SEQ CHAPTER \h \r 1 ENVIRONMENTAL PROTECTION AGENCY

40 CFR Part 82

[EPA-HQ-OAR-2002-0064; FRL-xxxx-x]

RIN 2060-AK26

Protection of Stratospheric Ozone:  Listing of Substitutes for
Ozone-Depleting

Substances–n-Propyl Bromide in Adhesives, Coatings, and Aerosols

AGENCY:  Environmental Protection Agency.

ACTION:  Notice of Proposed Rulemaking

SUMMARY:  Pursuant to the U.S. Environmental Protection Agency’s (EPA
or “we”) Significant New Alternatives Policy (SNAP) program, this
action proposes to list n-propyl bromide (nPB) as an unacceptable
substitute for methyl chloroform, chlorofluorocarbon (CFC)-113, and
hydrochlorofluorocarbon (HCFC)-141b when used in adhesives or in aerosol
solvents because nPB in these end uses poses unacceptable risks to human
health when compared with other substitutes that are available.  In
addition, EPA takes comment on alternate options that would find nPB
acceptable subject to use conditions in adhesives or in aerosol
solvents.  This action also proposes to list nPB as acceptable, subject
to use conditions, as a substitute for methyl chloroform, CFC-113, and
hydrochlorofluorocarbon (HCFC)-141b in the coatings end use.  This
proposal supersedes EPA’s proposal of June 3, 2003 on the
acceptability of nPB as a substitute for ozone-depleting substances for
aerosols and adhesives.

DATES:  Comments must be received in writing by [Insert date 60 days
after Federal Register publication date].  Under the Paperwork Reduction
Act, comments on the information collection provisions must be received
by the Office of Management and Budget (OMB) on or before [insert date
[thirty] days after date of publication in the Federal Register].  Any
person interested in requesting a public hearing, must submit such
request on or before [insert 30 days from date of publication in the
Federal Register].  If a public hearing is requested, a separate notice
will be published announcing the date and time of the public hearing and
the comment period will be extended until 30 days after the public
hearing to allow rebuttal and supplementary information regarding any
material presented at the public hearing.  Inquires regarding a public
hearing should be directed to the contact person listed below.

ADDRESSES:  Submit your comments, identified by Docket ID No.
EPA-HQ-OAR-2002-0064, by one of the following methods:

  HYPERLINK "http://www.regulations.gov"  http://www.regulations.gov .
Follow the on-line instructions for submitting comments.

E-mail<EMAIL_ADDRESS>
Mail:  Air and Radiation Docket, Environmental Protection Agency,
Mailcode 6102T, 1200 Pennsylvania Ave., NW, Washington, DC, 20460,
Attention Docket ID No. EPA-HQ-OAR-2002-0064.  In addition, please mail
a copy of your comments on the information collection provisions to the
Office of Information and Regulatory Affairs, Office of Management and
Budget (OMB), Attn: Desk Officer for EPA, 725 17th St. NW., Washington,
DC 20503.

Hand Delivery:  EPA Docket Center, (EPA/DC) EPA West, Room 3334, 1301
Constitution Ave., NW, Washington, D.C., Attention Docket ID No.
EPA-HQ-OAR-2002-0064.  Such deliveries are only accepted during the
Docket’s normal hours of operation, and special arrangements should be
made for deliveries of boxed information.

     Instructions:  Direct your comments to Docket ID No.
EPA-HQ-OAR-2002-0064.  EPA's policy is that all comments received will
be included in the public docket without change and may be made
available online at   HYPERLINK "http://www.regulations.gov"
www.regulations.gov , including any personal information provided,
unless the comment includes information claimed to be Confidential
Business Information (CBI) or other information whose disclosure is
restricted by statute.  Do not submit information that you consider to
be CBI or otherwise protected through www.regulations.gov or e-mail.
The www.regulations.gov website is an “anonymous access” system,
which means EPA will not know your identity or contact information
unless you provide it in the body of your comment.  If you send an
e-mail comment directly to EPA without going through
www.regulations.gov, your e-mail address will be automatically captured
and included as part of the comment that is placed in the public docket
and made available on the Internet.  If you submit an electronic
comment, EPA recommends that you include your name and other contact
information in the body of your comment and with any disk or CD-ROM you
submit.  If EPA cannot read your comment due to technical difficulties
and cannot contact you for clarification, EPA may not be able to
consider your comment.  Electronic files should avoid the use of special
characters, any form of encryption, and be free of any defects or
viruses.  For additional instructions on submitting comments, go to
Section I.B. of the SUPPLEMENTARY INFORMATION section of this document.

	Docket: All documents in the docket are listed in the   HYPERLINK
"http://www.regulations.gov"  www.regulations.gov  index.  Although
listed in the index, some information is not publicly available, i.e.,
CBI or other information whose disclosure is restricted by statute.
Certain other material, such as copyrighted material, is not placed on
the Internet and will be publicly available only in hard copy form.
Publicly available docket materials are available either electronically
in   HYPERLINK "http://www.regulations.gov"  www.regulations.gov  or in
hard copy at the Air and Radiation Docket, EPA/DC, EPA West, Room 3334,
1301 Constitution Ave., NW, Washington, DC.  The Public Reading Room is
open from 8:30 a.m. to 4:30 p.m., Monday through Friday, excluding legal
holidays.  The telephone number for the Public Reading Room is (202)
566-1744, and the telephone number for the Air and Radiation Docket is
(202) 566-1742.

FOR FURTHER INFORMATION CONTACT:  Margaret Sheppard, Stratospheric
Protection Division, Office of Atmospheric Programs, Mail Code 6205J,
Environmental Protection Agency, 1200 Pennsylvania Ave., NW.,
Washington, DC 20460; telephone number<PHONE_NUMBER>; fax number (202)
343-2362 e-mail address<EMAIL_ADDRESS> Notices and
rulemakings under the SNAP program are available on EPA’s
Stratospheric Ozone World Wide Web site at www.epa.gov/ozone/snap/regs.

SUPPLEMENTARY INFORMATION:

	Table of Contents

 TOC \f

I. 	General Information

A. 	Does this action apply to me?

B. 	What should I consider as I prepare my comments for EPA?

C.  	What acronyms and abbreviations are used in the preamble?

II.  	How does the Significant New Alternatives Policy (SNAP) program
work?

	A. 	What are the statutory requirements and authority for the SNAP
program?

	B. 	How do the regulations for the SNAP program work?

	C. 	Where can I get additional information about the SNAP program?

III.	What is EPA proposing today?

A. 	What is n-propyl bromide?

B.  	What industrial end uses are included in our proposed decision?

C.  	What is the proposed text for EPA’s listing decisions?

D.  	What does an unacceptability determination on adhesives and
aerosols mean?

E. 	What is the scope of the proposed determination for coatings?

IV.	What criteria did EPA consider in preparing this proposal?

	A.	Availability of alternatives to ozone-depleting substances

	B. 	Impacts on the atmosphere and local air quality

	C.	Ecosystem and other environmental impacts

	D.	Flammability and fire safety

	E.	Health impacts and exposure

V.	How did EPA assess impacts on human health?

	A.	Newly available exposure data

	B.	Newly available data on health effects

	C.	Evaluation of acceptable exposure levels for the workplace

	D.	Other analyses of nPB toxicity

	E.	Community exposure guideline

VI.	What listing is EPA proposing for each end use, and why?

	A.	Aerosol solvents

B.	Adhesives

C.	Coatings

VII.	What other regulatory options did EPA consider?

A.	 Alternative option for comment:  acceptable with use conditions
requiring exposure limit and monitoring

	B.	Regulatory options where nPB would be acceptable with use conditions
requiring 	certain equipment

VIII.	What are the anticipated costs of this regulation to the regulated
community?

IX. 	How do the decisions for EPA’s June 2003 proposal compare to
those for this proposal?

How can I use nPB as safely as possible?

Statutory and Executive Order Reviews

Executive Order 12866:  Regulatory Planning and Review

Paperwork Reduction Act

Regulatory Flexibility Act

Unfunded Mandates Reform Act

Executive Order 13132: Federalism

Executive Order 13175:  Consultation and Coordination with Indian Tribal
Governments

Executive Order 13045:  Protection of Children from Environmental Health
and Safety Risks

Executive Order 13211:  Actions that Significantly Affect Energy Supply,
Distribution, or Use

National Technology Transfer and Advancement Act

References

 I. 	General Information tc "I. 	General Information"   TC "I. 	General
Information" \f A \l "1"

	A.	Does this action apply to me?  tc "	A. Does this action apply to me?
" \l 2

	This proposed rule would regulate the use of n-propyl bromide as an
aerosol solvent and as a carrier solvent in adhesives and coatings.
Businesses in these end uses that currently might be using nPB, or might
want to use it in the future, include:

Businesses that manufacture electronics or computer equipment.

Businesses that require a high level of cleanliness in removing oil,
grease, or wax, such as for aerospace applications or for manufacture of
optical equipment.

Foam fabricators that glue pieces of polyurethane foam together or foam
cushion manufacturers that glue fabric around a cushion.

Furniture manufacturers that use adhesive to attach wood parts to
floors, tables and counter tops.

A company that manufactures ammunition for the U.S. Department of
Defense.

	Regulated entities may include:

Table 1–Potentially Regulated Entities, by North American Industrial
Classification System (NAICS) Code or Subsector

Category	NAICS code or subsector	Description of regulated entities

Industry	331	Primary Metal Manufacturing

Industry	332	Fabricated Metal Product Manufacturing

Industry/Military	332992 	Small Arms Ammunition Manufacturing

Industry	333	Machinery Manufacturing

Industry	334	Computer and Electronic Product Manufacturing

Industry	335	Equipment Appliance, and Component Manufacturing

Industry	336	Transportation Equipment Manufacturing

Industry	337	Furniture and Related Product Manufacturing

Industry	339	Miscellaneous Manufacturing

Industry	326150	Urethane and Other Foam Product (except Polystyrene)
Manufacturing

	This table is not intended to be exhaustive, but rather a guide
regarding entities likely to be regulated by this action.  If you have
any questions about whether this action applies to a particular entity,
consult the person listed in the preceding section, “FOR FURTHER
INFORMATION CONTACT.”

	B. 	What should I consider as I prepare my comments for EPA?  tc "	B.
What should I consider as I prepare my comments for EPA? " \l 2

		1.	Submitting Confidential Business Information (CBI).  Do not submit
this information to EPA through www.regulations.gov or e-mail.  Clearly
mark the part or all of the information that you claim to be CBI.  For
CBI information in a disk or CD ROM that you mail to EPA, mark the
outside of the disk or CD ROM as CBI and then identify electronically
within the disk or CD ROM the specific information that is claimed as
CBI.  In addition to one complete version of the comment that includes
information claimed as CBI, a copy of the comment that does not contain
the information claimed as CBI must be submitted for inclusion in the
public docket.  Information so marked will not be disclosed except in
accordance with procedures set forth in 40 CFR part 2.

		2.	Tips for Preparing Your Comments.  When submitting comments,
remember to:

Identify the rulemaking by docket number and other identifying
information (subject heading, Federal Register (FR) date and page
number).

Follow directions - The agency may ask you to respond to specific
questions or organize comments by referencing a Code of Federal
Regulations (CFR) part or section number.

Explain why you agree or disagree; suggest alternatives and substitute
language for your requested changes.

Describe any assumptions and provide any technical information and/or
data that you used.

If you estimate potential costs or burdens, explain how you arrived at
your estimate in sufficient detail to allow for it to be reproduced.

Provide specific examples to illustrate your concerns, and suggest
alternatives.

Explain your views as clearly as possible, avoiding the use of profanity
or personal threats.

Make sure to submit your comments by the comment period deadline
identified.

    	C.	What acronyms and abbreviations are used in the preamble?  tc
"C.  What acronyms and abbreviations are used in the preamble? " \l 2

	Below is a list of acronyms and abbreviations used in this document.

8-hr—eight hour

ACGIH–American Conference of Governmental Industrial Hygienists

AEL–acceptable exposure limit

ASTM–American Society for Testing and Materials

BMD–benchmark dose

BMDL–benchmark dose lowerbound, the lower 95%-confidence level bound
on the dose/exposure associated with the benchmark response

BSOC–Brominated Solvents Consortium

CAA–Clean Air Act

CAS Reg. No–Chemical Abstracts Service Registry Identification Number

CBI–Confidential Business Information

CEG–community exposure guideline

CERHR–Center for the Evaluation of Risks to Human Reproduction

CFC-113–the ozone-depleting chemical
1,1,2-trifluoro-1,2,2-trichloroethane, C2Cl3F3, CAS Reg. No. 76-13-1

CFC–chlorofluorocarbon

cfm–cubic feet per minute

CFR–Code of Federal Regulations

CNS–central nervous system

DNA—deoxyribonucleic acid

EDSTAC--The Endocrine Disruptor Screening and Testing Advisory Committee

EPA–the United States Environmental Protection Agency

FR–Federal Register

GWP—global warming potential

HCFC-141b–the ozone-depleting chemical 1,1-dichloro-1-fluoroethane,
CAS Reg. No. 1717-00-6

HCFC-225ca/cb–the commercial mixture of the two ozone-depleting
chemicals 3,3-dichloro- 1,1,1,2,2-pentafluoropropane, CAS Reg. No.
422-56-0 and 1,3-dichloro-1,1,2,2,3-pentafluoropropane, CAS Reg. No.
507-55-1

HCFC–hydrochlorofluorocarbon

HEC–human equivalent concentration

HFC-245fa–the chemical 1,1,3,3,3-pentafluoropropane, CAS Reg. No.
460-73-1

HFC-365mfc–the chemical 1,1,1,3,3-pentafluorobutane, CAS Reg. No.
405-58-6

HFC-4310mee –the chemical 1,1,1,2,3,4,4,5,5,5-decafluoropentane, CAS
Reg. No. 138495-42-8 HFC–hydrofluorocarbon

HFE–hydrofluoroether

HHE–health hazard evaluation

ICF–ICF Consulting

ICR–Information Collection Request

iPB–isopropyl bromide, C3H7Br, CAS Reg. No. 75-26-3, an isomer of
n-propyl bromide; also called 2-bromopropane or 2-BP

Koc–organic carbon partition coefficient, for determining the tendency
of a chemical to bind to organic carbon in soil

LC50 –the concentration at which 50% of test animals die

LOAEL–Lowest Observed Adverse Effect Level

Log Kow–logarithm of the octanol-water partition coefficient, for
determining the tendency of a chemical to accumulate in lipids or fats
instead of remaining dissolved in water

mg/l–milligrams per liter

MSDS–Material Safety Data Sheet

NAICS–North American Industrial Classification System

NIOSH–National Institute for Occupational Safety and Health

NOAEL–No Observed Adverse Effect Level

NOEL–No Observed Effect Level

nPB–n-propyl bromide, C3H7Br, CAS Reg. No. 106-94-5; also called
1-bromopropane or 1-BP

NPRM–Notice of Proposed Rulemaking

NTP–National Toxicology Program

NTTAA–National Technology Transfer and Advancement Act

ODP–ozone depletion potential

ODS–ozone-depleting substance

OEHHA–Office of Environmental Health Hazard Assessment of the
California Environmental Protection Agency

OMB–U.S. Office of Management and Budget

OSHA–the United States Occupational Safety and Health Administration

PCBTF–parachlorobenzotrifluoride, CAS Reg. No. 98-56-6

PEL–Permissible Exposure Limit

ppm–parts per million

RCRA–Resource Conservation and Recovery Act

RFA–Regulatory Flexibility Act

RfC–reference concentration

SIP–state implementation plan

SNAP–Significant New Alternatives Policy

TCA–the ozone-depleting chemical 1,1,1-trichloroethane, CAS Reg. No.
71-55-6; also called methyl chloroform, MCF, or 1,1,1

TCE—the chemical 1,1,2-trichloroethene, CAS Reg. No. 79-01-6, C2Cl3H;
also call trichloroethylene

TERA–Toxicological Excellence for Risk Assessment

TLV–Threshold Limit Value™

TSCA–Toxic Substances Control Act

TWA–time-weighted average

UMRA–Unfunded Mandates Reform Act

U.S.C.–United States Code

VMSs–volatile methyl siloxanes

VOC–volatile organic compound

II.  	How does the Significant New Alternatives Policy (SNAP) program
work? tc "II.  	How does the Significant New Alternatives Policy (SNAP)
program work?"

