decreasing
to
15.5%
at
the
lowest
dose.
Positive
and
solvent
control
values
were
appropriate.
No
induction
of
UDS
was
seen
at
any
concentration
of
ethylmethylhydantoin
evaluated.

This
study
is
classified
as
an
Acceptable/
guideline.
It
satisfies
the
requirements
for
FIFRA
Test
Guideline
§
84­
2
for
a
UDS
study
in
mammalian
cells
in
culture.

Substance:
Dimethylhydantoin
Unscheduled
DNA
Synthesis
in
Mamalian
Cells
in
Culture
EXECUTIVE
SUMMARY:
In
an
unscheduled
DNA
synthesis
(
UDS)
assay
in
rat
primary
hepatocytes
(
MRID
No.
132166,
TRID
No.
433401126),
cultures
of
primary
hepatocytes
from
adult
male
Sprague­
Dawley
rats
were
exposed
to
Dimethylhydantoin
(
purity
not
provided)
at
concentrations
of
20,
10,
1,
0.1,
0.01,
and
0.001
mg/
ml,
selected
on
the
basis
of
a
preliminary
cytotoxicity
test.
The
test
material
was
delivered
in
culture
medium
and
cells
were
exposed
for
18
hours.
The
autoradiographic
technique
was
used
to
detect
UDS.
Page
26
of
41
Viability
as
assessed
by
trypan
blue
exclusion
was
used
as
the
measure
of
cytotoxicity.
Cytotoxicity
relative
to
the
solvent
control
was
70.4%
at
the
highest
dose
tested,
although
the
same
dose
produced
relative
toxicity
of
only
26.21%
in
the
preliminary
assay.
Positive
and
solvent
control
values
were
appropriate.
No
induction
of
UDS
was
seen
at
any
concentration
of
dimethylhydantoin
evaluated.

This
study
is
classified
as
Acceptable/
guideline.
It
satisfies
the
requirements
for
FIFRA
Test
Guideline
§
84­
2
for
a
UDS
study
in
mammalian
cells
in
culture.

4.8
Neurotoxicity
Adequacy
of
data
base
for
Neurotoxicity:
These
studies
are
not
required
at
this
time.
No
neurotoxicity
studies
were
necessary.

870.6100
Delayed
Neurotoxicity
Study
­
Hen
Study
not
required,
DMH
is
not
an
organophosphate.

870.6300
Developmental
Neurotoxicity
Study
Study
not
required
4.9
Metabolism
Adequacy
of
data
base
for
metabolism:
The
data
base
for
metabolism
is
considered
to
be
complete.
No
additional
studies
are
required
at
this
time.

870.7485
Metabolism
­
Rat
(
MRID
#
4217390)
Under
the
conditions
of
this
study,
DMH
was
rapidly
absorbed
and
was
excreted
primarily
in
the
urine.
Most
of
the
radioactivity
was
recovered
in
the
first
12
hours
in
both
sexes
and
there
was
very
little
accumulation
in
the
tissue.

This
study
is
acceptable.
This
study
alone
does
not
satisfy
the
guideline
requirements
for
a
metabolism
study;
however,
an
additional
study
was
conducted
to
identify
the
metabolites
of
DMH
in
the
urine.

(
MRID
#
42123802)
Unmetabolized
14C­
MEH
recovered
in
the
urine
represented
more
than
89%
of
the
administered
dose
of
MEH.

This
study
is
supplementary.
The
sponsor
needs
to
supply
analytical
data
to
demonstrate
that
the
HPLC
methodology
was
validated
to
confirm
the
identity
of
the
metabolite
in
the
urine
samples.
This
study
may
be
upgraded
upon
receipt
and
evaluation
of
the
requested
data.
Page
27
of
41
5.0
TOXICITY
ENDPOINT
SELECTION
5.1
See
Section
9.2
for
Endpoint
Selection
Table.

5.2
Dermal
Absorption
There
are
no
dermal
absorption
data
available
for
5,5­
dimethylhydantoin.

5.3
Classification
of
Carcinogenic
Potential
5.3.1
5,5­
dimethylhydantoin
is
classified
as
`
not
likely'
to
be
a
carcinogen
based
upon
the
negative
evidence
for
a
carcinogenicity
in
both
the
rat
and
mouse
studies
as
well
as
the
negative
evidence
of
genotoxicity.

Formaldehyde
(
a
breakdown
product
of
the
hydantoins)
has
previously
been
classified
as
a
B1
(
probable)
carcinogen
based
upon
the
limited
evidence
in
humans
of
site­
specific
respiratory
neoplasms
following
inhalation
exposure
to
formaldehyde,
and
sufficient
evidence
in
animals,
based
on
squamous
cell
carcinoma
of
the
nasal
cavity
following
chronic
inhalation
exposure.

