Document ID: EPA-HQ-OPP-2005-0558-0006
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2006-01-25T05:00Z

Page
1
of
39
UNITED
STATES
ENVIRONMENTAL
PROTECTION
AGENCY
WASHINGTON,
D.
C.
20460
OFFICE
OF
PREVENTION,
PESTICIDES
AND
TOXIC
SUBSTANCES
January
17,
2006
MEMORANDUM
SUBJECT:
Coppers:
Second
Revised
Human
Health
Chapter
of
the
Reregistration
Eligibility
Decision
Document
(
RED).
Reregistration
Case
Numbers
0636,
0649,
4025,
and
4026.
DP
Barcode
D319683.

PC
Codes:
023401,
022901,
022702,
022703,
008001,
024405,
023503,
023501,
008101,
024401,
022501,
042401,
025601,
024403,
023104,
024407,
023306,
024409.

Regulatory
Action:
Phase
2
Reregistration
Action.
Risk
Assessment
Type:
Multiple
chemical/
no
aggregate
FROM:
Christina
Jarvis,
Risk
Assessor
Elissa
Reaves,
Ph.
D.,
Toxicologist
Alan
Nielsen,
Occupational/
Residential
Exposure
Reregistration
Branch
2
Health
Effects
Division
(
7509C)

AND
Tim
McMahon,
Risk
Assessor
Michelle
Centra,
Toxicologist
Jonathan
Chen,
Toxicologist
Doreen
Aviado,
Biologist
Antimicrobials
Division
(
7510C)

THROUGH:
William
Hazel,
Branch
Chief
Reregistration
Branch
2
Health
Effects
Division
(
7509C)

AND
Mark
Hartman,
Acting
Branch
Chief
Regulatory
Management
Branch
II
Page
2
of
39
Antimicrobials
Division
(
7510C)

TO:
Rosanna
Louie,
Chemical
Review
Manager
Special
Review
and
Reregistration
Division
(
7508C)

AND
Kathryn
Jakob,
Chemical
Review
Manager
Antimicrobials
Division
(
7510C)
Page
3
of
39
Executive
Summary
This
document
represents
the
second
revised
human
health
risk
assessment
chapter
of
the
Reregistration
Eligibility
Decision
(
RED)
document
for
coppers,
including
copper
II
compounds,
copper
sulfates,
copper
and
oxides,
copper
salts,
and
other
unscheduled
coppers.
Coppercontaining
compounds
are
used
in
pesticidal
products
as
fungicides,
bactericides,
algaecides,
herbicides,
anti­
foulants,
and
wood
preservatives,
and
are
applied
to
a
wide
variety
of
agricultural,
commercial,
and
residential
use
sites.
Since
copper
is
a
naturally
occurring
metal
that
is
efficiently
regulated
in
the
human
system,
and
since
there
is
a
lack
of
systemic
toxicity
associated
with
copper
exposure,
no
toxicological
endpoints
have
been
identified
for
risk
assessment
purposes.
Quantitative
dietary
and
occupational/
residential
exposure
assessments
have
not
been
conducted.

This
second
revised
risk
assessment
document
has
been
updated
to
reflect
comments
submitted
by
the
Copper
Reregistration
Task
Force,
Adchem
Australia
Pty
Ltd.,
and
by
the
Copper
Sulfate
Task
Force.

Copper
naphthenate,
copper
8­
quinolinolate,
and
cuprous
thiocyanate
will
be
assessed
individually
by
OPP's
Antimicrobials
Division
at
a
later
date.
The
purpose
of
listing
all
studies
(
including
copper
naphthenate,
copper
8­
quinolinolate,
and
cuprous
thiocyanate)
in
the
toxicity
data
summary
tables
in
Appendix
A
of
this
document
is
to
present
all
available
data
that
have
been
reviewed
and
considered
acceptable,
even
though
the
aforementioned
three
active
ingredients
are
not
included
in
the
scope
of
this
risk
assessment.

1.0
Introduction
1.1
Scope
of
Risk
Assessment
This
risk
assessment
is
unique
in
two
aspects:
first,
it
assesses
four
copper
cases
(
and
other
unscheduled
coppers)
in
one
comprehensive
document,
and
second,
as
copper
is
a
naturally
occurring
metal
that
is
also
an
essential
element
in
the
human
body,
no
toxicological
endpoints
have
been
selected
for
dietary
or
exposure
risk
assessment
purposes.

The
following
18
copper
cases
are
addressed
in
this
document:
copper
II
compounds
(
copper
hydroxide,
copper
carbonate,
copper­
ammonia
complex,
copper
ammonium
carbonate,
basic
copper
chloride,
copper
(
metallic)
in
the
form
of
chelates
of
copper
citrate
and
copper
gluconate,
copper
oxychloride
sulfate,
copper
oxychloride),
copper
sulfates
(
basic
copper
sulfate,
copper
sulfate
pentahydrate),
copper
and
oxides
(
copper
metallic,
cupric
oxide,
cuprous
oxide),
copper
salts
(
copper
from
triethanolamine
complex,
copper
salts
of
fatty
and
rosin
acids,
copper
as
elemental
from
copper­
ethylenediamine
complex),
and
other
unscheduled
coppers
(
copper
octanoate,
copper
ethanolamine
complex).

Table
1.
Summary
of
copper
cases
included
in
risk
assessment.
Case
Active
ingredient
PC
Code
Copper
II
compounds
(
0649)
Copper
hydroxide
023401
Page
4
of
39
Case
Active
ingredient
PC
Code
Copper
carbonate
022901
Copper­
ammonia
complex
022702
Copper
ammonium
carbonate
022703
Basic
copper
chloride
008001
Copper
(
metallic)
in
the
form
of
chelates
of
copper
citrate
and
copper
gluconate
024405
Copper
oxychloride
sulfate
023503
Copper
oxychloride
023501
Basic
copper
sulfate
008101
Copper
sulfates
(
0636)
Copper
sulfate
pentahydrate
024401
Copper
 
metallic
022501
Cupric
oxide
042401
Copper
and
oxides
(
4025)

Cuprous
oxide
025601
Copper
from
triethanolamine
complex
024403
Copper
salts
of
fatty
and
rosin
acids
023104
Copper
salts
(
4026)

Copper
as
elemental
from
copper­
ethylenediamine
complex
024407
Copper
octanoate
023306
Other
unscheduled
coppers
Copper
ethanolamine
complex
024409
1.2
Background
Copper
is
a
naturally
occurring
metal
that
is
also
an
essential
nutrient
in
the
human
body.
The
recommended
dietary
allowance
(
RDA)
of
copper,
as
established
by
the
National
Academy
of
Science,
ranges
from
340
micrograms
per
day
(
ug/
d)
in
young
children
to
900
ug/
d
in
adults.
The
RDA
of
copper
for
pregnant
and
lactating
females
is
slightly
higher,
with
a
range
of
1000
to
1300
ug/
d.
The
maximum
level
of
copper
that
may
be
consumed
with
no
likely
risk
of
adverse
effects
ranges
from
approximately
1000
ug/
d
to
10,000
ug/
d.
1
Organ
meats
(
particularly
liver),
seafood,
nuts,
seeds,
wheat
bran
cereals,
whole
grain
products,
and
cocoa
products
are
all
foods
rich
in
copper.
A
deficiency
of
copper
may
lead
to
a
variety
of
health
effects,
such
as
bone
abnormalities,
severe
anemia,
a
compromised
immune
function,
and
growth
retardation,
while
excessive
consumption
of
copper
may
cause
acute
gastrointestinal
distress,
including
nausea
and/
or
vomiting,
and/
or
chronic
liver
toxicity.

Copper
is
also
found
in
drinking
water,
often
as
a
result
of
the
use
of
copper
in
plumbing
fixtures
and
water
pipes.
Concentrations
of
copper
in
drinking
water
are
regulated
by
the
USEPA
under
1
Dietary
Reference
Intakes
for
Vitamin
A,
Vitamin
K,
Arsenic,
Boron,
Chromium,
Copper,
Iodine,
Iron,
Manganese,
Molybdenum,
Nickel,
Silicon,
Vanadium,
and
Zinc
(
2000).
Available
at:
http://
www.
nap.
edu/
openbook/
0309072794/
html/
Page
5
of
39
the
Safe
Drinking
Water
Act
(
SDWA).
Under
the
SDWA,
the
USEPA
sets
maximum
contaminant
level
goals
(
MCLGs)
for
chemicals
in
drinking
water
that
may
cause
human
health
problems.
The
MCLG
for
copper
in
drinking
water
is
set
at
1.3
parts
per
million
(
ppm).

1.2.1
Regulatory
History
Guidance
documents
for
the
reregistration
of
copper
sulfates
and
copper
II
compounds
were
prepared
in
March
1986
and
September
1986,
respectively.
In
1990,
HED
addressed
toxicology,
product
and
residue
chemistry,
dietary
exposure,
and
reentry
and
non­
dietary
exposure
issues
for
the
reregistration
of
copper
sulfate
and
copper
II
compounds
(
L.
Kutney,
8/
13/
1990).
At
that
time,
product
chemistry
data
gaps
were
identified
for
copper
sulfate
and
copper
II
compounds,
and
acute
toxicity
data
gaps
were
identified
for
copper
II
compounds,
including
acute
oral
and
acute
dermal
toxicity
studies,
and
primary
eye
and
primary
dermal
irritation
studies.

Additionally,
foliar
dissipation
and
post­
application
dermal
exposure
studies
were
required
for
copper
sulfate.
A
24­
hour
interim
reentry
interval
was
recommended
for
foliar
applications
for
copper
sulfate,
pending
the
submission
and
review
of
required
reentry
data.
However,
with
the
promulgation
of
the
Worker
Protection
Standard
for
Agricultural
Pesticide,
a
restricted­
entry
interval
for
each
copper
species
is
be
established
based
on
the
acute
toxicity
of
the
copper
species
(
see
discussion
later
in
this
document).

With
regards
to
tolerances,
HED
recommended
that
the
established
tolerances
for
potable
water
(
see
section
1.3.1
below)
be
revoked,
as
the
Office
of
Pesticide
Programs
no
longer
establishes
water
tolerances.
This
tolerance,
however,
is
still
established
at
1
ppm.

In
1993,
HED
completed
the
reregistration
eligibility
decision
document
on
copper
(
metallic),
cupric
oxide,
and
cuprous
oxide
(
A.
Aikens,
8/
6/
1993).
Due
to
eye
irritation
and
the
potential
for
inhalation
exposure,
protective
gear
was
recommended
for
mixers,
loaders,
and
applicators,
and
the
following
label
language
was
recommended:
"
May
cause
skin
sensitization
in
certain
individuals."
These
label
requirements
should
be
based
on
the
acute
toxicity
of
the
end­
use
products.

1.2.2
Summary
of
Pesticidal
Uses
Copper­
containing
compounds
are
used
in
pesticidal
products
as
fungicides,
bactericides,
algaecides,
herbicides,
anti­
foulants,
and
wood
preservatives.
Products
containing
copper
may
be
applied
to
a
wide
variety
of
agricultural,
commercial,
and
residential
use
sites,
and
are
formulated
as
dusts,
wettable
powders,
liquids
(
including
ready­
to­
use
liquids),
dry
flowables,
water
soluble
packets,
and
granulars.

Application
methods
are
as
varied
as
the
use
sites,
and
include
aerial,
airblast,
groundboom,
rights­
of­
way
equipment,
mechanical
duster
equipment,
low­
and
high­
pressure
handwand,
handgun
sprayer,
hose­
end
sprayer,
push­
type
spreader,
paint
sprayer,
brushes,
sponges,
rollers,
dips,
direct
pour,
aerosol
spray,
pressure
treatment
equipment,
or
drip
system.
Page
6
of
39
1.3
Tolerances
1.3.1
Established
tolerances
A
tolerance
is
established
for
residues
of
basic
copper
carbonate
in
or
on
pears
at
3
ppm
of
combined
copper
from
post­
harvest
use
(
impregnated
paper
wrappers)
(
40
CFR
§
180.136).

A
tolerance
is
established
for
residues
of
copper
in
potable
water
at
1
ppm,
resulting
from
the
use
of
basic
copper
carbonate,
copper
sulfate,
copper
monoethanolamine,
and
copper
triethanolamine
to
control
aquatic
plans
in
reservoirs,
lakes,
ponds,
irrigation
ditches,
and
other
potential
sources
of
potable
water
(
40
CFR
§
180.538).

1.3.2
Tolerance
exemptions
The
following
copper
products
are
exempt
from
tolerance
requirements
when
applied
as
a
fungicide
to
growing
crops
using
good
agricultural
practices:
Bordeaux
mixture,
basic
copper
carbonate,
copper
ethylenediamine
complex,
copper
hydroxide,
copper
lime
mixtures,
copper
linoleate,
copper
octanoate,
copper
oleate,
copper
oxychloride,
copper
sulfate
(
basic),
cupric
oxide,
and
cuprous
oxide
(
40
CFR
§
180.1021(
b)).

The
following
are
exempt
from
tolerance
requirements
in
meat,
milk,
poultry,
eggs,
fish,
shellfish,
and
irrigated
crops:
copper
sulfate,
basic
copper
carbonate,
copper
triethanolamine
and
copper
monoethanolamine,
and
cuprous
oxide
(
40
CFR
§
180.1021(
a)).

Copper
sulfate
pentahydrate
is
exempt
from
tolerance
requirements
when
applied
as
a
fungicide
to
growing
crops
or
raw
agricultural
commodities
after
harvest
(
40
CFR
§
180.1021(
c)).

Copper
(
II)
hydroxide
is
exempt
from
tolerance
requirements
when
applied
to
growing
crops
or
raw
agricultural
commodities
as
an
inert
ingredient
(
for
pH
control)
in
pesticide
products
(
40
CFR
§
180.1021(
d)).

2.0
Hazard
Characterization
and
Assessment
[
For
complete
details
regarding
the
hazard
characterization
and
assessment
of
coppers,
see
E.
Reaves
memo,
Appendix
A].

Acute
toxicity
studies
exist
for
most
copper
species,
with
the
exception
of
copper
ammonium
carbonate,
copper­
ammonia
complex,
chelates
of
copper
gluconate,
copper
oxychloride
sulfate,
basic
copper
sulfate,
copper
sulfate
anhydrous,
and
copper
ethanolamine
complex.
The
component
of
toxicological
interest
is
elemental
copper.
Copper
has
moderate
to
low
toxicity
(
toxicity
category
II,
II,
and
IV)
based
on
acute
oral,
dermal,
and
inhalation
studies
in
animals,
with
the
exception
of
cuprous
oxide,
which
has
a
toxicity
category
of
I
for
acute
inhalation.
Information
available
through
the
literature,
or
studies
provided
by
the
registrant,
warrants
the
limitation
of
excessive
inhalation
of
copper.
When
ingested
orally,
copper
can
be
a
gastric
irritant
and
produce
corrosion
of
the
gastric
and
intestinal
epithelium
(
IPCS
PIM
1991).
Page
7
of
39
Most
dermal
irritation
studies
indicate
copper
is
a
toxicity
category
III
or
IV;
however,
cuprous
oxide
and
naphthenate
forms
of
copper
produce
toxicity
category
I
and
II
irritation,
respectively.
Copper
is
generally
non­
sensitizing
in
guinea
pigs
and
rabbits,
except
for
copper
naphthenate,
which
was
a
skin
sensitizer.
A
human
skin
sensitization
study
indicates
copper
(
as
sulfate
pentahydrate)
was
a
sensitizer
to
human
skin.
Copper
in
certain
forms
is
a
severe
eye
irritant
(
toxicity
categories
I
and
II).