	A.  What are the statutory requirements and authority for the SNAP
program?

	Section 612 of the Clean Air Act (CAA) authorizes EPA to develop a
program for evaluating alternatives to ozone-depleting substances,
referred to as the Significant New Alternatives Policy (SNAP) program.
The major provisions of section 612 are:

Rulemaking–Section 612(c) requires EPA to promulgate rules making it
unlawful to replace any class I (chlorofluorocarbon, halon, carbon
tetrachloride, methyl chloroform, and hydrobromofluorocarbon) or class
II (hydrochlorofluorocarbon) substance with any substitute that the
Administrator determines may present adverse effects to human health or
the environment where the Administrator has identified an alternative
that (1) reduces the overall risk to human health and the environment,
and (2) is currently or potentially available.

Listing of Unacceptable/Acceptable Substitutes--Section 612(c) also
requires EPA to publish a list of the substitutes unacceptable for
specific uses.  We must publish a corresponding list of acceptable
alternatives for specific uses.

Petition Process--Section 612(d) grants the right to any person to
petition EPA to add a substitute to or delete a substitute from the
lists published in accordance with section 612(c).  EPA has 90 days to
grant or deny a petition.  Where the Agency grants the petition, we must
publish the revised lists within an additional six months.

90-day Notification--Section 612(e) requires EPA to require any person
who produces a chemical substitute for a class I substance to notify the
Agency not less than 90 days before new or existing chemicals are
introduced into interstate commerce for significant new uses as
substitutes for a class I substance.  The producer must also provide the
Agency with the producer's health and safety studies on such
substitutes.

Outreach--Section 612(b)(1) states that the Administrator shall seek to
maximize the use of federal research facilities and resources to assist
users of class I and II substances in identifying and developing
alternatives to the use of such substances in key commercial
applications.

Clearinghouse--Section 612(b)(4) requires the Agency to set up a public
clearinghouse of alternative chemicals, product substitutes, and
alternative manufacturing processes that are available for products and
manufacturing processes which use class I and II substances.

	B.  How do the regulations for the SNAP program work?

	On March 18, 1994, EPA published the original rulemaking (59 FR 13044)
that described the process for administering the SNAP program and issued
the first acceptability lists for substitutes in the major industrial
use sectors.  These sectors include:  refrigeration and air
conditioning; foam blowing; solvents cleaning; fire suppression and
explosion protection; sterilants; aerosols; adhesives, coatings and
inks; and tobacco expansion.  These sectors comprise the principal
industrial sectors that historically consumed large volumes of
ozone-depleting substances.

	Anyone who plans to market or produce a substitute for an
ozone-depleting substance (ODS) in one of the eight major industrial use
sectors must provide the Agency with health and safety studies on the
substitute at least 90 days before introducing it into interstate
commerce for significant new use as an alternative.  This requirement
applies to the person planning to introduce the substitute into
interstate commerce, typically chemical manufacturers, but may also
include importers, formulators or end-users when they are responsible
for introducing a substitute into commerce.

	The Agency has identified four possible decision categories for
substitutes:  acceptable; acceptable subject to use conditions;
acceptable subject to narrowed use limits; and unacceptable.  Use
conditions and narrowed use limits are both considered “use
restrictions” and are explained below.  Substitutes that are deemed
acceptable with no use restrictions (no use conditions or narrowed use
limits) can be used for all applications within the relevant sector
end-use.  Substitutes that are acceptable subject to use restrictions
may be used only in accordance with those restrictions.  It is illegal
to replace an ODS with a substitute listed as unacceptable.

	After reviewing a substitute, the Agency may make a determination that
a substitute is acceptable only if certain conditions of use are met to
minimize risks to human health and the environment.  We describe such
substitutes as "acceptable subject to use conditions."  If you use these
substitutes without meeting the associated use conditions, you use these
substitutes in an unacceptable manner and you could be subject to
enforcement for violation of section 612 of the Clean Air Act.

	For some substitutes, the Agency may permit a narrowed range of use
within a sector.   For example, we may limit the use of a substitute to
certain end-uses or specific applications within an industry sector or
may require a user to demonstrate that no other acceptable end uses are
available for their specific application.  We describe these substitutes
as “acceptable subject to narrowed use limits.”  If you use a
substitute that is acceptable subject to narrowed use limits, but use it
in applications and end-uses which are not consistent with the narrowed
use limit, you are using these substitutes in an unacceptable manner and
you could be subject to enforcement for violation of section 612 of the
Clean Air Act.

	The Agency publishes its SNAP program decisions in the Federal
Register.  For those substitutes that are deemed acceptable subject to
use restrictions (use conditions and/or narrowed use limits), or for
substitutes deemed unacceptable, we first publish these decisions as
proposals to allow the public opportunity to comment, and we publish
final decisions as final rulemakings.

In contrast, we publish substitutes that are deemed acceptable with no
restrictions in “notices of acceptability,” rather than as proposed
and final rules.  As described in the rule implementing the SNAP program
(59 FR 13044), we do not believe that rulemaking procedures are
necessary to list alternatives that are acceptable without restrictions
because such listings neither impose any sanction nor prevent anyone
from using a substitute.

	Many SNAP listings include “comments” or “further information.”
 These statements provide additional information on substitutes that we
determine are unacceptable, acceptable subject to narrowed use limits,
or acceptable subject to use conditions.  Since this additional
information is not part of the regulatory decision, these statements are
not binding for use of the substitute under the SNAP program.  However,
regulatory requirements listed in this column are binding under other
programs.  The further information does not necessarily include all
other legal obligations pertaining to the use of the substitute.
However, we encourage users of substitutes to apply all statements in
the “Further Information” column in their use of these substitutes.
In many instances, the information simply refers to sound operating
practices that have already been identified in existing industry and/or
building-code standards.  Thus, many of the comments, if adopted, would
not require the affected industry to make significant changes in
existing operating practices.

C.  Where can I get additional information about the SNAP program?

	For copies of the comprehensive SNAP lists of substitutes or additional
information on

SNAP, look at EPA’s Ozone Depletion World Wide Web site at
http://www.epa.gov/ozone/snap/lists/index.html.  For more information on
the Agency's process

for administering the SNAP program or criteria for evaluation of
substitutes, refer to the SNAP final rulemaking published in the Federal
Register on March 18, 1994 (59 FR 13044), codified at Code of Federal
Regulations at 40 CFR part 82, subpart G.  You can find a complete
chronology of SNAP decisions and the appropriate Federal Register
citations at http://www.epa.gov/ozone/snap/chron.html.

III.	What is EPA proposing today?  tc "III.	Is EPA listing n–propyl
bromide as an acceptable substitute for ozone-depleting substances?"

	In this action, EPA proposes to list n-propyl bromide (nPB) as (1)
unacceptable for use as a substitute for CFC-113, methyl chloroform and
HCFC-141b in the adhesive and aerosol solvent end uses; and (2)
acceptable subject to use conditions (limited to coatings at facilities
that, as of [INSERT DATE OF PUBLICATION], have provided EPA with
information demonstrating their ability to maintain acceptable workplace
exposures) as a substitute for methyl chloroform, CFC-113, and HCFC-141b
in the coatings end use.  This Notice of Proposed Rulemaking (NPRM)
supersedes the NPRM published on June 3, 2003 (68 FR 33284) for aerosol
solvents and adhesives.

	A.	What is n-propyl bromide?  tc "	B.   What is n-propyl bromide? " \l
2

	n-propyl bromide (nPB), also called 1-bromopropane, is a non-flammable
organic solvent with a strong odor.  Its chemical formula is C3H7Br.
Its identification number in Chemical Abstracts Service’s registry
(CAS Reg. No.) is 106-94-5.  nPB is used to remove wax, oil, and grease
from electronics, metal, and other materials.  It also is used as a
carrier solvent in adhesives.  Some brand names of products using nPB
are:  Abzol®, EnSolv®, and Solvon® cleaners; Pow-R-Wash® NR Contact
Cleaner, Superkleen Flux Remover 2311 and LPS NoFlash NU Electro Contact
Cleaner aerosols; and Whisper Spray and Fire Retardant Soft Seam 6460
adhesives.

	B. 	What industrial end uses are included in our proposed decision?

This proposal addresses the use of n-propyl bromide in the aerosol
solvent end use of the aerosol sector and the adhesives and coatings end
uses in the adhesives, coatings, and inks sector as discussed below.
EPA is issuing a decision on the use of nPB in metals, electronics, and
precision cleaning in a separate final rule.  EPA has insufficient
information for ruling on other end uses or sectors where nPB might be
used (e.g., inks, foam blowing, fire suppression).  tc "	C. 	What
industrial end uses are included in our proposed decision? " \l 2

1.	Aerosol Solvents  TC "Aerosol Solvents" \f A \l "3"

	We understand that nPB is being used as an aerosol solvent in:

     •    Lubricants, coatings, or cleaning fluids for electrical or
electronic equipment;

     •    Lubricants, coatings, or cleaning fluids for aircraft
maintenance; or

     •    Spinnerrette lubricants and cleaning sprays used in the
production of synthetic fibers.

2.	Adhesives  TC "Adhesives" \f A \l "3"

	Types of adhesives covered under the SNAP program are those that
formerly used methyl chloroform, specifically, adhesives for laminates,
flexible foam, hardwood floors, tire patches, and metal to rubber
adhesives.  Of these applications, nPB-based adhesives have been used
most widely in spray adhesives used in manufacture of foam cushions, and
to a lesser degree in laminate adhesives.

Coatings  TC "Coatings" \f A \l "3"

	The SNAP program regulates the use of carrier solvents in durable
coatings, including paints, varnishes, and aerospace coatings (59 FR
13118).  The SNAP program currently does not regulate carrier solvents
in lubricant coatings, such as silicone coatings used on medical
equipment (59 FR 13119).  Methyl chloroform has been used as a carrier
solvent in coatings, and to a much lesser degree, HCFC-141b also has
been a carrier solvent.  This rule responds to a submission from a
facility that is substituting methyl chloroform with nPB as an
ammunition coating (sealant).

C.	What is the proposed text for EPA’s listing decisions?  TC "5.
Proposed Listings" \f A \l "3"

	In the proposed regulatory text at the end of this document, you will
find our proposed decisions for those end uses for which we have
proposed nPB as unacceptable or acceptable subject to use conditions.
The proposed conditions listed in the “Use Conditions”column would
be enforceable while information contained in the “Further
Information” column of those tables provides additional
recommendations on the safe use of nPB.  Our proposed decisions for each
end use are summarized below in tables 2 through 4.

PROPOSED LISTINGS

Table 2.  AEROSOLS

PROPOSED UNACCEPTABLE SUBSTITUTES

End Use	Substitute	Decision	Further Information

Aerosol solvents	n-propyl bromide (nPB) as a substitute for CFC-113,
HCFC-141b, and methyl chloroform	Unacceptable	EPA finds unacceptable
risks to human health in this end use compared to other available
alternatives.  nPB, also known as 1-bromopropane, is Number 106-94-5 in
the CAS Registry.

Table 3.  ADHESIVES, COATINGS, AND INKS

PROPOSED UNACCEPTABLE SUBSTITUTES

End Use	Substitute	Decision	Further Information

Adhesives	n-propyl bromide (nPB) as a substitute for CFC-113, HCFC-141b,
and methyl chloroform	Unacceptable	EPA finds unacceptable risks to human
health in this end use compared to other available alternatives.  nPB,
also known as 1-bromopropane, is Number 106-94-5 in the CAS Registry.

Table 4.  ADHESIVES, COATINGS, AND INKS

SUBSTITUTES THAT ARE PROPOSED ACCEPTABLE SUBJECT TO USE CONDITIONS

End Use	Substitute	Decision	Use Conditions	Further Information

Coatings	n-propyl bromide (nPB) as a substitute for methyl chloroform,
CFC-113, and HCFC-141b	Acceptable subject to use conditions	Use is
limited to coatings at facilities that, as of [INSERT DATE OF
PUBLICATION], have provided EPA information demonstrating their ability
to maintain acceptable workplace exposures.

	EPA recommends the use of personal protective equipment, including
chemical goggles, flexible laminate protective gloves and
chemical-resistant clothing.

EPA expects that all users of nPB would comply with any final
Permissible Exposure Limit that the Occupational Safety and Health
Administration issues in the future under 42 U.S.C. 7610(a).

nPB, also known as 1-bromopropane, is Number 106-94-5 in the CAS
Registry.

Note:  As of [INSERT DATE OF PUBLICATION], the Lake City Army Ammunition
Plant is the only facility using nPB in coatings that has provided
information to EPA that meets this condition.

