1
The
petition
(
p.
1)
states
that
it
is
also
submitted
on
behalf
of
"
a
coalition
of
national
animal,
health,
and
environmental
protection
organizations"
including
Physicians
Committee
for
Responsible
Medicine,
American
Anti­
Vivisection
Society,
Alternatives
Research
and
Development
Foundation,
Doris
Day
Animal
League,
Earth
Island
Institute
(
Marine
Mammal
Project),
and
The
Humane
Society
of
the
United
States.

2
As
discussed
in
section
II.
D.
below,
the
voluntary
HPV
Challenge
Program
animal
welfare
principles
were
distributed
in
an
October
14,
1999,
EPA
letter
to
participants
in
the
voluntary
HPV
Challenge
Program.
A
copy
of
that
letter
is
attached
to
this
response
(
Attachment
1).
It
can
also
be
viewed
at
www.
epa.
gov/
chemrtk/
ceoltr2.
htm.
Also
as
described
in
section
II.
D.,
the
petition
references
some
related
discussion
in
EPA's
December
26,
2000,
Federal
Register
notice
at
65
FR
81686.
To
the
extent
that
the
description
of
these
principles
in
the
petition
differs
from
the
principles
as
originally
drafted,
EPA
presumes
that
the
petitioner
is
requesting
rulemaking
with
respect
to
the
principles
as
stated
in
the
petition.
RESPONSE
TO
"
PETITION
TO
COMPEL
THE
U.
S.
EPA
TO
PROMULGATE
A
RULE
RELATING
TO
ANIMAL
WELFARE
UNDER
THE
TOXIC
SUBSTANCES
CONTROL
ACT"

I.
Introduction
On
April
6,
2005,
the
U.
S.
Environmental
Protection
Agency
(
EPA)
received
a
petition
from
the
People
for
the
Ethical
Treatment
of
Animals
(
PETA)
1
requesting
that
the
Agency
initiate
rulemaking
to
require
that
(
1)
all
chemical
testing
conducted
in
connection
with
test
rules
and
voluntary
consent
orders
under
the
Toxic
Substances
Control
Act
(
TSCA),
as
well
as
testing
under
the
voluntary
High
Production
Volume
(
HPV)
Challenge
Program,
adhere
to
certain
animal
welfare
principles
contained
in
guidance
provided
to
participants
in
the
voluntary
HPV
Challenge
Program,
2
and
(
2)
EPA
enforce
those
guidelines
where
they
are
not
followed.
See
Petition
to
Compel
the
U.
S.
EPA
to
Promulgate
a
Rule
relating
to
Animal
Welfare
under
the
Toxic
Substances
Control
Act
(
April
5,
2005),
pp.
1­
2
and
23.
The
petitioner
asserts
that
the
petition
was
filed
under
§
21
of
TSCA,
15
U.
S.
C.
§
2620,
and
the
Administrative
Procedure
Act
(
APA),
5
U.
S.
C.
§
553(
e).

For
the
reasons
explained
in
this
response,
EPA
is
denying
the
petition.
EPA's
decision
in
no
way
reflects
any
change
in
the
Agency's
ongoing
commitment
and
efforts
to
appropriately
consider,
encourage,
and
facilitate
animal
welfare.
Rather,
the
decision
is
based
on
a
thorough
consideration
of
how
the
voluntary
HPV
Challenge
Program
animal
welfare
principles
best
fit
into
the
structure
and
implementation
of
the
various
TSCA
testing
authorities
and
related
voluntary
programs.

The
voluntary
HPV
Challenge
Program
animal
welfare
principles
were
developed
as
specific
guidance
for
this
Program
and
may
not
be
appropriate
in
other
contexts.
Given
this
2
3
TSCA
§
4(
b)(
1)
says
that
"
In
determining
the
standards
[
for
development
of
test
data]
...,
the
Administrator's
considerations
shall
include
the
relative
costs
.
.
.
and
the
reasonably
foreseeable
availability
of
the
facilities
and
personnel
.
.
.,"
but
says
nothing
about
animal
welfare
issues.
limitation,
EPA
needs
to
retain
flexibility
for
future
situations
not
related
to
this
Program.
In
accordance
with
TSCA,
the
Agency
is
called
upon
to
ensure
that
adequate
data
is
developed
on
chemical
substances
to
assess
their
risks
of
injury
to
health
and
the
environment.
The
Agency
has
nonetheless
demonstrated
its
commitment
to
reducing,
refining,
or
replacing
animal
testing
consistent
with
that
mission,
as
illustrated
below.

II.
Background
A.
TSCA
Statutory
Policy
Congress
enacted
the
Toxic
Substances
Control
Act
(
TSCA)
in
1976
with
"
the
primary
purpose
of
this
Act
to
assure
that
...
chemical
substances
and
mixtures
do
not
present
an
unreasonable
risk
of
injury
to
health
or
the
environment."
15
U.
S.
C.
§
2601(
b)(
3).
Toward
that
end,
Congress
declared
it
the
policy
of
the
United
States
that
"
adequate
data
should
be
developed
with
respect
to
the
effect
of
chemical
substances
and
mixtures
on
health
and
the
environment,"
15
U.
S.
C.
§
2601(
b)(
1),
and
that
"
adequate
authority
should
exist
to
regulate
chemical
substances
and
mixtures
which
present
an
unreasonable
risk
of
injury
to
health
or
the
environment.
.
."
15
U.
S.
C.
§
2601(
b)(
2).
Section
4(
b)(
2)(
A)
of
TSCA
specifically
sanctions
"
whole
animal
tests"
as
a
permissible
methodology
that
EPA
may
prescribe
in
a
standard
for
development
of
test
data.
TSCA
contains
no
provisions
related
to
animal
welfare.
3
B.
TSCA
Testing
Authorities
The
petition
requests
that
EPA
codify
the
voluntary
HPV
Challenge
Program
animal
welfare
principles
in
a
mandatory,
enforceable
rule
for
"
all
TSCA
testing
 
be
it
in
the
HPV
Program,
by
test
rule,
or
by
consent
order."
Petition
p.
23,
see
also
pp.
1­
2.
Beyond
testing
conducted
via
the
voluntary
programs,
EPA
can
issue
mandatory
chemical
testing
requirements
via
various
mechanisms
under
TSCA
§
4
and
§
5.
These
testing
authorities
include
§
4
test
rules
(
15
U.
S.
C.
§
2603,
40
CFR
Parts
790
­
799),
§
4
Enforceable
Consent
Agreements
(
15
U.
S.
C.
§
2603,
40
CFR
Parts
790
­
799),
and
§
5(
e)
Orders
(
15
U.
S.
C.
§
2604(
e)).

TSCA
§
4
provides
EPA
with
authority
to
promulgate
test
rules
to
require
health
and
environmental
effects
testing
of
chemical
substances
or
mixtures
for
which
certain
statutory
findings
are
made
(
see
TSCA
§
4(
a)).
EPA
has
broad
authority
to
specify
the
types
of
testing
required
by
a
test
rule,
i.
e.,
"
The
health
and
environmental
effects
for
which
standards
.
.
.
may
be
prescribed
include
carcinogenesis,
mutagenesis,
teratogenesis,
behavioral
disorders,
cumulative
or
synergistic
effects,
and
any
other
effect
which
may
present
an
unreasonable
risk
of
injury
to
health
or
the
environment."
TSCA
§
4(
b)(
2)(
A).
3
4
The
list
of
chemicals
included
in
the
voluntary
HPV
Challenge
Program
were
identified
based
on
production
volumes
reported
for
the
1990
Inventory
Update
Rule
(
IUR,
40
CFR
part
710,
subpart
B).
See
EPA,
OPPT.
Chemical
Hazard
Data
Availability
Study:
What
Do
We
Really
Know
About
the
Safety
of
High
Production
Volume
Chemicals?
(
April
1998)(
www.
epa.
gov/
opptintr/
chemtest/
hazchem.
htm).

5
For
more
on
the
OECD
SIDS,
see
OECD.
Decision­
Recommendation
of
the
Council
on
the
Cooperative
Investigation
and
Risk
Reduction
of
Existing
Chemicals
(
January
31,
1991),
and
OECD
Secretariat.
Manual
for
the
Investigation
of
HPV
Chemicals.
OECD
Programme
on
the
Co­
Operative
Investigation
of
High
Production
Volume
Chemicals.
Paris,
France.
December
2003.
Available
online
at
http://
www.
epa.
gov/
chemrtk/
guidocs.
htm
and
http://
www.
oecd.
org/
document/
7/
0,2340,
en_
2649_
34379_
1947463_
1_
1_
1_
1,00.
html/.
Additional
information
on
the
voluntary
HPV
Challenge
Program
is
available,
e.
g.,
at
www.
epa.
gov/
chemrtk/
volchall.
htm,
65
FR
81686­
81698,
Dec.
26,
2000,
and
"
Status
and
Future
Directions
of
the
High
Production
Volume
Challenge
Program,"
EPA­
743­
R­
04­
001,
Nov.
2004
(
http://
www.
epa.
gov/
chemrtk/
hpvstatr.
htm).
SIDS
Manual.
Third
Ed.
Screening
Information
Data
Set
Manual
of
the
OECD
Programme
on
the
Co­
Operative
Investigation
of
High
Production
EPA
also
has
authority
under
TSCA
§
4
to
negotiate
enforceable
consent
agreements
(
ECAs)
and
to
issue
orders
incorporating
these
agreements
(
see
40
CFR
part
790,
subparts
A,
B
and
D).
Such
agreements
may
be
used
where
a
consensus
exists
among
EPA
and
"
interested
parties,"
which
can
include
affected
manufacturers,
processors,
and
interested
members
of
the
public,
concerning
the
need
for
and
scope
of
testing.
Similar
to
its
authority
to
specify
the
types
of
testing
required
by
a
TSCA
§
4
test
rule,
EPA
may
negotiate
a
broad
range
of
testing
for
inclusion
in
an
ECA.

Section
5(
e)
of
TSCA
authorizes
EPA
to
issue
an
order
to
prohibit
or
limit
a
new
chemical
substance
or
a
chemical
substance
intended
for
a
significant
new
use.
Such
orders
are
typically
negotiated
as
Consent
Orders,
but
EPA
has
authority
under
§
5(
e)
to
seek
mandatory
compliance.
The
heading
of
§
5(
e)
of
TSCA
is
"
Regulation
Pending
Development
of
Information"
and
one
of
the
determinations
EPA
must
make
to
issue
an
order
under
TSCA
§
5(
e)
is
that
"
information
available
to
the
Administrator
is
insufficient
to
permit
a
reasoned
evaluation
of
the
health
and
environmental
effects
of
a
chemical
substance..."
TSCA
§
5(
e)(
1)(
A)(
i),
15
U.
S.
C.
§
2604(
e)(
1)(
A)(
i).

C.
The
Voluntary
HPV
Challenge
Program
EPA's
voluntary
HPV
Challenge
Program,
initiated
in
1998
as
part
of
the
Agency's
Chemical
Right­
to­
Know
Initiative
(
see
www.
epa.
gov/
chemrtk),
is
designed
to
provide
an
opportunity
to
manufacturers
of
chemicals
manufactured
or
imported
into
the
United
States
in
volumes
of
1
million
pounds
or
more
per
year4
to
make
publicly
available
the
baseline
level
Screening
Information
Data
Set
(
SIDS)
established
in
1990
and
1991
by
the
Organization
for
Economic
Cooperation
and
Development
(
OECD).
5
The
OECD
SIDS
is
an
internationally
4
Volume
Chemicals,
Paris,
France,
July
1997,
available
at
www.
epa.
gov/
chemrtk/
sidsappb.
htm
and
www.
oecd.
org/
ehs/
sidsman.
htm.
Additional
information
on
the
voluntary
HPV
Challenge
Program
is
available,
e.
g.,
at
www.
epa.
gov/
chemrtk/
volchall.
htm,
65
FR
81686­
81698,
Dec.
26,
2000,
and
"
Status
and
Future
Directions
of
the
High
Production
Volume
Challenge
Program,"
EPA­
743­
R­
04­
001,
Nov.
2004.

6
EPA,
OPPT.
Chemical
Hazard
Data
Availability
Study:
What
Do
We
Really
Know
About
the
Safety
of
High
Production
Volume
Chemicals?
(
April
1998)
(
www.
epa.
gov/
oppintr/
chemtest/
hazchem.
htm);
Environmental
Defense,
Toxic
Ignorance,
New
York,
New
York,
(
Summer
1997)
(
www.
edf.
org/
pubs/
reports/
toxicignorance);
American
Chemistry
Council,
Public
Availability
of
SIDS­
Related
Testing
Data
for
U.
S.
High
Production
Volume
Chemicals
(
June
12,
1998).

7
Id.
See
also
65
FR
81687.
agreed
upon
set
of
basic
tests
for
screening
high
production
volume
chemicals
for
human
and
environmental
hazards.
While
only
about
11
percent
of
all
chemical
substances
listed
on
the
TSCA
Inventory
of
Chemical
Substances
are
manufactured
at
1
million
pounds
or
more
annually,
these
chemicals
account
for
approximately
95
percent
by
volume
of
all
chemical
production
in
the
United
States.
65
FR
81662.
Studies
conducted
by
Environmental
Defense
(
formerly
the
Environmental
Defense
Fund),
EPA,
and
the
American
Chemistry
Council
(
ACC,
formerly
the
Chemical
Manufacturers
Association),
showed
a
dearth
of
publicly
available
basic
toxicity
data
on
many
of
these
chemicals.
6
EPA
found
that
only
7
percent
had
a
full
set
of
publicly
available
screening
data,
and
43
percent
had
no
publicly
available
basic
hazard
data.
7
The
remaining
chemicals
had
only
limited
data
available.
A
framework
for
the
voluntary
HPV
Challenge
Program
was
announced
jointly
on
October
9,
1998,
by
EPA,
Environmental
Defense,
ACC,
and
the
American
Petroleum
Institute.

EPA
has
indicated
that
the
voluntary
HPV
Challenge
Program
and
any
TSCA
§
4
HPV
SIDS
test
rules
"
will
generally
be
carried
out
in
a
manner
consistent
with
the
OECD
HPV
SIDS
Program"
to
ensure
that
data
developed
are
mutually
comparable
and
compatible,
and
to
enable
international
data
sharing
in
order
to
avoid
unnecessary
or
duplicative
testing
and
its
associated
costs.
65
FR
81689
and
81692.
On
December
26,
2000,
EPA
published
Federal
Register
notices
describing
the
voluntary
HPV
Challenge
Program
(
65
FR
81686)
and
proposing
the
first
TSCA
§
4
HPV
SIDS
test
rule
(
65
FR
81658).
The
December
26,
2000,
Federal
Register
notice
on
the
voluntary
HPV
Challenge
Program
identified
its
three
main
elements
as
"
1.
Fixed
timetable
and
fixed
list
of
chemicals...
2.
Continuous
public
access
to
program
status
and
results
....
3.
International
sharing
of
testing
responsibility."
65
FR
81692.

Participation
in
the
voluntary
HPV
Challenge
Program
is
completely
optional,
and
companies
participating
in
the
program
do
not
enter
into
enforceable
commitments.