The
human
body
appears
to
have
efficient
mechanisms
in
place
to
regulate
total
body
copper,
given
the
relatively
small
and
constant
body
pool
of
copper.
In
the
healthy
adult,
nearly
twothirds
of
the
body
copper
content
is
located
in
the
skeleton
and
muscle
(
due
to
their
large
tissue
masses),
with
the
liver
is
the
primary
organ
for
the
maintenance
of
plasma
copper
concentrations.
The
efficiency
of
copper
absorption
varies
greatly,
depending
on
dietary
intake.
When
dietary
copper
is
high
and
more
copper
is
absorbed,
mainly
through
the
gastrointestinal
tract,
endogenous
excretion
of
copper
increases,
protecting
against
excess
accumulation
of
copper
in
the
body.
When
copper
intake
is
low,
little
endogenous
copper
is
excreted,
protecting
against
copper
depletion.

Systemic
effects
from
oral
exposures
to
copper
are
rare.
In
an
acceptable
non­
guideline,
12­
day
dermal
toxicity
study
in
the
rat,
there
is
a
dose­
related
increase
in
dermal
irritation
but
no
systemic
toxicity
at
1000
mg/
kg/
day
(
HDT).
Short­
term
feeding
studies
with
rats
and
mice
indicate
decreased
food
and
water
intake
with
increasing
oral
concentrations
of
copper,
with
irritation
of
the
stomach
at
higher
copper
concentrations.
High
levels
of
excess
copper
administered
in
the
drinking
water
of
mice
at
50,
100,
200,
or
300
ppm
for
3
or
8
weeks
suggested
an
altered
immune
response;
however,
the
inhibition
of
immune
responses
is
not
unusual
since
other
trace
elements
have
been
linked
with
immuno­
suppression.
In
addition,
cations
like
zinc,
mercury,
and
lead
have
also
been
reported
to
alter
immune
responses.
The
mechanism
by
which
copper
may
be
exerting
a
response
in
the
immune
system
has
not
been
fully
determined.

As
observed
in
the
short­
term
feeding
studies,
longer
feeding
studies
indicate
decreased
feed
intake
with
reductions
in
body
weight
gains,
and
increased
copper
concentration
of
the
liver.
There
is
no
suggestion
or
evidence
that
copper
or
its
salts
are
carcinogenic
in
animals
having
normal
copper
homeostasis.
Copper
(
metallic)
is
currently
Group
D,
not
classifiable
as
to
human
carcinogenicity.
Chronic
inhalation
of
copper
may
become
cancerous
since
available
studies
from
the
literature
indicate
an
increased
incidence
of
lung
cancer
among
professional
vineyard
workers
exposed
chronically
to
Bordeaux
mixture
(
Viller,
1974;
Santic
et
al.
2005);
however,
this
information
is
not
definitive
since
no
information
is
available
on
the
level
of
exposure
to
workers,
to
either
Bordeaux
mixture
or
any
other
substances
with
which
they
might
have
come
into
contact.
Mutagenicity
studies
from
the
literature
indicate
copper
is
not
mutagenic.
There
is
no
indication
of
endocrine
disruption.

Reproductive
and
developmental
studies
available
by
the
oral
(
gavage
or
diet)
route
of
exposure
indicate
that,
in
general,
the
main
concern
in
animals
for
reproductive
and
teratogenic
effects
of
copper
has
usually
been
associated
with
the
deficiency
of
the
element
rather
than
the
excess.
Page
8
of
39
Reproductive
effects
such
as
fetal
death,
resorptions,
and
infertility
resulting
from
copper
deficiency
have
been
reported
in
rats
and
guinea
pigs.
In
a
developmental
toxicity
study
in
rabbits,
the
maternal
LOAEL
is
9
mg
Cu/
kg/
day,
based
on
decreased
body
weight
gains
and
decreased
food
consumption.
The
maternal
NOAEL
is
6
mg
Cu/
kg/
day.
The
developmental
LOAEL
is
18
mg
Cu/
kg/
day
(
HDT),
based
on
incidences
of
hemi­
vertebra,
a
malformation,
and
slight
increases
in
minor
variations
(
supernumerary
ribs
and
retarded
ossification
of
the
mandible,
skull,
and
pelvis).
The
developmental
NOAEL
is
9
mg
Cu/
kg/
day.

There
is
no
evidence
to
suggest
susceptibility
in
infants
and
children.
Since
copper
is
a
natural
essential
trace
element,
with
copper
deficiency
more
common
in
humans
than
toxicity
from
excess,
and
since
the
dietary
contribution
of
copper
to
the
total
diet
is
low,
the
additional
tenfold
FQPA
safety
factor
for
the
protection
of
infants
and
children
is
unnecessary.

No
endpoints
of
toxicological
concern
have
been
identified
for
risk
assessment
purposes.
Therefore,
dietary,
residential,
and
occupational
risk
assessments
have
not
been
conducted.

3.0
Incident
Report
[
M.
Hawkins.
Review
of
Copper
Incident
Reports.
D319175.
8/
22/
2005].

An
incident
report
prepared
for
copper
reflects
data
from
the
following
sources:
OPP
Incident
Data
System
(
IDS);
Poison
Control
Center;
California
Department
of
Pesticide
Regulation;
National
Pesticide
Information
Center
(
NPIC);
and
the
National
Institute
of
Occupational
Safety
and
Health's
Sentinel
Event
Notification
System
for
Occupational
Risks
(
NIOSH
SENSOR).

The
IDS
has
seven
recorded
pesticide
incidents
for
copper;
five
involve
copper
hydroxide
and
two
involve
copper
sulfate
pentahydrate.
The
majority
of
the
noted
effects
involved
skin
and
eye
irritation,
nausea,
vomiting,
and
headaches.

The
principle
types
of
copper
fungicides
included
in
the
Poison
Control
Center
data
(
1993
 
2003)
are
copper
sulfate
and
copper
hydroxide.
Of
the
82
copper
exposures
identified
in
the
Poison
Control
Center
data,
only
20
were
seen
in
a
health
care
facility,
and
just
three
cases
had
a
moderate
medical
outcome.
The
leading
symptoms
included
ocular
irritation,
vomiting,
nausea,
and
dermal
irritation.

Data
from
the
California
Department
of
Pesticide
Regulation
(
1982
 
2003)
show
that
156
cases
(
out
of
494)
were
due
to
copper
compounds.
The
majority
of
these
cases
show
eye
effects,
skin
effects,
or
systemic
effects
(
including
skin,
eye,
or
respiratory
effects).

Of
the
top
200
chemicals
for
which
the
NPIC
received
calls
from
(
1984­
1991),
copper
hydroxide
was
ranked
167th
and
copper
sulfate
was
ranked
179th,
with
15
and
13
reports
of
illness
to
humans,
respectively.

NIOSH
SENSOR
data
reveal
that
out
of
5899
reported
cases
between
1998
 
2003,
only
34
cases
were
documented
as
involving
copper
(
copper
sulfate
pentahydrate,
copper
hydroxide,
and
copper­
ammonia
complex).
Twenty­
five
of
the
34
documented
cases
were
from
California,
and
Page
9
of
39
most
likely
overlap
the
cases
discussed
above
from
the
California
Department
of
Pesticide
Regulation.

According
to
a
review
of
the
scientific
literature,
copper
compounds
formulated
as
dusts
and
as
powders
are
irritating
to
the
skin,
respiratory
tract,
and
the
eyes.
Most
copper
compounds
have
low
systemic
toxicity,
due
mainly
to
their
limited
solubility
and
absorption.
Occupational
exposure
to
copper
containing
compounds
frequently
results
in
irritation
effects.
These
findings
from
the
scientific
literature
reflect
the
reported
incidents
from
the
above­
referenced
databases.

4.0
Exposure
Assessment
4.1
Dietary
Exposure
(
food
and
drinking
water)

An
exposure
assessment
considers
the
different
pathways
(
food,
water,
occupational,
and
residential)
through
which
exposure
to
copper
may
occur.
Copper
occurs
naturally
in
foods
such
as
potatoes,
vegetables,
organ
meats
(
especially
liver),
poultry,
seafood,
beans,
nuts,
and
wholegrains
The
National
Academy
of
Science
establishes
recommended
daily
allowances
(
RDAs)
of
vitamins
and
minerals
for
the
diet.
The
RDA
for
copper
ranges
from
approximately
400
micrograms
per
day
(
ug/
d)
in
young
children
to
900
ug/
d
in
adults.
Additionally,
over­
thecounter
dietary
supplements
containing
copper
at
levels
ranging
from
0.33
mg
to
3
mg
are
available
for
individuals
with
low
levels
of
copper.
The
maximum
level
of
copper
that
may
be
consumed
with
no
likely
risk
of
adverse
effects
ranges
from
approximately
1000
ug/
d
to
10,000
ug/
d
(
1­
10
mg/
d).
The
estimated
total
daily
oral
intake
of
copper
(
food
plus
drinking
water)
is
between
1
and
2
mg/
d,
although
oral
intake
may
occasionally
exceed
5
mg/
d.

In
addition
to
exposure
from
naturally
occurring
levels
of
copper
in
food,
dietary
exposure
to
copper
may
also
occur
as
a
result
of
the
use
of
copper
as
a
pesticidal
product
on
a
variety
of
food
commodities,
including
fruit,
vegetable,
and
nut
crops.
However,
as
noted
in
Section
1.3.2,
the
use
of
various
copper
products
on
growing
crops
and/
or
raw
agricultural
commodities,
as
well
as
on
meat,
milk,
poultry,
eggs,
fish,
shellfish,
and
irrigated
crops,
is
exempt
from
tolerance
requirements.
This
is
due
in
part
to
the
difficulty
in
distinguishing
naturally
occurring,
background
levels
of
copper
from
levels
resulting
from
the
application
of
copper
as
an
active
ingredient
in
pesticide
formulations.

Copper
may
also
be
found
in
drinking
water,
commonly
due
to
the
use
of
copper
in
plumbing
fixtures
and
water
pipes.
Copper
may
also
enter
drinking
water
systems
via
contamination
from
mining
operations,
incineration,
industrial
discharges,
and
from
sewage
treatment
plants.
Residues
of
copper
in
drinking
water
are
regulated
under
the
SDWA.
A
MCLG
of
1.3
ppm
has
been
set
by
the
Agency
for
copper.
According
to
the
National
Research
Council's
Committee
on
Copper
in
Drinking
Water,
this
level
is
"
set
at
a
concentration
at
which
no
known
or
expected
adverse
health
effects
occur
and
for
which
there
is
an
adequate
margin
of
safety."
2
2
Copper
in
Drinking
Water.
Committee
on
Copper
in
Drinking
Water,
Board
on
Environmental
Studies
and
Toxicology,
Commission
on
Life
Sciences,
National
Research
Council.
2000.
Page
10
of
39
Given
the
role
copper
plays
as
an
essential
element
to
the
human
body,
its
ubiquitous
nature
in
food
and
drinking
water,
and
the
long­
standing
tolerance
exemptions
for
the
pesticidal
use
of
copper
on
growing
crops,
as
well
as
on
meat,
milk,
poultry,
eggs,
fish,
shellfish,
and
irrigated
crops,
a
dietary
risk
assessment
is
not
required.
Acute
and
chronic
dietary
endpoints
have
not
been
selected.

4.1.1
Tolerance
Reassessment
The
1
ppm
tolerance
for
copper
residues
in
potable
water
(
40
CFR
§
180.538)
should
be
revoked,
as
OPP
no
longer
establishes
water
tolerances.
This
tolerance
revocation
was
originally
recommended
by
HED
in
1990
(
see
L.
Kutney
memo,
8/
13/
1990):
"
The
tolerance
for
potable
water
should
be
revoked
because
OPP
no
longer
establishes
water
tolerances.
The
Office
of
Drinking
Water
should
be
advised
to
consider
a
1
ppm
Acceptable
Residue
Level
in
Drinking
Water
(
ARLDW)
for
residues
of
copper
sulfate."
The
Office
of
Ground
Water
and
Drinking
Water
currently
has
a
1.3
ppm
MCLG
and
a
1.3
ppm
Action
Level3
in
place
for
copper.

The
3
ppm
tolerance
for
residues
of
basic
copper
carbonate
in
or
on
pears
at
3
ppm
of
combined
copper
from
post­
harvest
use
(
40
CFR
§
180.136)
should
be
revoked.
This
tolerance
is
not
necessary
for
human
health
protection,
as
many
food
commodities
not
treated
with
coppercontaining
products
have
naturally
occurring
levels
of
copper
that
are
higher
than
those
found
in
or
on
pears,
as
a
result
of
the
use
of
treated
paper
wrappers.
In
addition,
toxicological
studies
support
the
view
that
residues
from
the
use
of
copper
carbonate
on
impregnated
pear
wrappers
do
not
pose
a
significant
risk
to
human
health.

The
coppers
are
currently
exempt
from
tolerance
requirements
on
all
raw
agricultural
commodities
[
40
CFR
§
180.1021].
As
part
of
the
reregistration
process
for
copper,
the
Agency
concludes
that
all
food
use
copper
formulations
are
still
exempt
from
the
requirement
of
a
tolerance.
Should
any
additional
copper
active
ingredients
be
registered
for
new
food
uses
in
the
future,
the
need
for
a
tolerance
for
these
formulations
will
be
evaluated
at
that
time.

The
following
list
represents
all
food
use
copper
formulations
that
are
exempt
from
tolerance
requirements
on
raw
agricultural
commodities.

 
copper
hydroxide
(
023401)
 
copper
carbonate
(
022901)
 
copper­
ammonia
complex
(
022702)
 
basic
copper
chloride
(
008001)
 
copper
(
metallic)
in
the
form
of
chelates
of
copper
citrate
and
copper
gluconate
(
024405)
 
copper
oxychloride
sulfate
(
023503)
 
copper
oxychloride
(
023501)
 
basic
copper
sulfate
(
008101)
 
copper
sulfate
pentahydrate
(
024401)

3
An
Action
Level
is
defined
by
the
EPA
as
"
the
level
of
lead
or
copper
which,
if
exceeded,
triggers
treatment
or
other
requirements
that
a
water
system
must
follow."
Page
11
of
39
 
cuprous
oxide
(
025601)
 
copper
from
triethanolamine
complex
(
024403)
 
copper
salts
of
fatty
and
rosin
acids
(
023104)
 
copper
as
elemental
from
copper­
ethylenediamine
complex
(
024407)
 
copper
octanoate
(
023306)
 
copper
ethanolamine
complex
(
024409)

4.2
Occupational
and
Residential
Exposure
[
For
complete
agricultural,
commercial,
and
residential
use
tables
for
all
registered
copper
products,
see
A.
Nielsen
memo,
D319173,
9/
1/
2005].