D.  What does an unacceptability determination on adhesives and aerosols
mean?  tc "	D. How would the proposed unacceptability determination on
adhesives work? " \l 2

	In this action, EPA is proposing to find nPB unacceptable as a
substitute for methyl chloroform, CFC-113, and HCFC-141b for use as a
carrier solvent in adhesives and as an aerosol solvent.  If this
proposal were to become final, it would be illegal to use nPB or blends
of nPB and other solvents in adhesives or in aerosol solvent
formulations as a substitute for ozone-depleting substances.

	E. What is the scope of the proposed determination for coatings?  tc "
E. How would the proposed regulatory restriction on coatings work? " \l
2

	We propose to list nPB as an acceptable substitute, subject to use
conditions, for methyl chloroform, CFC-113, and HCFC-141b in coatings
for facilities that, as of [INSERT DATE OF PUBLICATION], have provided
EPA information demonstrating their ability to maintain acceptable
workplace exposures.  EPA has received a petition to allow use of nPB
for the ammunition coating application at Lake City Army Ammunition
Plant.  This is the only coatings application or facility for which EPA
has exposure and usage data demonstrating an ability to maintain
workplace exposure levels below even the minimum level of the range of
exposures that EPA is considering to be potentially acceptable (i.e., 17
to 30 ppm) (see section IV.E for an  evaluation of the health risks
associated with nPB).  If other facilities are interested in using nPB
as a substitute for methyl chloroform, CFC-113, or HCFC-141b in their
coatings application, or if a person wishes to market nPB for such use,
then the interested party would need to make a submission under the SNAP
program.

IV.	What criteria did EPA consider in preparing this proposal? tc "IV.
What did EPA consider in preparing today’s proposal?"

	In the original rule implementing the SNAP program (March 18, 1994; 59
FR 13044, at 40 CFR 82.180(a)(7)), the Agency identified the criteria we
use in determining whether a substitute is acceptable or unacceptable as
a replacement for class I or II compounds:

(i) Atmospheric effects and related health and environmental impacts;
[e.g., ozone depletion potential]

(ii) General population risks from ambient exposure to compounds with
direct toxicity and to increased ground-level ozone;

(iii) Ecosystem risks [e.g., bioaccumulation, impacts on surface and
groundwater];

(iv) Occupational risks;

(v) Consumer risks;

(vi) Flammability; and

(vii) Cost and availability of the substitute.

	In this review, EPA considered all the criteria above.  However,
n-propyl bromide is used in industrial applications such as electronics
cleaning or spray adhesives used in foam fabrication.  In those consumer
products made using nPB, such as a piece of furniture or a computer, the
nPB would have evaporated long before a consumer would purchase the
item.  Therefore, we believe there is no consumer exposure risk to
evaluate in the end uses we evaluated for this rule.

	Section 612(c) of the Clean Air Act directs EPA to publish a list of
replacement substances (“substitutes”) for class I and class II
ozone depleting substances based on whether the Administrator determines
they are safe (when compared with other currently or potentially
available substitutes) for specific uses or are to be prohibited for
specific uses.  EPA must compare the risks to human health and the
environment of a substitute to the risks associated with other
substitutes that are currently or potentially available.  In addition,
EPA also considers whether the substitute for class I and class II ODSs
“reduces the overall risk to human health and the environment”
compared to the ODSs being replaced.  Our evaluation is based on the end
use; for example, we compared nPB as a carrier solvent in adhesives to
other available or potentially available adhesive alternatives.

	Although EPA does not judge the effectiveness of an alternative for
purposes of determining whether it is acceptable, we consider
effectiveness when determining whether alternatives that pose less risk
are available in a particular application within an end use.  There are
a wide variety of acceptable alternatives listed for aerosol solvents,
but not all may be appropriate for a specific application because of
differences in materials compatibility, flammability, degree of
cleanliness required, local environmental requirements, and other
factors.

	 EPA evaluated each of the criteria separately and then considered
overall risk to human health and the environment in comparison to other
available or potentially available alternatives.  We concluded that
overall, environmental risks were not sufficient to find nPB
unacceptable in any of the evaluated end uses.  However, the overall
risks to human health, and particularly the risks to worker health, are
sufficiently high in the adhesive and aerosol solvent end uses to
warrant our proposal to find nPB unacceptable.

A.	Availability of alternatives to ozone-depleting substances  tc
"Availability  " \l 3

Other alternatives are available in each end use considered in this
proposal.  Examples of other available alternatives for aerosol solvents
that have already been found acceptable or acceptable subject to use
conditions under the SNAP program include water-based formulations,
alcohols, ketones, esters, ethers, terpenes, HCFC-141b, HCFC-225ca/cb,
hydrofluoroethers (HFEs), hydrofluorocarbon (HFC)-4310mee, HFC-365mfc,
HFC-245fa, hydrocarbons, trans-1,2-dichloroethylene,  methylene
chloride, trichloroethylene (TCE), perchloroethylene, and
parachlorobenzotrifluoride (PCBTF).  Of these, hydrocarbons, alcohols,
blends of trans-1,2-dichloroethylene and HFEs or HFCs, and HCFC-225ca/cb
are most likely to be used in the same applications as nPB.  nPB is
already commercially available in aerosols.  Its use is primarily for
electrical contact cleaning, with some use for benchtop cleaning
applications (Williams, 2005).

	Many alternatives are also available for use in adhesives, coatings,
and inks:  water-based formulations, high solid formulations, alcohols,
ketones, esters, ethers, terpenes, HFEs, hydrocarbons,
trans-1,2-dichloroethylene, chlorinated solvents, PCBTF, and a number of
alternative technologies (e.g., powder, hot melt, thermoplastic plasma
spray, radiation-cured, moisture-cured, chemical-cured, and reactive
liquid).  Of these, the alternative adhesives most likely to be used in
the same applications as nPB are water-based formulations, adhesives
with methylene chloride, and flammable adhesives with acetone (IRTA,
2000).  nPB is already used in adhesives, and particularly in foam
fabrication and in constructing seating for aircraft (IRTA, 2000;
Seilheimer, 2001).

	To our knowledge, nPB is potentially available as a carrier solvent in
coatings, but has not yet been commercialized, except for use by one
facility, the Lake City Army Ammunition Plant.  The Lake City Army
Ammunition Plant evaluated twenty-nine carrier solvent alternatives to
methyl chloroform and determined that nPB is the only satisfactory
alternative for their application given the current process at that
facility (Harper, 2005).

		B. 	Impacts on the atmosphere and local air quality   TC "2.
Atmospheric effects" \f A \l "3"

	As discussed in the June, 2003 proposal, nPB emissions from the
continental United States are estimated to have an ozone depletion
potential (ODP) of approximately 0.013-0.018, (Wuebbles, 2002), lower
than that of the ozone depletion potential of the substances that nPB
would replace -- CFC-113 (ODP=1.0), and methyl chloroform and HCFC-141b
(ODPs = 0.12) (WMO, 2002).  Some other acceptable alternatives for these
ODSs also have low ODPs.  For example, HCFC-225ca/cb has an ODP of
0.02-0.03 (WMO, 2002) and is acceptable as an aerosol solvent.  There
are other acceptable solvents for aerosols, adhesives, and coatings that
essentially have no ODP--aqueous cleaners, HFEs, HFC-4310mee,
HFC-365mfc, HFC-245fa, hydrocarbons, volatile methyl siloxanes (VMSs),
methylene chloride, TCE, perchloroethylene, and PCBTF.  Based on this
information, we do not believe the use of nPB within the U.S., and
within the end-uses reviewed in this rulemaking, poses a significantly
greater risk to the ozone layer than other available substitutes.

	Comments on the June 2003 NPRM expressed concern that other countries,
particularly those in equatorial regions, might assume that nPB does not
pose a danger to the stratospheric ozone layer if the U.S. EPA’s SNAP
program finds nPB acceptable (Linnell, 2003; Steminiski, 2003).  Because
the ODP for nPB is higher when used in the tropics (see footnote ), we
recognize the concerns raised by these commenters.  However, EPA is
regulating use in the U.S. and cannot dictate actions taken by other
countries.  We believe the more appropriate forum to address this
concern is through the Parties to the Montreal Protocol.  At the most
recent Meeting of the Parties, the Parties made the following decision
with regard to n-propyl bromide, in order to “allow Parties to
consider further steps regarding n-propyl bromide, in the light of
available alternatives” (Decision XVIII/11):

1. To request the Scientific Assessment Panel to update existing
information on the ozone depletion potential of n-propyl bromide,
including ozone depleting potential depending on the location of the
emissions and the season in the hemisphere at that location;

2. To request the Technology and Economic Assessment Panel to continue
its assessment of global emissions of n-propyl bromide, …paying
particular attention to:

(a) Obtaining more complete data on production and uses of n-propyl
bromide as well as emissions of n-propyl bromide from those sources;

(b) Providing further information on the technological and economical
availability of alternatives for the different use categories of
n-propyl bromide and information on the toxicity of and regulations on
the substitutes for n-propyl bromide;

(c) Presenting information on the ozone depletion potential of the
substances for which n-propyl bromide is used as a replacement;

3. To request that the Technology and Economic Assessment Panel prepare
a report on the assessment referred to in paragraph 1 in time for the
twenty-seventh meeting of the Open-ended Working Group for the
consideration of the Nineteenth Meeting of the Parties. (MOP 18, 2006)

The global warming potential (GWP) index is a means of quantifying the
potential integrated climate forcing of various greenhouse gases
relative to carbon dioxide.  Earlier data found a direct 100-year
integrated GWP (100yr GWP) for nPB of 0.31 (Atmospheric and
Environmental Research, Inc., 1995).  More recent analysis that
considers both the direct and the indirect GWP of nPB found a 100-yr GWP
of 1.57 (ICF, 2003a; ICF, 2006a).  In either case, the GWP for nPB is
comparable to or below that of previously approved substitutes in these
end uses.

 	Use of nPB may be controlled as a volatile organic compound (VOC)
under state implementation plans (SIPs) developed to attain the National
Ambient Air Quality Standards for ground-level ozone, which is a
respiratory irritant.  Users located in ozone nonattainment areas may
need to consider using a substitute for cleaning that is not a VOC or if
they choose to use a substitute that is a VOC, they may need to control
emissions in accordance with the SIP.  Companies have petitioned EPA,
requesting that we exempt nPB from regulation as a VOC.  However, unless
and until EPA issues a final rulemaking exempting a compound from the
definition of VOC and states change their SIPs to exclude such a
compound from regulation, that compound is still regulated as a VOC.
Other acceptable ODS-substitute solvents that are VOCs for state air
quality planning purposes include most oxygenated solvents such as
alcohols, ketones, esters, and ethers; hydrocarbons and terpenes;
trichloroethylene; trans-1,2-dichloroethylene; monochlorotoluenes; and
benzotrifluoride.  Some VOC-exempt solvents that are acceptable ODS
substitutes include HFC-245fa, HCFC-225ca/cb, HFC-365mfc and HFC-4310mee
for aerosol solvents, and methylene chloride, perchloroethylene,
HFE-7100, HFE-7200, PCBTF, acetone, and methyl acetate for aerosol
solvents, adhesives, and coatings.

	C.	Ecosystem and other environmental impacts  TC "3.	Ecosystem and
other environmental impacts" \f A \l "3"

	EPA considered the possible impacts of nPB if it were to pollute soil
or water as a waste and compared these impacts to screening criteria
developed by the Endocrine Disruptor Screening and Testing Advisory
Committee (EDSTAC, 1998) (see Table 5).  Available data on the organic
carbon partition coefficient (Koc), the breakdown processes in water and
hydrolysis half-life, and the volatilization half-life indicate that nPB
is less persistent in the environment than many solvents and would be of
low to moderate concern for movement in soil.  Based on the LC50, the
acute concentration at which 50% of tested animals die, nPB’s toxicity
to aquatic life is moderate, being less than that for some acceptable
cleaners (for example, trichloroethylene, hexane, d-limonene, and
possibly some aqueous cleaners) and greater than that for some others
(methylene chloride, acetone, isopropyl alcohol, and some other aqueous
cleaners).  The LC50 for nPB is 67 milligrams per liter (mg/l), which is
greater and thus less toxic than an LC50 of 10 mg/l, one of EPA’s
criteria for listing under the Toxics Release Inventory (US EPA, 1992;
ICF, 2004a).  Based on its relatively low bioconcentration factor and
log Kow value (logarithm of the octanol-water partition coefficient),
nPB is not prone to bioaccumulation.  Table 5 summarizes information on
environmental impacts of nPB; trans-1,2-dichloroethylene, a
commonly-used solvent in blends for aerosol solvents, precision
cleaning, and electronics cleaning; acetone, a commonly-used carrier
solvent in adhesives; trichloroethylene, a solvent used for metals,
electronics, and precision cleaning that could potentially be used in
aerosol or adhesive end-uses; and methyl chloroform, an ODS that nPB
would replace.Table 5.  Ecosystem and Other Environmental Properties of
nPB and Other Solvents

Property	Description of environmental property	Value for nPB	Value for
trans-1,2-dichloro-ethylene	Value for acetone	Value for
trichloroethylene	Value for methyl chloroform

Koc, organic-carbon partition coefficient	Degree to which a substance
tends to stick to soil or move in soil.  Lower values (< 300)* indicate
great soil mobility; values of 300 to 500 indicate moderate mobility in
soil.	330 (Source: ICF, 2004a)	32 to 49 (Source:  ATSDR, 1996)	5.4
(Source:  ATSDR, 1994)	106 to 460 (Source:  ATSDR, 1997)	152 (Source: US
EPA, 1994a)

Break down in water	Mechanism and speed with which a compound breaks
down in the environment.  (Hydrolysis half-life values > 25 weeks* are
of concern.)	Hydrolysis is significant.  Hydrolysis half-life of 26 days
(Source: ICF, 2004a)	Photolytic decomposition, dechlorination and
biodegradation are significant; hydrolysis not significant (Source:
ATSDR, 1996)	Biodegrada-tion is most significant form of breakdown
(Source:  ATSDR, 1994)	Volatilization and biodegradation most
significant, with hydrolysis relatively insignificant.  Hydrolysis
half-life of 10.7 to 30 months (Source:  ATSDR, 1997)	Volatilization
most significant;  biodegradation and hydrolysis also occur (Source:
ATSDR, 2004)

Volatilization half-life from surface waters	Tendency to volatilize and
pass from water into the air.	3.4 hours-4.4 days (Source: ICF, 2004a)	3
to 6.2 hours (Source:  ATSDR, 1996)	7.8 to 18 hours (Source:  ATSDR,
1994)	3.4 hours to 18 days (Source:  ATSDR, 1997)	hours to weeks
(Source: US EPA, 1994a)

LC50 (96 hours) for fathead minnows	Concentration at which 50% of
animals die from toxicity after exposure for 4 days.	67 mg/L (Source:
Geiger, 1988)	108 mg/L (Source: US EPA, 1980)	7280 to 8120 mg/L (Source:
 Fisher Scientific, 2001)	40.7 to 66.8 mg/L (Source:  NPS, 1997)	52.8 to
105 mg/L (Source: US EPA, 1994a)

log Kow 	Logarithm of the octanol/water partition coefficient, a measure
of tendency to accumulate in fat.  Log Kow values >3* indicate high
tendency to accumulate.	2.10 (Source: ICF, 2004a)	-0.48 (Source:
LaGrega et al., 2001, p. 1119)	-0.24 (Source:  LaGrega et al., 2001, p.
1117)	2.38 (Source:  LaGrega et al., 2001, p. 1127)	2.50 (Source:
LaGrega et al., 2001, p. 1127)

Bioconcen-tration factor 	High factors (>1000)* indicate strong tendency
for fish to absorb the chemical from water into body tissues.	23
(Source:  HSDB, 2004)	5 to 23 (Source:  ATSDR, 1996)	<1 (Source:  ATSDR,
1994)	10 to 100 (Source:  ATSDR, 1997)	<9 (Source: US EPA, 1994a)

* Criteria from EDSTAC, 1998.

	nPB is not currently regulated as a hazardous air pollutant and is not
listed as a hazardous waste under the Resource Conservation and Recovery
Act (RCRA).  nPB is not required to be reported as part of the Toxic
Release Inventory under Title III of the Superfund Amendments and
Reauthorization Act.  Despite this, large amounts of nPB might be
harmful if disposed of in water.  We recommend that users dispose of nPB
as they would dispose of any spent halogenated solvent (F001 waste under
RCRA).  Users should not dump nPB into water, and should dispose of it
by incineration.  We conclude that nPB does not pose a significantly
greater risk to the environment than other available alternatives, and
that the use of nPB within the U.S. should not be prohibited under the
SNAP program on the basis of its environmental impacts.