EPA
posts
on
its
website
sponsor­
generated
robust
summaries
of
all
data
collected
in
the
5
8
Comments
on
test
plans
are
posted
on
EPA's
website
at
www.
epa.
gov/
opptintr/
chemrtk/
viewsrch.
htm
and
www.
epa.
gov/
chemrtk/
hpvrstp.
htm.

9
For
example,
as
of
July
2004,
92%
of
HPV
chemicals
had
been
sponsored.
Status
and
Future
Directions
of
the
High
Production
Volume
Challenge
Program,
EPA­
743­
R­
04­
001,
Nov.
2004,
p.
1.
See
also
the
related
discussion
in
section
III.
F.
below.

10
The
petition
omits
without
reference
an
item
that
was
listed
as
principle
number
9
in
EPA's
October
14,
1999,
letter.
That
principle
stated
(
in
part):
"
Testing
of
closed
system
intermediates,
which
present
less
risk
of
exposure,
shall
be
deferred
until
2003;
(
b)
Individual
chemicals
(
i.
e.,
those
HPV
chemicals
not
proposed
for
testing
in
a
category)
that
require
further
testing
on
animals
shall
be
deferred
until
November
2001."
EPA
presumes
that
the
petitioner
does
not
request
that
this
principle
be
incorporated
into
a
rule
because
the
dates
have
already
lapsed.
EPA's
response
reflects
the
same
listing
of
voluntary
HPV
Challenge
Program
animal
welfare
principles
as
in
the
petition.
voluntary
HPV
Challenge
Program
website.
8
Data
collected
via
the
voluntary
HPV
Challenge
Program
will
allow
the
Agency,
the
public,
and
others
to
better
assess
potential
risks
to
health
and
the
environment
from
these
chemicals.
As
appropriate,
this
information
will
be
used
to
ensure
a
scientifically
sound
basis
for
hazard
assessment
and
risk
screening,
assessment
and
management
actions.
The
voluntary
HPV
Challenge
Program
has
generated
significant
amounts
of
data,
including
data
generated
prior
to
the
inception
of
the
Program,
that
were
not
previously
publicly
available.
EPA
has
found
the
voluntary
HPV
Challenge
program
to
be
a
highly
effective
and
efficient
way
to
obtain
needed
data.
9
D.
The
Voluntary
HPV
Challenge
Program
Animal
Welfare
Principles
1.
The
October
14,
1999,
Letter
to
Voluntary
HPV
Challenge
Program
Participants
The
specific
set
of
voluntary
HPV
Challenge
Program
animal
welfare
principles
that
the
petitioner
urges
EPA
to
mandate
by
rule
were
distributed
in
an
October
14,
1999,
guidance
letter
from
Susan
H.
Wayland,
Deputy
Assistant
Administrator
of
EPA's
Office
of
Prevention,
Pesticides
and
Toxic
Substances
(
Attachment
1
to
this
petition
response).
This
letter
was
sent
to
all
persons
who
had
at
that
point
committed
to
participate
in
EPA's
voluntary
HPV
Challenge
Program.

In
this
letter,
which
petitioner
participated
in
developing,
EPA
asked
HPV
Challenge
Program
participants
to
observe
the
following
principles
as
they
proceed
with
the
program:
10
1.
In
analyzing
the
adequacy
of
existing
data,
participants
shall
conduct
a
thoughtful,
qualitative
analysis
rather
than
use
a
rote
checklist
approach.
Participants
may
conclude
that
there
is
sufficient
data,
given
the
totality
of
what
is
known
about
a
chemical,
including
human
experience,
6
and
that
certain
endpoints
need
not
be
tested.

2.
Participants
shall
maximize
the
use
of
existing
and
scientifically
adequate
data
to
minimize
further
testing.

3.
Participants
shall
maximize
the
use
of
scientifically
appropriate
categories
of
related
chemicals
and
structure
activity
relationships.

4.
Consistent
with
the
Screening
Information
Data
Set
(
SIDS)
program
of
the
Organization
for
Economic
Cooperation
and
Development
(
OECD),
participants
shall
not
conduct
any
terrestrial
toxicity
testing.

5.
Participants
are
encouraged
to
use
in
vitro
genetic
toxicity
testing
to
generate
any
needed
genetic
toxicity
screening
data,
unless
known
chemical
properties
preclude
its
use.

6.
Consistent
with
the
OECD/
SIDS
program,
participants
generally
should
not
develop
any
new
dermal
toxicity
data.

7.
Participants
shall
not
develop
sub­
chronic
or
reproductive
toxicity
data
for
the
HPV
chemicals
that
are
solely
closed
system
intermediates,
as
defined
by
the
OECD/
SIDS
guidelines.

8.
In
analyzing
the
adequacy
of
screening
data
for
chemicals
that
are
substances
Generally
Recognized
as
Safe
(
GRAS)
for
a
particular
use
by
the
Food
and
Drug
Administration
(
FDA),
participants
should
consider
all
relevant
and
available
information
supporting
the
FDA's
conclusions.
Participants
reviewing
the
adequacy
of
existing
data
for
these
chemicals
should
specifically
consider
whether
the
information
available
makes
it
unnecessary
to
proceed
with
further
testing
involving
animals.
As
with
all
chemicals,
before
generating
new
information,
participants
should
further
consider
whether
any
additional
information
obtained
would
be
useful
or
relevant.

9.
Companies
shall
allow
120
days
between
the
posting
of
test
plans
and
the
implementation
of
any
testing.

2.
Submission
of
Rationales
for
Conducting
Certain
Testing
The
petition
notes
that
EPA's
December
26,
2000,
Federal
Register
notice
on
the
voluntary
HPV
Challenge
Program
(
65
FR
81686)
"
expanded
on
several
items
including
the
following:"

(
a)
The
Agency
stressed
the
need
for
justification
if
any
proposed
genetic
toxicity
testing
was
not
to
be
conducted
in
vitro.
If
chemical
characteristics
of
the
substance
precluded
in
vitro
testing,
the
test
sponsors
were
asked
"
to
submit
to
EPA
the
rationale
for
conducting
one
of
these
alternative
[
in
vivo]
tests
as
part
of
7
the
test
plan."
(
p.
81695)

(
b)
The
EPA
endorsed
the
use
of
the
combined
repeateddose
reproductive/
developmental
toxicity
test
(
OCED
422),
which
uses
approximately
675
animals
per
test,
rather
than
conducting
separate
repeated­
dose,
reproductive
tests,
and
developmental
toxicity
tests,
which
kill
approximately
40,
1,300
and
1,300
animals,
respectively.
Again,
the
EPA
cautioned
that
where
the
combined
reproductive
screening
study
is
not
proposed,
"
test
sponsors
are
asked
to
submit
to
EPA
the
rationale
for
conducting
these
alternative
[
separate]
tests
as
part
of
the
test
plan"
(
pp.
81695
and
81697).

(
c)
With
respect
to
acute
fish
toxicity
testing,
EPA
stated
that
"
for
certain
HPV
chemicals,
acute
toxicity
studies
are
of
limited
value
in
assessing
the
substances'
aquatic
toxicity
Y
For
the
purposes
of
the
HPV
Challenge
Program
Y
EPA
believes
that
for
chemicals
determined
to
have
a
log
Kow
equal
to
or
greater
than
4.2,
the
following
tests
should
be
conducted:
chronic
toxicity
to
daphnia
(
in
place
of
the
acute
toxicity
tests
in
fish
and
daphnia
Y)"
(
p.
81695,
emphasis
supplied.)
"
A
sponsor
who
believes
that
acute
aquatic
fish
testing
is
appropriate
for
an
HPV
chemical
with
a
high
log
Kow
should
provide
in
its
submitted
test
plan
the
rationale
for
conducting
such
testing."

Petition
at
page
4.

3.
Guidance,
Not
Requirements
As
recognized
by
the
petitioner
(
Petition
pages
1,
4,
23
and
elsewhere),
the
voluntary
HPV
Challenge
Program
animal
welfare
principles
were
developed
as
guidance,
not
as
legally
binding
and
enforceable
mandates.
For
the
reasons
explained
in
section
IV
below,
EPA
believes
that
the
most
appropriate
way
to
apply
the
voluntary
HPV
Challenge
Program
animal
welfare
principles
is
as
guidance,
rather
than
as
mandatory
requirements.

III.
EPA's
Demonstrated
Commitment
to
the
Voluntary
HPV
Challenge
Program
Animal
Welfare
Principles
The
petition
principally
argues
that
the
voluntary
HPV
Challenge
Program
animal
welfare
principles
should
be
made
mandatory
because
they
have
been
"
consistently,
repeatedly
and
deliberately
disregarded"
by
both
industry
test
sponsors
and
by
EPA.
Petition
at
p.
4.
EPA
disagrees,
and
this
section
describes
numerous
ways
in
which
EPA
has
acted
to
communicate
and
realize
implementation
of
the
voluntary
HPV
Challenge
Program
animal
welfare
principles.
Discussion
of
how
industry
Challenge
sponsors
have
in
fact
generally
acted
in
accordance
with
these
principles
is
provided,
e.
g.,
in
section
III.
F.
8
11
There
were
two
slightly
different
versions
of
these
letters:
one
dated
October
25,
2000,
sent
by
Susan
Wayland
to
relevant
trade
associations,
and
another
dated
October
31,
2000,
sent
to
all
HPV
Challenge
participants
by
Charles
Auer,
then
Director
of
the
Chemical
Control
Division,
and
Oscar
Hernandez,
Director
of
the
Risk
Assessment
Division,
Office
of
Pollution
Prevention
and
Toxics.
EPA's
denial
of
this
petition
in
no
way
reflects
any
change
in
EPA's
ongoing
commitment
and
efforts
to
appropriately
consider,
encourage
and
facilitate
animal
welfare.
Rather
EPA's
denial
of
this
petition
is
based
on
a
thorough
consideration
of
how
the
voluntary
HPV
Challenge
Program
animal
welfare
principles
best
fit
into
the
structure
and
implementation
of
the
various
TSCA
testing
authorities
and
related
voluntary
programs.
As
noted
in
many
previous
letters
to
PETA,
EPA
has
demonstrated
its
commitment
to
reducing,
refining,
or
replacing
animal
testing
to
the
extent
testing
is
necessitated
by
the
important
work,
as
mandated
by
TSCA,
of
collecting
sufficient
information
on
chemical
substances
to
assess
their
risks
of
injury
to
health
and
the
environment.

Contrary
to
petitioner's
claim
that
EPA
has
"
consistently,
repeatedly
and
deliberately
disregarded"
the
voluntary
HPV
Challenge
Program
animal
welfare
principles,
EPA
has
been
both
public
and
consistent
in
communicating
and
realizing
implementation
of
the
Agency's
commitment
to
the
voluntary
HPV
Challenge
Program
animal
welfare
principles
in
the
context
of
the
voluntary
HPV
Challenge
Program
and
TSCA
§
4
HPV
SIDS
test
rules.
EPA
has
used
letters,
Federal
Register
notices
and
its
website
to
communicate,
and
in
so
doing,
encourage
sponsors
to
follow
the
voluntary
HPV
Challenge
Program
animal
welfare
principles.
EPA
has
applied
considerable
effort
to
realize
implementation
of
the
voluntary
HPV
Challenge
Program
animal
welfare
principles,
including
developing
guidance
documents,
commenting
on
individual
test
plans,
and
recommending
testing
alternatives.
The
following
are
tangible
examples
of
EPA's
substantial
efforts
to
promote
the
voluntary
HPV
Challenge
Program
animal
welfare
principles:

A.
Letters
to
HPV
Participants
First,
EPA's
Deputy
Assistant
Administrator
for
Prevention,
Pesticides
and
Toxics
sent
the
October
14,
1999,
letter,
dedicated
exclusively
to
promotion
of
the
voluntary
HPV
Challenge
Program
animal
welfare
principles,
to
all
participants
in
the
voluntary
HPV
Challenge
Program.
The
October
14,
1999,
letter
states
clearly
that
"
I
am
asking
you
and
your
fellow
HPV
Challenge
participants
to
observe
the
following
principles
as
we
proceed
with
the
program"
and
"
It
is
the
intention
of
the
Agency
that
the
HPV
Challenge
program,
including
the
test
rule(
s),
should
proceed
in
a
manner
that
is
consistent
with
these
principles
and
concerns."

Secondly,
in
October
2000,
the
Agency
sent
to
all
HPV
Challenge
participants
and
relevant
trade
associations
reminder
letters,
the
sole
purpose
of
which
was
to
"
reiterate
the
Agency's
commitment
to
the
principles
outlined
in
the
October
14,
1999,
letter
.
.
.
[
and
request]
that
all
participants
adhere
to
the
principles.
.
."
11
9
B.
Federal
Register
Notices
In
the
Agency's
December
26,
2000
Federal
Register
notices,
EPA
discussed
in
detail
the
October
14,
1999,
letter
and
how
animal
welfare
issues
are
being
addressed
in
the
voluntary
HPV
Challenge
Program
and
the
proposed
TSCA
§
4
HPV
SIDS
test
rule,
including
a
solicitation
of
"
comment
on
the
potential
approaches
that
may
be
used
to
incorporate
the
principles
contained
in
the
October
14,
1999,
letter
in
the
context
of
TSCA
§
4
HPV
SIDS
rulemakings."
See
in
particular
65
FR
81666,
81691
and
81693.
In
fact,
a
significant
portion
of
the
discussion
in
both
of
these
Federal
Register
notices
is
devoted
to
the
animal
welfare
principles,
including
entire
sections
on
animal
welfare
and
existing
data,
among
other
things.
Both
Federal
Register
notices
state
that
"
EPA
is
making
every
effort
to
ensure
that
.
.
.
unnecessary
or
duplicative
testing
is
avoided
and
the
use
of
animals
is
minimized."
65
FR
81666
and
81691.
Many
other
relevant
points
articulated
in
these
Federal
Notices
are
discussed
elsewhere
in
this
petition
response.

C.
Guidance
Documents
EPA
has
generated
and
posted
on
its
HPV
website
numerous
detailed
guidance
documents
(
often
lengthy)
promoting
and
facilitating
the
voluntary
HPV
Challenge
Program
animal
welfare
principles,
including
use
of
existing
data,
categories
and
structure
activity
relationship
(
SAR)
analysis,
in
vitro
testing,
etc.
See
www.
epa.
gov/
chemrtk/
guidocs.
htm.

Guidance
documents
posted
on
the
HPV
Challenge
website
include:


Fact
Sheet
on
Animal
Welfare
(
EPA
745­
F­
99­
003
(
July
2000)
at
www.
epa.
gov/
chemrtk/
anfacs2.
pdf;


Guidance
on
Searching
for
Chemical
Information
and
Data
at
www.
epa.
gov/
chemrtk/
srchguid.
htm;


Determining
the
Adequacy
of
Existing
Data
at
www.
epa.
gov/
chemrtk/
datadfin.
htm
and
www.
epa.
gov/
chemrtk/
datadeqfn.
pdf;


Development
of
Chemical
Categories
in
the
HPV
Challenge
Program
at
www.
epa.
gov/
chemrtk/
categuid.
htm
and
www.
epa.
gov/
chemrtk/
catdoc29.
pdf;


The
Use
of
Structure­
Activity
Relationships
(
SAR)
in
the
High
Production
Volume
Chemicals
Challenge
Program
at
www.
epa.
gov/
chemrtk/
sarfinl1.
htm
and
www.
epa.
gov/
chemrtk/
sarfinl1.
pdf;
and

Guidance
for
Testing
Closed
System
Intermediates
for
the
HPV
Challenge
Program
at
www.
epa.
gov/
chemrtk/
closed9.
htm
and
www.
epa.
gov/
chemrtk/
closed9.
pdf.;
and

Guidance
Document
on
Using
In
Vitro
Data
to
Estimate
In
Vivo
Starting
Doses
10
12
Comments
on
test
plans
are
posted
on
EPA's
website
at
www.
epa.
gov/
opptintr/
chemrtk/
viewsrch.
htm
and
www.
epa.
gov/
chemrtk/
hpvrstp.
htm.