6.0
FQPA
CONSIDERATIONS
6.1
Special
Sensitivity
to
Infants
and
Children
The
database
for
5,5­
dimethylhydantoin
is
considered
adequate
for
a
determination
as
to
potential
susceptibility
of
infants
and
children.

6.2
Recommendation
for
a
Developmental
Neurotoxicity
Study
A
developmental
neurotoxicity
study
is
not
required
for
5,5­
dimethylhydatoin.
The
weight
of
the
evidence
from
the
available
data
on
5,5­
dimethylhydantoin
indicate
no
neurotoxic
effects
of
this
chemical.
There
is
no
evidence
to
suggest
any
potential
neurotoxic
effects
from
exposure
to
5,5­
dimethylhydantoin
except
at
unrealistically
high
exposures.

7.0
ENDOCRINE
DISRUPTION
The
Agency
is
required
under
the
Federal
Food,
Drug
and
Cosmetic
Act
(
FFDCA),
as
amended
by
FQPA,
to
develop
a
screening
program
to
determine
whether
certain
substances
(
including
all
pesticide
active
and
other
ingredients)
"
may
have
an
effect
in
humans
that
is
similar
to
an
effect
produced
by
a
naturally
occurring
estrogen,
or
other
such
endocrine
effects
as
the
Administrator
may
designate."
Following
the
recommendations
of
its
Endocrine
Disruptor
Screening
and
Testing
Advisory
Committee
(
EDSTAC),
EPA
determined
that
there
was
scientific
bases
for
including,
as
part
of
the
program,
the
androgen
and
thyroid
hormone
systems,
in
addition
to
the
estrogen
hormone
system.
EPA
also
adopted
EDSTAC's
recommendation
that
the
Program
include
evaluations
of
potential
effects
in
wildlife.
For
pesticide
chemicals,
EPA
will
use
FIFRA
Page
28
of
41
and,
to
the
extent
that
effects
in
wildlife
may
help
determine
whether
a
substance
may
have
an
effect
in
humans,
FFDCA
authority
to
require
the
wildlife
evaluations.
As
the
science
develops
and
resources
allow,
screening
of
additional
hormone
systems
may
be
added
to
the
Endocrine
Disruptor
Screening
Program
(
EDSP).

8.0
OTHER
ISSUES
Based
upon
the
structural
similarity
of
dimethylhydantoin
to
diphenylhydantoin
(
a
known
teratogenic
and
carcinogenic
agent),
concern
was
expressed
by
the
Agency
as
to
the
valididty
of
the
use
of
dimethylhydantoin­
containing
products,
especially
for
use
in
pools
and
spas.
The
Agency
has
considered
toxicity
data
from
both
diphenylhydantoin
and
dimethylhydantoin
in
determining
that
there
is
no
significant
hazard
from
the
use
of
dimethylhydantoin
(
memorandum
from
Robert
P.
Zendzian
to
Arturo
Castillo,
dated
October
21,
1983).
First,
it
is
evident
that
the
biotransformation
and
excretion
of
dimethylhydantoin
and
diphenylhydantoin
differ.
Diphenylhydantoin
undergoes
extensive
metabolism
of
the
phenyl
group
with
the
production
of
an
arene
oxide
intermediate
(
believed
responsible
for
the
toxicity
of
the
chemical),
while
dimethylhydantoin
is
essentially
excreted
unchanged.
Second,
the
hazard
profile
for
dimethylhydantoin
differs
significantly
from
that
of
diphenylhydantoin.
Dimethylhydantoin
lacks
the
toxicity
present
with
diphenylhydantoin
and
shows
no
evidence
of
carcinogenicity
or
teratogenicity.
Page
29
of
41
9.0
REFERENCES
in
MRID
order
MRID
00252096
reference
information
not
available
MRID
265457(
1)
Lawlor,
T.
E.,
B.
Head,
V.
O.
Wagner,
B.
E.
Carter,
S.
M.
Olewine,
and
R.
J.
Plunkett
(
1986).
Salmonella/
mammalian
microsome
plate
incorporation
mutagenicity
assay
on
5,5­
dimethylhydantoin.
Microbiological
Associates
Inc.
Bethesda,
MD.
Study
No.
T4638.501.
April
1,
1986.
Unpublished.