	D.	Flammability and fire safety  tc "		4.	Flammability and fire safety
" \l 3

	A number of commenters on the June 2003 proposal provided additional
information on the flammability of nPB using standard test methods for
determining flash point, such as the American Society for Testing and
Materials (ASTM) D 92 open cup, ASTM D56 Tag closed cup, and ASTM D93
Pensky-Martens closed cup methods (BSOC, 2000; Miller, 2003; Morford,
2003a, 2003b, and 2003c; Shubkin, 2003; Weiss Cohen, 2003).  We agree
with the commenters that by these standard test methods, nPB displayed
no flash point.  Thus under standard test conditions, nPB is not
flammable, and it should not be flammable under normal use conditions.
With its low potential for flammability, nPB is comparable to
chlorinated solvents, HCFCs, HFEs, HFC-245fa, HFC-4310mee, and aqueous
cleaners, and is less flammable than many acceptable substitutes, such
as ketones, alcohols, terpenes, and hydrocarbons.  nPB exhibits lower
and upper flammability limits of approximately 3% to 8% (BSOC, 2000).  A
number of other solvents that are typically considered to be
non-flammable also have flammability limits (for example, methylene
chloride, HCFC-141b, and methyl chloroform).  If the concentration of
vapor of such a solvent falls between the upper and lower flammability
limits, it could catch fire in presence of a flame.  Such a situation is
unusual, but users should take appropriate precautions in cases where
the concentration of vapor could fall between the flammability limits.

	E.	Health impacts and exposure  tc "		5.	Impact on human health " \l 3

	In evaluating potential human health impacts of nPB used as a
substitute for ozone-depleting substances, EPA considered impacts on
both exposed workers and on the general population.  Using the same
approach finalized in the original SNAP rulemaking, EPA evaluated the
available toxicity data using EPA guidelines to develop health-based
criteria to characterize human health risks (US EPA, 1994b. Inhalation
Reference Concentration Guidelines; US EPA, 1991.  Guidelines for
Developmental Toxicity Risk Assessment; US EPA, 1995a.  Benchmark Dose
guidelines; US EPA, 1996.  Guidelines for Reproductive Toxicity Risk
Assessment).

	To assess human health risks, EPA followed the four basic steps of risk
assessment outlined by the National Academy of Sciences:  hazard
identification, dose-response relationship, exposure assessment, and
risk characterization (NAS, 1983).  First, EPA examined available
studies on nPB’s effects.  Second, EPA considered the acceptable
exposure levels for evaluating worker exposure and a community exposure
guideline (CEG) for evaluating exposure to the general population based
upon inhalation exposure.  Third, EPA compared the acceptable exposure
levels and CEG to available exposure data and projections of exposure
levels to assess exposure, including new exposure data available since
publication of the June 2003 NPRM.  Finally, EPA decided whether there
was sufficient evidence indicating that nPB could be used as safely as
other alternatives available in a particular end use.

Authority to set an acceptable exposure limit

	Two commenters on the June 2003 NPRM said that EPA has no jurisdiction
to develop any acceptable exposure limit (AEL) designed to be applicable
to a workplace environment and that only the Occupational Safety and
Health Administration (OSHA) has that authority (Stelljes, 2003;
Morford, 2003d).  In contrast, another commenter said that EPA has the
authority to set an AEL for nPB under section 612 of the Clean Air Act,
has done so in the past for other chemicals (e.g., HFC-4310mee,
HCFC-225ca/cb), and should require the AEL as a use condition (Risotto,
2003).

	EPA believes it has the authority to calculate exposure limits for the
workplace under section 612.  Section 612(c) specifically states that
“the Administrator shall issue regulations:

providing that it shall be unlawful to replace any class I or class II
substance with any substitute substance which the Administrator
determines may present adverse effects to human health or the
environment, where the Administrator has identified an alternative to
such replacement that--

		(1) reduces the overall risk to human health and the environment; and

		(2) is currently or potentially available.”

Thus, we must compare the risks to human health and the environment of a
substitute to the risks associated with other substitutes that are
currently or potentially available, as required by the Clean Air Act.
In order to compare risks to human health, EPA performs quantitative
risk assessments on different chemicals comparing exposure data and
exposure limits, following the process described above by the National
Academies of Science (NAS, 1983) and as described in the preamble to the
original final SNAP rule (March 18, 1994; 59 FR 13066).  Because most
humans who are exposed to nPB are exposed in the workplace, the
appropriate exposure data and exposure limits to protect human health
must include workplace exposure data and acceptable exposure limits for
the workplace.  Because there is wide disparity in acceptable exposure
limits for nPB developed by industry, ranging from 5 ppm to 100 ppm
(Albemarle, 2003; Chemtura, 2006; Docket A-2001-07, item II-D-19; Enviro
Tech International, 2006; Farr, 2003; Great Lakes Chemical Company,
2001), and because there is not a Permissible Exposure Limit for nPB set
by the Occupational Safety and Health Administration, EPA believes it is
appropriate to independently evaluate the human health risks associated
with use of nPB in the workplace.  Similarly, EPA has developed a
community exposure guideline to assess the human health effects of nPB
exposure to the general public.

Skin Notation

	Several commenters on the June 2003 proposal stated that a skin
notation for nPB is appropriate, while another commenter agreed with
EPA’s proposal that no skin notation was necessary (Smith, 2003;
HESIS, 2003; Werner, 2003, Weiss Cohen, 2003).  Rat studies indicate
that dermal exposure to nPB results in neither appreciable absorption
through the skin (RTI, 2005) nor systemic toxicity (Elf Atochem, 1995).
Unlike methyl chloride and dichlorvos, which are absorbed through the
skin and could contribute to systemic toxicity (ACGIH, 1991), EPA is not
proposing to include a skin notation for nPB in the information provided
to users associated with this rulemaking because of the relatively low
level of absorption.  The American Conference of Governmental Industrial
Hygienists (ACGIH) provides no skin notation in its documentation for
threshold limit values (TLVs) for several solvents, including nPB
(ACGIH, 2005), methylene chloride, and perchloroethylene, and there is
no evidence that absorption through the skin is greater for nPB than for
the other halogenated compounds.  Further, including a statement giving
advice about how to reduce skin exposure in the “Further
Information” column of listings is likely to be more informative to
workers than a skin notation.

Given the possibility that some nPB can be absorbed through the skin in
humans, and that the solvent can irritate the skin, EPA encourages users
to wear protective clothing and flexible laminate gloves when using nPB
and encourages vendors to include such precautions in their Material
Safety Data Sheets (MSDSs).   EPA requests comment on whether it would
be useful, in lieu of a skin notation to add the following statement in
the “further information” column of each end use where we find nPB
acceptable with restrictions:  “EPA recommends the use of personal
protective equipment, including chemical goggles, flexible laminate
protective gloves and chemical-resistant clothing, when using nPB.”

	EPA also considered the potential health effects of contamination of
nPB formulations with isopropyl bromide (iPB).  In the June 2003
proposed rule, we proposed as a use condition that nPB formulations
contain no more than 0.05% iPB by weight.  One commenter opposed the
proposed use condition, stating that it places an undue legal burden on
end users, rather than the manufacturers of raw materials, that it would
not benefit worker safety, and that the nPB industry has worked to
reduce iPB content below 0.05% (Morford, 2003e).  We agree that industry
has met this contamination limit for several years without regulation.
Furthermore, EPA agrees that if users are exposed to nPB concentrations
no higher than the highest potentially acceptable concentration (30
ppm), a worker’s exposure to iPB will be sufficiently low to avoid
adverse effects.  Therefore, this proposed rule does not include a use
condition limiting iPB content in nPB formulations.

1.	Workplace Risks

In the June 2003 NPRM, EPA proposed that an exposure limit of 25 ppm
would be protective of a range of effects observed in animal and human
studies, including reproductive and developmental toxicity,
neurotoxicity, and hepatotoxicity.  Reduction of sperm motility in rats,
noted across multiple studies at relatively low exposures, was
determined to be the most sensitive effect.  The Agency derived an
exposure limit of 18 ppm from a dose response relationship in male rat
offspring (“F1 generation”) whose parents were exposed to nPB from
prior to mating through birth and weaning of the litters (WIL, 2001).
We then proposed to adjust this value upwards to 25 ppm based on
principles of risk management, consistent with one of the original
“Guiding Principles” of the SNAP program (59 FR 13046, March 18,
1994).  As we discussed in the June 2003 NPRM, EPA noted that adhesives
users should be able to achieve an AEL of 25 ppm and that 25 ppm was
between the level based on the most sensitive endpoint (sperm motility
in the F1 offspring generation at 18 ppm) and the second most sensitive
endpoint (sperm motility in the F0 parental generation at 30 ppm).
Following SNAP program principles, we noted that “a slight adjustment
of the AEL may be warranted after applying judgment based on the
available data and after considering alternative derivations”(69 FR
33295).  Because the animals were exposed to nPB for some time periods
that would not occur during actual occupational exposure, we stated
further that “18 ppm is a reasonable but possibly conservative
starting point, and that exposure to 25 ppm would not pose substantially
greater risks, while still falling below an upper bound on the
occupation[al] exposure limit.”

Since the 2003 proposal, the Agency has reviewed both information
available at the time of the 2003 NPRM related to the health risks
associated with nPB use, as well as more recent case studies of nPB
exposures and effects in the workplace, newly published toxicological
studies, comments to the June 2003 NPRM, including new risk assessments
on nPB, and a new threshold limit value (TLV) issued by ACGIH.

OSHA has not developed a permissible exposure limit (PEL) for nPB that
EPA could use to evaluate toxicity risks from workplace exposure.  The
ACGIH, an independent organization with expertise in industrial hygiene
and toxicology, has developed a final workplace exposure limit of 10 ppm
(ACGIH, 2005); however, as discussed below, EPA has concerns about the
documentation and basis of ACGIH’s derivation.

The Agency reconsidered which exposure levels are likely to protect
against various health effects, based on review of all available
information.  We summarize benchmark dose data for a number of endpoints
found in these analyses in Table 6 below.  We examined these data to
assess the acceptability of nPB use in the aerosol solvent, adhesive and
coatings end uses reviewed in this proposed rule.  These data indicate
that, once uncertainty factors are applied consistent with EPA
guidelines, the lowest levels for acceptable exposures would be derived
for reproductive effects.  The data indicate that levels sufficient to
protect against male reproductive effects (e.g., reduced sperm motility)
would be in a range from 18 to 30 ppm, in the range of 17 to 22 ppm to
protect against female reproductive effects (e.g., number and length of
estrous cycles), and at approximately 20 ppm for effects related to
reproductive success (live litter size).

Table 6: Summary of endpoints using benchmark response modeling

Endpointa	Study	Benchmark Dose Lowerbound (BMDL)b

(ppm)	Human Equivalent Concentration (HEC)c

(ppm)

Liver Effectsd

Liver vacuolation in males

(F1 offspring generation)	WIL, 2001 as analyzed in ICF, 2002	110

	116

Liver vacuolation in males  (F0 parent generation)	WIL, 2001 as analyzed
in ICF, 2002	143

	150

Liver vacuolation	ClinTrials, 1997b as analyzed in ICF, 2002 and
Stelljes & Wood, 2004	226

	170

Reproductive Effects—Male

Sperm motility (F1 offspring generation)

	WIL, 2001 as analyzed in ICF, 2002	169	177

	WIL, 2001 as analyzed in Stelljes & Wood, 2004	156	164

Sperm motility (F0 parent generation)

	WIL, 2001 as analyzed in ICF, 2002	282	296

	WIL, 2001 as analyzed in Stelljes & Wood, 2004	263	276

Prostate weight (F0 parent generation)	WIL, 2001 as analyzed in TERA,
2004	190	200

Sperm count 	Ichihara et al., 2000b as analyzed in Stelljes & Wood, 2004
232	325

Sperm deformities (F0 parent generation)	WIL, 2001 as analyzed in
Stelljes & Wood, 2004	296	311

Reproductive Effects—Female

Number of estrus cycles during a 3 week period (F0 parent generation)
WIL, 2001 as analyzed in ICF, 2006	162	170

	WIL, 2001 as analyzed in ICF, 2006	208 	218

Estrous cycle length (F1 offspring generation)d 	WIL, 2001 as analyzed
in TERA, 2004	400 	420

Estrous cycle length (F0 parent generation)e 	WIL, 2001 as analyzed in
TERA, 2004	210 	220

No estrous cycle incidence (F1 offspring generation)	WIL, 2001 as
analyzed in TERA, 2004	180	189

No estrous cycle incidence (F0 parent generation)	WIL, 2001 as analyzed
in TERA, 2004	480	504

Reproductive Effects—Reproductive Success

Decreased live litter size (F1 offspring generation)	WIL, 2001 as
analyzed in TERA, 2004	190	200

Decreased live litter size (F2 offspring generation)	WIL, 2001 as
analyzed in TERA, 2004	170	179

Pup weight gain, post-natal days 21 to 28 (F1 offspring generation)	WIL,
2001 as analyzed in TERA, 2004	180	189

Developmental Effects

Fetal body weight	WIL, 2001 as analyzed in TERA, 2004	310	326

Fetal body weight	WIL, 2001 as analyzed in CERHR, 2002a	305	320

Nervous System Effects

Hindlimb strength	Ichihara et al, 2000a as analyzed in Stelljes and
Wood, 2004	214	300

a Unless explicitly stated, data are from a parental generation.  Of the
studies analyzed, only the WIL, 2001 study has multiple generations to
be analyzed.

b The benchmark response value represents a specified level of excess
risk above a control response.

c When considering workplace exposures, the human equivalent
concentration is the BMDL, adjusted to apply to a 40-hour work week in
which workers are exposed for 8 hours a day for five days per week.
Animals in the WIL, 2001 study were exposed for 6 hours a day, 7 days a
week.  Animals in the Ichihara, 2000a and 2000b studies were exposed for
8 hours a day, 7 days a week.  Animals in the ClinTrials, 1997b study
were exposed for 6 hours a day, 5 days a week.

d After applying an uncertainty factor of 3 for animal to human
extrapolation, acceptable levels of exposure to protect against liver
effects would be in the range of 39 to 57 ppm.

e Omits data from those animals that have stopped estrous cycling
altogether (TERA, 2004).