13
The
not
infrequent
disagreements
between
petitioner
and
EPA
regarding
the
proper
interpretation
and
application
of
some
of
the
voluntary
HPV
Challenge
Program
animal
welfare
principles
to
individual
test
plans
is
noted
in
section
IV.
of
this
response
document
as
underscoring
one
reason
that
these
generally
worded
principles
are
not
appropriate
for
codification
as
a
rule.

14
Examples
of
such
prior
correspondence
in
which
EPA
provided
explanations
in
response
to
petitioner's
criticisms
of
individual
test
plans
include:
letters
dated
December
19,
2002,
and
January
16,
2004,
from
Charles
Auer,
Director
of
EPA's
Office
of
Pollution
Prevention
and
Toxics,
to
Jessica
Sandler,
PETA's
Federal
Agency
Liaison,
and
a
February
25,
2005,
letter
from
Charles
Auer
to
Susan
L.
Hall,
PETA's
Legal
Counsel.
for
Acute
Toxicity
at
www.
epa.
gov/
chemrtk/
nih2001b.
pdf.

D.
EPA's
Comments
on
Test
Plans
There
are
numerous
examples
of
Agency
comments
on
test
plans
submitted
for
the
voluntary
HPV
Challenge
Program
that
promote
and
encourage
adherence
to
the
voluntary
HPV
Challenge
Program
animal
welfare
principles.
12
The
petition
(
pages
5­
20)
criticizes
approximately
50
of
the
333
EPA
comments
on
HPV
test
plans
that
the
Agency
has
posted
to
date,
and
characterizes
EPA's
comments
as
"
failing
to
abide
by"
the
voluntary
HPV
Challenge
Program
animal
welfare
principles.
Petition
p.
5.
First,
as
discussed
above,
the
voluntary
HPV
Challenge
Program
animal
welfare
principles
are
guidance,
which
EPA
has
asked
participants
to
observe.
It
should
also
be
noted
that
the
test
plan
comments
petitioner
criticizes
represent
only
about
15
percent
of
the
total
number
of
cases,
a
relatively
small
and
selective
fraction.
More
importantly,
for
the
reasons
explained
throughout
this
document,
the
Agency
does
not
agree
with
most,
if
not
all,
of
PETA's
criticisms.
13
While
the
Agency
is
confident
that
its
actions
are
consistent
with
the
voluntary
HPV
Challenge
Program
animal
welfare
principles
in
virtually
all
cases,
the
Agency
did
not
attempt
in
this
response
to
rebut
each
and
every
test
plan
criticism
in
the
petition.
In
replies
to
numerous
letters
from
petitioner,
EPA
has
already
responded
to
many
of
petitioner's
criticisms
of
test
plans,
some
of
which
petitioner
repeats
in
their
petition.
14
Petitioner
asserts
certain
recurring
criticisms
that
are
erroneous
and
evince
petitioner's
misunderstanding
of
the
voluntary
HPV
Challenge
Program
process.
For
example,
the
voluntary
HPV
Challenge
Program
does
not
contemplate
EPA,
in
its
test
plan
comments,
responding
to
stakeholder
comments
on
these
test
plans
(
including
petitioner's),
because
it
is
the
Challenge
sponsor's
responsibility
to
consider
all
comments
on
their
test
plans.
For
another
example,
EPA
is
not
involved
in
developing
categories
of
chemicals
under
the
voluntary
HPV
Challenge
Program,
which
again
is
the
responsibility
of
the
Challenge
sponsors.
11
Further,
in
Attachment
II
to
this
response
document,
EPA
provides
several
examples
highlighting
how
case­
specific
criticisms
in
the
petition
are
invalid
or
inaccurate.
For
example,
in
one
case
(
benzenmethanethiol),
the
petitioner
criticized
EPA
for
rejecting
use
of
existing
data
on
an
alleged
analogue
chemical
to
avoid
the
need
for
new
reproductive­
developmental
toxicity
test.
However,
in
EPA's
scientific
judgment,
the
proposed
analogue
belongs
to
a
different
chemical
class
than
the
sponsored
substance
and
the
resemblance
is
extremely
superficial
in
terms
of
their
biochemical
characteristics.

In
another
example
(
2­
vinylpyridine),
the
petitioner
criticized
EPA
for
seeking
systemic
toxicity
testing
on
a
corrosive
chemical.
However,
in
this
case,
the
test
chemical
has
been
shown
in
other
studies
to
exhibit
systemic
toxicity
that
does
not
follow
the
pattern
of
classic
acids
and
bases
that
are
typically
subject
to
concerns
regarding
corrosivity.
Furthermore,
in
this
case,
the
Agency
is
recommending
the
Combined
Repeated
Dose
Toxicity
Study
with
the
Reproduction/
Developmental
Toxicity
Screening
Test
(
40
CFR
799.9365,
OECD
422)
which
is
generally
viewed
as
being
consistent
with
the
voluntary
HPV
Challenge
Program
animal
welfare
principles.

Attachment
III
to
this
petition
response
provides
a
selection
of
additional
examples
of
EPA
comments
on
HPV
test
plans
where
EPA's
comments
clearly
promote
the
voluntary
HPV
Challenge
Program
animal
welfare
principles
by
suggesting
to
the
Challenge
sponsor
changes
from
what
the
sponsor
originally
proposed.
Examples
include
recommending
in
vitro
rather
than
in
vivo
genetic
toxicity
studies,
recommending
the
Combined
Repeated
Dose
Toxicity
Study
with
the
Reproduction/
Developmental
Toxicity
Screening
Test
(
40
CFR
799.9365,
OECD
422),
and
recommending
reliance
on
SAR
analysis
rather
than
new
testing.

E.
Testing
Alternatives
EPA
has
been
actively
participating
in
development
of
testing
alternatives
and
revisions
that
promote
animal
welfare.
EPA
has
repeatedly
stated
its
commitment
to
a
"
reduction,
replacement,
refinement"
strategy,
consistent
with
the
Interagency
Coordinating
Committee
on
the
Validation
of
Alternative
Methods
(
ICCVAM)
Authorization
Act.
42
U.
S.
C.
§
2851
et
seq.
"
Where
testing
must
be
conducted
to
develop
adequate
data,
the
Agency
is
committed
to
reducing
the
number
of
animals
used
for
testing,
to
replacing
test
methods
requiring
animals
with
alternative
test
methods
when
acceptable
alternative
methods
are
available,
and
to
refining
existing
test
methods
to
optimize
animal
use
when
there
is
no
substitute
for
animal
testing."
65
FR
81666
and
81691.

EPA
is
an
active
participant
with
several
organizations
involved
in
development
of
alternatives
to
animal
testing,
including
ICCVAM,
the
Organization
for
Economic
Cooperation
and
Development
(
OECD),
and
the
Johns
Hopkins
University
Center
for
Alternatives
to
Animal
Testing
(
CAAT).
As
part
of
these
efforts,
the
Agency
has
significantly
contributed
to
establishing
the
acceptability
of
alternative
methods,
including,
e.
g.,
working
with
OECD
to
develop
and
accept
the
Acute
Oral
Toxicity
 
Up­
and­
Down
Procedure
(
OECD
TG
425),
Acute
Oral
Toxicity
12
15
See
65
FR
81669
 
816970,
81684­
81685,
81695
 
81697,
Dec.
26,
2000.
 
Fixed
Dose
Procedure
(
OECD
TG
420),
and
the
Acute
Oral
Toxicity
 
Acute
Toxic
Class
Method
(
OECD
TG
423)
as
alternatives
to
the
LD50
study.
Additionally,
EPA's
Office
of
Research
and
Development
(
ORD)
is
conducting
research
under
its
Computational
Toxicology
initiative
that
will
advance
efforts
to
reduce
animal
use
in
regulatory
testing.

As
discussed
in
EPA's
Federal
Register
notices
associated
with
the
voluntary
HPV
Challenge
Program
and
proposed
TSCA
§
4
HPV
SIDS
test
rule15,
and
as
noted
by
petitioner
in
its
petition
(
see
page
4),
EPA
has
taken
specific
actions
to
promote
alternative
testing
approaches
specifically
for
animal
welfare
purposes.
EPA
dropped
its
preference
for
in
vivo
micronucleus
genotoxicity
testing
and
to
accept
either
in
vivo
or
in
vitro
studies
(
as
allowed
by
OECD).
In
its
voluntary
HPV
Challenge
Program
and
TSCA
§
4
HPV
SIDS
test
rules,
EPA
encourages
use
of
the
in
vitro
Mammalian
Chromosome
Aberration
Test
method
(
40
CFR
799.9537,
OECD
473)
and
urges
companies
to
submit
justifications
if
they
elect
to
use
the
in
vivo
method.
For
Challenge
sponsors
participating
in
the
voluntary
HPV
Challenge
Program,
these
justifications
of
alternative
testing
should
be
submitted
in
the
test
plans.
For
testing
that
would
be
conducted
pursuant
to
the
proposed
TSCA
§
4
HPV
SIDS
test
rule,
EPA
has
proposed
that
these
justifications
must
be
submitted
in
the
final
study
reports.
Similarly,
EPA
is
encouraging
use
of
the
Combined
Repeated
Dose
Toxicity
Study
with
the
Reproduction/
Developmental
Toxicity
Screening
Test
(
40
CFR
799.9365,
OECD
422),
and
urging
Challenge
sponsors
to
submit
a
rationale
if
they
propose
using
both
the
Reproduction/
Developmental
Toxicity
Screening
Test
(
40
CFR
799.9355,
OECD
421)
and
the
Repeated
Dose
28­
day
Oral
Toxicity
Study
(
40
CFR
799.9305,
OECD
407)
instead
of
the
combined
study.
Again,
for
the
voluntary
HPV
Challenge
Program,
these
justifications
should
be
submitted
in
the
test
plans,
and
for
the
TSCA
§
4
HPV
SIDS
test
rule,
EPA
has
proposed
that
these
justifications
must
be
submitted
in
the
final
study
reports.

Also,
EPA
is
discouraging
the
conduct
of
acute
aquatic
toxicity
testing
of
HPV
Challenge
Program
chemicals
with
high
octanol/
water
partition
coefficients
(
i.
e.,
log
Kow
values
of
4.2
or
greater)
by
indicating
in
the
voluntary
HPV
Challenge
Program
that
sponsors
of
such
chemicals
who
believe
that
acute
aquatic
toxicity
testing
is
appropriate
should
provide
their
rationale
in
their
test
plans.
Chemical
substances
that
are
dispersible
in
water
(
e.
g.,
surfactants,
detergents,
aliphatic
amines,
and
cationic
dyes)
may
have
log
Kow
values
of
4.2
or
greater
and
may
still
be
acutely
toxic
to
aquatic
organisms.
To
deal
with
such
chemicals
in
the
proposed
TSCA
§
4
HPV
SIDS
test
rule,
EPA
proposed,
as
one
alternative,
that
test
sponsors
who
wish
to
conduct
acute
toxicity
studies
on
chemicals
with
a
log
Kow
value
greater
than
or
equal
to
4.2
submit
to
EPA
for
approval
a
written
request
to
conduct
such
studies
prior
to
(
e.
g.,
90
days)
initiating
such
studies.
EPA
solicited
public
comment
in
its
TSCA
§
4
HPV
SIDS
proposed
rule
on
this
approach
as
well
as
other
alternative
approaches
in
this
area.
See
65
FR
81670.

In
April
1999,
several
EPA
personnel
gave
presentations
at
a
workshop
organized
by
the
Johns
Hopkins
University
Center
for
Alternatives
to
Animal
Testing.
The
subject
of
the
meeting
13
16
This
October
2001
HPV
Status
Report
is
posted
at
www.
epa.
gov/
chemrtk/
hpvstat.
htm.
EPA
provided
a
copy
to
petitioner
as
an
enclosure
to
an
October
30,
2001,
letter
from
Stephen
L.
Johnson,
then
Acting
Administrator
of
EPA's
Office
of
Prevention,
Pesticides
and
Toxics,
to
Jessica
Sandler,
PETA's
Federal
Agency
Liaison.
was
"
TestSmart,
an
efficient
and
humane
approach
to
collecting
SIDS
data
for
the
voluntary
HPV
Challenge
Program."
Charles
Auer,
then
Director
of
EPA's
Chemical
Control
Division,
gave
a
presentation
that
focused
heavily
on
animal
welfare
aspects
of
the
voluntary
HPV
Challenge
Program.

In
September
2001,
the
ICCVAM
recommended
that
in
vitro
cytotoxicity
test
methods
be
considered
as
a
tool
for
estimating
starting
doses
for
in
vivo
acute
systemic
toxicity
testing
studies
(
66
FR
49686­
49687,
September
28,
2001.)
The
recommendations
were
based
on
the
Report
of
the
International
Workshop
on
In
Vitro
Methods
for
Assessing
Acute
Systemic
Toxicity
(
ICCVAM,
2001a).
The
Guidance
Document
on
Using
In
Vitro
Data
to
Estimate
In
Vivo
Starting
Doses
for
Acute
Toxicity
(
ICCVAM,
2001b)
was
also
made
available
at
that
time.
The
guidance
document
provided
standard
operating
procedures
for
two
cytotoxicity
test
methods
and
instructions
for
using
these
assays
to
estimate
starting
doses
for
in
vivo
testing.
Federal
agency
responses
to
the
ICCVAM
test
method
recommendations
were
announced
on
March
10,
2004
(
69
FR
11448­
11449).
Federal
agencies
agreed
to
encourage,
to
the
extent
applicable,
the
use
of
in
vitro
tests
for
determining
starting
doses
for
acute
systemic
toxicity
testing.
EPA
developed
and
issued
a
guidance
document
specifically
encouraging
those
participating
in
the
HPV
Challenge
Program
to
consider
using
the
recommended
in
vitro
tests
as
a
supplemental
component
in
conducting
any
new
in
vivo
acute
oral
toxicity
studies
for
the
Program
(
www.
epa.
gov/
chemrtk/
toxprtow.
htm).

In
December
2002,
EPA
announced
revised
test
guidelines
for
acute
oral
toxicity
(
OPPTS
870.1100)
to
enhance
animal
welfare
while
providing
essential
data
needed
to
ensure
protection
of
human
health.
www.
epa.
gov/
chemrtk/
toxprtcl.
htm,
67
FR
77064,
Dec.
16,
2002,
and
68
FR
14635,
March
26,
2003.
The
revised
acute
oral
toxicity
"
Up­
and­
Down
Procedure,"
which
requires
fewer
animals,
replaces
the
traditional
Acute
Oral
Toxicity
test
guideline
(
LD50
study).