MRID
265457(
2)
Putman,
D.
L.,
M.
J.
Zito,
L.
J.
Belinsky,
D.
O.
Azorsa,
and
F.
K.
Garvert
(
1986).
Chromosome
aberration
assay
in
Chinese
Hamster
ovary
(
CHO)
cells.
Microbiological
Associates
Inc.
Bethesda,
MD.
Study
No.
T4638.337.
May
1,
1986.
Unpublished.

MRID
265457(
3)
Curren,
R.
D.,
L.
Dunn,
M.
Ernst,
N.
Durvasula,
and
V.
Portner
(
1986).
Unscheduled
DNA
Synthesis
in
rat
primary
hepatocytes.
Microbiological
Associates
Inc.
Bethesda,
MD.
Study
No.
T3638.380.
May
5,
1986.
Unpublished
MRID
42009201
Federici,
T.
M.
(
1991).
A
90
Day
Subchronic
Oral
Toxicity
Study
in
Rats
with
DMH.
Exxon
Biomedical
Sciences,
Inc.
East
Millstone,
N.
J.
Lab
study
No.
169070.
July
25,
1991.

MRID
42173901
Selim,
S.
(
1991).
Absorption,
Distribution,
Metabolism
and
Excretion
(
ADME)
Studies
of
5,5­
Dimethylhydantoin
in
the
Rat.
Lonza
Inc.
Fair
Lawn,
N.
J.
Lab
study
No.
P01982.
November
17,
1991.

MRID
42123802
Selim,
S.
(
1991).
Absorption,
Distribution,
Metabolism
and
Excretion
(
ADME)
Studies
of
5
Ethyl,
5­
Methylhydantoin
in
the
Rat.
Lonza,
Inc.
Fair
Lawn,
N.
J.
Study
No.
PO2000.
November
15,
1991.

MRID
42205401
Beyer,
B.
K.
(
1992).
Developmental
Toxicity
Study
in
Rabbits
with
5­
Ethyl­
5­
Methylhydantoin
(
MEH).
Exxon
Biomedical
Sciences,
Inc.,
Toxicology
Laboratory,
East
Millstone,
NJ
08875­
2350.
February
3,
1992.
Laboratory
Project
ID.
166834RB.
MRID
42205401.
Unpublished.

MRID
42413101
Nemec,
M.
D.
(
1992).
A
Developmental
Toxicity
study
of
Dimethylhydantoin
in
Rabbits.
WIL
Research
Laboratories,
Inc.
Ashland,
OH.
Lab
study
No.
WIL­
12174.
July
23,
1992.

MRID
42432701
Driscoll,
C.
D.
and
T.
L.
Neeper­
Bradley
(
1992).
Developmental
toxicity
Evaluation
of
5,5­
Dimethylhydantoin
(
DMH)
Administered
by
Gavage
to
CD
Rats.
Bushy
Run
Research
Center.
Export,
PA.
Study
No.
91N0048.
July
30,
1992.
Page
30
of
41
MRID
42462502
Nemec,
M.
D.
(
1992).
Two­
generation
Reproduction
Study
of
Dimethylhydantoin
Administered
Orally
in
Rats.
WIL
Research
Laboratories,
Inc.
Ashland,
OH.
Study
No.
WIL­
12153
August
25,
1992.

MRID
43173901
Chun,
J.
S.
and
K.
A.
Loughran
(
1994).
Ninety­
Day
Dermal
Toxicity
Study
with
5,5­
Dimethylhydantoin
(
DMH)
in
CD
Rats.
Bushy
Run
Research
Center,
Union
Carbide
Corp.
6702
Mellon
Road,
Export,
PA.
Study
No.
92N1016.
March
10,
1994.

MRID
43290601
Neeper­
Bradley,
T.
and
M.
Kubena
(
1994).
Two­
Generation
Reproduction
Study
in
CD
Rats
with
(
inert
ingredient)
Administered
in
the
Diet.
Bushy
Run
Research
Center.
Lab
project
No.
91N0094.
Unpublished.

MRID
43397701
Hermansky,
S.
J.
and
Loughran
(
1994).
Chronic
Dietary
Oncogenicity
Study
with
5,5­
Dimethylhydantoin
(
DMH).
Bushy
Run
Research
Center,
Union
Carbide
Corp.
6702
Mellon
Road,
Export,
PA.
Lab
study
No.
91N0112.
August
31,
1994.

MRID
43397702
Hermansky,
S.
J.
and
C.
L.
Benson
(
1994).
Chronic
Dietary
Toxicity/
Oncogenicity
Study
with
5,5­
dimethylhydantoin
(
DMH)
in
Rats.
Bushy
Run
Research
Center,
Union
Carbide
Corp.
6702
Mellon
Road,
Export,
PA.
Lab
project
No.
91N00113.
August
31,
1994.