2.	General population risks

EPA used a community exposure guideline of 1 ppm to assess potential
risks to the general population living near a facility using nPB (see
section V.E below).  Of the end uses covered in this rule, use of
nPB-based adhesives would result in the highest exposure levels, and so,
we first examined general population exposure from adhesives.  ICF
Consulting modeled inhalation exposure to nPB to people living near a
plant using nPB-based adhesives in several scenarios using the
Agency’s SCREEN3 model (US EPA, 1995b).  Based on this modeling, EPA
found that the exposure to individuals in the general population was
below the community exposure guideline.  The analysis indicates that nPB
is no greater a hazard to the general population than other acceptable
solvents under the SNAP program.  For further discussion, see the risk
screen for nPB (ICF, 2006a).

	Representatives from a state environmental agency and from a potential
user of nPB have asked EPA whether we had developed a reference
concentration (RfC).  We clarify that the community exposure guideline
is a value developed by the SNAP program for our risk assessment of nPB
following EPA’s RfC Guidelines.  However, it is not a formal RfC
developed by EPA’s National Center for Environmental Assessment and is
not in IRIS.  At this time, EPA does not have plans to issue an official
RfC for nPB.

How did EPA assess impacts on human health?

	A.	Newly available exposure data

	Since publication of the June 2003 NPRM, EPA has received additional
information on exposure levels in each end use discussed in this
proposal.

	In the adhesives end use, we considered new exposure modeling based on
information from site visits to facilities using spray adhesives (ICF,
2006a).  These data predicted that:

At average rates of ventilation and adhesive application, average
workplace exposures would be approximately 60 ppm.

Average adhesive application rates and poor ventilation rates resulted
in average exposures of approximately 250 ppm.

High (90th percentile) adhesive application rates and average
ventilation rates resulted in average exposures of approximately 600
ppm.

In the worst case scenario with high adhesive application rates and poor
ventilation, average workplace exposures would be as high as 2530 ppm.

	We compared the modeled data in the four exposure scenarios to measured
exposure data in three health hazard evaluations by the National
Institute for Occupational Safety and Health (NIOSH) (NIOSH 2002a,
2002b, 2003a).  Our understanding is that North Carolina OSHA received
complaints from workers and requested that NIOSH evaluate health hazards
at these three facilities.  NIOSH found average exposure levels of 68
ppm, 116 ppm, 127 ppm, and 195 ppm for sprayers actively using the
adhesive prior to installation of state-of-the-art ventilation systems
(NIOSH 2002a, 2002b, 2003a).  The plant with an average exposure level
of 68 ppm for sprayers (9 samples) had an average exposure level
comparable to the average concentration of 60 ppm in the modeling
scenario with average adhesive rates and average ventilation levels.
The other plants with average exposure levels of 116 to 127 ppm (20
samples), and of 195 ppm (36 samples) for sprayers had exposure levels
between the average modeled exposure for a facility with average
adhesive application rates and average ventilation (60 ppm) and the
average modeled exposure for a facility with average adhesive
application rates and poor ventilation (250 ppm).  Based on this
comparison, EPA believes the modeled exposure levels are a reasonable
predictor of actual exposure based on current industry practice in the
adhesive end use.

	In the aerosol solvent end use, we received a study on workplace
exposure levels of nPB-based aerosols from a commenter (Linnell, 2003).
This study was performed to simulate typical exposure levels in a number
of situations where nPB might be used in the workplace while using
different types of ventilation equipment, rather than using data from
current industry users of nPB-based aerosols in their actual
manufacturing or maintenance processes.  As discussed below in section
VI.A., we are concerned that the exposure data and ventilation levels in
this study may not be representative of use of nPB-based aerosols in
industry.  Personal breathing zone samples taken from the collars of
workers showed 8-hour time-weighted average (TWA) exposures of 5.5, 13,
and 32 ppm for workers using 310 g of nPB from a spray can (Linnell,
2003).  The two higher exposure levels occurred in the absence of any
local or regional ventilation; the use of both local and regional
ventilation equipment with ventilation levels around 1900 ft3/min was
associated with the lowest exposure level.  Short-term exposures of 370,
1,100 and 2,100 ppm taken from a room with regional ventilation at 640
cubic feet per minute (cfm), when averaged over an 8-hour period,
resulted in exposures of 12, 34, and 66 ppm (Linnell, 2003).  EPA
considers the highest of these 8-hour values, 66 ppm, not to be
representative of worker exposure from inhalation because the
measurement was taken from the worker’s wrist, rather than from his
breathing zone.  Another short-term exposure value of 190 ppm, taken
from a vented booth with local ventilation at 472 cfm, in addition to
the regional ventilation of 640 cfm, resulted in an 8-hour exposure of 6
ppm.  Similar measurements were made in another study we considered in
developing the June 2003 NPRM:  Eight hour (8-hr) TWA exposures of 11.3,
15.1, 17.0, and 30.2 ppm with regional ventilation of 300 cubic feet per
minute from a fan for the entire room (Confidential submission, 1998).

	Another commenter submitted information on aerosol exposures for a
number of other available alternative aerosols (Werner, 2003).  While
these data do not include nPB, based on the properties of aerosol
solvents, we believe it is reasonable to compare concentrations of these
different chemicals to potential nPB exposures.  The study compared
concentrations of eight different chemicals that are acceptable under
the SNAP program in aerosol formulations:  HFE-7100, HFE-7200,
trans-1,2-dichloroethylene, HCFC-225ca and -225cb, acetone, pentane, and
HFC-134a.  In this study, with ventilation of only 48 cfm, 8-hr TWA
exposure from the different chemicals varied from 35.5 ppm to 194.0 ppm,
below the recommended exposure levels for these particular chemicals
(ICF, 2006a) but above the range of exposure levels that EPA would
consider acceptable for nPB.

	In addition, we considered new information from modeling of nPB
exposures (ICF, 2006a).  The modeling examined exposure levels that
would be expected at ventilation levels of 450 cfm, 625 cfm, and 1350
ppm, considering the molecular weight of the compound and the
composition of different aerosol blends.  EPA’s SNAP program has
previously used these same levels to calculate potential aerosol
exposures, based upon exposure levels expected during benchtop cleaning.
 In a space with an air exchange rate of 450 ft3/minute or less, EPA’s
modeling predicts 8-hour average exposure of approximately 16 to 17 ppm
if a user sprays 450 g of nPB (approximately 1 lb), and corresponding
higher exposure values at higher spray rates (e.g., 33 ppm if the amount
of nPB sprayed is 900 g) (ICF, 2006a).  Exposure values were predicted
to be lower at higher ventilation rates.

	Since the June 2003 NPRM, EPA received a new submission for nPB in
coatings (Lake City Army Ammunition Plant, 2003).  The Lake City Army
Ammunition Plant provided data on workplace exposure to nPB (Lake City
Army Ammunition Plant, 2004).  The mean exposure at this facility was
3.7 ppm.  Out of 31 samples taken, 25 (approximately 80%) were below 5
ppm.  Only one of 31 samples had an exposure level above 10 ppm, and
that exposure value was approximately 21 ppm.

.	B.	Newly available data on health effects

Since publication of the June 2003 NPRM, EPA has examined additional
occupational (Table 7) and animal (Table 8) studies that have become
available:

Table 7. Recent Studies on nPB Occupational Exposure

Case Study	Sample Size/Population	Exposure Data	Observations	Remarks

Beck and Caravati, 2003	6 foam cushion factory workers (gluers)	Exposure
during 30-40 hr/wk for a 3-month period. Exposure measured in one day
was a mean of 130 ppm (range, 91-176 ppm). 	Lower leg weakness
accompanied by pain and difficulty with standing and walking, numbness
of legs and feet, hyperreflexia and hypertonicity of lower extremities,
dizziness and shortness of breath, and peripheral neurotoxicity.
Measured serum bromide levels were elevated, range 44-170 mg/dL.	Small
sample size studied.  Possible interference or synergistic effects from
other adhesive ingredients (1,2-epoxybutane and styrene-butadiene).

Majersik et al., 2004; Majersik et al., 2005 * 	6 foam cushion factory
workers (gluers)	5-8 hr/day for at least 2 years with mean air
concentration of 130 ppm on last day of study.  Measurements taken over
9 hours (equivalent to 92-127 ppm with mean of 108 ppm for an 8-hour
TWA).	Subacute onset of lower extremity pain, difficulty walking, and
high serum bromide levels in blood.  Neurotoxic symptoms persisted for
at least 2 years after exposure ended.	Follow-up to Beck and Caravati
(2003). Chronic nPB exposure associated with incapacitating neurotoxic
syndrome.  Initial report from Utah OSHA indicated erroneously that
workers were not spraying while measurements were taken.  In fact,
adhesives were being sprayed and fans were being used only for portions
of the day that measurements were taken, making measurements likely to
be representative of conditions during the past several months at the
plant.

Ichihara et al., 2004a	37 chemical plant workers (24 males and 13
females)	12 hour shifts over 2-day period, mean concentration of 82 ppm
(range, 0-170 ppm) 	Mucosal irritation (nose, throat), headache,
dizziness, constipation, intoxication, and feeling light-headed or
heavy-headed.  Four female workers complained of disruption or cessation
of menstruation.  No severe chronic symptoms of neurological damage at
less than 170 ppm.  Several workers had hemoglobin and hematocrit values
outside of the normal range and were diagnosed with mild anemia; most of
these cases also showed signs of iron deficiency.	Inadequate exposure
characterization and exposure to other potential toxicants, small sample
size, and no appropriate control group.  Healthy worker effect possible,
where more sensitive workers left the factory between 1996 and 1999.

Ichihara et al., 2004b	27 female chemical plant workers (23 age matched
with 23 females from a beer factory control group)	1-day exposure
period, range of exposure, 0.34-49 ppm	Responses indicated anxiety,
fatigue, confusion, tension, and depression.  Changes in menstrual
status but not statistically significant.  Effects on peripheral and
central nervous system —diminished vibration sensation of the foot;
significantly longer distal latency in the tibial nerve; decreased
values in sensory nerve conduction velocity in the sural nerve; and
lower scores on memory and perceptual tests.  No comparable effects seen
in control group. 	No long-term exposure measurements, small sample
size; lack of controls for age, height, and body-weight.  Low B vitamin
levels in normal range in some workers but researchers concluded this
did not cause observed neurological effects.  Additionally, the study
did not indicate any significant differences in the prevalence of
menstrual cycle abnormalities.

Nemhauser, 2005 *	Foam cushion factory workers (gluers) in North
Carolina 	In 1999 study, 16 workers exposed to mean air concentration of
116 ppm, and 12 sprayers exposed to mean concentration of 108 ppm with
range of 58 to 254 ppm.  In 2001 study, 13 workers exposed to nPB mean
air concentration of 46 ppm and 12 sprayers were exposed to mean
concentration of 101 ppm, with range of 38 to 281 ppm.	Higher exposure
to nPB and dose-dependent relationship among those who reported anxiety,
headache, and ataxia.  No reproductive abnormalities reported in medical
survey for men or women.  Semen analysis found no differences between
exposed and unexposed workers.	Small sample sizes studied with moderate
worker participation.  Healthy worker effect likely occurred: those that
had most significant health effects had already removed themselves from
workplace by the time of the study.  No arsenic found at the plant.
Neurotoxic effects caused by nPB.  See related Health Hazard Evaluation
(HHE): NIOSH, 2003a.

NIOSH, 2003a	16 workers in 1999 evaluation; 13 workers in 2001 follow-up
evaluation. 	1999 Initial Site Visit: geometric mean nPB concentration
(from personal samples), 81.2 (range, 18-254 ppm); 2001 follow-up:
geometric mean, 81.2 ppm (range, 7-281 ppm)	Most workers exposed to nPB
levels >25 ppm.  Exposure concentrations lower in 2001 than 1999, but
difference not statistically significant.  Headache, anxiety, feeling
drunk associated with nPB exposure.  Hematological endpoints unaffected
in exposed group.  No correlation of nPB exposure with sperm or semen
indices or with neurological abnormalities.  	Arsenic was not attributed
to occupational exposure.  The National Institute for Occupational
Safety and Health (NIOSH) stated that neurological symptoms may have
been related to excess exposure to nPB, but that no other effects could
conclusively be related to nPB exposure.

Raymond and Ford, 2005*	4 foam cushion factory workers (gluers) in North
Carolina	Exposure study conducted 9 months after index patient became
ill indicated workers exposed to mean nPB air concentration of 116 ppm.
4 workers exposed for 2-3 weeks before initial symptoms detected.
Dizziness, numbness, ocular symptoms, lower extremity weakness and
unsteady gait, weakness, hypesthesia, and ataxic gait in all four
workers.  Symptoms decreased over time but after six years, at least one
worker re-exposed twice at other furniture plants; one or more still
suffer from ataxia.	Small sample size, possible confounding effect from
arsenic.