In
sum,
EPA
has
taken
numerous
concrete
actions
that
promote
the
voluntary
HPV
Challenge
Program
animal
welfare
principles.
When
these
serious
efforts
are
considered
in
combination
with
the
sound
legal,
policy,
and
procedural
reasons
for
denying
this
petition,
EPA's
commitment
to
animal
welfare
is
irrefutable.

F.
Evidence
of
Success
An
October
12,
2001,
"
Status
Report
on
the
High
Production
Volume
(
HPV)
Challenge
Program"
examined
the
first
46
test
plans
posted
on
EPA's
HPV
website.
16
The
report
concluded
that
"
sponsors
have
made
maximum
use
of
the
guidance
concerning
the
use
of
SAR
and
category
proposals,
and
in
combination
with
the
significant
amount
of
unpublished
data
made
available
14
17
The
October
2001
HPV
Status
Report
noted
that,
in
a
few
cases,
"
sponsors
were
not
adequately
explaining
why
they
were
proposing
tests
that
were
beyond
the
base
set
of
screening
tests
and/
or
were
not
consistent
with
EPA's
[
October
14,
1999]
guidance"
and
"
it
would
be
helpful
for
submitters
to
explain
the
rationale
for
any
testing
that
is
proposed
beyond
the
SIDS
endpoints"
(
for
example,
this
could
be
intended
to
satisfy
non­
US
testing
requirements).
As
noted
below
in
sections
IV.
E.
6.
and
IV.
F.
6.,
EPA
has
taken
steps
to
urge
sponsors
to
submit
their
rationale
for
pursuing
testing
that
deviates
from
the
voluntary
HPV
Challenge
Program
animal
welfare
principles,
including
urging
submission
of
such
rationale
with
test
plans.

18
Status
and
Future
Directions
of
the
High
Production
Volume
Challenge
Program,
EPA­
743­
R­
04­
001,
Nov.
2004.

19
The
listed
endpoints
are
fate,
physical
chemical
properties,
human
health,
and
ecotoxicity.

20
"
As
of
July
2004,
of
the
353
submitted
test
plans,
114
contain
category
proposals
covering
1,027
chemicals.
These
1,027
chemicals
represent
81%
of
the
chemicals
addressed
by
test
plans."
Nov.
2004
HPV
Status
Report,
p.
45.
through
the
robust
summaries,
only
a
minimal
amount
of
[
new]
testing
has
been
proposed..
.
.
[
T]
he
overall
amount
of
proposed
[
new]
testing
is
less
than
10
percent."
Id.
"
Sponsors
are
using
category
approaches,
SAR,
and
other
estimation
techniques
to
reduce
costs
and
the
need
for
new
testing.
The
net
result
is
that
new
testing
is
being
proposed
for
about
six
percent
of
the
health
and
ecological
endpoints,
due
in
large
part
to
the
amount
of
test
data,
particularly
unpublished
data,
brought
forward."
17
EPA's
more
extensive
November
2004
HPV
Status
Report18
covering
353
test
plans
submitted
by
July
2004
continues
to
confirm
the
findings
of
the
earlier
report.
It
provides
factual
statistical
information
demonstrating
that
a
very
substantial
portion
of
the
identified
data
needs
can
and
have
been
filled
via
existing
data
and
SAR
rather
than
new
testing.
The
"
Endpoint
Data
Sources"
table
on
pages
8
and
44
shows
that
"
New
testing
has
been
proposed
for
fewer
than
10%
of
the
chemicals'
endpoints."
19
The
table
shows
further
that,
depending
on
endpoint,
between
50
and
62
percent
of
the
data
have
come
from
existing
data,
and
31
to
44
percent
of
the
data
have
come
from
SAR
and
similar
techniques.
The
report
notes
that
"
81%
of
all
chemicals
addressed
in
test
plans
have
been
included
in
a
category."
20
These
numbers
demonstrate
that
the
Agency's
efforts
to
communicate
and
realize
implementation
of
the
voluntary
HPV
Challenge
Program
animal
welfare
principles
have,
in
fact,
been
highly
successful.
15
IV.
Petition
Response
A.
Summary
of
Rationale
EPA
is
denying
the
petition
for
the
reasons
detailed
below.
These
can
be
summarized
as
follows:

(
1)
Petitioner's
criticisms
notwithstanding,
evidence
shows
that
these
principles
have
provided
effective
guidance
to
voluntary
HPV
Challenge
Program
sponsors
and
EPA,
and
have
been
highly
effective
in
minimizing
animal
testing
under
the
Program.

(
2)
In
other
contexts,
EPA
effectively
factors
in
concerns
about
animal
welfare
in
practice
as
EPA
solicits
existing
test
data,
often
pursuant
to
a
statutory
requirement.

(
3)
It
is
doubtful
that
EPA
can
require
sponsors
in
the
voluntary
HPV
Challenge
Program
to
adhere
to
the
Program's
animal
welfare
principles.

(
4)
Companies
are
often
motivated
by
financial
considerations
to
adhere
to
many
of
the
principles
that
reduce
new
animal
testing
in
order
to
reduce
expenditures.

(
5)
Though
EPA
believes
in
the
"
reduction,
replacement,
refinement"
strategy
for
animal
testing
and
works
towards
that
end,
the
primary
mission
and
statutory
mandate
under
TSCA
is
to
gather
and
assess
data
pertaining
to
the
effects
of
chemical
substances
and
mixtures
on
health
and
the
environment
and
to
regulate
where
appropriate
to
prevent
unreasonable
risk
of
injury
to
health
and
the
environment.
Implementation
of
other
goals,
however
desirable,
must
be
approached
in
a
manner
that
does
not
jeopardize
the
statutory
mandate.
TSCA
authorizes
animal
tests
and
says
nothing
about
animal
welfare.

(
6)
The
animal
welfare
principles
in
the
October
14,
1999,
letter
are
intentionally
phrased
in
general
terms
that
do
not
easily
lend
themselves
to
rulemaking.

(
7)
The
principles
were
developed
as
guidance
for
HPV
SIDS
screening
level
testing
and
may
not
apply
in
other
contexts,
so
EPA
needs
to
retain
case­
specific
flexibility
for
future
situations.
16
21
For
example,
§
4
authorizes
EPA
to
promulgate
rules
providing
for
fair
and
equitable
reimbursement
from
manufacturers
and/
or
processors
who
are
granted
exemptions
from
test
rule
requirements
to
manufacturers
and/
or
processors
who
actually
conduct
the
testing.
15
U.
S.
C.
§
§
2603(
c)(
3)(
A),
(
4)(
A).
Under
petitioner's
reasoning,
a
denial
of
a
petition
for
a
new
B.
Applicability
of
TSCA
§
21
The
petition
states
that
it
is
submitted
under
§
21
of
TSCA
(
15
U.
S.
C.
§
2620).
Petition
at
1.
Although
EPA
believes
that
a
petition
requesting
a
generic
animal
welfare
rule
is
not
authorized
by
§
21,
the
Agency
is
nonetheless
responding
to
the
petition
in
90
days,
as
requested
by
the
petitioner.

Section
21(
a)
provides
in
part
that
a
person
may
petition
EPA
"
to
initiate
a
proceeding
for
the
issuance,
amendment,
or
repeal
of
a
rule
under
section
2603
[
i.
e.,
TSCA
§
4]
.
.
.
of
this
title."
15
U.
S.
C.
§
2620(
a).
Notwithstanding
the
references
in
§
21
to
§
4
generally,
EPA
believes
that
§
21
is
properly
interpreted
to
apply
only
to
chemical­
specific
legislative
rules
that
have
been
or
could
be
issued
under
the
authority
of
§
4(
a)
(
i.
e.,
§
4
test
rules).
To
adopt
a
broader
interpretation
would
lead
to
internal
inconsistencies
within
§
21.
In
particular,
§
21(
b)(
4)(
B)
provides
for
de
novo
review
of
an
EPA
denial
of
a
petition
for
the
issuance
of
a
new
rule
under
§
4.
To
succeed
in
such
a
proceeding,
the
petitioner
must
demonstrate
by
a
preponderance
of
the
evidence
that:

(
I)
information
available
to
the
Administrator
is
insufficient
to
permit
a
reasoned
evaluation
of
the
health
and
environmental
effects
of
the
chemical
substance
to
be
subject
to
such
rule.
.
.;
and
(
II)
in
the
absence
of
such
information,
the
substance
may
present
an
unreasonable
risk
to
heath
or
the
environment,
or
the
substance
is
or
will
be
produced
in
substantial
quantities
and
it
enters
or
may
reasonably
be
anticipated
to
enter
the
environment
in
substantial
quantities
or
there
is
or
may
be
significant
or
substantial
human
exposure
to
it.

15
U.
S.
C.
§
2621(
b)(
4)(
B)(
i)
(
emphasis
supplied).
By
its
terms,
§
21(
b)(
4)(
B)
can
only
apply
to
review
of
EPA
denials
of
petitions
to
issue
new
chemical
substance­
specific
rules,
such
as
§
4
test
rules.
The
factors
that
the
court
must
consider
in
this
de
novo
proceeding
have
no
relevance
when
the
petitioner's
requested
rule
does
not
pertain
to
specific
chemical
substances
or
mixtures,
21
and
Congress
could
thus
not
have
intended
that
they
apply.
Moreover,
these
factors
17
reimbursement
rule
would
entitle
a
petition
to
de
novo
review
under
§
21(
b)(
4)(
B).
However,
the
factual
demonstrations
a
petitioner
is
required
to
make
in
a
de
novo
proceeding
could
not
be
reconciled
with
a
review
of
fair
and
equitable
reimbursement.
Thus
petitioner's
assumption
C
that
any
rule
or
guidance
issued
pursuant
to
TSCA
§
4
is
subject
to
petition
under
§
21
C
renders
§
21'
s
de
novo
review
provision
nonsensical.
are
nearly
identical
to
certain
findings
that
EPA
must
make
when
it
issues
a
§
4
test
rule
on
its
own
initiative.
See
15
U.
S.
C.
§
2603(
a).

This
interpretation
of
§
21
makes
sense
from
a
policy
perspective.
EPA
believes
that
Congress
enacted
§
21
in
order
to
ensure
expedited
consideration
of
petitions
related
to
chemicalspecific
rulemakings,
in
view
of
the
potentially
urgent
need
for
EPA
to
address
chemical
risk
issues
and
the
direct
and
immediate
impacts
such
rules
have.

C.
Lack
of
Statutory
Mandate
regarding
Animal
Welfare
Congress
enacted
the
Toxic
Substances
Control
Act
(
TSCA)
in
1976
with
"
the
primary
purpose
of
this
Act
to
assure
that
...
chemical
substances
and
mixtures
do
not
present
an
unreasonable
risk
of
injury
to
health
or
the
environment."
15
U.
S.
C.
§
2601(
b)(
3).
Toward
that
end,
Congress
declared
it
the
policy
of
the
United
States
that
"
adequate
data
should
be
developed
with
respect
to
the
effect
of
chemical
substances
and
mixtures
on
health
and
the
environment,"
15
U.
S.
C.
§
2601(
b)(
1),
and
that
"
adequate
authority
should
exist
to
regulate
chemical
substances
and
mixtures
which
present
an
unreasonable
risk
of
injury
to
health
or
the
environment.
.
."
15
U.
S.
C.
§
2601(
b)(
2).
To
promote
those
statutory
purposes,
Congress
included
in
TSCA
specific
provisions
authorizing
EPA
to
require
chemical
testing
and
regulate
to
protect
against
potential
unreasonable
risks.

The
primary
section
of
TSCA
concerning
testing
of
chemical
substances
is
§
4.
TSCA
§
4(
b)(
2)(
A)
specifically
authorizes
"
whole
animal
tests"
as
an
acceptable
test
methodolgy,
and
§
4(
b)(
1)
says
that
"
In
determining
the
standards
[
for
development
of
test
data]
.
.
.,
the
Administrator's
considerations
shall
include
the
relative
costs
...
and
the
reasonably
foreseeable
availability
of
the
facilities
and
personnel
.
.
."
TSCA
does
not
address
animal
welfare.

Consistent
with
the
National
Institutes
of
Health
Revitalization
Act
of
1993
and
the
ICCVAM
Authorization
Act,
the
Agency
has
pursued
a
"
reduction,
refinement,
replacement"
strategy,
which
EPA
views
as
appropriate
and
successful.
Ultimately,
EPA
is
handling
animal
welfare
issues
in
a
manner
consistent
with
its
relevant
mandates
and
the
congressional
statement
of
policy
in
TSCA
§
2(
b)
to
develop
adequate
data
with
respect
to
the
effect
of
chemical
substances
and
mixtures
on
health
and
the
environment
in
order
to
assure
that
chemical
18
22
Though
the
voluntary
HPV
Challenge
Program
is
not
a
TSCA
regulatory
program,
its
goals
are
consistent
with
one
of
the
major
policies
of
the
statute,
set
forth
at
TSCA
§
2(
b)(
1),
that
"
adequate
data
should
be
developed
with
respect
to
the
effect
of
chemical
substances
and
mixtures
on
health
and
the
environment
and
that
the
development
of
such
data
should
be
the
responsibility
of
those
who
manufacture
and
those
who
process
such
chemical
substances
and
mixtures."
Among
the
test
methodologies
specifically
sanctioned
by
TSCA
is
"
whole
animal
tests."
TSCA
§
4(
b)(
2)(
A).
substances
and
mixtures
do
not
present
an
unreasonable
risk
of
injury
to
health
or
the
environment.
As
elaborated
below,
EPA
does
not
believe
that
the
rulemaking
requested
by
petitioner
is
necessary.

C.
Voluntary
HPV
Challenge
Program
The
purpose
of
the
voluntary
HPV
Challenge
Program
is
to
gather
data
on
chemicals
manufactured
in
large
volumes
and
make
those
data
publicly
available.
22
This
purpose
is
achieved
through
a
voluntary
commitment
by
companies
to
search
for
existing
data
or
develop
new
data.
Although
EPA
coordinates
the
voluntary
HPV
Challenge
Program,
EPA
is
not
in
a
position
to
dictate
to
sponsors
in
a
voluntary
Program.
When
a
sponsor
submits
a
test
plan,
EPA,
concurrently
with
other
commenters,
provides
comments
on
the
test
plan
to
the
sponsor.
Although
EPA
desires
that
sponsors'
participation
be
guided
by
the
animal
welfare
principles
in
the
October
14,
1999,
letter,
and
the
Agency's
comments
are
often
informed
by
these
principles,
EPA
has
never
assumed
the
responsibility
of
ensuring
that
sponsors
adhere
to
these
principles,
nor
could
it.
Thus,
test
plan
comments
from
the
petitioner
and
other
stakeholders
are
directed
to
the
Challenge
sponsor,
not
to
EPA.

Consistent
with
this,
it
is
doubtful
that
EPA
has
authority
to
promulgate
rules
to
enforce
the
animal
welfare
principles
within
the
voluntary
HPV
Challenge
program,
because
no
authority
within
TSCA
or
elsewhere
requires
that
Challenge
sponsors
or
other
manufacturers
and
processors
of
HPV
chemicals
participate
in
the
program
or
that
they
adhere
to
the
guidelines
in
the
Program.
TSCA
§
4
requires
testing
where
EPA
has
made
the
requisite
findings,
and
contains
provisions
regarding
test
standards.
But
§
4
does
not
apply
to
a
voluntary
program
not
based
on
§
4
findings,
and
thus
conveys
no
authority
to
require
that
testing
in
a
non­
section
4
program
proceed
in
a
specified
fashion.
Nor
do
other
sections
of
TSCA,
nor
any
other
statutory
authority
of
which
EPA
is
aware,
bind
the
voluntary
HPV
Challenge
Program
sponsors
to
specific
testing
procedures.