MRID
43654101
Naas,
D.
(
1995).
An
Acute
Inhalation
Toxicity
Study
of
BCDMH
in
Albino
Rats.
WIL
Research
Labs,
Inc.
Lab
project
No.
WIL­
12358.
Unpublished.

MRID
4553101
Goldenthal,
Edwin
I.
(
1995).
Evaluation
of
Dimethylhydantoin
(
DMH)
in
a
One­
Year
Chronic
Dietary
Toxicity
Study
in
Dogs.
Lonza
Inc.
17­
17
Route
208,
Fair
Lawn,
NJ.
Study
No.
647­
004.

MRID
44063901
Naas,
D.
J.
(
1996).
18­
Month
Dietary
Oncogenicity
Study
in
Mice
with
DMH.
WIL
Research
Laboratories,
Inc.
Ashland,
OH.
Lab
Study
No.
WIL­
12257.
May
23,
1996.
Unpublished.

MRID
44095901
Naas,
D.
(
1996).
Combined
24­
month
toxicity/
oncogenicity
study
in
rats
with
DMH.
WIL
Research
Laboratories,
Inc.
Ashland,
Ohio.
Lab
study
No.
WIL­
12258.
July
30,
1996.
Unpublished.

MRID
44243001
supplement
to
multi­
generation
reproduction
Page
31
of
41
10.0
APPENDICES
Tables
for
Use
in
Risk
Assessment
Page
32
of
41
10.1
Toxicity
Profile
Summary
Tables
10.1.1
Acute
Toxicity
Table
­
See
Section
4.1
10.1.2
Subchronic,
Chronic
and
Other
Toxicity
Tables
Guideline
No./
Study
Type/
Substance
Purity
MRID
No.
(
year)/
Classification/
Doses
Results
Subchronic
Toxicity
870.3100
90­
Day
oral
toxicity
rodents
­
Rat
1DMH
purity
>
99.5%
42009201
(
1991)
Acceptable/
guideline0,
100,
300,
1000
mg/
kg/
day
NOAEL
=
greater
than
or
equal
to
1000
mg/
kg/
day
(
highest
dose
tested)
LOAEL
=
greater
than
1000
mg/
kg/
day
(
not
established).

28­
Day
oral
toxicity
­
Mouse
DMH
purity
100%
45738402
NOAEL
=
greater
than
or
equal
to
50,000
ppm
[
males:
10,057,
females:
14,972
mg/
kg/
day]
(
highest
dose
tested)
LOAEL
=
greater
than
50,000
ppm
[
males:
10,057,
females:
14,972
mg/
kg/
day]
(
not
established).

870.3150
90­
Day
oral
toxicity
in
nonrodents
No
study
available.

870.3200
21/
28­
Day
dermal
toxicity
No
study
available.

870.3250
90­
Day
dermal
toxicity
DMH
purity
99.8%
43173901
(
1994)
core/
guideline
0,
39,
130,
390
mg/
kg/
day
This
study
is
classified
as
Acceptable­
Guideline
and
it
satisfies
the
guideline
requirements
for
a
subchronic
toxicity
study
[
OPPTS
870.3250
(
§
82­
1b)]
in
rats.
Higher
doses
of
DMH
were
not
possible
in
this
study;
thus,
although
a
limit
dose
was
not
tested,
the
study
is
considered
acceptable.
NOAEL
=
greater
than
or
equal
to
390
mg/
kg/
day
(
highest
dose
tested)
LOAEL
=
greater
than
390
mg/
kg/
day
(
not
established)
Page
33
of
41
Guideline
No./
Study
Type/
Substance
Purity
MRID
No.
(
year)/
Classification/
Doses
Results
870.3465
90­
Day
inhalation
toxicity
No
study
available.

Developmental/
Reproductive
Toxicity
870.3700
Prenatal
developmental
in
rats
DMH
purity
99.8%
42432701
(
1992)
Core
Minimum/
Guideline
0,
100,
300,
1000
mg/
kg/
day
Maternal
Toxicity
NOAEL
=
300
mg/
kg/
day
Maternal
Toxicity
LOAEL
=
1000
mg/
kg/
day
based
on
the
transient
decrease
in
body
weight
gain
during
gestation
days
9­
12.