Toraason et al., 2006	 41 and 22 foam cushion factory workers (gluers)
at 2 facilities	1-3 days up to 8 hrs per day, with concentrations of
 0.2 – 271 ppm at facility A, 4 - 27 ppm at facility B.	No
statistically significant differences in DNA damage with worker’s nPB
exposure.  In vitro results showed nPB increased DNA damage.	Authors
find limited evidence that nPB poses a “small risk” for DNA damage.

	*Presentation at North American Congress of Clinical Toxicology on
September 14, 2005.

Table 8. Recent Animal Studies of nPB Effects

Citation	Population/

sample size	Exposure	Observations	Comments

Fueta et al., 2002	24 male Wistar rats (12 control, 12 exposed)	6
hr/day, 5 day/wk for 8 weeks at 700 ppm	No apparent morphological
defects in the brain.	Only one exposure concentration was used (which is
higher than the level already associated with other toxic effects in
rodents [400 ppm]) and a shorter exposure duration (8 weeks) was used
than the other subchronic studies that have shown effects (13 weeks).

Fueta et al., 2004	58 male Wistar rats (29 experimental and 29 in
control group)	6 hr/day, 5 day/wk for 4 to 8 weeks,, 700 ppm	No apparent
morphological defects in the brain.  Chronic inhalation changes brain
enzyme levels and electrical activity that is reversible after exposure.
Unclear how nPB and/or its metabolites directly act on receptors or
channels in the brain.

Furuhashi et al., 2006	80 Wistar rats (pups and their dams)	1) 8 hr/day
(4 hr, followed by 2.5-hr rest period, followed by 4 hr exposure), 7
day/wk during gestation and  nursing at  0, 100, 400, 800 ppm in first
experiment.

2)  Dams exposed (800 ppm) during gestation (Group A),  offspring not
exposed during nursing.  Offspring of Group (B) of unexposed dams were
nursed by exposed dams.  Offspring in control groups C and D not
exposed.	1) At 800 ppm: most rat offspring died within 2 days of birth
or in utero;.  body weights of dams significantly lower, organ weights
of offspring   significantly lower after weaning at 800 ppm in males,
and 800 and 400 ppm in females.  Most sperm and estrous indicators did
not differ among the groups, although the rate of sperm arrival to the
cauda epididymis was significantly lower in the 400 ppm group.
Inconsistent or no changes in biochemical indicators.

2) Second experiment No difference in body weights and pregnancy
endpoints between exposed (800 ppm) and unexposed dams. Live offspring
at birth, survival rates, body weights, significantly decreased, number
of dead offspring, significantly increased in 800-ppm groups.  	Authors
concluded that exposure to nPB during pregnancy and lactation adversely
affects growth and survival of offspring.  Low numbers of offspring
in 400- and 800-ppm exposure groups prevent statistical testing.

 liver cells ≥ 250 ppm (males) and ≥ 500 ppm (females), with
increased severity at higher doses.  No adverse central nervous system
(CNS) effects or histopathology reported.	Unpublished study.
Conclusions drawn from a review of raw data from the National Toxicology
Program (NTP) web site.  In general, the severity of effects (in
non-reproductive organs) is slightly higher at lower concentrations in
male rats than in females.

RTI, 2005/Garner et al., 2006	Female and male B6C3F1mice and Fisher 344N
 rats, four to six animals in each test trial	Exposure via several
injection routes (intraperitoneal, intravenous, cannuliz-ation),
inhalation, and dermal. Injection conducted via bolus dosing at 5, 20,
or 100 mg/kg body weight.  Inhalation concentrations of 70, 240, 800,
and 2700 ppm administered in a single acute exposure.  A dose of 96
mg/kg was applied to a shaved area on the backs of six male rats with a
non-occlusive charcoal filter covering (that is, one that does not
prevent evaporation).  	nPB cleared by mice after 48 hours as follows:
45% as volatiles in the breath, 28% as CO2 in the breath, 26% in urine,
<3% in feces, and 2% retained in the body.  Distribution was similar in
male rats, although amounts in urine and volatiles in breath were higher
in mice.  At higher doses, the amount of nPB excreted in urine and as
CO2 decreased, with a much greater change in rats compared to mice.

After pretreatment with a cytochrome P450 inhibitor, a decrease in nPB
cleared as CO2 (80%) and urine (40%); pretreatment with a glutathione
inhibitor reduced  nPB cleared as CO2 by 10% and urine by 4%.

The Vmax, a measure of the maximum initial rate of an enzyme-catalysed
reaction, is 0.227 for male rats, 0.143 for female rats, 0.329 for male
mice and 0.234 for female mice.  Half-lives were comparable between
males and females at ≤ 800 ppm.

For rats exposed to nPB through skin, 37% of the dose was excreted in
volatiles, 1.2 % in urine, 1.7% as CO2, and 35.7% was on the applicators
or in the skin washes.  Only 0.32% remained in tissues.  Airborne
concentrations of nPB in the chamber were 4 to 10 ppm after dosing.	The
study authors concluded that:

nPB administered via intraperitoneal injection or inhalation is
eliminated mostly through the breath, with urine as a secondary path.

Metabolism of nPB appears to be primarily through cytochrome P450
enzymes (CYP2E1), particularly in mice; glutathione conjugation still
plays an important role in rats.

At high concentrations, female rats may have a decreased capacity to
metabolize nPB compared to male rats.

nPB decreases glutathione levels in the liver after a one-time exposure
to nPB at concentrations as low as 70 ppm.

nPB is not appreciably absorbed (~3-27%) in rats following dermal
application.

EPA agrees with these points, except we found that gender differences
were only apparent in rats at very high concentrations (2700 ppm and
greater).  We also note that:

Inhalation tests were only one-time exposures at very high
concentrations (240 to 2700 ppm), and thus, are not comparable to
long-term dosing at the lower levels expected in the workplace.

Results of dermal testing are not conclusive because of potential for
inhalation exposure.

Sohn et al., 2002	40 male and 40 female Sprague-Dawley rats	6 hr/day, 5
day/wk for 13 weeks, test groups (10/sex/dose) were exposed to 0, 200,
500 or 1250 ppm	No effects on mortality, activity, weight gain, food
consumption, urinalysis, or histological effects in the brains and
spinal cords. 	The differences between the various studies may be due to
variability in exposure methodology and achieved concentrations of nPB.

Stump, 2005* 	125 female/125 male rats in first generation and 100
female/100 male rats in offspring generation	Both test groups of 25 male
rats/ 25 female rats exposed to 0, 100, 200, 250, 500 and 750 ppm nPB
for 10 weeks	Decreased litter size at 250 and 500 ppm in both
generations. Decreased fertility at 100 and 250 ppm in offspring
generation.

ignificant decrease in antral follicles at ≥ 200 ppm, and a decrease
in the number of female rats exhibiting regular estrous cycles in
400-ppm females during 7-9 weeks of exposure and at 2-3 weeks at the
800-ppm dose.	Data suggest that nPB is affecting the maturation of
ovarian follicles.  A no observed adverse effect level (NOAEL) of 200
ppm is identified with a LOAEL of 400 ppm for the changes in estrus
cycles.

*Presentation at North American Congress of Clinical Toxicology on
September 14, 2005

In general, the recent animal studies collectively show a range of
effects associated with nPB exposure that are qualitatively consistent
with previously published findings.  (Exceptions to this are the
negative results regarding central nervous system toxicity in the NTP
(2003) study and the Sohn (2002) study on rats.)  Some general
conclusions we draw from the new studies include:

Case reports of nPB exposure in the workplace indicate that severe,
possibly irreversible, neurological effects may occur at sustained
concentrations of approximately 100 ppm or greater (Beck and Caravati,
2003; Majersik et al, 2004; Majersik et al., 2005; Ichihara et al.,
2002a; Miller, 2005; Raymond and Ford, 2005).  In other cases, similar
or higher concentrations up to 170 ppm caused less severe nervous system
effects (Nemhauser, 2005; NIOSH, 2003a; Ichihara, 2004a).  Some
neurological effects occurred in workers at levels of less than 50 ppm
(Ichihara et al., 2004b).  Because of design and methodological
limitations, such as small numbers of subjects and limited exposure
information, these studies do not provide a sufficient quantitative
basis to derive an acceptable exposure limit.

Data on female rats indicate that nPB affects the maturation of ovarian
follicles and the ovarian cycle (Yamada et al., 2003), consistent with
previously reviewed data (WIL , 2001; Sekiguchi et al., 2002).

Some data on occupation exposure suggest that workers exposed to nPB may
have experienced menstrual disorders (Ichihara et al., 2002; Ichihara et
al., 2004b).  However, the data are not statistically significant and
are not sufficient to conclude that nPB exposure caused these female
reproductive effects.

Data on DNA damage in workers exposed to nPB was not statistically
significant (Toraason et al., 2006).

Metabolic data on mice and rats indicate some species differences.
Metabolism of nPB appears to be primarily through cytochrome P450
enzymes, particularly in mice; glutathione conjugation also plays a
role, and a bigger role for rats than for mice (RTI, 2005).

New data from toxicological studies on nervous system effects remain
inconsistent and equivocal concerning the level at which nervous system
effects occur (Fueta et al., 2002; Fueta et al., 2004; Honma et al.,
2003; Ishidao et al., 2002, NTP, 2003; Sohn et al. 2002, Wang et al.,
2003).

A number of commenters on the June 2003 NPRM suggested that EPA should
consider neurotoxicity as the endpoint in deriving an AEL for nPB
(Linnell, 2003; Werner, 2003; Rusch and Bernhardt, 2003, Rusch, 2003).
In particular, they requested that EPA consider the study conducted by
Wang (2003) and epidemiological data on neurotoxic effects of nPB.  As
discussed above, the data on neurotoxic effects of nPB on workers are
limited and are not sufficient to determine acceptable levels of
exposure.  In the study on rats by Wang et. al (2003), measurements
found a decrease in enzymes in the spinal cord and brain at 200, 400,
and 800 ppm, but the animals displayed no physical or behavioral
changes.  Because of the lack of physical symptoms or behavioral
changes, EPA does not believe that the decrease in enzyme levels in the
central nervous system are toxicologically relevant.  Other studies
examining neurological effects of nPB showed those effects to be
transient and reversible at and above 200 ppm (Ichihara et al., 2000a).
Exposures of 200 ppm and above for three weeks had no effect on memory,
learning function, or coordination of limbs (Honma, 2003); the effect of
spontaneous locomotor activity seen in this study at 50 ppm and above
was not considered adverse by the authors.  In other studies,
neurological effects were absent after extended periods of
exposure—after 28 days of exposure at concentrations > 400 ppm
(ClinTrials, 1997a) and after 90 days of exposure at concentrations up
to 600 ppm (ClinTrials, 1997b).  Thus, although neurological effects
have been associated with nPB exposure, the data are currently
insufficient to quantify and determine acceptable exposure levels based
on this endpoint.

One commenter on the June 2003 NPRM requested that EPA evaluate a study
by Yamada et al (2003), a study published just prior to the June 2003
NPRM.  In response to the comment, EPA reexamined Yamada et al., 2003
and re-evaluated the literature (Ichihara et al., 1999, 2002, 2004a,b;
Sekiguchi, 2002, Yamada et al., 2003; WIL, 2001) to assess potential
reproductive toxicity in females (ICF, 2006a, Att. A).  A peer review of
these effects is in the public docket (ICF, 2004b).  Multiple benchmark
analyses found a statistically significant decrease in the number of
estrous cycles and increase in estrous cycle length associated with nPB
exposure, consistent with other reproductive endpoints, namely
reductions in sperm motility, decreased live litter size, and change in
prostate weight (ICF, 2002a; ICF, 2006a; Stelljes and Wood, 2004; TERA,
2004).

	Reproductive effects are seen in males, females, and offspring, and in
different generations of the two-generation study (WIL, 2000).  They
also are consistent with results seen in one-generation reproductive
studies, such as Ichihara et al. (2000b) and Yamada (2003).  See Table 6
above in section IV.E.1. for a more complete list of the different
health effects.  EPA believes that the preponderance of the data
indicate that exposure levels sufficient to protect against male
reproductive effects (e.g., reduced sperm motility) would be in a range
from 18 to 30 ppm, in the range of 17 to 22 ppm to protect against
female reproductive effects (e.g., number and length of estrous cycles),
and at approximately 20 ppm for effects related to reproductive success
(live litter size).  We have not determined what specific level within
those ranges (an overall range of 17 to 30 ppm) is most appropriate for
evaluating whether a substitute may be used safely and consider these
exposure levels to be potentially acceptable.  Therefore, we assessed
the acceptability of nPB by considering whether it could be used safely
in the three end-uses.  For end-uses with likelihood of exposures above
the range we are considering, while following typical industry
practices, we are proposing an unacceptability determination.  For
end-uses that as their normal practice meet exposure levels below the
range we are considering, we are proposing an acceptability
determination.  It is not necessary for 100% of exposure data for an end
use to be above or below the range of 17 to 30 ppm in order to make a
determination on the acceptability of an end use because there may be
occasional cases that are not following common industry practices.
Unusual events would not indicate the industry’s likelihood of keeping
exposures at safe levels, and thus, should not be the determining factor
in our decision.  Rather, we consider the overall likelihood that
typical industry use would consistently result in acceptably low or
unacceptably high exposures.

	In the June 2003 NPRM, EPA used a BMDL of 169 ppm as a point of
departure for developing an AEL.  Some commenters stated that data from
the F1 generation is inappropriate for calculating occupational
exposure, citing statements from toxicologists, such as, “occupational
exposure involves adults only.”  They also stated that EPA has not
required this for other chemicals and that the resulting value is more
conservative than what is normal and appropriate for industrial
toxicology (Morford, 2003f, Ruckriegel, 2003).  Others stated that sperm
motility effects on the F1 generation are appropriate to consider
(Risotto, 2003; Farr, 2003), particularly because of the potential for
in utero effects and because of the consistent presence of these
reproductive effects in both generations and at multiple levels.  EPA
acknowledges that using data from the F1 offspring generation may be
conservative because the pups in the F1generation were exposed to nPB
between weaning and sexual maturity (WIL, 2001).  During occupational
exposure, this period of exposure would not occur because children under
age 16 are not allowed to work in industrial settings.  However, EPA
believes that because of the potential for in utero effects that would
only be seen in the offspring generation, looking only at the F0
parental generation could underestimate the adverse health impacts of a
chemical.  Therefore, we believe it is appropriate to consider effects
seen in both the F0 parental generation and the F1 offspring generation.
 Further, effects on sperm motility in the parental and offspring
generations are seen at levels generally consistent with multiple
reproductive effects seen in both generations and both sexes exposed to
nPB, such as estrous cycle length, lack of estrous cycling, the number
of estrous cycles in a given period of time, fertility indices, and the
number of live pup births (TERA, 2004; ICF, 2006a; SLR International,
2001).  Therefore, we believe that the available data indicate that in
order to protect against adverse reproductive effects, an exposure level
within the range of 17 to 30 ppm, would potentially be acceptable.  We
would reach the same proposed decisions of unacceptability based upon
data from the F0 generation.