Even
assuming
EPA
has
authority
to
promulgate
the
rule
requested
by
petitioner,
the
Agency
does
not
believe
it
is
necessary
or
appropriate
to
do
so.
For
example,
as
shown
by
the
statistical
evidence
in
section
III.
F.
above,
the
voluntary
HPV
Challenge
Program
animal
welfare
19
23
Supporting
Statement
for
a
Request
for
OMB
Review
under
the
Paperwork
Reduction
Act,
EPA
ICR
#
1139.07
(
January
25,
2005).

24
65
FR
81666
and
81691.
March
15,
2000,
letter
from
Susan
H.
Wayland,
EPA's
Acting
Assistant
Administrator
for
Prevention,
Pesticides
and
Toxics,
to
Senator
Bob
Smith.
See
also
footnote
13.
principles
have
in
fact
motivated
the
chemical
industry
to
make
public
large
amounts
of
existing
data
that
were
previously
unavailable,
thus
reducing
the
need
to
conduct
new
testing
in
many
instances.
Those
numbers
demonstrate
that
the
Agency's
efforts
to
communicate
and
realize
implementation
of
the
voluntary
HPV
Challenge
Program
animal
welfare
principles
have,
in
fact,
been
highly
successful.

It
is
not
surprising
that
sponsors
have
operated
consistently
with
these
principles,
since
it
is
generally
less
expensive
to
identify
and
submit
existing
data
and
to
utilize
SAR
and
category
approaches
than
to
conduct
new
testing.
The
estimated
cost
of
completing
the
full
suite
of
HPV
SIDS
testing
(
in
2003
dollars)
is
$
288,568.23
The
Combined
Repeated
Dose
Toxicity
Study
with
the
Reproduction/
Developmental
Toxicity
Screening
Test
(
40
CFR
799.9365,
OECD
422),
for
example,
is
estimated
to
cost
$
113,977.

Thus,
even
assuming
EPA
could
promulgate
the
requested
rules,
it
would
not
be
an
effective
or
prudent
use
of
EPA's
limited
resources,
given
that
the
principles
have
operated
effectively
as
guidance
and
that
the
requested
rule
would
not
advance
the
Agency's
mandate
under
TSCA.

D.
TSCA
§
4
HPV
SIDS
Test
Rules
1.
General
In
the
context
of
TSCA
§
4
HPV
SIDS
test
rules,
EPA
has
committed
to
adopt
approaches
that
are
consistent
with
the
voluntary
HPV
Challenge
Program
animal
welfare
principles
that
originated
in
the
voluntary
HPV
Challenge
Program.
The
Agency's
October
14,
1999,
letter
committed
to
proceeding
with
TSCA
§
4
HPV
SIDS
test
rules
in
a
manner
consistent
with
the
voluntary
HPV
Challenge
Program
animal
welfare
principles
contained
within
the
letter,
and
EPA
has
reiterated
this
commitment
in
subsequent
letters
and
HPV
Federal
Register
notices.
24
Due
to
inherent
differences
between
the
voluntary
HPV
Challenge
Program
and
TSCA
20
25
EPA
has
authority
under
TSCA
§
4(
b)(
1)
to
issue
"
standards
for
the
development
of
test
data."

26
TSCA
§
4(
a)(
1)(
A)(
ii)
and
(
iii)
and
§
4(
a)(
1)(
B)(
ii)
and
(
iii),
see
also
the
related
discussion
for
the
proposed
TSCA
§
4
HPV
SIDS
test
rule
at
65
FR
81664
 
81665
and
81667
 
81668.
§
4
rulemaking
procedures
(
per
40
CFR
part
790),
the
voluntary
HPV
Challenge
Program
animal
welfare
principles
in
the
October
14,
1999,
letter
have
had
to
be
adapted
to
the
exigencies
of
testing
via
rule.
The
following
discussion
explains
how
EPA
is
applying
these
principles
in
the
current
TSCA
§
4
HPV
SIDS
test
rule
(
and
intends
to
in
future
TSCA
§
4
HPV
SIDS
test
rules).

In
sum,
EPA
concludes
that
promulgation
of
the
rules
requested
by
the
petition,
even
assuming
they
are
authorized
under
TSCA
§
4,25
would
be
an
unnecessary
and
unproductive
use
of
Agency
resources.
The
Agency
findings
required
under
TSCA
§
4
and
EPA's
commitments
regarding
HPV
rulemaking
help
to
ensure
that
animal
welfare
considerations
are
factored
into
TSCA
§
4
HPV
SIDS
test
rules.
Further,
the
petitioners
will
have
the
opportunity
to
comment
on
any
individual
TSCA
§
4
HPV
SIDS
test
rules
(
and
have
done
so
extensively
on
the
proposed
HPV
test
rule),
and
any
such
rules
will
be
subject
to
judicial
review.
In
addition,
it
should
be
noted
that,
even
if
EPA
were
to
issue
the
requested
rules,
the
Agency
always
has
authority
to
later
modify
those
rules
as
applied
in
subsequent
rulemaking,
so
the
requested
rules
would
not
bind
EPA
in
this
regard.

2.
Maximizing
the
Use
of
Existing
Data
and
Analogue
Data
Several
of
the
voluntary
HPV
Challenge
Program
animal
welfare
principles
involve
the
idea
that
certain
testing
may
be
unnecessary
due
to
the
availability
of
existing
data
on
the
specific
chemical,
or
closely
related
"
analogue"
substances,
often
referred
to
as
categories
or
Structure
Activity
Relationship
(
SAR)
analysis.

In
order
to
promulgate
any
test
rules
under
§
4
of
TSCA,
the
Agency
must
make
certain
findings
stipulated
in
the
statute.
Among
those
findings,
EPA
must
find
that
there
are
"
insufficient
data
and
experience
upon
which
the
effects
of
such
manufacture,
distribution
in
commerce,
processing,
use,
or
disposal
of
such
substance
or
mixture
or
of
any
combination
of
such
activities
on
health
or
the
environment
can
reasonably
be
determined
or
predicted"
and
that
"
testing
of
such
substance
or
mixture
with
respect
to
such
effects
is
necessary
to
develop
such
data."
26
With
respect
to
any
substance
for
which
sufficient
data
already
exist,
EPA
would
be
unable
to
make
these
statutorily
required
findings
for
promulgation
of
a
test
rule.
Therefore,
by
statute,
EPA
will
not
require
unnecessary
testing
in
TSCA
§
4
HPV
SIDS
test
rules
nor
in
any
other
test
rules.
21
27
See,
e.
g.,
Fact
Sheet
on
Animal
Welfare,
EPA
745­
F­
99­
003
(
July
2000),
page
1
at
www.
epa.
gov/
chemrtk/
anfacs2.
pdf
("
Chemicals
for
which
adequate
SIDS
data
already
exist
will
not
be
retested
under
the
HPV
Challenge
Program
or
any
associated
test
rule(
s)
that
are
limited
to
SIDS
testing.")

28
EPA
has
noted
these
conflicting
interpretations
in
several
letters
to
petitioner:
"
We
appreciate
the
time
and
effort
that
PETA
and
PCRM
[
Physicians
Committee
for
Responsible
Medicine]
are
committing
to
the
development
of
comments
on
the
test
plans
submitted
under
the
HPV
Challenge
Program.
EPA
also
spends
considerable
time
and
effort
on
the
review
of
these
test
plans.
In
fact,
on
occasion,
our
reviews
have
identified
similar
issues
associated
with
a
test
plan.
However,
the
primary
goal
of
this
program
is
to
identify
critical
gaps
in
publicly
available
information
and
to
fill
those
gaps,
when
they
exist,
with
appropriate
data,
based
on
the
OECD's
internationally
agreed
upon
SIDS
testing
menu.
While
we
recognize
your
desire
that
this
be
handled
in
every
instance
without
the
use
of
animal
testing,
at
the
present
time,
this
is
not
possible.
Based
on
our
differing
positions
on
this
issue,
it
is
clear
that
coming
to
agreement
on
those
test
plans
that
propose
new
animal
testing
to
fill
these
critical
data
gaps
will
be
very
difficult."
May
31,
2002,
letter
from
William
H.
Sanders
III,
Director
of
EPA's
Office
of
Pollution
EPA
has
indicated
in
the
Federal
Register
notices
describing
the
Voluntary
HPV
Challenge
Program
and
proposed
TSCA
§
4
HPV
SIDS
test
rule
that
these
efforts
are
"
designed
to
make
maximum
use
of
scientifically
adequate
existing
test
data
and
to
avoid
unnecessary,
duplicative
testing,
thereby
avoiding
the
excessive
use
of
animal
testing.
If
at
any
time,
including
after
this
rule
is
finalized,
the
Agency
receives
adequate
existing
data
that
fulfill
a
specific
data
gap,
EPA
will
ensure
that
unnecessary
testing
is
not
conducted."
65
FR
81664,
section
F.,
see
also
65
FR
81690,
section
D.
Further,
EPA
noted
that
for
certain
"
well­
tested
chemicals"
SIDS
level
testing
"
would
not
further
our
understanding
of
the
chemicals'
properties"
and
is
not
warranted.
65
FR
81689.
EPA
does
not
intend
to
promulgate
a
TSCA
§
4
rule
mandating
SIDS
testing
for
such
chemicals.
27
In
addition,
many
of
the
voluntary
HPV
Challenge
Program
animal
welfare
principles
are
intentionally
worded
generally
such
that
it
would
be
difficult
to
promulgate
them
as
enforceable
standards.
These
include
the
principles
that
say
"[
i]
n
analyzing
the
adequacy
of
existing
data,
participants
shall
conduct
a
thoughtful,
qualitative
analysis
rather
than
use
a
rote
checklist
approach,"
"
maximize
the
use
of
existing
and
scientifically
adequate
data,"
or
"
maximize
the
use
of
scientifically
appropriate
categories
of
related
chemicals
and
structure
activity
relationships."
This
is
not
a
defect
in
the
principles;
rather
it
reflects
EPA's
intent
that
they
serve
as
non­
binding,
flexible
guidance
for
promotion
of
animal
welfare
in
the
voluntary
HPV
Challenge
Program,
and
to
the
extent
applicable,
in
TSCA
§
4
HPV
SIDS
test
rules.
In
fact,
the
subjectivity
of
these
generally
worded
voluntary
HPV
Challenge
Program
animal
welfare
principles
and
how
they
apply
to
individual
situations
is
underscored
by
the
numerous
differing
interpretations
that
EPA
and
the
petitioner
apply
to
individual
test
plans
submitted
for
the
voluntary
HPV
Challenge
Program.
28
22
Prevention
and
Toxics,
to
Jessica
Sandler,
PETA's
Federal
Agency
Liaison.
"
As
we
have
stated
before,
the
Agency
is
committed
to
ensuring
that
the
animal
welfare
principles
outlined
in
the
October
14,
1999,
letter
to
HPV
Challenge
participants
are
being
followed
and
that
sincere
efforts
are
made
to
reduce
and
avoid
the
use
of
animal
testing.
As
you
know,
there
have
been
numerous
test
plans
where
we
reached
the
same
conclusion
in
our
comments
after
careful
consideration
and
there
have
been
others
where
we
did
not.
In
all
instances,
however,
the
Agency
has
made
every
effort
to
ensure
that
unnecessary
testing
is
avoided."
January
16,
2004,
letter
from
Charles
Auer,
Director
of
EPA's
Office
of
Pollution
Prevention
and
Toxics,
to
Jessica
Sandler,
PETA's
Federal
Agency
Liaison.
As
stated
elsewhere,
EPA
intends
that
any
TSCA
§
4
HPV
SIDS
test
rules
will
be
consistent
with
the
voluntary
HPV
Challenge
Program
animal
welfare
principles,
to
the
extent
applicable.
For
example,
the
first
proposed
TSCA
§
4
HPV
SIDS
test
rule
(
65
FR
81665
and
81668)
did
not
include
any
chemicals
that
are
Generally
Recognized
as
Safe
(
GRAS)
for
a
particular
use
by
the
Food
and
Drug
Administration
(
FDA).
This
will
allow
additional
time
to
determine
the
adequacy
of
existing
data
for
those
chemicals.
However,
these
GRAS
chemicals
may
be
included
in
a
future
HPV
SIDS
test
rule
where
data
needs
remain.

3.
Terrestrial
and
Dermal
Tests
Consistent
with
the
voluntary
HPV
Challenge
Program
animal
welfare
principles,
no
terrestrial
or
dermal
tests
are
included
in
EPA's
proposed
TSCA
§
4
HPV
SIDS
test
rule.

4.
Reduced
Testing
on
Closed
System
Intermediates
Consistent
with
the
voluntary
HPV
Challenge
Program
animal
welfare
principles,
the
Agency
has
committed
to
a
policy
in
the
Voluntary
HPV
Challenge
Program
and
in
TSCA
§
4
HPV
SIDS
test
rules
that
"
closed
system
intermediates"
(
as
described
by
the
OECD/
SIDS
guidelines)
are
eligible
for
a
reduction
in
testing.
65
FR
81671
and
81695.
Specifically,
the
reduced
testing
consists
of
the
SIDS
battery
minus
the
tests
for
repeated
dose
toxicity
and
reproductive
toxicity
but
including
a
developmental
toxicity
test.
In
the
Federal
Register
notice
for
the
proposed
TSCA
§
4
HPV
SIDS
test
rule,
EPA
requested
commenters
to
identify
chemicals
which
qualify
as
closed
system
intermediates.
Id.

5.
120
Days
between
Posting
Test
Plan
and
Testing
Consistent
with
the
voluntary
HPV
Challenge
Program
animal
welfare
principles,
EPA
is
providing
a
120
day
period
to
comment
on
both
test
plans
in
the
voluntary
HPV
Challenge
23
29
See
65
FR
81669
 
816970,
81684­
81685,
81695
 
81697,
Dec.
26,
2000.
Program,
as
well
as
on
the
TSCA
§
4
HPV
SIDS
proposed
test
rules.
Among
other
things,
this
provides
an
opportunity
to
identify
situations
where
adequate
data
already
exist.
For
the
first
proposed
TSCA
§
4
HPV
SIDS
test
rule
(
65
FR
81658),
EPA
allowed
a
120­
day
comment
period
(
twice
the
usual
60­
day
comment
period)
to
mirror
the
120­
day
public
comment
period
for
the
review
of
test
plans
under
the
voluntary
HPV
Challenge
Program.
The
Agency
intends
that
all
TSCA
§
4
HPV
SIDS
test
rules
will
provide
this
120
day
comment
period
on
the
proposed
rule.
See
65
FR
81690.
EPA's
designation
in
the
proposed
test
rule
of
the
tests
and
test
methods
to
be
required
for
each
chemical
is
equivalent
to
the
"
test
plan"
in
the
voluntary
HPV
Challenge
Program.
The
rulemaking
process
provides
the
public
with
ample
notice
of
chemical
testing
requirements
sufficiently
in
advance
of
the
initiation
of
testing
to
allow
the
public
to
conduct
searches
for
existing
data,
submit
data
to
EPA,
comment
on
testing
requirements
and
methods,
and
prevent
unnecessary
and
duplicative
testing.