Copper
formulations
are
used
on
a
variety
of
agricultural,
commercial,
and
residential
use
sites
as
fungicides,
bactericides,
algaecides,
herbicides,
wood
preservatives,
and
anti­
fouling
agents.
There
is
potential
for
exposure
to
occupational
mixers,
loaders,
and
applicators
of
copper
formulations,
as
well
as
to
residential
homeowners
who
may
apply
copper­
containing
products
in
and
around
their
homes;
however,
no
dermal,
oral,
or
inhalation
endpoints
of
toxicological
concern
have
been
identified
for
copper.
Therefore,
an
occupational/
residential
exposure
assessment
is
not
required.

Some
copper
species
may
cause
dermal
and
eye
irritation
(
Toxicity
Category
I/
II)
in
occupationally
or
non­
occupationally
exposed
individuals.
Since
no
toxicological
endpoints
of
concern
were
identified
for
dermal
exposures
to
copper
species,
no
post­
application
dermal
risk
was
assessed.
For
uses
within
the
scope
of
the
Worker
Protection
Standard
for
Agricultural
Pesticides
(
40
CFR
170),
a
restricted
entry
interval
(
REI)
must
be
established.
For
each
copper
species,
the
REI
should
be
based
on
the
category
assigned
to
the
acute
dermal
toxicity,
skin
irritation
potential,
and
eye
irritation
potential
of
the
active
ingredient.
The
appropriate
REI
is
48
hours
if
any
of
the
three
categories
is
classified
as
a
category
one;
the
appropriate
REI
is
24
hours
if
any
of
the
three
categories
is
classified
as
category
two.
If
all
three
categories
are
classified
as
category
three
or
four,
the
appropriate
REI
is
12
hours.
If
no
data
are
available
on
the
acute
dermal
toxicity,
skin
irritation
potential,
and
eye
irritation
potential
of
the
active
ingredient,
then
a
default
REI
of
48
hours
is
appropriate.

For
commercial
uses
of
copper­
containing
products,
dermal,
eye,
and
respiratory
irritation
effects
are
addressed
through
precautionary
labeling
requirements
for
use
of
Personal
Protective
Equipment
(
PPE).
In
addition,
protection
is
provided
with
the
use
of
engineering
controls
for
industrial
applications.
For
airborne
concentrations
in
industrial
workplace
settings,
OSHA
has
set
a
permissible
exposure
limit
(
PEL)
(
8­
hour
time
weighted
average,
or
TWA)
of
1.0
mg/
m3
for
dusts
and
mists
(
as
Cu).

For
copper
species
used
in
residential
settings,
dermal
and
eye
irritation
effects
will
be
addressed
through
end­
use
product
labeling
language.

The
following
is
a
summary
of
the
various
agricultural,
commercial,
and
residential
uses
of
copper
formulations:
Page
12
of
39
Agricultural
Uses:
Twelve
species
of
copper
are
registered
for
use
on
agricultural
crops.
In
agricultural
settings,
copper
formulations
are
most
commonly
used
as
fungicides,
but
may
also
be
used
as
bactericides,
herbicides,
and
algaecides.
Formulation
types
include
dusts,
liquid
concentrates,
dry
flowables,
wettable
powders,
and
wettable
powders
in
water
soluble
packets.
Application
methods
include
aerial,
airblast,
groundboom,
rights­
of­
way
equipment
and
mechanical
duster
equipment,
low­
and
high­
pressure
handwand
sprayers,
and
handgun
sprayers.
Agricultural
use
sites
include:

 
Virtually
all
food,
feed,
fiber,
and
specialty
crops,
 
All
ornamental
crops
grown
in
greenhouses
and
nurseries,
and
 
Turfgrass
(
i.
e.,
sod
farms).

Commercial
Uses:
Sixteen
species
of
copper
are
registered
for
commercial
use,
typically
as
fungicides,
bactericides,
herbicides,
algaecides,
and
insecticides.
Formulation
types
include
wettable
powders,
wettable
powders
in
water
soluble
packets,
liquid
concentrates,
granules,
water
dispersible
granules,
powders,
and
ready­
to­
use
liquids,
aerosols,
and
solids.
Application
methods
include
groundboom,
low­
pressure
handwand,
handgun
sprayer,
push­
type
spreader,
paint
sprayer,
brushes,
sponges,
rollers,
dips,
direct
pour,
industrial
coating
equipment,
pressure
treatment
equipment,
drip
system
or
pump
metering,
and
other
specialty
equipment.
Commercial
use
sites
include:

 
Planter,
seed
handling
equipment,
nursery
containers,
and
similar
agricultural
equipment,
 
Industrial
use
fabrics,
 
Aquatic
sites
(
swimming
pools,
ornamental
ponds
and
fountains,
potable
water,
lakes,
rivers,
irrigation
systems,
stock
watering
tanks,
troughs),
 
Household
sewers,
feedlot
lagoons,
animal
confinement
pits,
other
organic
sludges,
storm
drains,
sewers,
sewer
pumps,
and
force
mains,
 
Turfgrass
(
golf
courses,
cemeteries,
home
lawns,
industrial
and
municipal
turf
areas,
 
Industrial
recirculating
cooling
systems,
 
Wood
and
wood
products,
 
Boats
and
other
marine
equipment,
 
Textiles,
 
Materials
such
as
paints,
adhesives,
plastics,
fibers,
coatings,
sealants,
clay,
china,
ceramic,
sand,
and
grout
(
incorporated
during
manufacturing
processes),
 
Paper
products,
and
 
Environmental
surfaces
(
paint,
varnish,
concrete,
brick,
glass,
tile,
metals,
plastics,
wood,
paper,
leather,
textiles,
asphalt
shingle).

Residential
(
Homeowner)
Uses:
There
are
seventeen
species
of
copper
that
have
registered
residential
(
homeowner)
uses.
In
residential
settings,
copper
formulations
are
used
as
fungicides,
bactericides,
herbicides,
and
algaecides.
Formulations
include
dusts,
liquid
concentrates,
dry
flowables,
wettable
powders,
Page
13
of
39
granules,
and
ready­
to­
use
solids,
aerosols,
and
liquids.
Application
methods
include
lowpressure
handwand,
hose­
end
sprayer,
brush,
roller,
paint
sprayer,
automatic
metering
systems,
dipping,
direct
pour,
or
aerosol
spray.
Residential
use
sites
are
as
follows:

 
Virtually
all
food
and
specialty
garden
crops,
 
All
ornamental
crops,
 
Turfgrass,
 
Aquatic
sites
(
aquariums,
swimming
pools,
ornamental
ponds
and
fountains),
 
Household
sewer
systems,
 
Wood
and
wood
products,
 
Boats,
 
Environmental
surfaces
(
paint,
varnish,
concrete,
brick,
glass,
tile,
metals,
plastics,
wood,
paper,
leather,
textiles,
asphalt
shingles),
 
Residential
outdoor
surfaces
(
roofs,
decks,
patios,
sidewalks,
driveways),
 
Textiles,
and
 
Compost.

5.0
Summary
Copper
is
an
ubiquitous,
naturally
occurring
metal
that
is
essential
to
human
health.
It
is
found
at
low
levels
in
a
variety
of
food
products,
as
well
as
in
drinking
water.
Copper
may
also
be
used
on
a
wide
variety
of
agricultural,
commercial,
and
residential
use
sites
as
a
fungicide,
bactericide,
algaecide,
herbicide,
wood
preservative,
and
anti­
fouling
agent.
Copper
has
moderate
to
low
toxicity
(
toxicity
category
II,
II,
and
IV)
based
on
acute
oral,
dermal,
and
inhalation
studies
in
animals,
with
the
exception
of
cuprous
oxide,
which
has
a
toxicity
category
of
I
for
acute
inhalation.
In
some
forms,
it
is
a
severe
eye
irritant,
and
copper
sulfate
pentahydrate
may
be
a
dermal
sensitizer
to
human
skin.

Acute
toxicity
data
gaps
(
acute
oral,
dermal,
and
inhalation;
primary
eye
irritation;
dermal
irritation;
and
dermal
sensitization
studies)
exist
for
the
following
copper
species:
chelates
of
copper
gluconate,
copper
ammonium
carbonate,
copper­
ammonia
complex,
copper
oxychloride
sulfate,
basic
copper
sulfate,
and
copper
ethanolamine
complex.

Due
to
its
ubiquitous
nature,
and
because
naturally
occurring
levels
of
copper
on
raw
agricultural
commodities
cannot
be
distinguished
from
levels
that
are
the
result
of
pesticidal
use,
many
copper
species
are
exempt
from
tolerance
requirements
for
use
on
most
raw
agricultural
commodities.
A
tolerance
(
3
ppm)
exists
for
the
use
of
copper
carbonate
in/
on
pears,
and
a
1
ppm
tolerance
exists
for
residues
of
copper
in
potable
water.

With
respect
to
dietary
issues,
HED
recommends
that
the
tolerance
exemption
be
expanded
to
include
all
existing
food
use
copper
formulations,
with
the
exception
of
three
species
that
do
not
currently
have
registered
food
uses.
HED
also
recommends
the
tolerance
in/
on
pears
be
revoked,
as
well
as
the
tolerance
in
potable
water.
Residues
of
copper
in
drinking
water
are
currently
addressed
by
the
Agency's
Office
of
Ground
Water
and
Drinking
Water.
Page
14
of
39
In
order
to
address
potential
post­
application
exposure
from
agricultural
uses
of
copper
species,
HED
recommends
the
establishment
of
a
REI
of
12,
24,
or
48
hours,
depending
on
the
availability
and
adequacy
of
acute
toxicity
studies.
If
no
data
are
available
on
the
acute
dermal
toxicity,
skin
irritation
potential,
and
eye
irritation
potential
of
the
active
ingredient,
then
a
default
REI
of
48
hours
is
appropriate.
Commercial
uses
of
copper­
based
pesticides
will
be
adequately
protected
through
label­
specified
PPE
(
based
on
the
toxicity
categories
of
the
end­
use
product),
industrial
workplace
safety
standards,
and
engineering
controls.
For
formulations
with
residential
uses,
dermal
and
eye
irritation
effects
will
be
addressed
via
end­
use
product
labeling
language.

In
summary,
humans
have
a
unique
ability
to
maintain
appropriate
copper
stores
in
the
body.
Exposure
is
primarily
through
food
that
is
consumed
with
established
Recommended
Daily
Allowances
(
RDAs)
for
adults,
children,
and
infants.
Copper
may
be
irritating
to
the
skin,
eyes,
and
lung.
Copper
residues
from
the
use
as
a
pesticidal
active
ingredient
are
not
expected
to
significantly
contribute
to
the
naturally
occurring
levels
of
copper
in
foods;
therefore,
toxicological
endpoints
have
not
been
established
and
dietary,
occupational,
and
residential
risk
assessments
are
not
required.
Page
15
of
39
Appendix
A
Hazard
Assessment
of
Copper
The
hazard
profile
and
characterization
for
this
risk
assessment
is
unique
since
four
copper
cases
(
0649,
0636,
4025,
4026)
as
well
as
other
unscheduled
coppers
will
be
assessed
in
a
single
document.
The
copper
cases
include
the
copper
compounds
(
PC
Codes:
008001,
024405,
022703,
022901,
023401,
022702,
023501,
023503),
copper
sulfates
(
008101,
024408,
024401),
copper
and
oxides
(
022501,
042401,
025601),
copper
salts
(
024403,
024407,
023104),
and
other
unscheduled
coppers
(
023306,
024409).

Copper
naphthenate,
copper
8­
quinolinolate,
and
cuprous
thiocyanate
will
be
assessed
individually
by
OPP's
Antimicrobials
Division
at
a
later
date.
The
purpose
of
listing
all
studies
(
including
copper
naphthenate,
copper
8­
quinolinolate,
and
cuprous
thiocyanate)
in
the
toxicity
data
summary
tables
in
Appendix
A
is
to
present
all
available
data
that
have
been
reviewed
and
considered
acceptable,
even
though
the
aforementioned
three
active
ingredients
are
not
included
in
the
scope
of
this
risk
assessment.

A.
Hazard
Profile:

The
following
hazard
presentation
will
describe
the
toxicology
of
copper,
with
the
component
of
toxicological
interest
as
elemental
copper.
The
available
toxicity
studies
submitted
for
reregistration
for
each
of
the
coppers
differs
and
are
difficult
to
separate
since
many
of
the
toxicity
studies
are
old
and
do
not
specify
the
percent
of
elemental
copper
used
in
the
studies.
However,
studies
have
been
separated
by
their
respective
PC
Code
for
ease
of
documentation.
Please
see
the
toxicity
profile
tables
in
Section
K
for
the
available
toxicity
studies
for
the
different
copper
cases.
The
following
hazard
section
also
includes
review­
type
articles
or
published
studies.
Information
from
the
WHO
Guidelines,
ATSDR
(
2004),
Food
and
Agriculture
Organization
(
FAO),
IOM
(
2001),
National
Research
Council
(
2000),
International
Programme
on
Chemical
Safety
(
IPCS),
and
National
Toxicology
Program
(
NTP)
have
also
been
included
in
this
assessment.

Copper
is
a
naturally
occurring
element
that
is
essential
for
the
homeostasis
of
life.
The
role
of
copper
in
maintaining
normal
health
both
in
animals
and
humans
has
been
recognized
for
many
years.
Sources
of
human
and
environmental
copper
include
windblown
dust,
volcanoes,
decaying
vegetation,
forest
fires
and
sea
spray.
Copper
is
also
found
naturally
in
various
foods,
including
organ
meats
(
liver),
seafood,
beans,
nuts,
and
whole
grains.
It
has
been
estimated
that
approximately
40%
of
dietary
copper
is
consumed
from
yeast
breads,
white
potatoes,
tomatoes,
cereals,
beef
and
dried
beans
and
lentils
(
Subar
et
al.,
1998).
In
most
foods,
copper
is
present
bound
to
macromolecules
rather
than
as
a
free
ion
(
IOM,
2001).
Additional
copper
also
may
be
consumed
from
drinking
water
from
copper
pipes,
and
using
copper
cookware.
Anthropogenic
emissions
include
smelters,
iron
foundries,
power
stations
and
combustion
sources
such
as
municipal
incinerators.
An
estimate
for
the
agricultural
use
of
copper
products
was
approximately
2%
of
copper
released
to
soil.
(
IPCS,
1998).
Page
16
of
39
The
mechanisms
that
regulate
the
metabolism
of
copper
in
humans
are
not
yet
well
understood.
However,
the
mechanisms
regulating
total
body
copper
seem
efficient,
given
the
relatively
small
and
constant
body
pool
of
copper.
In
fact,
an
estimate
of
80
to
150
mg
may
be
found
in
the
body
at
any
given
point
(
FAO/
WHO,
1970;
Turnlund,
1998).
In
the
healthy
adult,
nearly
twothirds
of
the
body
copper
content
is
located
in
the
skeleton
and
muscle
(
due
to
their
large
tissue
masses),
with
the
liver
as
the
primary
organ
for
the
maintenance
of
plasma
copper
concentrations
(
FAO/
WHO
1970;
WHO
1974).
In
newborns
it
is
reported
that
the
liver
contains
the
majority
(
50­
60%)
of
the
body
copper
(
Luza
and
Speisky,
1996).