C.	Evaluation of acceptable exposure levels for the workplace

	To calculate acceptable exposure levels for nPB, EPA uses standard risk
assessment methods delineated in Agency guidance (US EPA, 1994b) in
evaluating data, choosing a benchmark dose level or a NOAEL, and making
the adjustments and uncertainty factors prescribed to account for
differences in the duration of exposure and in sensitivity between and
within species.

		Adjustment for Occupational Exposure Pattern

To account for differences between the exposure pattern used in the WIL
study (6 hours per day for 7 days per week) when compared to a typical
workweek of 8 hours per day and 5 days a week, a “human equivalent
concentration” (HEC) is first calculated by adjusting the benchmark
dose level:

(BMDL in ppm x 6 hours/8 hours) x 7 days/5days = HEC ( ppm)

HECs for the major health endpoints are shown in Table 6 above in
section IV.E.1. 		Uncertainty Factors

According to EPA risk assessment guidance for reference concentrations
(RfC) (EPA 1994a), uncertainty factors of up to 10 may be applied to the
HEC for each of the following conditions:

Data from animal studies are used to estimate effects on humans;

Data on healthy people or animals are adjusted to account for variations
in sensitivity among members of the human population (inter-individual
variability);

Data from subchronic studies are used to provide estimates for chronic
exposure;

Studies that only provide a LOAEL rather than a NOAEL or benchmark dose;
or

An incomplete database of toxicity information exists for the chemical.

EPA believes that two uncertainty factors are appropriate for this
database to account for that: (1) physiological differences between
humans and rats; and (2) variability within the working population.  The
rationale for the use of these two uncertainty factors is described
below.

EPA RfC guidelines state that an uncertainty factor of 10 may be used
for potential differences between study animals and humans.  This factor
of 10 consists in turn of two uncertainty factors of 3 – the first to
account for differences in pharmacodynamics and the second to account
for differences in pharmacokinetics between the study animal and humans.
(The value of three is the square root of 10 rounded to one digit, with
10 representing an order of magnitude (EPA,1994a).  In practice, EPA
uses the square root of 10 when there are two or four uncertainty
factors of 3, yielding a total uncertainty factor of 10 or 100, and we
use a value of 3 when multiplying by an uncertainty factor of 10).  By
EPA RfC guidelines (US EPA, 1994b), no adjustment for differences in
pharmacokinetics is necessary in this instance because the blood/air
partition coefficient for nPB in the human (7.1) is less than in the rat
(11.7), indicating that the delivered dose of nPB into the bloodstream
in rats is slightly higher than in humans.  Consistent with Appendix J
of EPA’s RfC guidelines for an inhaled compound that exerts its
effects through the bloodstream, EPA applies an uncertainty factor of 1
for pharmacokinetics.

	However, EPA recognizes that the lack of an uncertainty adjustment for
pharmacokinetic differences between animals and humans rests on a
default approach applied to category 3 gases described in Appendix J of
its guidelines for deriving an inhalation RfC.  This default approach
assumes that nPB’s toxicokinetics follow a model in which: (1) the
toxicity is directly related to the inhaled parent compound in the
arterial blood, and (2) the critical metabolic pathways scale across
species, with respect to body weight, in the same way as the ventilation
rate.  Given the hypothesized metabolic pathways for nPB (ICF, 2002a;
CERHR, 2002a), it is plausible that toxicity in rats may be related to a
reactive metabolite in the target tissue rather than the blood level of
the parent compound.  EPA is not aware of any quantitative data on nPB
metabolism in humans, or evidence implicating the biologically active
agent or mode of action.  Some commenters on the June 2003 NPRM stated
that EPA should use an uncertainty factor of 1 or 2 to extrapolate from
animals to humans (Weiss Cohen, 2003), while others suggested
uncertainty factors of 2 or 3 for pharmacokinetics, or an overall
uncertainty factor of 10 for rat to human extrapolation because of a
lack of information on the metabolism and mode of action of nPB and
because the rat is an insensitive model for effects on male reproduction
in humans (Werner, 2003; Rusch and Bernhardt, 2003).  Commenters
provided no data to indicate that (1) the toxicity is not directly
related to the inhaled parent compound in the arterial blood, or (2) the
critical metabolic pathways do not scale across species, with respect to
body weight, in the same way as the ventilation rate.  Recent studies
provide additional data regarding metabolism of nPB in rats and mice
(RTI, 2005), but data on human metabolism are still lacking.

One analysis of these metabolic data suggested that mice are less
sensitive to the effects of nPB than rats and hypothesized that humans
would also be less sensitive than rats (Stelljes, 2005).  However, this
analysis makes numerous assumptions about toxic nPB metabolites and
metabolic activation pathways that have not been confirmed by
experimental data.  A review of this analysis is available in the public
docket (ICF, 2006c).  Despite the difference in metabolic pathways for
nPB in mice and rats (RTI, 2005), EPA finds no significant
species-specific differences in toxicity exist between rats and mice at
inhaled concentrations <500 ppm for 13 weeks (NTP, 2003; ICF, 2006b).
These metabolic and subchronic inhalation studies conducted under the
National Toxicology Program did not specifically examine for
reproductive toxicity or nPB metabolism in target organs that control
reproductive function.  In summary, there are little available data
about the metabolic activation or reactive metabolites responsible for
reproductive toxicity in rodents.  Similarly, for nPB, there is little
information available about differences and similarities between rodents
and humans.  Given this circumstance, EPA assumes, in the absence of
evidence to the contrary, that nPB toxicity is directly related to the
inhaled parent compound in the arterial blood and that the critical
metabolic pathways scale across species in a manner similar to the
ventilation rate.  Therefore, the Agency is proposing to apply an
uncertainty factor of 1 to account for interspecies differences in
pharmacokinetics.

EPA requests additional data and comment from the public on the
pharmacokinetics, metabolism, and mode of action of nPB that will help
determine whether an interspecies uncertainty factor greater than the
default value of 1 is warranted to account for pharmacokinetics.  If
data become available indicating that nPB does not conform to the
constraints assumed by the default pharmacokinetic model in the RfC
guidelines, we would revise our risk assessment for nPB as necessary,
and apply an uncertainty factor for pharmacokinetics consistent with the
RfC guidelines in extrapolating from animal to humans.  Depending on the
resulting difference in the acceptable exposure levels, we would also
revise our acceptability determinations accordingly.  Given the
available data on the blood/air partition coefficient and EPA RfC
guidance in the absence of other information, EPA is applying the same
rationale used for other compounds reviewed under EPA’s SNAP program
with a comparable amount of data where an uncertainty factor of 1 for
pharmacokinetics was applied.  To account for uncertainty in
pharmacodynamics of nPB, EPA is applying the default uncertainty factor
of 3.  This follows the procedures in EPA’s RfC guidelines for
situations where there are no data to compare pharmacodynamics in rats
versus humans (US EPA, 1994b).  Recently published data on humans and
rodents do not decrease the uncertainty regarding the pharmacodynamics
of nPB; therefore, modification of the uncertainty factor of 3 for
differences between species is not justified.

One commenter stated that EPA did not cite any data that describes the
size, condition, or very existence of a subpopulation of men especially
sensitive to the effects of nPB.  In addition, this commenter asserted
that sensitive populations are not traditionally considered when
deriving an occupational exposure limit, and that EPA has never
mentioned a concern with sensitive subpopulations in previous SNAP
reviews.

EPA disagrees with the comments.  There are preexisting reproductive
conditions as well as significant variability in fertility among
otherwise healthy adults in the workplace.   Women over age 35 and men
over age 40 have fertility rates up to three times lower than those of
people in their twenties, with effects on the ovarian cycle and on sperm
motility as major factors changing with increasing age for women and
men, respectively (Dunson et al., 2002).  Adding damage from other
factors, such as smoking or occupation exposure to chemicals such as
nPB, therefore, can potentially harm an individual’s ability to
reproduce further (Dunson, et al. 2002).  In addition, we note that EPA
has used uncertainty factors in the past to protect sensitive
subpopulations on other chemicals reviewed under the SNAP program (e.g.,
trifluoroiodomethane at 69 FR 58907, October 1, 2004).  For deriving
AELs from health endpoints such as liver effects and neurotoxicity, the
SNAP program typically has assigned an uncertainty factor of 1 for
sensitive subpopulations because we assume that individuals who are
especially susceptible to these effects will have greater difficulty
working than most people.  However, there is no connection between the
ability to reproduce and the ability to work in the industrial sectors
discussed in this rule.  Thus, we find it appropriate to apply an
uncertainty factor greater than 1 for reproductive effects.

Some commenters on the June 2003 NPRM said that an uncertainty factor of
1 is appropriate for variability within the working population because
sensitive subpopulations will not be present in the working population
(Stelljes, 2003, Morford, 2003f).  Other commenters stated that there
will be very little difference in variability between the worker
population and the general population and that it is unclear why EPA
selected an uncertainty factor of 3 instead of 10 (Werner, 2003).
Commenters suggested uncertainty factors for variability in the working
population of 1, 2, and 5 (Stelljes, 2003; Weiss Cohen, 2003; Werner,
2003).

EPA’s RfC guidelines recommend an uncertainty factor of 10 to account
for intraspecies variability within the general population.  However, in
deriving an acceptable exposure limit, EPA’s focus is on worker
exposure, which excludes some particularly vulnerable populations, such
as children, most adolescents, and the elderly.  Thus, we believe that a
full uncertainty factor of 10, as for the general population, may be
higher than necessary to protect workers.  However, because of
variability in reproductive function due to factors present among
workers, such as aging, smoking, and sexually transmitted disease, and
because there is no screening of workers that would make workers more
likely to have healthy reproductive systems than non-workers of the same
age, we believe than an uncertainty factor of 1 is not sufficiently
protective.  Under EPA guidelines, 3 is a default value for an
uncertainty factor where there is indication that a value less than an
order of magnitude (10) but greater than one is appropriate, and where
the available data are not sufficiently quantified to select a specific
value.  Therefore, EPA is again proposing to assign an uncertainty
factor of 3 to account for difference between individuals in the working
population.

The uncertainty factors of 3 for animal-human extrapolation and 3 for
variability within the human working population (each representing the
square root of ten, half an order of magnitude) yield a composite
uncertainty factor of 10.  This factor was applied to all HECs derived
from reproductive studies summarized in Table 6 in section IV.E.1 above.
 The resultant values are higher than the value that would have been
obtained had EPA used the TLV of 10 ppm developed by the ACGIH.  EPA
believes that the benchmark dose approach more accurately characterizes
the observed effects and provides a more robust utilization of the data.

D.	Other analyses of nPB toxicity

Analyses reviewed during preparation of June 2003 NPRM

One commenter on the June 2003 NPRM stated that documents by Drs. Doull,
Rozman, Stelljes, Murray, Rodricks, and the KS Crump Group were not
acknowledged (Morford, 2003f, g, and h).  EPA specifically mentioned and
responded to the occupational exposure limit recommendations from Drs.
Rozman, Doull, and Stelljes in the preamble to the June 2003 NPRM at 68
FR 33298-33299.  In addition, EPA included more detailed written
responses to these derivations and the evaluation by Dr. Rodricks in the
online docket prior to proposal (EPA-HQ-OAR-2002-0064-0017, -0018, and
-0019).  We considered these documents in preparation of the June 2003
proposal as well as this proposal.

In general, we disagree that the neurotoxicity endpoint selected by Drs.
Rozman and Doull is the most appropriate endpoint for setting an AEL and
we agree with Dr. Stelljes that sperm motility in the F1 offspring
generation of the WIL, 2001 2-generation study is an appropriate
endpoint  We agree with a number of these documents that data from the
F1 generation may be conservative because workplace exposure would not
include exposure to the F1 animals during the four-week period from
weaning to sexual maturity.  However, EPA believes that because of the
potential for in utero effects that would only be seen in the offspring
generation, looking only at the F0 parental generation could
underestimate the adverse health impacts of a chemical.  Therefore, it
was appropriate for us to consider effects seen in both the F0 parental
generation and the F1 offspring generation.  Further, effects on sperm
motility in the parental and offspring generations are seen at levels
generally consistent with multiple reproductive effects seen in both
generations and both sexes exposed to nPB, such as estrous cycle length,
lack of estrous cycling, the number of estrous cycles in a 3-week
period, and the number of live pup births (TERA, 2004; ICF, 2006a; SLR
International, 2001; Stelljes and Wood, 2004).  We believe that the
document from the K. S. Crump group, a survey of the ratio of points of
departure to TLVs set by the ACGIH, is not relevant now that the ACGIH
has issued a TLV specifically for nPB.  ACGIH appears to set an AEL for
nPB that is a factor of 10 lower than the endpoint cited as lowest (100
ppm for effects on pup weight) (ACGIH, 2005).  Thus, ACGIH has used an
approach for nPB consistent with the total uncertainty factor of 10
assigned by EPA.  In general, we find that these documents submitted by
the commenter assigned uncertainty factors in a manner inconsistent with
EPA guidance.  This would result in a higher AEL than we would determine
following the approach EPA has used on other chemicals, as well as an
AEL that in our view would not sufficiently protect human health from
nPB’s effects because of multiple sources of uncertainty in available
data (e.g., variability within the working population, differences
between animals and humans in how nPB affects the reproductive system).

Since the 2003 NPRM, a number of reviews of nPB toxicity have been
issued, several of which include recommendations for occupational
exposure limits.  CERHR, 2003a and 2004a are similar to CERHR, 2002a,
the expert panel report for nPB for the Center for the Evaluation of
Risks to Human Reproduction (CERHR).  CERHR, 2003b and 2004b are similar
to CERHR, 2002b, the CERHR expert panel’s report for iPB.  These
documents discuss the usefulness of data in available studies for
assessing nPB’s health impacts and establish No Observed Adverse
Concentration levels of 100 ppm for both male and female reproductive
effects in animals, but do not derive an AEL.  Rozman and Doull, 2005
derived an AEL of 25 ppm for nPB based on neurotoxicity, using more
recent information than Rozman and Doull, 2002.