6.
Submission
of
Rationales
for
Conducting
Certain
Testing
The
petition
(
p.
4)
notes
that
EPA's
December
26,
2000,
Federal
Register
notice
on
the
voluntary
HPV
Challenge
Program
(
65
FR
81686)
"
expanded
on
several
items"
beyond
the
animal
welfare
principles
articulated
in
EPA's
October
14,
1999,
letter
to
voluntary
HPV
Challenge
Program
participants.
These
provisions,
extracted
from
the
December
26,
2000,
Federal
Register
notice
on
the
voluntary
HPV
Challenge
Program,
pertain
to
EPA
encouraging
Challenge
sponsors
to
submit
justifications
if
they
propose
to
pursue
certain
testing.
As
discussed
in
EPA's
Federal
Register
notices
associated
with
the
voluntary
HPV
Challenge
Program
and
proposed
TSCA
§
4
HPV
SIDS
test
rule29,
and
as
noted
by
petitioner
in
its
petition
(
p.
4),
EPA
has
taken
specific
actions
to
promote
alternative
testing
approaches
specifically
for
animal
welfare
purposes.
For
testing
conducted
pursuant
to
the
proposed
TSCA
§
4
HPV
SIDS
test
rule,
EPA
encourages
use
of
the
in
vitro
Mammalian
Chromosome
Aberration
Test
method
(
40
CFR
799.9537,
OECD
473)
and
requires
companies
to
submit
justifications
in
their
final
study
reports
if
they
elect
to
use
the
in
vivo
method.
Similarly,
EPA
is
encouraging
use
of
the
Combined
Repeated
Dose
Toxicity
Study
with
the
Reproduction/
Developmental
Toxicity
Screening
Test
(
40
CFR
799.9365,
OECD
422),
and
proposed
to
require
test
sponsors
to
submit
a
rationale
in
their
final
study
reports
if
they
use
both
the
Reproduction/
Developmental
Toxicity
Screening
Test
(
40
CFR
799.9355,
OECD
421)
and
the
Repeated
Dose
28­
day
Oral
Toxicity
Study
(
40
CFR
799.9305,
OECD
407)
instead
of
the
combined
study.

Also,
EPA
is
discouraging
the
conduct
of
acute
aquatic
toxicity
testing
of
HPV
chemicals
with
a
high
log
K
ow
(
4.2
or
greater).
Chemical
substances
that
are
dispersible
in
water
(
e.
g.,
surfactants,
detergents,
aliphatic
amines,
and
cationic
dyes)
may
have
log
K
OW
values
greater
than
4.2
and
may
still
be
acutely
toxic
to
aquatic
organisms.
To
deal
with
such
chemicals,
EPA
recommended
in
the
proposed
HPV
test
rule
that
Challenge
sponsors
who
wish
to
conduct
acute
24
toxicity
studies
on
chemicals
with
a
log
K
OW
greater
than
or
equal
to
4.2
submit
to
EPA
for
approval
a
written
request
to
conduct
such
studies
90
days
prior
to
conducting
such
studies.
EPA
solicited
public
comment
on
this
approach
as
well
as
other
alternative
approaches
in
this
area,
but
did
not
receive
comments
(
including
from
petitioner).
See
65
FR
81670.

E.
Non­
HPV
Testing
Requirements
1.
General
EPA
issues
mandatory
chemical
testing
requirements
under
several
different
authorities.
These
testing
authorities
include
§
4
test
rules
(
15
U.
S.
C.
§
2603,
40
CFR
Parts
790
­
799),
§
4
Enforceable
Consent
Agreements
(
15
U.
S.
C.
§
2603,
40
CFR
Parts
790
­
799),
and
§
5(
e)
Consent
Orders
(
15
U.
S.
C.
§
2604(
e)).
In
the
following
discussion,
these
regulatory
testing
requirements
will
often
be
referred
to
generically
as
"
TSCA
testing
requirements"
or
"
mandatory
TSCA
testing."

As
noted
above,
EPA
believes
that
financial
cost
savings
will
motivate
compliance
with
the
voluntary
HPV
Challenge
Program
animal
welfare
principles,
such
as
avoidance
of
new
testing,
even
absent
any
legal
mandate
to
do
so.
While
EPA
is
committed
to
promoting
animal
welfare,
EPA
does
not
believe
the
voluntary
HPV
Challenge
Program
animal
welfare
principles,
as
a
whole,
would
be
appropriate
as
a
mandatory
rule
that
would
apply
to
all
TSCA
testing
requirements.
As
noted,
these
animal
welfare
principles
were
developed
in
the
specific
context
of
the
voluntary
HPV
Challenge
program
involving
OECD's
Screening
Information
Data
Set
(
SIDS).
The
principles
are
tailored
specifically
for
SIDS
screening
level
testing,
and
may
not
be
appropriate
for
other
kinds
of
testing
EPA
might
require
under
TSCA.

2.
Maximizing
the
Use
of
Existing
Data
and
Analogue
Data
Several
of
the
voluntary
HPV
Challenge
Program
animal
welfare
principles
involve
the
idea
that
certain
testing
may
be
unnecessary
due
to
the
availability
of
existing
data
on
the
specific
chemical,
or
closely
related
"
analogue"
substances,
often
referred
to
as
categories
or
Structure
Activity
Relationship
(
SAR)
analysis.
EPA
already
avoids
unnecessary
testing
where
adequate
data
already
exist
by
simply
not
requiring
those
tests.

As
discussed
above
in
section
IV.
E.
2.,
EPA
lacks
legal
authority
to
require
testing
under
TSCA
§
4
where
sufficient
data
already
exist.
This
is
also
true
for
the
ability
to
issue
orders
under
§
5(
e).
Thus,
where
EPA
determines
that
existing
data
is
sufficient,
EPA
will
ensure
that
unnecessary
testing
is
not
required.
EPA
will
consider
whether
existing
data
suffices
to
obviate
25
30
For
example,
EPA
is
now
in
the
process
of
taking
a
direct
final
action
to
amend
the
final
TSCA
§
4
test
rule,
In
Vitro
Dermal
Absorption
Rate
Testing
of
Certain
Chemicals
of
Interest
to
the
Occupational
Safety
and
Health
Administration
(
69
FR
22402,
April
26,
2004),
by
removing
the
requirements
that
testing
be
conducted
to
determine
permeability
constants
(
Kp)
for
methyl
isoamyl
ketone
(
CAS
No.
110­
12­
3)
and
dipropylene
glycol
methyl
ether
(
CAS
No.
34590­
94­
8).
EPA
is
basing
its
decision
to
revoke
these
testing
requirements
on
information
it
received
after
publication
of
the
final
rule.
EPA
has
determined
that
these
existing
data
satisfy
the
testing
needs
identified
in
the
test
rule
so
that
conducting
these
test
is
no
longer
necessary.

31
For
example,
EPA
revoked
a
number
of
§
5(
e)
Consent
Orders
on
acrylates
and
methacrylates
based
on
2­
year
cancer
bioassays
on
a
few
representative
chemicals
conducted
under
an
agreement
between
the
Agency
and
the
Specialty
Acrylates
and
Methacrylates
(
SAM)
Panel
of
the
Chemical
Manufacturers
Association
(
CMA,
now
the
American
Chemistry
Council
or
ACC).
Based
on
currently
available
information,
EPA
no
longer
considers
such
testing
necessary
on
new
chemical
acrylates
or
methacrylates
as
a
category
based
on
health
concerns.
See
the
need
for
new
testing
at
any
time,
even
after
a
TSCA
testing
requirement
is
finalized.
30
See,
e.
g.,
65
FR
81658,
81664,
Dec.
26,
2000.

Again,
as
noted
in
section
IV.
E.
2.
above,
many
of
the
voluntary
HPV
Challenge
Program
animal
welfare
principles
are
worded
generally
and
are
not
well
suited
to
an
enforceable
standard.
These
include
the
principles
that
say
"[
i]
n
analyzing
the
adequacy
of
existing
data,
participants
shall
conduct
a
thoughtful,
qualitative
analysis
rather
than
use
a
rote
checklist
approach,"
"
maximize
the
use
of
existing
and
scientifically
adequate
data,"
or
"
maximize
the
use
of
scientifically
appropriate
categories
of
related
chemicals
and
structure
activity
relationships."

The
test
rule
regulations
at
40
CFR
Part
790
already
contain
provisions
in
subpart
E
(
§
790.80
et.
seq.)
for
exemptions
from
§
4
test
rules
based
on
the
equivalence
between
a
chemical
for
which
exemption
is
sought
and
a
chemical
for
which
test
data
have
been
or
are
being
submitted
in
accordance
with
a
test
rule.
"
Equivalent
means
that
a
chemical
substance
or
mixture
is
able
to
represent
or
substitute
for
another
in
test
or
series
of
tests,
and
that
the
data
from
one
substance
can
be
used
to
make
scientific
and
regulatory
decisions
concerning
the
other
substance."
§
790.3.

Please
note
that
in
the
TSCA
§
5
New
Chemicals
Program,
analogue
data
already
figure
prominently
and
have
done
so
for
many
years.
EPA's
hazard
assessments
for
new
chemicals
are
often
based
on
analogue
data.
(
See
Chemical
Categories
Report
at
www.
epa.
gov/
oppt/
newchems/
chemcat.
htm
and
references
for
use
of
SAR.)
Further,
for
§
5(
e)
Consent
Orders
that
require
testing
on
a
new
chemical
substance,
if
the
Agency
is
presented
with
suitable
surrogate/
analogue
data,
EPA
can
and
would
consider
the
alternate
data
and
modify
or
revoke
the
Consent
Order
requirements
as
appropriate
based
on
the
newly
presented
data.
31
26
www.
epa.
gov/
oppt/
newchems/
cat02.
htm#
Acrylates/
Methacrylates.
Since
§
5(
e)
orders
are
authorized
where
"
the
information
available
to
the
Administrator
is
insufficient
to
permit
a
reasoned
evaluation
of
the
health
and
environmental
effects
of
a
chemical
substance",
the
Agency
is
precluded
from
imposing
an
order
where
adequate
data
exist,
including
analogue
data.

3.
Terrestrial
and
Dermal
Tests
Some
of
the
voluntary
HPV
Challenge
Program
animal
welfare
principles
state
that
certain
types
of
tests
should
be
avoided,
specifically
terrestrial
toxicity
testing
and
dermal
toxicity
testing.
While
EPA
has
dealt
with
this
issue
in
the
context
of
the
voluntary
HPV
Challenge
Program
and
TSCA
§
4
HPV
SIDS
test
rules
(
see
65
FR
81658,
81666,
Dec.
26,
2000),
the
Agency
cannot
rule
out
the
possibility
that
such
testing
might
be
necessary
in
other
circumstances.
Nor
does
the
statute
restrict
the
type
of
health
or
environmental
effects
testing
which
may
be
relevant
to
a
determination
as
to
whether
a
chemical
substance
may
present
an
unreasonable
risk
(
see
TSCA
§
4(
b)(
2)(
A)).

4.
Reduced
Testing
on
Closed
System
Intermediates
Voluntary
HPV
Challenge
Program
participants
were
asked
not
to
develop
repeated
dose
and
reproductive
toxicity
testing
for
closed
system
intermediates.
The
meaning
of
"
closed
system
intermediates"
in
the
voluntary
HPV
Challenge
Program
is
the
same
as
the
OECD
SIDS
description.
According
to
this
description,
a
closed
system
intermediate
is
removed
from
the
manufacturing
equipment
and
may
even
be
transported
to
other
facilities.
Recognizing
that
a
closed
system
intermediate
does
have
potential
for
exposure,
the
voluntary
HPV
Challenge
Program
does
not
completely
exempt
them,
but
rather
includes
certain
animal
testing
for
closed
system
intermediates,
such
as
acute
toxicity
and
genetic
toxicity.
For
the
same
reason
(
i.
e.,
potential
exposures),
EPA
does
not
agree
that
repeated
dose
and
reproductive
toxicity
testing
for
closed
system
intermediates
would
never
be
appropriate
under
TSCA.

5.
120
Days
between
Posting
Test
Plan
and
Testing
Voluntary
HPV
Challenge
Program
animal
welfare
principle
number
9
says:
"
Companies
27
32
As
discussed
in
section
II.
D.
1.
above,
this
principle
is
listed
as
number
9
in
the
petition,
although
it
was
number
10
in
the
Agency's
October
14,
1999,
letter
to
voluntary
HPV
Challenge
Program
participants.
will
allow
120
days
between
the
posting
of
test
plans
and
the
implementation
of
any
testing."
32
While
EPA
has
committed
to
providing
a
120
day
comment
period
on
proposed
TSCA
§
4
HPV
SIDS
test
rules,
EPA
is
not
willing
to
require
a
120
day
comment
period
for
all
TSCA
testing
requirements.
Neither
TSCA
nor
the
Administrative
Procedure
Act
(
5
U.
S.
C.
§
551
et.
seq.)
specify
the
duration
of
a
minimum
period
for
comment.
EPA's
standard
comment
period
for
non­
HPV
proposed
§
4
test
rules
has
been
60
days,
although
there
are
case­
specific
examples
where
EPA
granted
extensions
or
adopted
different
comment
periods
to
meet
the
needs
of
the
situation.
EPA
does
not
see
the
value
and
is
unwilling
to
commit
to
a
120­
day
comment
period
across
the
board
for
all
future
non­
HPV
test
rules.
Mandating
additional
time
for
the
public
to
comment
on
proposed
test
plans
could
unnecessarily
prolong
an
already
lengthy
rulemaking
process
and
delay
moving
forward
to
protect
against
unreasonable
risks
to
human
health
and
the
environment.
Moreover,
timing
may
be
urgent
or
different
in
certain
cases.
Thus,
the
Agency
needs
to
retain
case­
specific
flexibility
for
future
non­
HPV
testing
requirements.

6.
Submission
of
Rationales
for
Conducting
Certain
Testing
The
petition
(
p.
4)
notes
that
EPA's
December
26,
2000,
Federal
Register
notice
on
the
voluntary
HPV
Challenge
Program
(
65
FR
81686)
"
expanded
on
several
items"
beyond
the
animal
welfare
principles
articulated
in
EPA's
October
14,
1999,
letter
to
voluntary
HPV
Challenge
Program
participants.
These
provisions,
extracted
from
the
December
26,
2000,
Federal
Register
notice
on
the
voluntary
HPV
Challenge
Program,
pertain
to
EPA
encouraging
Challenge
sponsors
to
submit
justifications
if
they
propose
to
pursue
certain
testing.
Again,
these
tests
include
in
vivo
genotoxicity
testing;
separate
Reproduction/
Developmental
Toxicity
Screening
Test
(
40
CFR
799.9355,
OECD
421)
and
Repeated
Dose
28­
day
Oral
Toxicity
Study
(
40
CFR
799.9305,
OECD
407)
instead
of
the
Combined
Repeated
Dose
Toxicity
Study
with
the
Reproduction/
Developmental
Toxicity
Screening
Test
(
40
CFR
799.9365,
OECD
422);
and
acute
aquatic
toxicity
testing
of
HPV
chemicals
with
a
log
K
ow
of
4.2
or
greater.