The
efficiency
of
copper
absorption
varies
greatly,
depending
on
dietary
intake.
Changes
in
efficiency
of
absorption
help
to
regulate
the
amount
of
copper
retained
by
the
body.
In
fact,
when
dietary
copper
is
high
and
more
copper
is
absorbed,
mainly
through
the
gastrointestinal
tract,
excretion
of
endogenous
copper
increases,
protecting
against
excess
accumulation
of
copper
in
the
body.
Depending
on
the
copper
status
in
the
body
at
the
time,
approximately
20
to
60%
of
dietary
copper
may
be
absorbed
(
JECFA
#
551).
Copper
absorption
is
also
affected
by
other
factors
such
as
species,
age,
chemical
form,
physiological
status
(
e.
g.
pregnancy)
and
various
dietary
components.
When
copper
intake
is
low,
little
endogenous
copper
is
excreted,
protecting
against
copper
depletion.

The
proper
regulation
of
copper
in
humans
involves
both
the
carrying
protein
ceruloplasmin
and
the
excretion
of
copper
mainly
in
the
bile.
Dietary
copper
absorbed
through
the
intestinal
mucosa
is
transported
via
the
portal
blood
to
the
liver.
Copper
that
is
taken
up
by
the
liver
is
then
incorporated
into
ceruloplasmin,
released
into
the
blood,
and
delivered
to
tissues
(
Turnlund,
1998,
WHO
Guidelines,
2004).
Approximately
60%
to
95%
of
the
copper
in
systemic
circulation
is
bound
by
ceruloplasmin
(
IOM
2001,
NRC
2000,
IPCS
1998,
Luza
and
Speisky,
1996).
It
has
been
reported
that
humans
generally
have
more
of
these
ceruloplasmin
proteins
than
animals,
thereby
enhancing
copper
efficiency
in
humans
(
IPCS
PIM,
1991).
Most
endogenous
copper
is
excreted
in
the
bile,
another
component
in
the
regulation
of
the
total
body
level
of
copper.
Very
little
copper
is
lost
in
the
urine
and
sweat.
The
biological
half­
life
of
copper
in
humans
has
been
estimated
to
be
about
4
weeks
(
Strickland
et
al.,
1972;
Dekaban
et
al.,
1975).

The
amount
of
copper
that
is
retained
in
the
body
from
the
diet
and
drinking
water
typically
depend
on
the
copper
status
of
the
individual
at
the
time.
A
positive
copper
balance
for
humans
is
generally
maintained
if
the
dietary
intake
is
approximately
2
mg/
day.
As
copper
intake
increases
there
is
generally
an
increase
in
the
amount
retained,
up
to
an
intake
of
about
8
mg/
day.
Copper
intake
beyond
this
rate
generally
results
in
no
significant
increase
in
the
amount
of
copper
retained
(
Schroeder
et
al.,
1966;
Evans,
1973).

In
pregnant
women,
it
is
hypothesized
that
increased
levels
of
plasma
copper
are
not
due
to
a
greater
efficiency
of
intestinal
absorption
of
copper,
but
rather
to
increased
biosynthesis
of
ceruloplasmin
and
mobilization
of
liver
copper
stores
(
Markowitz
et
al.,
1955).
Page
17
of
39
Improper
Metabolism
of
Copper
in
Humans:

Copper
is
an
essential
cofactor
for
approximately
a
dozen
copper­
binding
proteins
for
the
proper
regulation
of
copper
homeostasis.
A
deficiency
of
copper
or
a
defect
in
copper
carrying
proteins
may
result
in
symptoms
such
as
anemia,
defective
blood
vessel
development,
copper
toxicity,
or
connective
tissue
symptoms
(
Danks,
1988;
Pena
et
al.,
1999;
Prohaska
and
Gybina,
2004).

Some
genetic
conditions
in
humans
may
produce
abnormal
copper
metabolism,
thus
resulting
in
either
copper
toxicity
or
deficiency.
Autosomal
recessive
disorders
such
as
Wilson's
Disease,
OHS
(
Occipital
Horn
Syndrome),
TIC
(
Tyrolean
Infantile
Cirrhosis),
ICC
(
Indian
Childhood
Cirrhosis),
ICT
(
Idiopathic
Copper
Toxicosis),
and
aceruloplasminanemia,
result
in
copper
toxicity.
For
example,
Wilson's
disease
is
due
to
the
inability
for
biliary
excretion
of
copper
which
leads
to
the
gradual
accumulation
of
copper
predominately
in
the
liver
and
brain.
In
contrast,
Menkes
disease
is
an
X­
linked
neurodegenerative
disorder
in
infants
characterized
by
poor
growth
and
unusual
"
kinky"
hair
texture.
In
Menkes
disease,
clinical
effects
include
low
ceruloplasmin
concentrations
and
decreased
concentrations
of
copper
in
the
liver
and
brain
(
Danks,
1995).
The
major
cause
of
this
copper
deficiency
is
minimal
copper
absorption
by
the
intestinal
mucosa
and
transport
of
copper
across
the
blood­
brain­
barrier,
independent
of
copper
intake
(
Danks
et
al.,
1972).

B.
Mode
of
Action:

Copper
salts
such
as
copper
sulfate
are
gastric
irritants
and
produce
corrosion
of
the
gastric
and
intestinal
epithelium.
Copper
ion
may
oxidize
oxyhemoglobin
from
the
ferrous
to
the
ferric
form.
In
the
ferric
form,
hemoglobin
loses
its
oxygen­
binding
capacity
resulting
in
methemoglobinemia
and
cyanosis
(
IPCS
PIM,
1991).

C.
Available
In­
House
Studies
and
Literature
Database
Description:

Acute
Studies:
(
Please
see
Section
J
for
Acute
Toxicity
Tables)

Acute
toxicity
studies
for
the
routes
of
exposure,
namely,
oral,
dermal,
and
inhalation,
exist
for
almost
all
copper
species.
However,
none
of
the
acute
toxicity
studies
are
available
for
copper
ammonium
carbonate,
copper­
ammonia
complex,
chelates
of
copper
gluconate,
copper
oxychloride
sulfate,
basic
copper
sulfate,
copper
sulfate
anhydrous,
and
copper
ethanolamine
complex.
Copper
has
moderate
to
low
toxicity
(
toxicity
category
II,
II,
and
IV)
based
on
acute
oral,
dermal,
and
inhalation
studies
in
animals,
with
the
exception
of
cuprous
oxide,
which
has
a
toxicity
category
of
I
for
acute
inhalation.
However,
copper
may
be
a
severe
eye
irritant.
Most
dermal
irritation
studies
indicate
Toxicity
Category
III
or
IV,
however,
cuprous
oxide
and
copper
naphthenate
produced
Toxicity
Category
I
irritation.
Copper
was
generally
non­
sensitizing
in
guinea
pigs
and
rabbits,
except
for
copper
naphthenate
which
was
a
skin
sensitizer.
An
available
human
skin
sensitization
study
indicated
copper
(
as
sulfate
pentahydrate)
was
a
sensitizer
to
human
skin
and
warrants
the
avoidance
of
dermal
exposure
to
copper.
Page
18
of
39
Subchronic
Studies:

Copper
is
generally
less
toxic
when
administered
in
the
diet
than
when
administered
in
drinkingwater
or
by
gavage.
Orally,
copper
is
irritative
to
the
gastrointestinal
tract,
with
few
systemic
effects
reported.

Short­
term
feeding
studies
with
rats
and
mice
indicate
decreased
food
and
water
intake
with
increasing
oral
concentrations
of
copper
with
irritation
of
the
stomach
at
higher
copper
concentrations.
The
irritating
effects
of
copper
were
demonstrated
in
an
NTP
study
(
Hebert
et
al.,
1993).
The
study
was
designed
to
examine
the
effects,
if
any,
of
cupric
sulfate
pentahydrate
when
administered
in
the
drinking
water
for
2
weeks
only
(
300
to
10,000
ppm
estimated
at
41/
58
to
524/
683
M/
F
mg/
kg/
day
mice
and
41/
39
to
140/
120
M/
F
mg/
kg/
day
rats)
or
diet
for
2
weeks
(
1,000
to
16,000
ppm
estimated
at
168/
210
to
2817/
3068
M/
F
mg/
kg/
day
mice
and
92/
89
to
1275/
1121
M/
F
mg/
kg/
day
rats)
and
13
weeks
(
500
to
16,000
ppm
estimated
at
173/
205
(
1,000
ppm)
to
3201/
4157
M/
F
mg/
kg/
day
mice
and
32/
34
to
551/
528
(
8,000
ppm)
M/
F
mg/
kg/
day
rats)
in
B6C3F1
mice
and
F344/
N
rats.
Dehydration
accounted
for
the
deaths
of
rats
and
mice
in
the
high
dose
groups
in
the
drinking
water
study.
Decreased
body
weight
and
food
consumption
was
also
observed
in
the
two
highest
dose
groups
of
rats
and
mice
in
the
feeding
study.
In
summary,
cupric
sulfate
administered
to
rats
in
feed
or
drinking
water
resulted
in
gastric
changes
(
hyperplasia
and
hyperkeratosis
of
the
squamous
epithelium
on
the
limiting
ridge
of
the
forestomach)
and
hepatic
(
inflammation),
and
renal
(
increased
number
and
size
of
protein
droplets
in
epithelium
of
the
renal
cortical
tubules)
damage.
Alterations
consistent
with
microcytic
anemia
were
observed
in
rats,
but
not
in
mice,
in
the
13­
week
study.
Cupric
sulfate
produced
no
effects
on
any
of
the
reproductive
parameters
(
sperm
morphology,
vaginal
cytology)
measured
in
rats
or
mice
of
either
sex.

The
role
of
trace
metals
such
as
copper
in
the
regulation
of
the
immune
system
is
not
understood.
A
short­
term
drinking
water
study
examined
the
influence
of
excess
copper
on
the
immune
response
of
mice
(
Pocino
et
al.,
1991).
Mice
receiving
50,
100,
200,
or
300
ppm
of
copper
in
the
drinking
water
for
3
to
10
weeks
had
the
same
general
health
as
controls
with
no
changes
in
food
ingestion
or
in
mean
body
weight.
Immune
response
was
reported
 "
to
be
altered
in
a
fashion
related
to
the
dose
and
duration
of
treatment".
However,
administration
of
copper
in
the
drinking
water
resulted
in
diminished
water
consumption,
"
which
was
lower
as
the
concentration
of
copper
increased".
The
amount
of
water
that
was
consumed
by
the
mice
was
not
reported.
In
addition,
zinc
was
not
measured
in
this
study
and
since
zinc
and
copper
have
antagonistic
interactions,
a
zinc
deficiency
simultaneously
with
excess
copper
could
also
produce
inhibited
immune
responses
observed
in
mice
receiving
excess
copper.
Therefore,
it
is
not
known
whether
the
dehydration
of
the
animal
and
a
possible
zinc
deficiency
contributed
significantly
to
any
immune
response
detected
in
this
study.

An
older
report
of
a
rabbit
inhalation
study
with
copper
sulfate
indicated
lung
lesions
were
observed
in
rabbits
kept
in
compartments
continuously
saturated
with
a
fine
spray
of
Bordeaux
mixture
(
copper
sulfate
neutralized
with
hydrated
lime),
generated
from
a
Flit
spray
gun,
over
a
period
of
5.5
months
(
MRID
00078547,
00062081).
However,
any
possible
contamination
with
arsenic
was
not
reported
in
this
dated
report.
Although
this
report
is
old
and
not
up
to
current
Page
19
of
39
standard
guidelines,
the
reports
do
provide
some
insight
into
potential
inhalation
hazards
of
copper.
This
study
was
conducted
in
animals
to
substantiate
the
lesions
observed
in
workers
who
chronically
sprayed
vineyards
with
Bordeaux
mixture.
In
addition,
results
of
a
12­
day
dermal
toxicity
study
in
the
rat
indicated
a
dose
related
increase
in
dermal
irritation
but
with
no
systemic
toxicity
at
1000
mg/
kg/
day
(
MRID
44127507).

Long­
Term/
Chronic
Studies:

As
observed
in
the
short­
term
feeding
studies,
longer
feeding
studies
indicate
decreased
feed
intake
with
reductions
in
body
weight
gains,
and
increased
copper
concentration
of
the
liver.
Wistar
rats
were
given
either
a
standard
diet
with
10­
20
mg
copper/
kg
feed
or
diets
supplemented
with
3000,
4000,
or
5000
mg
of
copper/
kg
feed
for
15
weeks.
Dietary
copper
concentrations
were
approximately
0.5­
1.0,
150,
200,
or
250
mg
copper/
kg
bw/
day.
Copper
concentrations
increased
in
the
livers
of
the
rats
on
supplemental
copper
at
3­
4
weeks,
decreased
significantly
at
6
weeks,
but
were
still
elevated
at
15
weeks.
Hepatocellular
necrosis
was
observed
in
all
supplemental
groups
from
weeks
1­
6,
with
regeneration
beginning
after
3­
5
weeks.
Adaptation
of
the
liver
indicated
by
decreased
liver
copper
concentration,
regeneration,
growth,
and
then
tolerance
was
observed
in
livers
of
rats
on
3000
to
5000
mg
copper
supplement
for
52
weeks.
Rats
on
6,000
mg/
kg
copper
maintained
hepatic
overload
and
did
not
recover
(
Haywood
and
Loughran,
1985).

A
number
of
older
studies
with
various
copper
compounds
have
examined
the
carcinogenicity
in
laboratory
animals,
but
all
these
studies
are
considered
inadequate
by
current
methodologies
(
NRC,
2000).
Regardless
of
the
age
of
the
studies,
there
is
no
suggestion
or
evidence
that
copper
or
its
salts
are
carcinogenic
in
animals
having
normal
copper
homeostasis.
Copper
(
metallic)
is
currently
Group
D,
not
classifiable
as
to
human
carcinogenicity.

Reproductive
and
Developmental
studies:

Reproductive
and
developmental
studies
available
by
the
oral
(
gavage
or
diet)
route
of
exposure
indicate
that
in
general,
the
main
concern
in
animals
for
reproductive
and
teratogenic
effects
of
copper
has
usually
been
associated
with
the
deficiency
of
the
element
rather
than
excess.
Copper
is
a
nutritionally
required
trace
element
that
is
necessary
for
maintaining
the
health
of
embryos,
fetus,
newborn,
and
infant.
Reproductive
effects
such
as
fetal
death,
resorptions,
and
infertility
resulting
from
copper
deficiency
have
been
reported
in
rats
and
guinea
pigs
(
Oster
and
Salgo,
1977).