The Stelljes and Wood (2004) analysis is similar in its results to SLR
International (2001), a study by the same authors.  EPA previously
reviewed SLR International, 2001 in developing the June 2003 NPRM.  Both
studies by Stelljes and Wood concluded with a recommended AEL of 156
ppm, based on male reproductive effects and uncertainty factors of 1 in
driving the AEL.  Stelljes (2005) reviews RTI’s 2005 study on
metabolism of nPB in mice and rats and other literature and speculates
that humans should be less sensitive to nPB than either mice or rats
based on differences in metabolite production.  Stelljes (2005)
recommends that no uncertainty factor is required to extrapolate from
animals to humans and that an uncertainty factor of no more than 2 is
appropriate to account for differences within the working population.
All of these documents assigned uncertainty factors in a manner that is
not sufficiently supported by the available data and that is
inconsistent with EPA’s guidance.  For example, Stelljes (2005)
discusses metabolic data in rats and mice from RTI, 2005 and concludes
that on this basis, the uncertainty factor for extrapolation from
animals to humans should be 1.  However, the metabolic data relate to
pharmacokinetics--the activity of chemicals in the body--and do not
address EPA’s proposed uncertainty factor of 3 related to
pharmacodynamics (the biochemical and physiological effects of chemicals
in the body and the mechanism of their actions).  Using the AEL from one
of these documents would result in a higher, less protective AEL than we
would determine following the approach EPA has used for other chemicals
under the SNAP program and would not consider multiple sources of
uncertainty in health effects (i.e., variability within the working
population and differences between animals and humans in how nPB affects
the reproductive system).  Thus, we are concerned that the AELs based on
these documents would not be sufficiently protective and would result in
an inappropriate acceptability decision.  Detailed reviews of these
documents are available in the public docket.

Toxicological Excellence in Risk Assessment (TERA), 2004 reviews other
AEL derivations for nPB, performs a benchmark dose (BMD) analysis, and
recommends an AEL of 20 ppm based on live litter size.  This analysis is
consistent with EPA guidance for BMD modeling and for assigning
uncertainty factors.  A review of this document is available in the
public docket (ICF, 2004c).

ICF (2004b, 2006a) derived an AEL for nPB based upon female reproductive
effects.  ICF (2004b, 2006a) discussed the relevant literature (Ichihara
et al, 1999, 2002, 2004a, 2004b; Sekiguchi, 2002; Yamada et al., 2003;
WIL, 2001) and calculated mean estrous cycle length and the mean number
of estrous cycles occurring during a three-week period at different
exposure levels in the WIL, 2001 2-generation study.  ICF (2004b, 2006a)
found statistically significant reductions in the number of estrous
cycles in a three-week period, both including and excluding females that
had stopped their estrous cycles, at 250, 500, and 750 ppm in the F0
parental generation and at 500 and 750 ppm in the F1 generation.  ICF
(2004b, 2006a) conducted BMD modeling and calculated BMDL values of the
number of estrous cycles in a three-week period that varied from 102 to
208 ppm, depending upon the model used and the benchmark criteria
selected.  All data were calculated based on the mean reductions in
estrous cycle number calculated from the WIL, 2001 study.  Values were
calculated for the F0 generation; the number of data for the F1
generation was too small for statistical analysis.  The BMDLs that ICF
calculated for the number of estrous cycles in a three-week period were
162 ppm and 208 ppm, depending on the benchmark response criteria (10%
change in response vs. one standard deviation) and using a
linear-heterogeneous model.

The California Environmental Protection Agency’s Office of
Environmental Health  Hazard Assessment (OEHHA) listed both nPB and iPB
as reproductive toxins on the basis of developmental, male reproductive,
and female reproductive toxicity under the State’s Safe Drinking Water
and Toxic Enforcement Act of 1986, also known as Proposition 65 (OEHHA,
2006).  Under this law, California is required to list chemicals known
to be carcinogenic or to be reproductive toxins and to update that list
at least annually.

	The American Conference of Government Industrial Hygienists (ACGIH)
issued a recommended Threshold Limit Value™ (TLV) of 10 ppm
(time-weighted average) for nPB (ACGIH, 2005).  ACGIH summarized
numerous studies showing different effects of nPB and identified no
observed effect levels (NOELs) of 200 ppm for hepatotoxicity
(ClinTrials, 1997b) and less than 100 ppm for developmental toxicity, as
evidenced by decreased fetal weight (Huntingdon Life Sciences, 2001).

	OSHA has not developed a permissible exposure limit (PEL) for nPB that
EPA could use to evaluate toxicity risks from workplace exposure.  In
prior SNAP reviews, EPA has used ACGIH TLVs where available in assessing
a chemical’s risks and determining its acceptability if OSHA has not
set a PEL.  ACGIH is recognized as an independent, scientifically
knowledgeable organization with expertise in issues of toxicity and
industrial hygiene.  However, in this case, EPA believes that ACGIH’s
TLV for nPB of 10 ppm has significant limitations as a reliable basis
for an acceptable exposure limit, especially given the availability of
other, more comprehensive analyses described in this proposal.  First,
according to the authors of the Huntingdon Life Sciences study, the
decrease in fetal weight was an artifact of sampling procedure that
biased the data (test animals were only sacrificed at the end of the day
rather than at random).  The CERHR expert panel excluded “aberrantly
low” fetal weights from one litter in this study and calculated a BMDL
greater than 300 ppm for this endpoint after removing those outlier data
(CERHR, 2002a, 2003a, and 2004a).  TERA calculated a similar BMDL when
analyzing the same data set (TERA, 2004).  Further, the reference list
in the documentation on the TLV indicates that ACGIH did not review and
evaluate all the studies available prior to the development of the
recommended exposure limit.  For example, key supporting articles that
reported disruption of estrous cycles (Yamada et al., 2003 and Sekiguchi
et al., 2002) were not discussed in the TLV documentation.  Further,
ACGIH did not provide sufficient reasoning for the selection of the
chosen endpoint over others (e.g., reproductive toxicity and/or
neurotoxicity).  The lack of discussion of applied uncertainty factors
also prevents a determination of how ACGIH arrived at a TLV of 10 ppm.
In summary, EPA is not basing its proposed acceptability determination
for nPB on the ACGIH TLV because: (1) other scientists evaluating the
database for nPB did not find the reduced pup weight to be the most
sensitive endpoint; (2) benchmark dose (BMD) analysis of the reduced pup
weight data (CERHR, 2002a; TERA, 2004) results in a higher BMDL (roughly
300 ppm) than those for reproductive effects; and (3) ACGIH may not have
reviewed the complete body of literature as several studies discussing
neurotoxicity and female reproductive effects were omitted from the list
of references.  A number of reviews of this document are available in
the public docket (ICF, 2004d; O’Malley, 2004).

	We note that, even if EPA had selected the ACGIH TLV as our basis for
assessing the risks of nPB, we would have proposed the same
determinations.  In the specific coatings application that we propose to
find acceptable subject to use conditions at the Lake City Army
Ammunition Plant, exposure data showed an ability to meet an exposure
level of 10 ppm, with the vast majority of measurements below that
value.  Thirty-four of 35 samples had concentrations below 10 ppm, and
the mean concentration for the plant was less than 4 ppm (Lake City Army
Ammunition Plant, 2004).  For the aerosol and adhesive end uses, it
would be even more difficult to achieve an exposure level of 10 ppm than
to achieve a level in the range that EPA is considering (17 to 30 ppm).
Thus, we would have proposed the same decisions for nPB of acceptable,
subject to use conditions for coatings and unacceptable for aerosols and
adhesives using the ACGIH’s TLV of 10 ppm to assess health risks.
Despite some flaws in its derivation, the TLV of 10 ppm is less than
two-fold lower than the low end of the range of acceptable exposure
levels based on the most sensitive reproductive endpoints.  This small
difference is well within the uncertainty required to extrapolate a
benchmark dose from an experimental study in rats to an occupational
exposure limit in humans.

	E.	Community exposure guideline tc "		2.	CEG " \l 3

	In this proposal, EPA is using a community exposure guideline (CEG) of
1 ppm to evaluate potential health risks among populations living near
facilities using nPB.  This community exposure guideline is an estimate
of a continuous inhalation exposure (averaged over 24 hours per day, 7
days per week) to the general public (including sensitive subgroups)
that is likely to be without an appreciable risk of adverse health
effects during a lifetime.

	Based on EPA risk assessment guidelines (US EPA, 1994b), the CEG was
derived using the lowest BMDL from effects listed in Table 6 as the
point of departure (110 ppm for vacuolation in the liver of animals in
the F1 generation of WIL, 2001).  The HEC was calculated as follows:

110 ppm x (6 hours exposure in study/24 hours avg time) x (7 days/7
days) = 28 ppm

EPA used an uncertainty factor of 3 for extrapolation from animals to
humans, as discussed above in section VI.A, and an uncertainty factor of
10 for variability within the general population, consistent with
EPA’s RfC guidelines.  Dividing the HEC of 28 ppm by 30 yields a
community exposure guideline of approximately 1 ppm.  If we had used
sperm motility (HEC of 42 ppm based on a BMDL of 169 ppm) or number of
estrous cycles (HEC of 40 ppm based on a BMDL of 162 ppm) as starting
points, we would calculate the same approximate CEG value.  We note
that, following RfC guidelines, EPA’s community exposure guideline
includes a number of conservative assumptions, including exposure
adjustments to protect an individual exposed for up to 24 hours a day
for 70 years (US EPA, 1994b, p. 1-5).

	EPA evaluated general population exposure using EPA’s SCREEN3 (US
EPA, 1995b) air dispersion model to assess the likely maximum
concentration of nPB from single sources.  EPA used data collected from
actual facilities (Swanson, 2002) to characterize two scenarios:  (1) a
typical large, high-use adhesive application facility where the closest
resident is 100 meters away; and (2) a smaller facility with average-use
adhesive application in an urban area, where the nearest resident is
only 3 meters away.  The results indicated that modeled exposures in
either scenario did not exceed the CEG of 1 ppm.  The highest exposure
modeled was 0.24 ppm at a distance of 3 meters away from the source in
the urban scenario, while most other exposures were at least an order of
magnitude lower (ICF, 2003; ICF, 2006a).  Because the community exposure
guideline was not exceeded for any of the exposure scenarios in this
conservative screening approach, EPA has concluded that nPB exposure to
populations living close to facilities using nPB is not a concern for
purposes of determining the acceptability of nPB under the SNAP program.

VI.	What listing is EPA proposing for each end use, and why?  tc "C.
What  proposals is EPA making for each sector or end use based on these
criteria? " \l 2

	In this rule, EPA is proposing to find nPB unacceptable in adhesive and
aerosol solvent end uses, and acceptable subject to use conditions in
the coatings end use.  The proposed listings, summarized in Table 9, are
intended to allow the use of nPB where it does not pose a human health
risk significantly greater than other substitutes and prohibit nPB’s
use where nPB exposure cannot be maintained, or is unlikely to be
maintained, at even the highest level considered in this proposal (i.e.,
30 ppm).   We also are taking comment on an alternate approach of
finding nPB acceptable subject to use conditions in the above end uses
(see Section VII.A).

Table 9.  Proposed Decisions by End Use and Sector

For nPB in this sector and end use:	Our proposal is to list nPB as:	And
our proposed alternate approach is:

Aerosols

Aerosol solvents	Unacceptable	Acceptable, subject to use conditions2

Adhesives, Coatings, and Inks

Coatings	Acceptable, subject to use conditions1	Acceptable, subject to
use conditions2

Adhesives	Unacceptable	Acceptable, subject to use conditions2

 1  Use of nPB in this end use is limited to coatings at facilities
that, as of [INSERT DATE OF PUBLICATION], have provided EPA information
demonstrating their ability to maintain acceptable workplace exposures
(i.e., the Lake City Army Ammunition Plant).

2  Use conditions would include proposed requirements that users must
(1) meet an exposure limit of 20 ppm on an eight-hour time-weighted
average, (2) monitor workers’ exposure to nPB using a personal
breathing zone sampler on an eight-hour time-weighted average initially
and periodically (every 6 months or longer, depending on the
concentration during initial monitoring), and (3) keep records of the
worker exposure data on site at the facility for at least three years
from the date of the measurement.

A.		Aerosol Solvents  tc "2.	Aerosol Solvents " \l 3

	In this rule, EPA proposes to find nPB unacceptable in the aerosol
solvent end use.  There are a number of aerosol solvent alternatives
that do not pose any risk for ozone depletion or for ground level smog
formation.  EPA’s greatest concern with nPB-based aerosols is that
users of nPB as an aerosol solvent cannot reliably maintain exposures at
sufficiently low levels to ensure that workers are protected.  This
finding is based on measured exposure data and model estimations
indicating the likelihood of elevated concentrations associated with
nPB-based aerosols given typical ventilation conditions.  A number of
other acceptable solvent alternatives are available that can be used at
exposure levels below their respective acceptable exposure limits.

	Ventilation conditions are an important consideration in evaluating
potential risks within this end-use category.  “Benchtop cleaning”
of individual parts, which is feasible under exhaust hoods or in spray
booths with adequate ventilation, comprises 25% or less of the market
involving ODS substitutes for aerosols (US EPA, 2004).  According to
industry information and several commenters, the majority of the market
for nPB-based aerosols involves in-place applications requiring a
portable aerosol, such as cleaning energized electrical contacts and
switches, maintenance in underground mines, or cleaning active elevator
motors (CSMA, 1998; US EPA, 2004; Williams, 2005).  These applications
often occur in tightly confined spaces where it is not feasible to
install ventilation equipment or remove parts to ventilated areas (CSMA,
1998; Linnell; 2003; Werner, 2003).  Other acceptable substitutes, such
as blends of HFEs or HFCs and trans-dichloroethylene, are available in
these end uses.  One commenter also suggested that a user of an
nPB-based aerosol will assume that they are being provided with a
product that offers similar margins of safety as the product being
replaced (i.e., HCFC-141b) and therefore can be used under the same
conditions (Werner, 2003).

	The likelihood that nPB aerosol solvents would be used in poorly
ventilated spaces is of particular concern given the likelihood of
elevated exposure levels.  The exposure data from aerosol solvent use
are extremely limited.  These data are from simulations of a number of
situations where nPB might be used, such as benchtop cleaning of
electronics and cleaning automotive brakes, rather than data from
facilities currently using nPB in manufacturing or maintenance
processes.  Thus, the available exposure data may not be representative
of ventilation levels normally used with nPB-based aerosols and may not
adequately represent exposure levels during in-place cleaning,