Section
IV.
E.
6.
above
explains
how
the
proposed
TSCA
§
4
HPV
SIDS
test
rule
will
address
these
situations
by
requiring
persons
who
conduct
these
tests
to
submit
such
rationales
in
their
final
study
reports.
However,
in
some
future
non­
HPV
test
rules
that
go
beyond
basic
SIDS
testing,
EPA
may
deem
it
necessary
and
appropriate
to
require
those
tests
that
are
associated
with
submission
of
justifications
under
the
voluntary
HPV
Challenge
Program
and
TSCA
§
4
HPV
SIDS
test
rule.
EPA,
therefore,
does
not
consider
it
appropriate
to
promulgate
a
rule
that
would
limit
agency
discretion
in
this
regard.
28
IV.
Conclusion
While
EPA
is
committed
to
reducing,
refining
and
replacing
animal
testing,
for
the
aforementioned
reasons,
EPA
continues
to
believe
that
the
most
reasonable,
balanced
and
appropriate
way
to
communicate
and
realize
implementation
of
the
objectives
of
the
voluntary
HPV
Challenge
Program
animal
welfare
principles
is
as
guidance,
rather
than
as
mandatory
requirements.
Therefore,
the
petition
is
denied.
ATTACHMENT
II
Selected
Rebuttals
of
Petitioner's
Criticisms
of
EPA's
Comments
on
HPV
Test
Plans
Petition
Page:
8
Chemical:
2­
hydroxy­
4­
n­
octoxybenzophenone
(
CAS
No.
1843­
05­
6)

Petition
Criticism:
"
Cytec
Industries
and
Ciba's
test
plan
for
`
2­
hydroxy­
4­
noctoxybenzophenone
was
posted
in
November
2001.
It
proposed
no
further
testing.
EPA,
however,
requested
that
a
reproductive/
developmental
toxicity
test
be
conducted,
even
though
the
company
had
submitted
data
for
a
study
that
evaluated
reproductive
and
developmental
toxicity
over
four
generations
of
animals
at
a
high
dose
level
that
should
have
been
adequate
to
meet
HPV
screening
requirements.
Even
though
this
test
was
not
considered
GLP,
the
HPV
Program
does
not
require
GLP,
and
the
vast
majority
of
published
data
are
not
GLP.
EPA's
request
ignored
`
existing
and
scientifically
adequate
data'
and
exemplified
check­
the­
box
testing
rather
than
a
thoughtful
approach
to
toxicology."

EPA
Rebuttal:
The
reason
EPA
considered
the
existing
data
inadequate
was
related
not
to
GLP,
but
rather
to
study
design.
EPA
recommended
an
OECD
TG
421
study
because
the
sponsor's
4­
generation
study
was
conducted
at
only
one
dose
level
that
showed
no
toxicity
and
was
about
one­
third
of
the
normal
recommended
limit
dose
(
a
limit
dose
is
a
high
dose,
usually
1000
mg/
kg
body
weight/
day,
suggested
in
OECD
guidelines
that
can
be
used
as
a
single
dose;
if
the
study
using
a
limit
dose
shows
no
observable
toxic
effects,
then
a
full
study
using
several
doses
may
not
be
necessary).
No
explanation
was
given
as
to
why
only
one
dose
at
this
level
was
chosen
for
the
study.
To
obtain
screening­
level
data,
the
study
should
be
conducted
using
a
limit
dose,
showing
no
toxicity,
or
at
multiple
dose
levels
with
the
highest
dose
resulting
in
toxicity.

Petition
Page:
8
Chemical:
Propylene
Streams
Category
Petition
Criticism:
"
ACC's
November
2001
test
plan
for
the
`
propylene
streams'
category
proposed
additional
testing
for
developmental
toxicity
and
in
vivo
genetic
toxicity
for
propylene.
In
its
public
comments,
the
animal
protection
community
pointed
out
the
fact
that
these
compounds
are
well­
characterized
and
have
clearly
documented
toxicological
mechanisms,
the
most
important
of
which
is
the
fact
that
these
compounds
are
rapidly
expelled
from
the
body.
Despite
the
abundant
existing
information
on
their
toxicity
and
metabolism
 
 
including
extensive
animal
testing
 
 
EPA
did
not
raise
any
concerns
about
the
irrelevance
of
further
testing
of
these
2
compounds.
This
well­
known
information
was
corroborated
by
the
results
of
the
redundant
testing
that
was
conducted
on
these
compounds.
Because
EPA
did
not
object
to
ACC's
use
of
the
separate
developmental
toxicity
testing
and
in
vivo
genetic
toxicity
testing,
at
least
1,380
animals
were
killed
to
again
demonstrate
that
a
non­
toxic
substance
was,
in
fact,
non­
toxic.
Both
the
Sponsor
and
EPA
flagrantly
violated
the
animal
welfare
guidelines."

EPA
Rebuttal:
EPA
commented
as
follows:
"
The
submitter
indicates
that
the
data
for
HPV
purposes
are,
or
will
become,
available
from
other
testing
programs
for
the
acute,
genetic,
repeated
dose,
reproductive,
and
developmental
toxicity
end
points
of
propylene
and
propane.
The
submitter
states
that
it
will
provide
a
technical
narrative
that
evaluates
the
data
from
these
other
programs
that
are
applicable
to
the
propylene
streams
category...
EPA
will
evaluate
both
the
propylene
and
propane
data
after
the
propylene
test
plan
has
been
submitted.
The
ultimate
acceptability
of
the
present
category
test
plan
depends
on
the
acceptability
of
the
referenced
test
plan."
Thus,
EPA
withheld
judgment
on
this
category
and
petitioner's
characterization
of
EPA's
comments
is
inaccurate.

Petition
Page:
9
Chemical:
Tricresyl
Phosphate
(
CAS
No.
1330­
78­
5)

Original
EPA
Comments:
"
Developmental
Toxicity.
The
submitter
acknowledged
a
lack
of
developmental
toxicity
data
and
noted
that
testing
is
needed
for
this
endpoint.
EPA
strongly
recommends
that
the
submitter
conduct
a
developmental
toxicity
study
according
to
OECD
Guideline
414
because
adverse
effects
on
testes
were
observed
in
the
reproduction
studies
and
there
is
a
concern
for
potential
effects
on
the
developing
fetus."

Petition
Criticism:
"
In
November
2001,
Great
Lakes
Chemical
Corporation
(
GLCC)
submitted
a
test
plan
for
`
phosphoric
acid
tris
(
methylphenyl)
ester
(
tricresyl
phosphate),'
which
called
for
a
developmental
toxicity
study.
The
test
plan
was
extremely
sloppy
and
lacked
the
necessary
information
on
basic
physiochemical
properties.
The
animal
protection
community
asked
that
EPA
fulfill
its
role
in
proactively
addressing
the
submission
of
such
inadequate
plans
under
the
HPV
Program.
Nevertheless,
EPA
approved
the
testing.
In
violation
of
the
guidance
to
minimize
the
number
of
animals
used,
EPA
"
strongly"
recommended
that
an
OECD
414
(
1,300
animals)
be
conducted
on
this
reproductive
toxicant
rather
than
(
1)
requesting
that
the
combined
reproductive/
developmental
toxicity
test,
which
uses
half
the
number
of
animals
be
used,
and/
or
(
2)
recognizing
that
existing
data
show
that
this
substance
apparently
interferes
with
reproduction.
EPA
also
asked
for
fish
toxicity
testing
and
the
sponsor
complied
with
both
demands.
Despite
repeated
requests
by
the
animal
protection
community
spanning
several
years
for
an
explanation
of
EPA's
demand
that
an
OECD
414
be
conducted,
EPA
has
never
provided
a
response."

EPA
Rebuttal:
Multiple
significant
effects
on
both
male
and
female
reproductive
organs
in
a
3
majority
(
or
all)
of
the
animals
tested
at
certain
doses
were
observed
in
repeated­
dose
or
reproductive
studies.
Pup
viability
and
litter
size
were
also
affected
after
TCP
exposure.
Because
of
the
severity,
high
incidence,
and
nature
of
these
effects,
EPA
believed
it
important
to
conduct
a
complete
developmental
study
(
OECD
TG
414)
for
this
compound
to
determine
whether
developmental
effects
might
also
be
observed.

Petition
Page:
9
Chemical:
Fatty
Nitrogen
Derived
Cationics
Category
Petition
Criticism:
"
In
January
2002,
ACC's
test
plan
was
posted
for
`
fatty
nitrogen­
derived
cationics,'
which
did
not
call
for
any
additional
animal
testing.
In
yet
another
example
of
checkthe
box
toxicology,
EPA
called
for
a
reproductive/
developmental
toxicity
test
without
apparently
considering
the
results
of
two
multigenerational
reproduction
studies
that
were
referenced
in
the
test
plan,
and
which
demonstrated
no
adverse
reproductive
effects.
Further,
the
Sponsor
provided
developmental
toxicity
data
for
nine
of
the
13
chemicals
in
this
category,
none
of
which
showed
evidence
of
adverse
developmental
effects."

EPA
Rebuttal
:
Although
petitioner
states
that
data
were
available
from
two
multigeneration
studies,
these
data
were
submitted
for
two
analogs
and
not
for
the
category
members.
One
of
the
multigeneration
studies
could
not
be
considered
at
all
because
the
analog
was
not
appropriate
to
represent
the
category
members.
Also,
histopathology
data
on
reproductive
organs
from
subchronic
studies
were
available
for
only
two
category
members.
Therefore,
EPA
recommended
conducting
a
reproduction/
developmental
screening
test
(
OECD
Guideline
421)
on
one
of
the
chemicals
(
CAS
No.
68607­
29­
4)
to
represent
the
monoalkyl
category
members.
In
a
category
of
thirteen
substances,
it
is
important
to
have
adequate
data
to
address
adequately
the
basic
screening
level
endpoints
for
the
entire
category.

Petition
Page:
12
Chemical:
(
alkyl
diphenyl
oxide
disulfonates)
(
ADPODS)
category
Petition
Criticism:
"
the
test
plan
called
for
two
repeated­
dose/
reproductive/
developmental
toxicity
tests
on
two
chemicals
that
were
not
part
of
the
HPV
Program."

"
EPA
agreed
with
the
test
plan
even
though
the
robust
summaries
contained
no
fewer
that[
n]
11
chronic
and
subchronic
studies
that
examined
reproductive
organs,
as
well
as
a
developmental
study"

EPA
Rebuttal:
It
is
appropriate
and
encouraged
to
include
non­
HPV
chemicals
to
strengthen
the
basis
for
the
category.
For
a
category,
data
are
needed
for
enough
members
to
show
a
trend
or
4
pattern,
or
an
absence
of
effects.
To
address
the
developmental
toxicity
for
the
category,
only
one
test,
of
limited
value,
was
submitted
on
a
chemical
at
one
end
of
the
category
range.
Thus,
the
data
were
too
limited
to
adequately
address
the
endpoint
for
the
category,
and
more
data
were
needed
to
characterize
the
category.

Subchronic
study
data
on
reproductive
organs
in
the
absence
of
adequate
developmental
toxicity
data
are
not
sufficient
to
address
the
reproductive
endpoint.
EPA,
therefore,
recommended
a
combined
reproductive/
developmental
toxicity
screening
test
(
OECD
TG
421)
which
uses
fewer
animals
than
the
submitter­
proposed
combined
repeated­
dose/
reproductive/
developmental
toxicity
screening
test
(
OECD
TG
422).

Petition
Page:
14
Chemical:
Lubricating
Oil
Basestocks
Category
Petition
Criticism:
"
In
April
2003,
EPA
posted
API's
test
plan
for
the
`
lubricating
oil
basestocks
category,'
which
proposed
a
repeated­
dose,
reproductive,
and
developmental
toxicity
test
and
a
reproductive/
developmental
toxicity
test.
API's
proposal
failed
to
provide
any
chemical
analyses
or
characterizations
of
these
materials,
including
basic
compositional
information.
It
also
ignored
existing
data
on
the
toxicology
and
hazards
of
petroleum
fractions,
which
constitute
the
toxic
components
of
this
category,
and
failed
to
group
these
substances
with
similar
substances
such
as
API's
own
waxes
and
related
substances
category.
Rather
than
request
a
more
thorough
and
thoughtful
analysis,
EPA
requested
that
several
additional
tests
be
conducted."

EPA
Rebuttal:
The
test
plan
is
on
36
complex
petroleum
streams,
each
containing
up
to
hundreds
of
components.
The
sponsor
characterized
them
in
terms
of
molecular
weight
ranges,
physicochemical
characteristics
and
predominating
structural
components,
such
as
naphthenic
and
paraffinic,
and
broke
them
down
into
three
subcategories
based
on
degree
of
processing.
The
petroleum
fractions
mentioned
by
petitioner
may
contribute
to
but
do
not
account
for
or
characterize
the
composition
of
these
streams.
The
thoughtful
strategy
behind
the
sponsor's
test
plan
was
to
test
the
hypothesis
that
the
comparative
toxicity
and
environmental
behavior
of
these
streams
is
based
on
the
degree
to
which
the
streams
have
been
processed
to
remove
impurities,
as
well
as
their
bioavailability
as
a
function
of
molecular
weight.
The
sponsor
proposed
testing
representative
streams
within
each
subcategory
to
test
this
hypothesis,
and
EPA
agreed,
pointing
out
where
certain
tests
appeared
to
be
inadequate
or
where
members
selected
for
testing
were
not
representative
of
the
subcategory.
It
was
understood
that
a
good
representative
data
set
for
each
of
the
subcategories
would
preclude
the
need
for
testing
other
members
of
this
very
large
category.

For
health
effects,
EPA
agreed
with
the
sponsor's
proposal
for
reproductive
or
developmental
toxicity
testing
of
representative
members
of
two
subcategories
where
no
data
existed
but
5
recommended
the
oral
route
rather
than
the
sponsor's
proposed
dermal
route.
EPA
also
proposed
in
vitro
but
not
in
vivo
genotoxicity
tests
for
representative
streams
because
of
inadequacies
in
the
test
data
submitted.
EPA
also
recommended
a
combined
repeated
dose
and
reproductive
&
developmental
toxicity
screen
for
a
representative
member
of
one
of
the
subcategories
because
of
inadequacies
in
the
test
data
submitted,
but
offered
the
submitter
the
option
of
providing
additional
information
on
the
submitted
studies
to
render
them
adequate
for
the
purposes
of
the
HPV
Challenge
Program.

EPA
made
similar
comments
on
other
parts
of
the
test
plan,
encouraging
the
sponsor
to
provide
further
study
details
or
use
data
from
other
studies
to
meet
HPV
testing
needs.
For
example,
for
ecological
effects,
EPA
requested
the
submission
of
robust
summaries
or
additional
study
details
as
an
alternative
to
further
testing
wherever
submitted
data
on
the
ecotox
endpoints
appeared
to
be
inadequate
for
a
representative
of
each
of
the
subcategories.

Thus,
the
sponsor
provided
a
thoughtful
approach
and
EPA
responded
with
a
thoughtful,
testminimizing
analysis
of
the
test
plan.

Petition
Page:
18
Chemical:
2­
vinylpyridine
(
CAS
No.
100­
69­
6)

Petition
Criticism:
"
The
animal
protection
community
objected
strenuously
to
this
plan
as,
according
to
the
Sponsor,
the
substance
is
"
corrosive
to
tissues,
flammable,
and
acutely
toxic
by
the
oral
and
dermal
routes."
Its
comments
included
the
fact
that
"
chemicals
that
are
classified
as
irritating
will
not
likely
cause
systemic
toxicity
at
doses
which
do
not
also
cause
significant
local
gastrointestinal
effects.
All
three
cited
repeated­
dose
studies
shared
this
principle."