Reproductive
parameters
measured
in
rats
and
mice
from
exposure
to
administered
(
water
or
diet)
cupric
sulfate
(
2
to
13
weeks)
at
doses
ranging
from
500
ppm
to
8000
ppm
(
Hebert
et
al.,
1993)
indicated
no
significant
differences
from
control
values
for
any
of
the
following
reproductive
parameters:
testis,
epididymis
and
cauda
epididymis
weights,
spermatid
count,
spermatid
number
per
testis
or
per
gram
testis,
spermatozoal
motility
and
concentration,
estrous
cycle
length
or
relative
length
of
time
spent
in
the
various
estrous
stages.
Page
20
of
39
As
with
any
substance,
high
concentrations
of
copper
(
CuSO4)
may
result
in
the
toxicity
of
the
developing
organism.
Sexually
mature
mice
(
2
strains)
were
fed
0.5,
1.0,
1.5,
2.0,
3.0,
or
4.0
g
copper
per
kg
food
until
day
19
of
gestation
(
Lecyk,
1980).
Copper
at
doses
of
0.5
to
1.0
g/
kg
had
no
harmful
effect
on
embryonic
growth
or
development.
Copper
at
doses
of
3
and
4
g/
kg
resulted
in
increased
mortality
and
malformations.
Mortality
in
C57BL
mice
at
3
and
4
g/
kg
doses
was
21.4%
(
15/
70)
and
28.6%
(
10/
45),
respectively
compared
to
14.5%
(
11/
76)
in
controls.
Mortality
in
DBA
mice
at
3
and
4
g/
kg
doses
was
20%
(
14/
70)
and
26.2%
(
16/
60),
respectively,
compared
to
13.6%
(
12/
88)
in
controls.
In
C57BL
mice
at
the
3
and
4
g/
kg
doses,
1.8%
(
1/
55)
and
8.5%
(
3/
35)
of
living
fetuses
had
a
malformation,
respectively.
In
DBA
mice,
3.7%
(
2/
56)
and
7.4%
(
4/
45)
of
living
fetuses
had
a
malformation,
respectively.
Malformations
were
not
observed
in
any
lower
dose
of
copper
or
in
control
groups.
Malformations
observed
were
likely
due
to
the
toxic
effects
of
copper.

In
a
developmental
toxicity
study
(
MRID
46377502),
copper
hydroxide
technical
(
61.14%
Cu,
Lot
#
021121/
1)
in
0.5%
aqueous
methylcellulose
was
administered
daily
via
oral
gavage
to
22
time­
mated
New
Zealand
White
rabbits/
group
at
dose
levels
of
0,
6,
9,
or
18
mg
Cu/
kg/
day
at
a
dose
volume
of
1
mL/
kg
from
gestation
day
(
GD)
7
through
28.
At
18
mg
Cu/
kg/
day,
three
rabbits
were
found
dead
prior
to
scheduled
termination.
Diarrhea,
red
cageboard­
staining,
weakness,
and
irregular
respiration
preceded
death
on
GD
10
in
one
of
these
animals.
The
other
two
animals
were
found
dead
on
GD
9
and
16
and
appeared
normal
prior
to
death;
however,
dark
colored
spots
or
dark
mottling
were
observed
in
the
lungs
in
these
animals
at
necropsy.
In
addition,
two
does
in
this
dose
group
aborted
on
GD
22.
Staining
of
the
fur,
tail,
and/
or
cage
board
was
noted
in
animals
in
this
group
and
corresponded
to
the
diarrhea
and/
or
abortions.
Ulceration
and/
or
hemorrhage
in
the
stomach
was
observed
in
4/
21
does
at
this
dose
compared
to
0/
22
controls.
There
were
no
other
treatment­
related
mortalities,
abortions,
or
clinical
signs
of
toxicity.

Body
weight
gains
were
decreased
during
GD
7­
10
at
9
mg
Cu/
kg/
day
(­
125.4
g)
and
18
mg
Cu/
kg/
day
(­
259.2
g)
compared
to
controls
(
2.2
g).
Additionally
at
18
mg
Cu/
kg/
day,
body
weight
gains
for
the
overall
(
GD
7­
29)
treatment
period
were
decreased
(
p#
0.05),
when
the
gravid
uterine
weight
was
included
(
972%)
or
when
correcting
for
the
gravid
uterine
weight
(
9101%).
Body
weights
were
decreased
(
p#
0.05)
by
5%
at
this
dose
compared
to
controls
on
GD
10
and
11.
There
were
no
other
treatment­
related
effects
on
body
weights
or
body
weight
gains.
Individual
gravid
uterine
weights
were
not
reported.

Food
consumption
was
decreased
at
9
mg
Cu/
kg/
day
during
GD
7­
10
(
952%)
and
GD
10­
13
(
932%),
resulting
in
decreased
(
p#
0.05)
food
consumption
for
the
overall
(
GD
7­
29)
treatment
period
(
917%).
At
18
mg
Cu/
kg/
day,
food
consumption
was
decreased
throughout
the
treatment
period
(
911­
89%;
p#
0.05,
except
not
significant
for
GD
25­
29).
The
only
finding
at
6
mg
Cu/
kg/
day
was
a
transient
decrease
(
914%;
p#
0.05)
in
food
consumption
during
GD
7­
10.
The
maternal
LOAEL
is
9
mg
Cu/
kg/
day
based
on
decreased
body
weight
gains
and
food
consumption.
The
maternal
NOAEL
is
6
mg
Cu/
kg/
day.

There
were
no
premature
deliveries
or
dead
fetuses.
There
were
no
effects
of
treatment
on
the
numbers
of
litters,
live
fetuses,
dead
fetuses,
resorptions
(
early,
late,
total,
or
complete
litter),
or
Page
21
of
39
on
sex
ratio
or
post­
implantation
loss.
There
were
no
treatment­
related
effects
on
fetal
body
weights.
The
following
incidences
of
retarded
ossification
were
noted
at
18
mg
Cu/
kg/
day
(
vs
0
controls)
and
were
considered
treatment­
related:
(
i)
mandible
(
0.8%
fetuses;
6.7%
litters);
(
ii)
pelvis
(
1.6%
fetuses;
6.7%
litters);
and
(
iii)
skull
(
4.0%
fetuses;
13.3%
litters),
resulting
in
a
significant
positive
trend
for
this
finding.
There
were
no
treatment­
related
external
or
visceral
variations.
A
dose­
dependent
increase
in
the
fetal
incidences
of
supernumerary
ribs,
a
variation,
was
noted
in
all
treated
groups
(
67.1­
87.3%
fetuses)
compared
to
controls
(
63.6%
fetuses),
resulting
in
a
significant
(
p<
0.05)
positive
trend.
However,
because
the
fetal
incidence
was
only
minimally
increased
over
controls
at
6
and
9
mg
Cu/
kg/
day
(
67.1­
79.9%
fetuses)
compared
to
controls
(
63.6%
fetuses),
only
the
incidence
at
18
mg
Cu/
kg/
day
(
87.3%)
is
considered
adverse.
All
litters,
with
the
exception
of
one
litter
at
9
mg
Cu/
kg/
day
(
95.2­
100%
litters),
had
fetuses
with
supernumerary
ribs.
There
were
no
treatment­
related
external
or
visceral
malformations.
Hemi
vertebra,
a
malformation,
was
noted
in
2
fetuses
(
1.6%)
in
2
litters
(
13.3%)
at
18
mg
Cu/
kg/
day
(
vs
0
controls),
resulting
in
a
significant
(
p<
0.05)
positive
trend.
In
the
absence
of
historical
control
data,
this
finding
is
considered
treatment­
related.
The
developmental
LOAEL
is
18
mg
Cu/
kg/
day
based
on
incidences
of
hemi­
vertebra,
a
malformation,
and
on
slight
increases
in
minor
variations
(
supernumerary
ribs
and
retarded
ossification
of
the
mandible,
skull,
and
pelvis).
The
developmental
NOAEL
is
9
mg
Cu/
kg/
day.

Excess
dietary
copper
in
young
Fischer
344
rats
caused
increased
hepatic
copper
concentration
associated
with
morphologic
and
biochemical
indicators
of
liver
injury
(
Fuentealba
et
al.,
2000).
Adult
(
N=
5/
11
male/
female
rats,
respectively)
and
young
(
N=
8/
8
male/
female)
female
and
male
rats
were
fed
a
diet
containing
1500
ppm
copper
(
CuSO4)
for
18
weeks,
or
from
birth
until
16
weeks
of
age.
Control
rats
(
N=
4/
sex/
age
group)
of
similar
ages
received
less
than
10
ppm
copper.
All
rats
receiving
copper
loaded
diets
had
significantly
increased
hepatic
copper
concentrations
compared
to
controls.
Young
copper­
loaded
rats
accumulated
more
hepatic
copper,
had
more
severe
liver
changes,
and
higher
serum
liver
enzyme
activities
than
adult
rats.
Hemolysis
was
not
observed
in
rats
with
excess
dietary
copper.
Measurement
of
zinc
accumulation
between
copper­
loaded
and
control
adult
rats
were
similar.
A
sex­
dependent
statistical
significance
was
not
achieved
in
this
study.
However,
2
of
8
young
female
rats
died
during
the
experiment
and
young
female
rats
accumulated
almost
100
ppm
more
copper
than
young
male
rats.
Discussion
of
the
results
of
the
study
indicated
that
copper
absorption
may
not
be
saturable
in
suckling
and
weanling
rats.
The
authors
also
suggested
that
a
combination
of
factors
including
immaturity
of
the
biliary
system
in
young
rats
and
high
efficiency
of
copper
absorption
may
result
in
hepatic
accumulation
of
copper
culminating
with
liver
injury.
Since
the
metabolism
and
saturation
point
of
the
young
rat
versus
the
young
human
are
not
known,
but
likely
different,
it
is
difficult
to
extrapolate
to
the
human.
It
should
also
be
noted
that
the
copper
concentration
in
human
newborn
liver
is
reportedly
10
times
higher
than
that
of
adult
liver.

A
review
was
undertaken
by
the
Advisory
Committee
on
Pesticides
in
1999
to
evaluate
the
use
of
copper
compounds
in
antifouling
products.
A
mammalian
toxicology
chapter
presented
similar
data
as
that
discussed
here
in.
Overall
the
Advisory
Committee
on
Pesticides
concluded
copper
is
absorbed
readily
by
rats
and
humans
with
the
acute
oral
toxicity
of
copper
compounds
variable.
The
potential
for
dermal
and
eye
irritation
is
dependent
on
the
form
of
copper
with
skin
sensitization
studies
in
the
guinea
pig
negative.
Feeding
studies
in
rats
and
mice
are
variable
Page
22
of
39
depending
on
the
dose
and
duration.
Overall,
copper
was
an
irritant
to
the
gastrointestinal
tract
with
higher
doses
causing
protein
droplets
in
the
cytoplasm
and
lumen
of
the
renal
cortical
tubules,
liver
inflammation,
depletion
of
haematopoietic
cells,
and
reduced
weight
gain
and
food
intake.
Additionally,
studies
presented
for
the
potential
genotoxicity
of
copper
compounds
were
equivocal
or
negative.
Overall
the
conclusion
was
that
no
evidence
indicated
copper
or
its
compounds
are
carcinogenic
with
the
unlikelihood
that
copper
is
a
carcinogenic
hazard.

Reports
on
single­
generation
and
teratogenicity
studies
presented
by
the
Committee
were
not
to
recognized
guidelines.
The
effects
reported
in
each
of
the
studies
were
thought
to
be
associated
with
fetal
toxicity
and
therefore
not
directly
attributable
to
any
teratogenic
properties
of
copper.
In
addition,
no
teratogenic
effects
were
noted
as
a
result
of
implantation
of
copper
wire
or
rings
into
the
uteri
of
rats,
rabbits
or
hamsters.
Similarly
no
malformations
in
human
embryos
were
observed
after
the
presence
of
approximately
70
ug/
day
copper
from
intrauterine
devices.
Overall
the
Advisory
Committee
on
Pesticides
concluded
that..."
the
intrinsic
hazards
posed
by
copper
and
those
of
its
compounds
were
low...".

Genotoxicity:

Mutagenicity
studies
available
from
registrants
indicate
copper
as
cuprous
oxide
or
copper
sulfate
pentahydrate
are
negative.
(
Section
J,
Tables
8
&
9)
Literature
studies
report
mixed
results
depending
on
the
strain/
cell
type,
concentrations,
and
type
of
copper
compound.
The
majority
of
the
genotoxicity
studies
reported
have
been
conducted
using
copper
sulfate,
presumably
because
of
its
solubility.
From
the
available
data
it
is
difficult
to
draw
firm
conclusions
on
the
potential
genotoxicity
of
copper
compounds.
A
number
of
the
apparently
positive
results
may
be
considered
equivocal
or
negative
when
the
data
are
examined
more
closely.

Available
human
data
(
literature):

The
metabolism
and
sensitivity
to
the
effects
of
copper
vary
among
animal
species
and
are
therefore
inappropriate
for
extrapolation
to
humans.
Information
from
the
published
literature
are
provided
below
for
characterization
of
the
nutritional
requirement
of
copper
and
sensitivity
of
copper
in
humans.

Effects
on
humans:

Copper
is
an
essential
element
and
adverse
health
effects
are
related
to
deficiency
as
well
as
excess.
Copper
deficiency
is
associated
with
anemia,
neutropenia,
and
bone
abnormalities
but
clinically
evident
deficiency
is
relatively
infrequent
in
humans.
At
least
12
major
proteins
require
copper
as
an
integral
part
of
their
structure.
Copper
is
essential
for
the
utilization
of
iron
in
the
formation
of
hemoglobin.
The
IP
EHC
set
the
lower
limit
of
the
acceptable
range
of
oral
intake
at
20
Fg/
kg
body
weight/
day
(
IPCS,
1998).
The
figure
was
based
on
the
adult
basal
requirement
with
an
allowance
for
variations
in
copper
absorption,
retention
and
storage
(
WHO,
1996).
In
infancy,
this
figure
is
50
ug/
kg
body
weight/
day.
The
IP
EHC
determined
the
"
available
data
on
toxicity
in
animals
were
considered
unhelpful
in
establishing
the
upper
limit
Page
23
of
39
of
the
acceptable
range
of
oral
intake,
owing
to
uncertainty
about
an
appropriate
model
for
humans.
Moreover,
traditional
methodology
for
safety
assessment,
based
on
application
of
uncertainty
factors
to
data
in
animals,
does
not
adequately
address
the
special
attributes
of
essential
elements
such
as
copper....
there
is
greater
risk
of
health
effects
from
deficiency
of
copper
intake
than
from
excess
copper
intake."