Developmental
Toxicity
NOAEL
=
greater
than
or
equal
to1000
mg/
kg/
day
(
highest
dose
tested)
Developmental
Toxicity
LOAEL
=
greater
than
1000
mg/
kg/
day
(
not
established)

870.3700
Prenatal
developmental
in
nonrodents
­
Rabbits
DMH
purity
96­
98.7%
42413101
(
1992)
core/
guideline
0,
100,
500,
1000
mg/
kg/
day
Maternal
Toxicity
NOAEL
=
500
mg/
kg/
day
Maternal
Toxicity
LOAEL
=
1000
mg/
kg/
day
based
on
decreased
body
weight
gain
and
food
consumption
during
the
dosing
period.

Developmental
Toxicity
NOAEL
=
100
mg/
kg/
day
Developmental
Toxicity
LOAEL
=
500
mg/
kg/
day
based
on
the
increased
incidence
of
the
27th
presacral
vertebrae.

870.3700
Prenatal
developmental
in
nonrodents
­
Rabbits
2EMH
purity
>
99.5%
42205401
(
1992)
acceptable
Phase
I:
0,
50,
125,
or
375
mg/
kg/
day
Phase
II:
0
or
1000
mg/
kg/
day
Maternal
Toxicity
NOAEL
=
375
mg/
kg/
day
Maternal
Toxicity
LOAEL
=
1000
mg/
kg/
day,
based
on
mortality,
reduced
body
weights
gains
and
reduced
food
consumption.

Developmental
Toxicity
NOAEL
=
375
mg/
kg/
day
Developmental
Toxicity
LOAEL
=
1000
mg/
kg/
day,
based
on
decreased
fetal
body
weights.

870.3800
Reproduction
and
fertility
effects
DMH
purity
96­
98.7%
42462502
(
1992)
Core/
Guideline
0,
250,
500,
1000
mg/
kg/
day
(
20,000
ppm)

20,000
ppm
(
1322
and
1602
mg/
kg/
day,
respectively)
for
male
and
female
rats
Parental/
Systemic
NOAEL
=
greater
than
or
equal
to1000
mg/
kg/
day
(
highest
dose
tested)
Parental/
Systemic
LOAEL
=
greater
than
1000
mg/
kg/
day
(
not
established).

Offspring
Toxicity
NOAEL
=
greater
than
or
equal
to1000
mg/
kg/
day
(
highest
dose
tested)
Offspring
Toxicity
LOAEL
=
greater
than
1000
mg/
kg/
day
(
not
established).

Chronic
Toxicity/
Carcinogenicity
Page
34
of
41
Guideline
No./
Study
Type/
Substance
Purity
MRID
No.
(
year)/
Classification/
Doses
Results
870.4100
Chronic
toxicity
rodents
DMH
purity
99.8%
43397702
(
1994)
core/
guideline
[
870.4300
(
§
83­
5)]
0,
100,
300,
1000
mg/
kg/
day
Systemic
Toxicity
NOAEL
=
300
mg/
kg/
day
Systemic
Toxicity
LOAEL
=
1000
mg/
kg/
day,
based
on
decreases
in
body
weight
and
body
weight
gain
in
females
and
hyperplasia
of
submandibular
lymph
nodes
in
males.

No
evidence
of
carcinogenicity
870.4100
Chronic
toxicity
rodents
DMH
purity
97.3%,
97.1%,
and
93.5%
44095901
(
1996)
acceptable/
guideline
0,
100,
320,
1000
mg/
kg/
day
Systemic
Toxicity
NOAEL
=
320
mg/
kg/
day
Systemic
Toxicity
LOAEL
=
1000
mg/
kg/
day,
based
on
enlarged
pituitary
glands
in
decedents
of
both
sexes,
increased
mortality
occurring
early
in
(
especially)
females,
increased
mammary
galactoceles
in
early
decedents
of
both
sexes
and
testicular
fibroid
vascular
degeneration
in
early
decedent
males.

At
the
doses
tested,
there
was
not
a
treatment
related
increase
in
tumor
incidence
after
105
weeks
of
treatment
with
DMH.
No
evidence
of
carcinogenicity
870.4100
Chronic
toxicity
dogs
DMH
purity
97.4%
43813301
(
1996)
NOAEL
=
greater
than
1000
mg/
kg/
day
(
highest
dose
tested
LOAEL
=
greater
than
1000
mg/
kg/
day
(
not
established)

870.4100
Chronic
toxicity
dogs
DMH
purity
98.9%
43553101
(
1995)
acceptable
Males:
0,
120,
342,
or
1506
mg/
kg/
day
Females:
0,
121,
414,
or
1352
mg/
kg/
day
NOAEL
=
12000
ppm
(
342
mg/
kg/
day)
LOAEL
=
40000
ppm
(
1506
mg/
kg/
day),
based
on
enlarged
adrenal
glands
in
male
dogs,
shown
by
microscopic
examination
to
exhibit
hypertrophy
in
the
adrenal
cortex.