EPA
Rebuttal:
The
voluntary
HPV
Challenge
Program
seeks
to
provide
a
reasonable
set
of
screening
information
on
the
HPV
chemicals.
The
Agency
considers
on
a
case­
by­
case
basis
all
data
provided
in
a
submission.
Every
effort
is
made
to
use
all
existing
information
in
a
weight­
ofevidence
approach
to
avoid
excessive
testing
recommendations,
especially
for
endpoints
such
as
acute
toxicity.
The
Agency
is,
however,
very
concerned
with
filling
major
data
gaps
in
the
reproductive
and
developmental
area,
especially
when
there
are
data
indicating
a
basis
for
such
concern.
6
Concerns
regarding
testing
of
corrosive
chemicals
are
generally
associated
with
severity
of
the
tissue
response
which
either
restricts
further
dosing,
reduces
the
animal
viability,
or
restricts
feeding.
A
chemical
with
potential
to
be
corrosive
or
reactive
is
reviewed
from
the
perspective
of
concern
for
potential
for
low
doses
to
be
associated
with
reproductive
or
developmental
toxicity
versus
the
practicality
of
conducting
longer
term
studies.
When
there
is
evidence
that
longer
term
testing
is
both
practical
and
needed,
such
as
in
this
case,
where
a
90­
day
repeated­
dose
study
had
been
done
using
a
corn
oil
vehicle,
EPA
recommends
further
testing
 
in
this
case
the
combined
repro/
developmental
study
to
fill
data
gaps
for
reproductive
and
developmental
toxicity
 
because
it
will
provide
data
for
the
endpoints
at
minimal
loss
of
animal
life.

While
reactive
as
a
monomer,
2­
vinylpyridine
exhibits
systemic
toxicity
(
changes
in
organ
weights
including
testes,
alterations
in
hematological
parameters...)
that
does
not
follow
the
pattern
of
classic
acids
or
bases
that
are
generally
the
focus
of
concern
for
corrosivity.

Petition
Page:
19
Chemical:
Benzenemethanethiol
(
benzyl
mercaptan;
CAS
No.
100­
53­
8)

Petition
Criticism:
"
The
Sponsor
proposed
using
existing
data
on
a
more
acutely
toxic
analogue
that
also
causes
reproductive
and
developmental
effects
in
animals
in
order
to
avoid
conducting
a
new
reproductive/
developmental
toxicity
test
on
this
substance.
Despite
this
conservative
and
more
protective
approach,
EPA
rejected
the
use
of
the
analogue
and
stated
that
a
repeateddose
reproductive/
developmental
toxicity
test
should
be
conducted
(
which
uses
675
animals
rather
than
the
proposed
test
that
would
have
used
40
animals).
In
its
comments,
posted
almost
eight
months
after
the
close
of
the
public
comment
period,
EPA
ignored
the
animal
welfare
ramifications
as
well
as
thoughtful
toxicology."

EPA
Rebuttal:
In
its
posted
comments,
EPA
stated
that
"
For
human
health,
EPA
does
not
consider
phenyl
mercaptan
(
thiophenol)
appropriate
for
use
as
an
analogue
for
benzyl
mercaptan.
The
metabolic
profiles
of
these
chemicals
are
expected
to
be
very
different.
Phenyl
mercaptan
is
expected
to
be
metabolized
like
a
typical
aromatic
substrate
while
metabolism
of
benzyl
mercaptan
is
likely
to
focus
on
the
methanethiol
group."
EPA
has
stated
from
the
outset
of
the
program
that
the
use
of
analogue
data
is
acceptable
where
it
is
scientifically
justified.
The
proposed
analog
belongs
to
a
different
chemical
class
than
the
sponsored
substance
and
their
structural
resemblance
is
extremely
superficial.
To
consider
these
substances
analogous
would
violate
fundamental
chemistry
and
biochemistry
principles
and
would
not
reflect
"
thoughtful
toxicology."
Therefore,
the
proposed
analog
may,
in
fact,
not
represent
a
conservative
position
and
relevant
data
are
needed.
ATTACHMENT
III
Additional
Examples
of
EPA
Comments
on
HPV
Test
Plans
that
Promote
the
Voluntary
HPV
Challenge
Program
Animal
Welfare
Principles
Acute
testing;
In
vivo
genetic
toxicity
testing
Chemical:
Isopropylated
Triphenyl
Phosphate
Summary:
EPA
recommended
use
of
available
data
as
alternative
to
conducting
oral
acute
study.

EPA
Comments:
"
Except
for
the
dermal
study,
all
the
acute
toxicity
studies
are
inadequate.
However,
EPA
believes
that
the
submitter
may
be
able
to
enhance
the
data
on
the
acute
oral
toxicity
endpoint
by
utilizing
the
dosing
data
from
the
28­
day
repeat­
dose
study
to
estimate
an
acceptable
LD50."

Chemical:
2,3­
Dihydro­
2,2­
dimethyl­
7­
benzofuranol
Summary:
The
sponsor
proposed
to
conduct
an
acute
dermal
toxicity
study,
an
in
vivo
genotoxicity
study
and
a
combined
repeat
dose/
reproductive/
developmental
toxicity
study.
EPA
discouraged
the
acute
dermal
and
in
vivo
tests.

EPA
Comments:
"
Acute
Toxicity.
Acute
dermal
testing
is
not
an
element
of
the
Challenge
program.
Although
the
acute
inhalation
toxicity
study
is
considered
inadequate,
the
existence
of
an
adequate
acute
oral
toxicity
study
is
sufficient
for
this
endpoint
for
the
purposes
of
the
U.
S.
HPV
Challenge
Program.
Genotoxicity.
EPA
encourages
conducting
an
in
vitro
genotoxicity
study
rather
than
an
in
vivo
study
unless
the
properties
of
the
chemical
indicate
otherwise."

Chemical:
Metal
Carboxylates
Category
Summary:
EPA
discouraged
a
proposed
in
vivo
mutagenicity
testing
not
part
of
Challenge
Program.

EPA
Comments:
"
The
test
plan
indicates
that
chromosomal
aberration
testing
is
planned
for
cobalt
neodecanoate;
Table
I
implies
that
this
will
be
an
in
vivo
test,
which
is
beyond
the
scope
of
the
U.
S.
HPV
Challenge
Program.
The
plan
included
no
rationale
for
conducting
an
in
vivo
study;
the
nature
of
the
planned
testing
needs
clarification."

Chemical:
Isocyanic
acid,
m­
phenylenediiso­
propylidene
Summary:
EPA
discouraged
unnecessary
testing
because
adequate
data
already
exist.

EPA
Comments:
"
Adequate
data
are
available
for
acute
toxicity,
repeated­
dose
toxicity,
and
gene
mutation.
The
submitter
plans
to
conduct
tests
for
chromosomal
aberrations
and
developmental
toxicity
but
did
not
specify
protocols.
EPA
recommends
the
OECD
473
(
in
vitro
cytogenetic
2
assay)
and
421
(
combined
reproductive/
developmental
toxicity)
Guidelines."

Combined
Repeated
Dose
Reproductive­
Developmental
Toxicity
Testing
Chemical:
Diphenyl
Spiropentylphosphite
Summary:
EPA
recommended
combined
repeated
dose
reproductive­
developmental
toxicity
test
(
OECD
422)
instead
of
separate
studies.

EPA
Comments:
"
Proposed
health
endpoint
testing:
Developmental
toxicity.
The
proposal
includes
conducting
a
combined
repeat
dose/
reproductive/
developmental
toxicity
screening
test
(
OECD
Test
Guideline
422)
in
addition
to
a
pre­
natal
developmental
toxicity
test
(
OECD
414).
There
is
no
rationale
presented
for
conducting
both
tests.
The
OECD
422
screening
study
is
sufficient
to
cover
all
three
endpoints
(
repeat
dose,
reproductive
and
developmental
toxicity)
for
the
purposes
of
the
U.
S.
HPV
Challenge
Program."

Chemical:
Ethyl
Dimethyl
(
aminoiminomethyl)
methylcarbamate
Hydrochloride
Summary:
EPA
encouraged
combined
study.

EPA
Comments:
"...
EPA
therefore
reserves
judgment
on
whether
carbamate
hydrochloride
meets
the
criteria
for
a
`
closed
system
intermediate,'
pending
the
submission
of
additional
information.
Alternatively,
the
submitter
may
conduct
a
combined
repeated­
dose/
reproductive/
developmental
toxicity
screening
test
(
OECD
TG
422)
instead
of
the
proposed
developmental
toxicity
study
(
OECD
TG
414),
which
would
then
satisfy
the
repeated­
dose
and
reproductive
toxicity
endpoints
and
obviate
the
need
to
sustain
a
`
closed
system
intermediate'
claim."

Chemical:
Alkyl
(
C12­
14)
Glycidyl
Ether
Summary:
EPA
recommended
reliance
on
existing
data
instead
of
a
new
reproductive
study.

EPA
Comments:
"
Reproductive
Toxicity.
Data
are
available
for
a
13­
week
repeated­
dose
dermal
study
in
rats
for
which
reproductive
organs
were
examined
histopathologically,
and
no
adverse
effects
were
observed.
This
study
together
with
the
adequate
developmental
toxicity
study
is
considered
adequate
for
the
reproductive
toxicity
endpoint."

Chemical:
Diallyl
Oxydiethylene
Dicarbonate
Summary:
EPA
recommended
combined
repeated
dose
reproductive­
developmental
study
and
referenced
Challenge
guidance
on
addressing
reproductive
effects
without
conducting
a
separate
reproductive
study.

EPA
Comments:
"
Repeated­
dose
toxicity.
...
EPA
disagrees
with
the
submitter's
plan
to
evaluate
toxicity
to
reproductive
organs
in
the
proposed
90­
day
repeated­
dose
study.
This
approach
is
not
adequate
for
the
purposes
of
the
HPV
Challenge
Program.
EPA's
HPV
Challenge
Guidance
3
specifies
that
such
an
assessment
of
toxicity
to
reproductive
organs
is
acceptable
only
in
the
case
of
an
existing
90­
day
study
when
an
acceptable
developmental
toxicity
study
is
available.
EPA
recommends
that
the
submitter
conduct
a
Combined
Repeated­
dose
Toxicity
Study
with
the
Reproduction/
Developmental
Toxicity
Screening
Test
(
OECD
422)
to
address
this
endpoint."

Chemical:
2­
Chloropyridine
Summary:
EPA
recommended
combined
study.

EPA
Comments:
"
EPA
agrees
that
testing
is
needed
for
the
repeated­
dose,
reproductive,
and
developmental
toxicity
endpoints.
However,
EPA
recommends
that
the
submitter
conduct
a
combined
repeated­
dose/
reproductive/
developmental
toxicity
screening
test
(
OECD
TG
422)
rather
than
the
proposed
separate
tests
(
OECD
TGs
407
and
421)."

Chemical:
Benzenesulfonic
Acid
Summary:
EPA
recommend
considering
harsh
chemical
properties
vis­
a­
vis
further
testing.

EPA
Comments:
"
The
submitted
data
for
the
acute
and
genetic
toxicity
endpoints
are
adequate
for
the
purposes
of
the
HPV
Challenge
Program.
Although
the
submitter
has
proposed
conducting
a
combined
screening
test
to
address
repeated­
dose,
reproductive
and
developmental
endpoints,
based
on
the
strong
acidic
and
corrosive
nature
of
the
substance,
EPA
believes
that
the
sponsor
needs
to
consider
whether
the
proposed
testing
would
yield
meaningful
results.
Therefore,
the
submitter
needs
to
reconsider
the
testing
proposal
before
conducting
such
studies
and
better
characterize
the
corrosivity
with
available
in
vitro
methods."

Chemical:
Triisopropylborate
Summary:
EPA
recommended
that
analog
data
plus
physical­
chemical
data
could
satisfy
endpoint
without
further
testing.

EPA
Comments:
"
Adequate
information
was
available
for
acute
toxicity.
No
data
were
provided
for
repeated­
dose,
developmental
and
reproductive
effects
and
a
combined
test
addressing
these
endpoints
(
OECD
TG
422)
was
proposed.
However,
if
hydrolysis
is
sufficiently
rapid
at
the
physiologically
important
pH
of
1.2
in
the
stability
in
water
test,
then
data
on
the
break­
down
products
(
isopropanol
and
boric
acid)
could
be
used
to
address
these
endpoints.
Testing
was
proposed
for
assessing
chromosomal
aberrations
(
OECD
TG
473).
Information
provided
on
the
reverse
mutation
assay
in
Salmonella
typhimurium
was
missing
details
concerning
the
conditions
of
the
test
and
whether
a
closed­
system
was
used.
If
volatility
is
more
predominant
than
hydrolysis
under
the
conditions
of
the
test,
then
a
closed­
system
approach
is
needed."

Use
of
ECOSAR
Modeling
for
Ecotoxicity
4
Chemical:
Dimethyl
3,3'­
thiobispropionate
Summary:
EPA
acknowledged
SAR
would
be
acceptable
to
satisfy
ecotox
endpoint
without
testing
(
if
measured
data
on
analog
is
provided).

EPA
Comments:
"
For
all
ecological
endpoints,
the
submitter
provided
only
estimated
data
using
ECOSAR.
In
order
to
meet
the
guidelines
of
the
HPV
Challenge
Program,
the
submitter
needs
to
provide
either
measured
data
on
the
subject
chemical
or
predicted
SAR
values
plus
measured
data
on
an
analogue."

Chemical:
Rxn
Pdct
(
Cyclododecanol/­
anone/
Nitric
Acid),
High­
Boiling
Frxn
(
Corfree
(
R)
M1)

Summary:
EPA
accepted
partial
data
plus
ECOSAR
to
satisfy
endpoint
without
further
testing.

EPA
Comments:
"
Fish
and
Invertebrates.
The
fish
and
daphnia
acute
toxicity
tests
were
conducted
with
shorter
(
48­
hour
fish,
24­
hour
daphnia))
than
required
(
96­
hour
fish,
48­
hour
daphnia)
test
durations.
Although
no
new
testing
is
proposed,
EPA
agrees
with
the
submitter
that
this
chemical
is
expected
to
show
low
toxicity
based
on
measured
data
and
the
ECOSAR
predicted
values
(>
100
mg/
L).
The
submitter,
however,
needs
to
provide
model
input
parameters
for
the
ECOSAR
predictions."

Chemical:
Ketoacids
Category
Summary:
EPA
accepted
analog
data
plus
ECOSAR
to
satisfy
endpoint
without
further
testing.

EPA
Comments:
"
No
data
on
EtKeto
acid
were
provided
in
the
summary
to
satisfy
any
of
the
ecotoxicity
endpoints.
The
test
plan
indicates
that
data
for
BuKeto
acid
will
be
used
to
satisfy
the
endpoints
for
EtKeto
acid.
This
is
acceptable
given
the
structural
similarity
of
the
two
chemicals.
In
addition,
ECOSAR
values
calculated
by
EPA
support
the
conclusion
that
BuKeto
acid
is
expected
to
be
more
toxic
than
EtKeto
acid."