Clinical
signs
of
acute
poisoning
from
ingestion
of
copper
salts
(
10
to
15
mg)
may
include:
metallic
taste,
abdominal
pain,
nausea,
vomiting,
epigastric
burning
and
diarrhea,
and
in
severe
cases
gastrointestinal
bleeding
and
ulceration.
Lethargy,
headache,
muscular
weakness
and
dizziness,
hypotension
and
shock
may
precede
coma
and
death
(
IPCS
PIM
1991).
The
estimated
mean
lethal
dose
is
approximately
10
grams
(
10,000
mg),
or
approximately
140
mg/
kg
(
IPCS
PIM
1991).
A
recent
review
by
ATSDR
(
2004)
indicates
deaths
due
to
copper
poisoning
were
due
to
ingestion
of
large
doses
of
copper
sulfate
(
6
to
637
mg/
kg
Cu).
However,
the
amount
was
self
reported
and
therefore,
doses
likely
inaccurate.
In
addition,
no
studies
were
reported
by
the
ATSDR
for
systemic
effects
regarding
endocrine,
dermal,
ocular,
or
metabolic
effects
following
oral
exposure
to
copper.

Copper
Deficiency
in
Humans:

Adverse
health
effects
associated
with
copper
deficiency
include
anemia,
neutropenia
and
bone
abnormalities.
Clinically
evident
copper
deficiency
is
relatively
infrequent
in
humans.
(
IPCS
1998).

Excessive
Copper
in
Humans:

An
acute
exposure
to
a
large
concentration
of
copper
may
produce
a
metallic
taste,
abdominal
pain,
nausea
and
vomiting,
or
diarrhea,
especially
if
copper
is
taken
on
an
empty
stomach,
taken
with
acidic
foods
or
beverages,
or
with
other
supplements.
These
effects
are
largely
due
to
the
irritating
effects
of
copper.
More
severe
cases
may
involve
lethargy,
headache,
muscular
weakness
and
dizziness,
with
hypotension
and
shock
possibly
proceeding
coma
and
death.

Chronic
exposure
to
higher
amounts
of
copper
may
lead
to
adverse
effects
on
the
liver.
Jaundice,
elevation
of
serum
transaminase
and
serum
bilirubin
levels,
enlargement
and
tenderness
of
the
liver,
centriblobular
necrosis
and
biliary
stasis
of
the
liver
may
occur
from
chronic
exposure
to
high
levels
of
copper.
Haemoglobinemia,
haemolysis,
haemoglobinuria
and
haematuria,
cyanosis
may
also
occur
from
chronic
exposure
to
copper.
(
IPCS
PIM,
1991).

Inhalation
Exposure
in
Humans:

The
inhalation
of
copper
as
dusts
or
mists
are
likely
irritating
to
the
respiratory
system
similar
to
the
irritating
effects
of
copper
when
ingested
(
ATSDR
2004).
Acute
LC50
data
from
animal
studies
are
available
in
Section
J.
The
acute
toxicity
of
the
different
copper
compounds
differs
but
is
mainly
Toxicity
Category
III.
Cuprous
oxide
was
more
toxic
with
a
Toxicity
Category
I
study.
Chronic
inhalation
of
copper
may
become
cancerous
since
available
studies
from
the
literature
indicate
an
increased
incidence
of
lung
cancer
among
professional
vineyard
workers
Page
24
of
39
exposed
chronically
to
Bordeaux
mixture
(
Viller,
1974;
Santic
et
al.
2005);
however,
this
information
is
not
definitive
since
no
information
is
available
on
the
level
of
exposure
to
these
workers,
to
either
the
Bordeaux
mixture
or
any
other
substances
with
which
they
might
have
come
into
contact.
Copper
is
considered
the
etiologic
agent
in
the
occupational
disease
referred
to
as
"
vineyards
sprayer's
lung"
and
is
reviewed
in
ATSDR
2004.
A
recent
review
by
ATSDR
(
2004)
indicated
no
studies
were
available
for
systemic
effects
regarding
cardiovacular,
musculoskeletal,
renal,
dermal,
or
body
weight
effects
in
humans
or
animals
following
inhalation
exposure
to
copper.

Guinea
pigs
exposed
to
copper
oxide
aerosol
for
60
minutes
displayed
few
effects
on
pulmonary
parameters
with
no
long
lasting
effects
(
Chen
et
al.,
1991).
Male
guinea
pigs
were
exposed
to
ultrafine
particles
of
copper
oxide
produced
from
a
furnace
system
designed
to
mimic
primary
emissions
from
smelters
(
Hartley,
N=
10)
at
1.6
±
0.10
mg/
m3
for
60
minutes
to
determine
the
effect
on
pulmonary
parameters
(
intrapleural
pressure,
tidal
volume,
flow
rate).
Animals
were
also
monitored
for
60
minutes
after
exposure
to
the
copper
aerosol.
Slight
changes
in
pulmonary
parameters
included
decreased
resistance
values
(
5%),
compliance
(
17%),
and
tidal
volume
(
5%
to
9.5%).
No
other
effects
of
the
aerosol
on
the
pulmonary
system
were
reported.

Information
available
either
through
the
literature
or
studies
provided
by
the
registrant
warrant
the
limitation
of
the
inhalation
of
copper.

D.
Dietary:
Acceptable
Daily
Intakes:

Estimated
and
Acceptable
Intake
Levels
for
Humans:
See
Table
1
below.

Copper
is
a
naturally
occurring
element
that
is
essential
for
the
homeostasis
of
life.
Sources
of
human
and
environmental
copper
include
windblown
dust,
volcanoes,
decaying
vegetation,
forest
fires
and
sea
spray.
Copper
is
also
found
naturally
in
various
foods,
including
organ
meats
(
liver),
seafood,
beans,
nuts,
and
whole­
grains.
It
has
been
estimated
that
approximately
40%
of
dietary
copper
comes
from
yeast
breads,
white
potatoes,
tomatoes,
cereals,
beef
and
dried
beans
and
lentils
(
WHO,
2004).
It
has
been
estimated
that
approximately
3.2
mg
of
copper
is
consumed
daily
in
food
with
water
providing
an
additional
40­
500
picograms
(
pg)
of
copper
(
WHO,
1974).
In
most
foods,
copper
is
present
bound
to
macromolecules
rather
than
as
a
free
ion
(
IOM,
2001).
Additional
copper
may
come
from
drinking
water
from
copper
pipes,
and
using
copper
cookware.
Anthropogenic
emissions
include
smelters,
iron
foundries,
power
stations
and
combustion
sources
such
as
municipal
incinerators.
An
estimate
for
the
agricultural
use
of
copper
products
was
approximately
2%
of
copper
released
to
soil.
(
IPCS,
1998).

The
estimated
mean
daily
dietary
intake
of
copper
in
non­
occupationally
exposed
humans
(
adults)
ranges
between
0.9
and
2.2
mg.
The
estimated
contribution
of
daily
intake
of
copper,
particularly
in
homes
without
copper
piping,
seldom
exceeds
0.1
mg/
day.
The
estimated
total
daily
oral
intake
of
copper
(
food
plus
drinking­
water)
is
between
1
and
2
mg/
day,
although
may
occasionally
exceed
5
mg/
day.
Page
25
of
39
Copper
supplements
are
available
as
over
the
counter
for
individuals
that
are
lower
in
status
of
copper
in
order
to
prevent
or
treat
copper
deficiency.
Supplements
range
from
0.33
mg
to
3
mg
and
are
recommended
from
once
to
two
or
three
times
a
day.
Surveys
in
the
USA
indicate
that
approximately
15%
of
the
population
uses
a
nutritional
supplement
containing
copper
(
IOM,
2001).

Acceptable
daily
intake
is
2
to
5
mg
Cu/
day.
Almost
none
of
the
copper
is
retained
and
the
body
content
of
copper
in
adults
is
constant
at
100
to
150
mg
(
Scheinberg,
1983).

Average
daily
dietary
requirement
for
copper
(
cupric
sulphate)
in
the
adult
human
was
estimated
at
2
mg
and
for
infants
and
children
at
0.05
mg/
kg
bw.
NRC
(
1980)
reported
"
estimated
safe
and
adequate"
daily
dietary
intakes
of
copper
ranging
from
0.5
to
0.7
mg/
day
for
infants
6
months
of
age
or
less
up
to
2­
3
mg/
day
for
adults.
The
recommended
daily
allowance
(
RDA)
for
adult
men
and
women
is
900
Fg/
day
(
0.9
mg/
day).
(
IOM,
2001).

In
adults,
it
is
generally
agreed
that
average
daily
intake
of
copper
is
between
1­
3
mg,
or
about
15­
45
Fg/
kg
bw.
From
the
WHO
report,
FDA
(
1978)
data
indicated
the
average
adult
intake
of
copper
in
the
US
was
estimated
to
equal
1.6
mg/
day
from
a
3000
calorie
diet
and
2.1
mg/
day
from
a
3900
calorie
diet.

According
to
the
National
Academy
of
Sciences
(
IOM
2001),
an
NHANES
III
assessment
indicated
the
highest
median
intake
of
copper
from
the
diet
and
supplements
for
any
gender
and
life
stage
group
was
approximately
1,700
Fg/
day
(
1.7
mg/
day)
for
men
(
19­
50
years)
and
approximately
1,900
Fg/
day
(
1.9
mg/
day)
for
lactating
women.
However,
the
highest
reported
copper
intake
from
food
and
supplements
at
the
99th
percentile
was
4,700
Fg/
day
(
4.7
mg/
day)
in
lactating
women.
The
Tolerable
Upper
Intake
Level
(
UL)
for
adults
is
10,000
Fg/
day
(
10
mg/
kg),
which
was
based
on
protection
from
liver
damage
as
the
critical
adverse
effect.
Page
26
of
39
Table
1.
Average,
Estimate,
and
Mean
Daily
Intake
Values
for
Copper
Source
Estimate
Value
Age
Notes
IPCS
1998
mean
daily
intake
0.9
to
2.2
mg
nonoccupationally
exposed
adults
0.1
mg/
day
Contribution
of
daily
intake
w/
out
Cu
pipping
IPCS
1998
estimated
total
daily
oral
intake
(
food
+
water)
1
and
2
mg/
day
adults
IPCS
PIM
1991
Acceptable
Daily
Intake
(
ADI)
2
to
5
mg/
day
adults
JECFA
No.
551
Average
daily
dietary
requirement
(
Cupric
Sulfate)
2
mg
0.05
mg/
kg
bw
adults
infants
&
children
JECFA
No.
551
estimated
safe
and
adequate
daily
dietary
intake
0.5
to
0.7
mg/
day
to
2­
3
mg/
day
infants
<
6
mos
adults
WHO
2004,
FDA
1978
average
adult
intake
1.6
mg/
day
2.1
mg/
day
3000
calorie
diet
3900
calorie
diet
IOM
2001
highest
median
intake
from
diet
and
supplements
1.7
mg/
day
1.9
mg/
day
men
(
19­
50
yrs)
lactating
women
99th
percentile
4.7
for
lactating
women
IOM
2001
Tolerable
Upper
Intake
Level
(
UL)
10
mg/
day
adults
based
on
protection
from
liver
damage
WHO
2004,
IOM
2001
RDA,
recommended
dietary
allowance
900
ug/
day
(
0.9
mg/
day)
adult
men
and
women
(
19
to
>
70
yrs)

IOM
2001
RDA
Children
0.34
mg/
day
0.44
mg/
day
1­
3
years
4­
8
years
IOM
2001
RDA
Boys
&
Girls
0.70
mg/
day
0.89
mg/
day
9­
13
years
14­
18
years
IOM
2001
RDA
for
Pregnancy
RDA
for
Lactation
1.0
mg/
day
1.3
mg/
day
14­
50
years
14­
50
years
Page
27
of
39
Dietary
Endpoints
Dietary
endpoints
are
not
appropriate
at
this
time
for
the
copper
risk
assessment
since
copper
is
an
essential
element
and
is
exempt
from
a
requirement
of
a
tolerance
(
list
CFR
notices
or
see
section
of
risk
assessment).
Copper
carbonate
(
022901)
has
a
3
ppm
tolerance
as
copper
impregnated
paper
wrap
for
pears.

E.
Classification
of
Carcinogenic
Potential:

Copper
(
metallic)
is
currently
Group
D,
not
classifiable
as
to
human
carcinogenicity.
However,
the
only
evidence
of
carcinogenicity
is
in
workers
exposed
chronically
to
inhalation
of
Bordeaux
mixture
in
the
vineyard
developing
lung
tumors.
However,
the
compound
causing
lung
lesions
in
workers
is
still
under
evaluation
since
arsenic
is
also
present
in
the
Bordeaux
mixture.
A
review
by
ATSDR
(
2004)
failed
to
locate
studies
regarding
carcinogenic
effects
in
humans
following
oral
exposure
to
copper.
Mutagenicity
studies
from
the
literature
indicate
copper
is
not
mutagenic.
Copper
chloride
at
0.001­
10M
concentrations
was
negative
in
the
rec
assay
with
Bacillus
subtilis
and
negative
in
the
reverse
mutation
assay
with
E.
coli
and
Salmonella
strains
(
Kanematsu
et
al.,
1980).

F.
Uncertainty
Factors:

The
application
of
uncertainty
factors
is
not
warranted
for
this
assessment.
Dietary
endpoints
are
not
required
for
this
assessment
and
therefore
application
of
uncertainty
factors
is
not
required.

G.
Endocrine
Disruption:

Following
recommendations
of
its
Endocrine
Disruptor
and
Testing
Advisory
Committee
(
EDSTAC),
EPA
determined
that
there
was
a
scientific
basis
for
including,
as
part
of
the
endocrine
disruption
screening
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
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).

It
is
notable
that
based
on
the
available
toxicology
studies
and
literature
for
copper,
there
is
currently
no
indication
of
endocrine
disruption.

H.
FQPA
and
Special
Considerations
for
Infants
and
Children:

In
humans
there
does
not
appear
to
be
any
reports
in
the
literature
of
teratogenesis
induced
by
excess
copper
(
IPCS
PIM,
1991).
The
only
teratogenic
effects
observed
in
Page
28
of
39
available
animal
studies
occurred
after
exposure
with
copper
salts
at
high
doses,
in
which
doses
were
likely
at
maternally
toxic
concentrations.
Likewise,
based
on
the
available
toxicity
information
from
available
studies
and
published
literature,
there
is
no
evidence
to
suggest
susceptibility
in
infants
and
children.
The
current
RDA
(
Recommended
Daily
Allowance)
for
copper
in
infants
and
children
is
340
Fg/
day
compared
to
900
Fg/
day
in
adults.
Since
copper
is
a
natural
essential
trace
element,
with
deficiency
more
common
in
humans
than
toxicity
from
excess,
and
the
dietary
contribution
of
copper
to
the
total
diet
is
low,
then
endpoints
are
not
required
and
therefore
not
subject
to
the
FQPA
Uncertainty
Factor.
The
additional
tenfold
safety
factor
for
the
protection
of
infants
and
children
is
currently
not
required.