870.4200
Carcinogenicity
rats
DMH
purity
99.8%
43397702
(
1994)
core/
guideline
0,
100,
300,
1000
mg/
kg/
day
See
Chronic
Toxicity
in
Rodents
­
Rats
No
evidence
of
carcinogenicity
There
were
no
increases
in
tumor
incidences
for
the
DMH
treated
groups
when
compared
to
the
control
group.
This
study
is
classified
as
870.4200
Carcinogenicity
rats
DMH
purity
97.3%,
97.1%,
and
93.5%
44095901
(
1996)
acceptable/
guideline
0,
100,
320,
1000
mg/
kg/
day
See
Chronic
Toxicity
in
Rodents
­
Rats
No
evidence
of
carcinogenicity
Page
35
of
41
Guideline
No./
Study
Type/
Substance
Purity
MRID
No.
(
year)/
Classification/
Doses
Results
870.4300
Carcinogenicity
mice
DMH
purity
99.8%
43397701
(
1994)
Acceptable­
guideline
[
870.4200
(
§
83­
2)]
0,
400,
1850,
8500
ppm
(
0,
100,
300,
1000
mg/
kg/
day)
Systemic
Toxicity
NOAEL
=
300
mg/
kg/
day
Systemic
Toxicity
LOAEL
=
1000
mg/
kg/
day
based
on
decreases
in
body
weight
and
body
weight
gain
in
males.

No
evidence
of
carcinogenicity
870.4300
Carcinogenicity
mice
DMH
purity
94.9­
97.1%
44063901
(
1996)
Acceptable/
guideline
[
870.4200
(
§
83­
2b)]
0,
100,
320,
1000
mg/
kg/
day
Systemic
Toxicity
NOAEL
=
greater
than
or
equal
to
1000
mg/
kg/
day
(
highest
dose
tested).
Systemic
Toxicity
LOAEL
=
greater
than
1000
mg/
kg/
day
(
not
established).

Under
the
conditions
of
this
study,
there
was
no
evidence
of
carcinogenic
potential
in
mice
following
treatment
with
DMH
and
the
dosing
was
considered
adequate
because
the
highest
dose
of
1000
mg/
kg/
day
represents
a
"
limit
dose."

No
evidence
of
carcinogenicity
Mutagenicity
Gene
Mutation
870.5100
Ames
Salomella
Assay
DMH
purity
97.0%
164036
(
265457)
(
1986)
acceptable
100,
500,
2500,
5000,
10000

g/
plate
No
evidence
of
a
mutagenic
response
Gene
Mutation
870.5100
Ames
Salomella
Assay
EMH
purity
not
reported
137095
(
1982)
acceptable
67,
333,
1667,
3333
or
6666
µ
g/
plate
No
evidence
of
a
mutagenic
response
Gene
Mutation
870.5100
Ames
Salomella
Assay
DMH
purity
not
reported
137100
(
1982)
acceptable
No
evidence
of
a
mutagenic
response
Page
36
of
41
Guideline
No./
Study
Type/
Substance
Purity
MRID
No.
(
year)/
Classification/
Doses
Results
Gene
Mutation
870.5300
In
vitro
Mammalian
Cell
Assay
EMH
purity
not
reported
137089
(
1982)
acceptable
S9­:
751,
1001,
1335,
1780,
2373,
3164,
4219,
5000,
5625,
7500
µ
g/
mL
S9+:
563,
751,
1001,
1780,
2373,
3164,
4219,
5625,
7500,
10,000
µ
g/
mL
No
evidence
of
genotoxic
effects
Gene
Mutation
870.5300
In
vitro
Mammalian
Cell
Assay
DMH
purity
not
reported
132165
(
1983)
acceptable
S9­:
563,
1001,
1335,
1780,
2373,
3164,
4219,
5625,
7500,
or
10,000

g/
mL.
S9+:
751,
1001,
1335,
1780,
2373,
3164,
4219,
5625,
7500,
or
10,000

g/
mL.
No
evidence
of
a
genotoxic
response
Cytogenetics
870.5375
In
vitro
Chromosome
Aberration
Assay
DMH
purity
97.0%
164037
(
265457)
(
1986)
acceptable
200,
500,
1000,
2000