I.
Conclusions:

Copper
is
a
natural
trace
element
required
for
the
homeostasis
of
life
with
humans
having
a
unique
ability
to
maintain
appropriate
copper
stores
in
the
body.
As
such,
it
is
inappropriate
to
compare
the
toxicity
of
copper
in
laboratory
animals
for
extrapolation
to
human
toxicity.
Humans
are
exposed
primarily
through
the
food
that
is
consumed
with
RDAs
established
for
adults,
infants,
and
children.
The
irritating
properties
of
copper
to
the
gastrointestinal
tract
are
a
mechanism
by
which
excess
orally
absorbed
copper
is
prevented.
Copper
may
be
irritating,
however,
to
the
skin,
eyes,
and
lungs
and
should
therefore
be
avoided
by
these
routes
of
exposure.
Copper
residues
from
the
use
as
a
pesticidal
active
ingredient
are
not
expected
to
significantly
contribute
to
the
naturally
occurring
levels
of
copper
in
foods,
therefore,
toxicological
endpoints
have
not
been
established
for
copper.

J.
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1985,
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1986.
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DM
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GW
(
1973).
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JE,
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EM,
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GM
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2000).
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dietary
copper
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M.
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CD,
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MR,
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GS,
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CJ,
and
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JR
(
1993).
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of
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sulfate
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in
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2001)
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reference
intakes
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A,
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K,
Arsenic,
Boron,
Chromium,
Copper,
Iodine,
Iron,
Manganese,
Molybdenum,
Nickel,
Silicon,
Vanadium,
and
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subcommittees
on
upper
reference
levels
of
nutrients
and
of
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use
of
dietary
reference
intakes,
and
the
standing
committee
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the
scientific
evaluation
of
dietary
reference
intakes.
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National
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IPCS
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1998).
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IPCS
PIM
(
1991).
Poison
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G002.
Copper
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Http://
www.
inchem.
org/
documents/
pims/
chemical/
pimg002.
htm
JECFA
#
551.
Joint
WHO/
FAO
Expert
Committee
on
Food
Additives
JECFA.
Copper.
WHO
Food
Additives
Series
17.
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http://
www.
inchem.
org/
documents/
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jecmono/
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html
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N,
Hara
M,
and
Kada
T
(
1980).
Rec
assay
and
mutagenicity
studies
on
metal
compounds.
Mutation
Research
77:
109­
116.
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30
of
39
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CS
and
Speisky
HC
(
1996).
Liver
copper
storage
and
transport
during
development:
implications
for
cytotoxicity.
63:
812S­
820S.

Lecyk
M
(
1980).
Toxicity
of
CuSO4
in
mice
embryonic
development.
Zoologica
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28(
2):
101­
105.

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H
et
al.
(
1955).
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on
copper
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XIV.
Copper
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ceruloplasmin
and
oxidase
activity
in
sera
of
normal
human
subjects,
pregnant
women,
and
patients
with
infection,
hepatolenticular
degeneration
and
the
nephrotic
syndrome.
J.
Clin.
Invest.
34:
1498­
1508.

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Toxicology
Program
(
1993).
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Technical
Report
on
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Studies
of
Cupric
Sulfate
Administered
in
Drinking
Water
and
Feed
to
F344/
N
Rats
and
B6C3F1
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(
2000).
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in
Drinking
Water.
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on
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in
Drinking
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on
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Studies
and
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Commission
on
Life
Sciences.
National
Academy
Press.

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O
and
Salgo,
MP
(
1977).
Copper
in
mammalian
reproduction.
Avd.
Pharmacol.
Chemother.
14:
327.

Pena
MO,
Lee
J,
and
Thiele
DJ
(
1999).
A
delicate
balance:
Homeostatic
control
of
copper
uptake
and
distribution.
J
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129:
1251­
1260.

Pocino
M.,
Baute
L.,
and
Malave
I
(
1991).
Influence
of
the
oral
administration
of
excess
copper
on
the
immune
response.
Fund.
and
Appl.
Tox.
16:
249­
256.

Prohaska
JR
and
Gybina
AA
(
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HI
(
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Parmeggiani,
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and
safety,
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HA,
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IH,
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JJ
(
1966).
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J.
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Turnlund,
J
(
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Geneva,
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23pp.

K.
Toxicity
Profile
Tables
for
the
Cases
of
Copper:

A.
Acute
Toxicity
Studies:

I.
Acute
Studies
for
Copper
Compounds
Table
2.
Available
Acute
Toxicity
Studies
for
the
Copper
Compounds
Copper
Type
PC
Code
Acute
Oral
LD50
(
mg/
kg)
Acute
Dermal
LD50
(
mg/
kg)
Acute
Inhalation
(
mg/
L)
Primary
Eye
Irritation
Dermal
Irritation
Dermal
Sensitization
Acute
Studies
Copper
Chloride
(
57.7%
Cu)
008001
M=
1796
F=
2006
Tox
Cat.
III
43769501
>
2000
(
M
&
F)
Tox
Cat
III
43769502
NA
Corneal
opacity
cleared
by
21
days
Tox
Cat.
II
43769503
Non­
irritating
Tox
Cat.
IV
43769504
NA
Chelates
of
Copper
Gluconate
024405
None
Available
Copper
Ammonium
Carbonate
022703
None
Available
Copper
Carbonate
(
96%)
022901
>
2000
Tox
Cat
III
41889302
NA
NA
Corrosive,
opacity
at
21
days
Tox
Cat
I
41889301
Non­
irritating
Tox
Cat
IV
41889302
NA
Page
32
of
39
Table
2.
Available
Acute
Toxicity
Studies
for
the
Copper
Compounds
Copper
Hydroxide
(
77%)
023401
M
=
2253
F=
2160
Tox
Cat.
III
41421602
>
2000
Tox
Cat
III
00159371
00259424
77%
M=
1.53
mg/
L
F
=
1.04
mg/
L
00160580
88%
F
=
0.5
mg/
L
Tox
Cat.
III
Irritative
Corneal
opacity,
iris
irritation,
chemosis,
invasion
of
cornea
by
blood
vessels
Tox.
Cat.
I
At
72
hrs,
very
slight
erythema
Tox
Cat.
IV
Non­
sensitizing
Guinea
Pig
Copper­
Ammonia
Complex
022702
None
Available
Copper
oxychloride
(
94.1%)
023501
M=
1537
F=
1370
Tox
Cat.
III
00155931
M&
F=
710
(
281­
1791)
Tox
Cat
II
>
1.7
mg/
L
Tox
Cat.
III
00155932
Corneal
opacity
redness
and
vascularization
Tox
Cat.
I
00155934
Non­
irritating
Tox
Cat
IV
00155935
Nonsensitizing
00155936
Copper
oxychloride
sulfate
023503
None
Available
II.
Acute
Studies
for
Copper
Sulfates
Table
3.
Available
Acute
Toxicity
Studies
for
the
Copper
Sulfates
Copper
Type
PC
Code
Acute
Oral
LD50
(
mg/
kg)
Acute
Dermal
LD50
(
mg/
kg)
Acute
Inhalation
(
mg/
L)
Primary
Eye
Irritation
Dermal
Irritation
Dermal
Sensitization
Acute
Studies
Basic
Copper
sulfate
008101
None
Available
Copper
sulfate
anhydrous
024408
None
Available
Copper
sulfate
pentahydrate
(
99%)
024401
M=
790
F=
450
Tox
Cat
II
43396201
>
2000
Tox
Cat
IV
43452201
Severe
eye
irritation
day
1
to
day
21
Tox
Cat.
I
43396201
Non­
irritating
Tox
Cat
IV
43396201
Human
Study
produced
sensitization
00099581
TXR
004457
Page
33
of
39
III.
Acute
Studies
for
Copper
and
Oxides
Table
4.
Available
Acute
Toxicity
Studies
for
the
Copper
and
Oxides
(
mg/
kg)

Copper
Type
PC
Code
Acute
Oral
LD50
(
mg/
kg)
Acute
Dermal
LD50
(
mg/
kg)
Acute
Inhalation
(
mg/
L)
Primary
Eye
Irritation
Dermal
Irritation
Dermal
Sensitization
Acute
Studies
Copper
metallic
022501
50%
copper
M=
1414
F=
1625
Tox
Cat.
III
00162424
8.5%
elemental
>
2000
Tox
Cat.
III
00150641
23%
metallic
>
0.1
but
<
0.59
Tox
Cat
III
00156396
50%
metallic
opacity,
irritation,
redness,
chemosis,
cleared
by
day
21
Tox
Cat.
II
00126194
50%
metallic
erythema,
edema,
irritation,
cleared
day
14
Tox
Cat.
IV
00126194
26%
metallic
nonsensitizing
guinea
pig
00144555
8.5%
elemental
nonsensitizing
rabbit
00152166
cupric
oxide
(
97.6%)
042401
>
5050
(
M&
F)
Tox
Cat
IV
41502401
>
2020
(
M&
F)
Tox
Cat
III
41502402
>
2.08
(
M&
F)

Tox
Cat
III
41502403
Irritation
cleared
in
7
days
Tox
Cat
III
41502404
Irritation
cleared
day
21
PI
Index=
1.49
Tox
Cat
III
41502405
Non­
sensitizing
(
guinea
pig)
41502406
cuprous
oxide
(
57%)
025601
>
5000
Tox
Cat
IV
00078971
>
2000
slight
erythema,
edema
Tox
Cat
III
00245650
40.9%
ai
0.1
to
0.59
Tox
Cat
I
42240303
Opacity,
iris
irritation,
redness,
and
chemosis
clearing
by
day
14
Tox
Cat
II
00078974
Severe
erythema,
edema
PIS=
6.1/
8
Tox
Cat
I
00078970
Non­
sensitizing
(
guinea
pig)

00078970
IV.
Acute
Studies
for
Copper
Salts
Table
5.
Available
Acute
Toxicity
Studies
for
the
Copper
Salts
(
mg/
kg)

Copper
Type
PC
Code
Acute
Oral
LD50
(
Mg/
kG)
Acute
Dermal
LD50
(
mg/
kg)
Acute
Inhalation
(
mg/
L)
Primary
Eye
Irritation
Dermal
Irritation
Dermal
Sensitization
Acute
Studies
Copper
from
triethanolamine
complex
[
K­
TEA]
024403
99%
M=
1170
F=
1312
Tox
Cat.
III
41759301
99%
>
2000
mg/
kg
No
deaths
Tox
Cat.
III
41759302
NA
99%
moderate
irritation
of
cornea,
iris,
conjunctive
cleared
by
day
7.
Tox
Cat.
III
41759303
99%
mild
irritation
cleared
by
day
3
Tox
Cat.
IV
41759304
NA
Copper
8­
quinolinolate
024002
99.5%
>
5000
M&
F
Tox
Cat.
IV
99.5%
>
2000
M&
F
Tox
Cat.
III
43558501
96%
0.09
M&
0.03
F
Tox
Cat.
II
43611901
98%
corneal
opacity,
redness
to
day
21
Tox
Cat.
I
99.7%
Non­
irritating
Tox
Cat.
IV
99.7%

Nonsensitizing
guinea
pig
Page
34
of
39
Table
5.
Available
Acute
Toxicity
Studies
for
the
Copper
Salts
(
mg/
kg)

Copper
Type
PC
Code
Acute
Oral
LD50
(
Mg/
kG)
Acute
Dermal
LD50
(
mg/
kg)
Acute
Inhalation
(
mg/
L)
Primary
Eye
Irritation
Dermal
Irritation
Dermal
Sensitization
Acute
Studies
elemental
copper
(
ethyenediam
ine)
024407
KOMEEN
96%,
K­
Tea
99%
M=
527
F=
462
Tox
Cat.
II
41759201
KOMEEN
&
K­
Tea
>
2000
Tox
Cat.
III
41759202
KOMEEN
&
KTea
M=
1.36
F=
0.56
Tox
Cat.
III
42130001
KOMEEN
&
K­
Tea
moderate
irritation
Tox
Cat.
III
41759203
KOMEEN
&
KTea
redness,
edema,
cleared
by
day
3
41759204
KOMEEN
&
K­
Tea
non
sensitizing
guinea
pig
42130002
Copper
naphthenate
023102
8%
Cu
M=
>
5050
F=
>
5050
Tox
Cat.
IV
43643701
8%
Cu
M=
>
2020
F=
>
2020
Tox
Cat.
III
43643702
9.5%
Cu
M&
F=>
2.96
Tox
Cat.
III
1.
8%
Cu
irritation,
chemosis,
cleared
by
48
hrs,
Tox
Cat.
III
43643703
2.
45%
Cu
opacity,
redness,
chemosis
&
discharge
at
72
hrs
Tox
Cat.
I
00266172
8%
Cu
erythema/
eschar
slight
edema
PIS=
1.1
Tox
Cat.
III
43642704
2.
80%
Cu
72
hrs
severe
erythema,
edema
Tox
Cat.
II
00260891
9.5%
Cu
sensitizer
Copper
octanoate,
10%
fatty
acids
023306
>
2000
M&
F
Tox
Cat.
III
43947504
>
2000
M&
F
Tox
Cat.
III
43947505
>
0.38
M&
F
Tox
Cat.
III
43970201
irritation,
cleared
by
48
hrs.
Tox
Cat.
IV
43937506
slight
erythema,
edema,
cleared
by
72
hrs.
Tox
Cat.
IV
43947507
Nonsensitizing
guinea
pig
44116101
Copper
salts
of
fatty
and
rosin
acids
(
Cu
&
zinc
neoisoate
35%)
023104
>
7000
Tox
Cat.
IV
>
2000
Tox
Cat.
III
NA
no
irritation
Tox
Cat.
IV
Edema,
erythema,
PIS=
1.0
Tox
Cat
III
NA
Page
35
of
39
V.
Acute
Studies
for
Other
Unscheduled
Coppers
Table
6.
Available
Acute
Toxicity
Studies
for
the
other
Unscheduled
Coppers
(
mg/
kg)

Copper
Type
PC
Code
Acute
Oral
LD50
Acute
Dermal
LD50
Acute
Inhalation
Primary
Eye
Irritation
Dermal
Irritation
Dermal
Sensitization
Acute
Studies
Cuprous
thiocyanate
(
99%)
025602
>
5000
Tox
Cat
IV
40834601
>
2000
Tox
Cat
III
40834601
>
0.5
mg/
L
Tox
Cat.
II
40834605
non­
irritant
40834605
non­
irritant
40834604
non­
sensitizing
40834603
Copper
ethanolamine
complex
024409
None
Available
B.
Tables
of
Other
Toxicity
Studies
by
Case
of
Copper.