g/
mL
No
cytotoxic
or
clastogenic
effects
observed
Cytogenetics
870.5375
In
vitro
Chromosome
Aberration
Assay
3DEMH
purity
not
reported
40348201
(
1987)
acceptable
S9­:
8,
15,
30,
or
60
µ
g/
ml
S9+:
15,
30,
60,
or
120
µ
g/
ml
No
evidence
of
structural
chromosomal
aberration
Cytogenetics
870.5375
In
vitro
Chromosome
Aberration
Assay
EMH
purity
not
reported
137096
(
1982)
acceptable
5739.80,
7653.06,
or
10204.08
µ
g/
ml
A
2­
fold
or
greater
increase
in
the
percentage
of
cells
with
structural
chromosomal
aberrations,
excluding
gaps,
was
seen
at
two
non­
consecutive
doses
after
treatment
in
the
presence
of
S9­
mix.
No
dose
response
was
evident.
Results
from
the
treatments
in
the
absence
of
S9­
mix
were
negative
at
all
doses.
No
increase
in
polyploid
cells
was
observed
in
treated
or
in
positive
control
cultures.
Page
37
of
41
Guideline
No./
Study
Type/
Substance
Purity
MRID
No.
(
year)/
Classification/
Doses
Results
Cytogenetics
870.5375
In
vitro
Chromosome
Aberration
Assay
DMH
purity
not
reported
137101
(
1982)
acceptable
S9­:
11250,
15000,
or
20,000
µ
g/
ml
S9+:
8457.5,
11250,
or
15000
µ
g/
ml.
No
evidence
of
structural
chromosomal
aberration
Cytogenetics
870.5375
In
vitro
Chromosome
Aberration
Assay
DMH
purity
not
reported
MRID:
N/
A
TRID:
470264004
(
1986)
acceptable
80,
400,
or
800
µ
g/
ml
No
evidence
of
structural
chromosomal
aberration
Cytogenetics
870.5375
In
vitro
Chromosome
Aberration
Assay
DMH
purity
100%
MRID:
N/
A
TRID:
470264005
(
1986)
acceptable
10,
20,
40,
80,
160,
320,
640,
1280,
2560,
5120,
10240,
or
20480
µ
g/
ml
No
evidence
of
structural
chromosomal
aberration
Other
Effects
870.5550
Unscheduled
DNA
Synthesis
Assay
in
Rat
Hepatocytes
DMH
purity
97.0%
164038
(
265457)
(
1986)
acceptable
100,
300,
600,
1000,
3000,
6000,
10000

g/
mL
No
evidence
of
a
genotoxic
response
Other
Effects
870.5550
Unscheduled
DNA
Synthesis
Assay
in
Rat
Hepatocytes
EMH
purity
not
reported
137097
(
1982)
acceptable
0.1,
0.5,
1,
5,
10,
or
15
mg/
mL
No
evidence
of
a
genotoxic
response
Other
Effects
870.5550
Unscheduled
DNA
Synthesis
Assay
in
Rat
Hepatocytes
DMH
purity
not
reported
132166
(
1982)
acceptable
0.001,
0.01,
0.1,
1,
10,
or
20
mg/
ml
No
evidence
of
a
genotoxic
response
Neurotoxicity
Page
38
of
41
Guideline
No./
Study
Type/
Substance
Purity
MRID
No.
(
year)/
Classification/
Doses
Results
870.6300
Developmental
neurotoxicity
Not
required
Metabolism/
Pharmacokinetics
870.7485
Metabolism
and
pharmacokinetics
DMH
purity
radiolabeled
98.8%
nonradiolabeled
99.5%
42173901/
42123802
(
1991)
acceptable
100,
1000
mg/
kg
DMH
was
rapidly
absorbed
and
excreted,
primarily
in
the
urine
(>
89%).
There
was
little
accumulation
in
the
tissues.

1
DMH=
dimethylhydantoin
2
EMH=
ethylmethylhydantoin
3
DEMH=
dichloroethylmethylhydantoin
Page
39
of
41
10.2
Summary
of
Toxicological
Dose
and
Endpoints
for
5,5­
dimethylhydantoin
for
Use
in
Human
Risk
Assessment1
Exposure
Scenario
Dose
Used
in
Risk
Assessment,
UF
FQPA
SF
and
Endpoint
for
Risk
Assessment
to
be
completed
later
for
risk
assessment
Study
and
Toxicological
Effects
Acute
Dietary
females
13­
50
years
of
age
NOAEL
=
100
mg/
kg/
day
UF
=
100
Acute
RfD
=
1
mg/
kg
FQPA
SF
=
1
aPAD
=
acute
RfD
FQPA
SF
=
1
mg/
kg/
day
developmental
toxicity
­
rabbit
developmental
LOAEL
=
500
mg/
kg/
day
based
on
skeletal
variations.
(
MRID
42413101)