BI.
Other
Studies
for
Copper
Compounds
Table
7.
Other
Available
Toxicity
Studies
for
Copper
Compounds
(
mg/
kg)

Copper
Type
PC
Code
Guideline
Study
MRID
Results
Copper
hydroxide,
technical
61.14%
023401
83­
3b
46377502
46377501
0,
6,
9,
or
18
mg
Cu/
kg/
day
at
1
mL/
kg
from
GD
7
to
GD
28.
Maternal
LOAEL
9
mg/
kg/
day,
based
on
decreased
body
weight
gains
and
food
consumption.
NOAEL
6
mg/
kg/
day.
Developmental
LOAEL
18
mg/
kg/
day,
based
on
incidences
of
hemvertebra
and
slight
increased
in
minor
variations
(
supernumerary
ribs,
retarded
ossification
of
the
mandible,
skull,
and
pelvis).
NOAEL
9
mg/
kg/
day.
Acceptable/
Guideline
No
other
studies
available
for
any
of
the
copper
compounds
(
PC
Codes:
008001,
024405,
022703,
022901,
022702,
023501,
023503).

BII.
Other
Studies
for
Copper
Sulfates
Table
8.
Other
Available
Toxicity
Studies
for
Copper
Sulfates
(
mg/
kg)

Copper
Type
PC
Code
Guideline
Study
MRID
Results
Cu
sulfate,
pentahydrate
024401
82­
1
subchronic
rat
00058020
00075116
NOEL
not
determined
Cu
sulfate,
pentahydrate
024401
83­
4
1­
Gen
Repro
0,
500,
1000,
1500,
2000,
3000,
&
4000
ppm
Page
36
of
39
Cu
sulfate,
pentahydrate
024401
Mutagenic­
Ames
84­
2
00085218
Negative
in
S.
typhimurium
LT­
2
and
for
gene
mutation
o
S.
cerevisiase
D­
7
Cu
sulfate,
pentahydrate
024401
Metabolism
85­
1
00062085
Intraperitoneal
doses
of
0.625­
3.75
mg/
kg
daily
with
sacrifice
at
24
hrs,
1,
2,
6,
12,
and
18
weeks.
Cu
accumulated
in
all
tissues
at
the
high
level.
As
little
as
0.3
mg/
kg
of
i.
p.
Cu
for
18
wks.
will
elevate
hepatic
Cu.

BIII.
Other
Studies
for
Copper
and
Oxides
Table
9.
Other
Available
Toxicity
Studies
for
Copper
and
Oxides
(
mg/
kg)

Copper
Type
PC
Code
Guideline
Study
MRID
Results
Cuprous
oxide
025601
84­
2
NA
No
significant
mutagenic
activity
with/
without
metabolic
(
S­
9)
activation.
Strains
tested:
Salmonella
TA1535,
TA
1537,
TA
98,
TA
100;
E.
coli
WP2
uvrA.
Doses
tested:
0,
20,
100,
500,
2500,
5000
ug.

Cupric
oxide
042401
None
Available
Copper
metallic
022501
None
Available
BIV.
Other
Studies
for
Copper
Salts
A.
Cu
8­
Quinolinolate
Table
10.
Other
Available
Toxicity
Studies
for
Copper
8­
Quinolinolate
(
mg/
kg)

Copper
Type
PC
Code
Guideline
Study
MRID
Results
Cu
8­
quinolinolate
024002
82­
1a
subchronic
dog
42986802
99.5%,
capsule
for
13
weeks
at
0,
5,
50,
or
250
mg/
kg/
day.
NOAEL
is
5
mg/
kg/
day
LOAEL
=
50
mg/
kg/
day,
based
on
vomiting,
reduced
total
plasma
protein
and
albumin,
reddened
mucosa
and
hyperemia
in
stomach
or
small
intestine.
Acceptable/
Guideline
Cu
8­
quinolinolate
024002
82­
1a
subchronic
rat
42986801
99.5%,
dietary
intake
for
13
weeks
to
0,
30,
100,
300,
and
1000/
700
mg/
kg/
day;
high
dose
decreased
to
700
due
to
toxicity;
NOAEL=
30
mg/
kg/
day,
LOAEL
=
100
mg/
kg/
day
is
based
on
statistically
significant
ALT,
AST
and
billirubin
in
males,
increased
spleen
weights
in
females,
increased
incidence
of
diffuse
degeneration,
focal
necrosis,
extramedullary
hematopoieses
in
liver.
Acceptable/
Guideline
Cu
8­
quinolinolate
024002
82­
1a
subchronic
mouse
43572401
97%,
dietary
intake
of
0,
300,
1000,
3000,
or
6000
ppm
(
0,
50,
148,
438,
and
979
M
and
0,
67,
200,
578,
and
1066
mg/
kg/
day
F)
for
13
weeks.

NOAEL
979
M
and
1066
F
mg/
kg/
day
(
HDT)

LOAEL
not
established.

Acceptable/
Guideline
Page
37
of
39
Table
10.
Other
Available
Toxicity
Studies
for
Copper
8­
Quinolinolate
(
mg/
kg)

Cu
8­
quinolinolate
024002
82­
1a
subchronic
mouse
42937301
99.9%,
dietary
intake
of
0,
100,
300,
or
476
mg/
kg/
day
for
6
to
13
weeks.
No
toxicity
at
highest
dose.
Supplemental/
Not
Upgradeable
Cu
8­
quinolinolate
024002
82­
1a
subchronic
mouse
42957801
Oxine
Cu
dietary
exposure
13
weeks
of
0,
300,
1000,
3000,
or
6000
ppm
(
conversion
of
42.8,
142.8,
428.6,
857.1
mg/
kg/
day).
NOAEL
=
142.8
mg/
kg/
day
LOAEL=
428.6
mg/
kg/
day,
based
on
abnormal
coloring
and
thickening
of
glandular
mucosa
of
stomach,
high
dose
effects
of
cysts
on
ovaries
and
slightly
decreased
absolute
and
relative
spleen
weight.

Cu
8­
quinolinolate
024002
82­
2
28­
dermal
42957802
99.7%
moistened
and
applied
to
gauze
patches
on
intact
skin
at
doses
of
0,
50,
200,
or
1000
mg/
kg/
day
for
6
hrs./
day
for
4
weeks.
High
dosed
produced
necrosis
of
the
thymic
lymphocytes
in
males.
dermal
NOAEL
=
1000
mg/
kg/
day,
systemic
NOAEL
=
200
mg/
kg/
day,
systemic
LOAEL
=
1000
mg/
kg/
day
based
on
necrosis
of
thymic
lymphocytes.

Cu
8­
quinolinolate
024002
83­
2
carcinogen.
Mice
43267201
80­
week
onco
feeding
study
at
0,
100,
400,
1500,
or
6000
ppm
corresponding
to
0,
14.5,
57.1,
207.7,
and
855.8
mg/
kg/
day
for
males,
0,
16.1,
66.2,
246.2,
and
855.8
mg/
kg/
day
for
females.
NOAEL
=
57.1
M
and
66.2
F
LOAEL
=
207.7
M
and
246.2
F,
based
on
increased
incidence
of
stomach
ulcers
in
males;
mild
anemia
and
adverse
liver
effects
in
females.
No
dose­
related
increase
in
individual
neoplastic
lesions
was
observed.
Acceptable/
Guideline
Cu
8­
quinolinolate
024002
83­
3a
develop.
Rat
42986803
oxine
Cu
by
gavage
on
Gds
6­
15
inclusive
at
0,
50,
200,
or
800
mg/
kg/
day.
maternal
NOAEL
=
200
mg/
kg/
day
maternal
LOAEL
=
800
mg/
kg/
day,
based
on
increased
clinical
signs
(
piloerection,
poor
general
condition,
encrustation
of
nose
and
mouth),
and
decreased
body
weight
and
gain.
developmental
NOAEL
=
800
mg/
kg/
day,
no
developmental
toxicity
was
observed.
developmental
LOAEL
>
800
mg/
kg/
day.
Acceptable/
Guideline
Cu
8­
quinolinolate
024002
83­
4
reproduct.
Rat
43267202
Diet
at
0,
25,
250,
or
2500
ppm
(
0,
1.8/
2,
18.2/
20.8,
181/
203
mg/
kg/
day
M/
F
F0
and
2/
2.2,
19.8/
22.8,
196/
218
mg/
kg/
day
M/
F
F1).
Parental
NOAEL
=
250
ppm,
LOAEL
=
2500
ppm
based
on
increase
liver
weight
in
F1
males.
reproductive
NAOEL
=
250
ppm,
LOAEL
=
2500
ppm,
based
on
decreased
mean
number
of
live
pups
at
birth
(
85%
of
controls)
and
decreased
litter
weights
at
day
0
and
during
lactation
in
F1
generation.
Acceptable/
Guideline
Cu
8­
quinolinolate
024002
84­
2
muta
Ames
00248746
Doses
tested:
0.001,
­
0.3
ul/
plate
(
0.2
and
0.3
ul
were
toxic).
Induced
increases
in
histidine
revertants
in
one
strain
TA100,
possibly
also
TA1538
and
TA98
with
metabolic
activation
(
weak
mutagen).
Acceptable/
Guideline
Cu
8­
quinolinolate
024002
84­
4
muta
00248746
no
induced
increases
in
tryptophan
revertants
at
mutagenic
conducted
with
and
without
metabolic
activation.
Doses
tested:
0.0005
­
1.0
ul/
plate
(
1.0
said
to
be
toxic­
no
survival
data).
Acceptable/
Guideline
Page
38
of
39
Table
10.
Other
Available
Toxicity
Studies
for
Copper
8­
Quinolinolate
(
mg/
kg)

Cu
8­
quinolinolate
024002
85­
1
42962304
42962305
14C­
labeled
oxine
copper
at
oral
doses
of
30
or
1000
mg/
kg,
repeated
oral
doses
(
14
daily)
unlabeled
oxine
copper
at
30
mg/
kg
followed
by
single
oral
labeled
oxine
copper
at
30
mg/
kg.
Major
route
of
excretion
via
urine
(
62­
86%)
and
feces
(
8­
26%)
within
48
hrs.
Rapid
absorption
inferred
by
rapid
excretion
of
metabolites
in
urine.
radioactivity
in
tissue
residues
very
low
in
all
tissues
including
blood
(<
0.05%).
Bioaccumulation
minimal.
Radioactivity
in
urine
associated
with
parent
(
5­
16%)
and
sulfate
(
12­
18%)
and
glucuronide
conjugates
(
36­
66%)
of
the
parent.
In
feces,
radioactivity
associated
with
parent
(
4­
23%)
and
glucuronide
conjugate
of
the
parent
(
0.1­
4%).
Acceptable/
Guideline
B.
Studies
available
for
the
other
copper
salts
Table
11.
Other
Available
Toxicity
Studies
for
Copper
Salts
(
mg/
kg)

Copper
Type
PC
Code
Guideline
Study
MRID
Results
Cu
octanoate
023306
None
available
Cu
salts
of
fatty
and
rosin
acids
023104
None
available
Cu
triehanolamine
complex
024403
82­
2
12
day
dermal
rat
44127507
K­
TEA
applied
at
100
or
1000
mg/
kg/
day
for
6
hrs/
day
for
12
days.
Volume­
dosage
of
0.09
and
0.86
ml/
kg
bw.
Dose­
related
increase
in
dermal
irritation
(
erythema,
edema,
fissuring,
desquamation
and
eschar
were
noted
at
100
while
exfoliaion
and
clear
exudate
limited
to
1,000
mg/
kg
group.
No
evidence
of
systemic
toxicity.
systemic
LOAEL
>
1000
mg/
kg
and
systemic
NOAEL
>
1000
dermal
LOAEL
=
100
mg/
kg
M&
F;
dermal
NOAEL
<
100
mg/
kg
Acceptable/
Non­
guideline
Elemental
Cu
024407
82­
2
12
day
dermal
rat
44127507
8%
a.
i.,
rats
treated
topically
at
100
or
1000
mg/
kg/
day
hrs/
day
for
12
days.
dose­
related
increase
in
dermal
irritation.
no
systemic
toxicity
noted.
systemic
LOAEL
>
1000
mg/
kg/
day,
systemic
NOAEL
>
1000
dermal
LOAEL
=
100
M
&
F,
dermal
NOAEL
<
100
mg/
kg/
day
Acceptable/
Non­
guideline
Cu
naphthenate
023102
82­
3
9.5%
Cu,
Crl:
CD
(
BR)
albino
rats
dermally
exposed
to
0,
100,
300,
or
1000
mg/
kg/
day
hrs/
day/
5
days/
week
for
13
weeks.
slight
systemic
toxicity
as
reduced
body
weight
gain
&
food
efficiency
in
high
dose
males
along
with
increase
in
kidney
weight
and
decrease
in
testes
weight.
No
other
signs.
systemic
NOAEL
=
300
mg/
kg/
day,
systemic
LOAEL
=
>
1000
mg/
kg/
day,
based
on
reduced
food
efficiency
and
body
wt.
gain/
dermal
NOAEL
=
100
mg/
kg/
day,
dermal
LOAEL
=
300
mg/
kg/
day.
Acceptable/
Guideline
Cu
naphthenate
023102
83­
3
develop,
0,
30,
100,
or
300
mg/
kg,
GD
6­
15
inclusive
maternal
NOAEL=
30
mg/
kg
maternal
LOAEL=
100
mg/
kg,
based
on
decreased
body
weight,
food
consumption,
increase
early
resorptions,
losses
at
HDT.
developmental
NOAEL
>
300
mg/
kg,
Page
39
of
39
Table
11.
Other
Available
Toxicity
Studies
for
Copper
Salts
(
mg/
kg)

Elemental
Cu
024407
83­
3a
develop
rat
44127507
Komeen
(
8%
Cu)
gavage
at
0,
100,
or
500
mg/
kg/
day
GD
6­
15.
Maternal
toxicity
at
500
mg/
kg/
day
by
decrease
body
weight
and
food
consumption,
no
frank
toxicity.
Maternal
LOAEL=
500
mg/
kg/
day
Maternal
NOAEL=
100
mg/
kg/
day
No
developmental
toxicity
developmental
NOAEL=
500
mg/
kg/
day
developmental
LOAEL
not
established
UNACCEPTABLE:
limit
dose
not
reached,
a
detailed
fetal
exam
should
be
conducted
to
investigate
developmental
potential
Cu
triehanolamine
complex
024403
83­
3
develop
rat
44127506
8
Cu
(
a.
i.)
In
water
(
5
ml/
kg)
at
0,
100,
or
700
mg/
kg/
day
from
GD
6­
15
inclusive.
1
F
at
700
d
ied
GD10.
Transient
weight
loss
and
food
consumption
during
first
two
days
of
dosing
in
high
group.
maternal
NOAEL
=
100
mg/
kg/
day
maternal
LOAEL
=
700
mg/
kg/
day,
based
on
weight
loss
and
food
consumption.
No
developmental
toxicity,
increased
post­
implantation
loss
at
high
dose.
developmental
NOAEL
=
100
mg/
kg/
day,
developmental
LOAEL
=
700
mg/
kg/
day,
based
on
increased
post­
implantation
loss.
Acceptable/
Non­
guideline
BV.
Other
Studies
for
the
Other
Unscheduled
Coppers
No
data
available.