Chronic
Dietarya
all
populations
NOAEL=
300
mg/
kg/
day
UF
=
100
Chronic
RfD
(
gen
Pop.)
=
3
mg/
kg/
day
FQPA
SF
=
1
cPAD
=
chr
RfD
FQPA
SF
=
3
mg/
kg/
day
chronic
toxicity/
carcinogenicity
­
rats
LOAEL
=
1000
mg/
kg/
day
based
on
decreased
body
weight/
weight
gain
and
lymph
node
hyperplasia.
(
MRID
43397702)

Chronic
Dietarya
females
13­
50
NOAEL=
100
mg/
kg/
day
UF
=
100
Chronic
RfD
(
females
13­
50)
=
1
mg/
kg/
day
FQPA
SF
=
1
cPAD
=
chr
RfD
FQPA
SF
=
1
mg/
kg/
day
developmental
toxicity
­
rabbit
developmental
LOAEL
=
500
mg/
kg/
day
based
on
skeletal
variations.
(
MRID
42413101)

Short­
Term
Oral
(
1­
7
days)

(
Incidental)
oral
study
NOAEL=
500
mg/
kg/
day
MOE
=
100
(
Residential,
includes
the
FQPA
SF)
developmental
toxicity
­
rabbit
maternal
LOAEL
=
1000
mg/
kg/
day
based
on
decreased
body
weight
gain
in
maternal
rabbits.
(
MRID
42413101)

Intermediate­
Term
Oral
(
1
week
­
several
months)

(
Incidental)
oral
study
NOAEL=
300
mg/
kg/
day
MOE
=
100
(
Residential,
includes
the
FQPA
SF)
subchronic
oral
toxicity
­
rat
LOAEL
=
1000
mg/
kg/
day
based
on
decreased
body
weight
and
liver
weight.
(
MRID
42009201)
Page
40
of
41
Exposure
Scenario
Dose
Used
in
Risk
Assessment,
UF
FQPA
SF
and
Endpoint
for
Risk
Assessment
to
be
completed
later
for
risk
assessment
Study
and
Toxicological
Effects
Short­
Term
Dermal
(
1­
7
days)

(
Occupational/
Residential)
dermal
study
NOAEL=
390
mg/
kg/
day
(
HDT)
MOE
=
100
(
Occupational)

MOE
=
100
(
Residential,
includes
the
FQPA
SF)
subchronic
dermal
toxicity
­
rats
No
systemic
toxicity
at
the
highest
dose
tested
(
MRID
43173901)

Intermediate­
Term
Dermal
(
1
week
­
several
months)

(
Occupational/
Residential)
dermal
study
NOAEL=
390
mg/
kg/
day
(
HDT)
MOE
=
100
(
Occupational)

MOE
=
100
(
Residential,
includes
the
FQPA
SF)
subchronic
dermal
toxicity
­
rats
No
systemic
toxicity
at
the
highest
dose
tested
Long­
Term
Dermal
(
several
months
­
lifetime)

(
Occupational/
Residential)
dermal
stud1y
NOAEL=
390
mg/
kg/
day
(
HDT)
MOE
=
100
(
Occupational)

MOE
=
100
(
Residential,
includes
the
FQPA
SF)
subchronic
dermal
toxicity
­
rats
No
systemic
toxicity
at
the
highest
dose
tested
Short­
Term
Inhalation
(
1­
7
days)

(
Occupational/
Residential)
Oral
NOAEL=
100b
mg/
kg/
day
(
inhalation
absorption
rate
=
100%)
MOE
=
100
(
Occupational)

MOE
=
100
(
Residential,
includes
the
FQPA
SF)
developmental
toxicity
­
rabbit
developmental
LOAEL
=
500
mg/
kg/
day
based
on
skeletal
effects
in
offspring.
(
MRID
42413101)

1
UF
=
uncertainty
factor,
FQPA
SF
=
FQPA
safety
factor,
NOAEL
=
no
observed
adverse
effect
level,
LOAEL
=
lowest
observed
adverse
effect
level,
PAD
=
population
adjusted
dose
(
a
=
acute,
c
=
chronic)
RfD
=
reference
dose,
MOE
=
margin
of
exposure
AThe
HIARC
selected
separate
chronic
RfDs
for
females,
ages
13­
50,
and
the
general
population
because
this
was
an
unusual
case
where
the
developmental
NOAEL
was
lower
than
the
lowest
Page
41
of
41
NOAEL
available
for
chronic
toxicity.
The
rabbit
developmental
toxicity
was
therefore
selected
to
provide
adequate
protection
for
the
female
(
age
13­
50)
subpopulation.

BA
100%
inhalation
absorption
value
is
used
for
route­
to­
route
extrapolation.