# Occupational Exposure to Methylene Chloride

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URL: https://www.frixlaw.com/law-library/documents/fr%3A97-198

## Record

- **Collection:** Federal Register
- **Document type:** Rule
- **Published:** January 10, 1997
- **Citation:** 62 FR 1494

## Text

SUMMARY: The Occupational Safety and Health Administration (OSHA)
hereby amends its existing regulations for employee exposure to
methylene chloride (MC), (also known as methylene dichloride,
dichloromethane or DCM). OSHA has determined, based on animal and human
data, that the current permissible exposure limits (PELs) allow
employee exposure to a significant risk of material impairment of
health. OSHA is reducing the existing 8-hour time-weighted average
(TWA) exposure from 500 parts MC per million parts (ppm) of air to 25
ppm. Also, OSHA is deleting the existing ceiling limit concentration of
1,000 ppm and is reducing the existing short-term exposure limit from
2,000 ppm (measured over five minutes in any 2 hour period) to 125 ppm,
measured as a 15-minute TWA. In addition, the Agency is setting an
``action level'' of 12.5 ppm, measured as an 8-hour TWA. The final rule
also contains provisions for exposure control, personal protective
equipment, employee exposure monitoring, training, medical
surveillance, hazard communication, regulated areas, and recordkeeping.
Together, these provisions will substantially reduce significant risk
to the extent feasible. This standard applies to all employment in
general industry, shipyards and construction. Small employers, for
purposes of the Regulatory Flexibility Act, 5 U.S.C. 601, are defined
as firms with fewer than twenty employees. The final standard will
prevent an estimated 31 cancer deaths per year and an estimated three
deaths per year from acute central nervous system and
carboxyhemoglobinemic effects, and will also reduce cardiovascular
disease and material impairment of the central nervous system. The
estimated cost, on an annualized basis, is $101 million per year.

DATES: This final rule becomes effective April 10, 1997.
Compliance: Start-up dates for specific provisions are set in
Sec. 1910.1052(n) of the regulatory text. However, affected parties do
not have to comply with the information collection requirements in
Sec. 1910.1052(d) exposure monitoring, Sec. 1910.1052(e) regulated
areas, Sec. 1910.1052(j) medical surveillance, Sec. 1910.1052(l)
employee information and training; and Sec. 1910.1052(m) recordkeeping,
until the Department of Labor publishes in the Federal Register the
control numbers assigned by the Office of Management and Budget (OMB).
Publication of the control numbers notifies the public that OMB has
approved these information collection requirements under the Paperwork
Reduction Act of 1995.
Comments: Interested parties may submit comments on the information
collection requirements for this standard until March 11, 1997.

ADDRESSES: In compliance with 28 U.S.C. 2112(a), the Agency designates
the Associate Solicitor for Occupational Safety and Health, Office of
the Solicitor, Room S-4004, U.S. Department of Labor, 200 Constitution
Avenue, NW., Washington, D.C. 20210, as the recipient of petitions for
review of the standard.
Comments on the paperwork requirements of this final rule are to be
submitted to the Docket Office, Docket No. ICR96-15, U.S. Department of
Labor, Room N-2625, 200 Constitution Ave., NW., Washington D.C. 20210,
telephone (202) 219-7894. Written comments limited to 10 pages or less
in length may also be transmitted by facsimile to (202) 219-5046.
Copies of the referenced information collection request are
available for inspection and copying in the Docket Office and will be
mailed immediately to persons who request copies by telephoning Vivian
Allen at (202) 219-8076. For electronic copies of the Methylene
Chloride Final Standard and the Information Collection Request, contact
OSHA's WebPage on Internet at http://www.osha.gov/.

FOR FURTHER INFORMATION CONTACT: Bonnie Friedman, Director, OSHA Office
of Public Affairs, Room N-3647, U.S. Department of Labor, 200
Constitution Avenue, NW, Washington, D.C. 20210; Telephone (202) 219-
8148.

SUPPLEMENTARY INFORMATION:

Collections of Information: Comment Request

The Department of Labor, as part of its continuing effort to reduce
paperwork and respondent burden, conducts a preclearance consultation
program to provide the general public and Federal agencies with an
opportunity to comment on proposed and/or continuing collections of
information in accordance with the Paperwork Reduction Act of 1995
(PRA95) (44 U.S.C. 3506(c)(2)(A)). This program helps to ensure that
requested data can be provided in the desired format, reporting burden
(time and financial resources) is minimized, collection instruments are
clearly understood, and the impact of collection requirements on
respondents can be properly assessed. Currently, OSHA is soliciting
comments concerning the proposed approval for the paperwork
requirements of the Methylene Chloride Final Standard. Written comments
should:
Evaluate whether the proposed collection of information is
necessary for the proper performance of the functions of the agency,
including whether the information will have practical utility;
Evaluate the accuracy of the agency's estimate of the
burden of the proposed collection of information, including the
validity of the methodology and assumptions used;
Enhance the quality, utility, and clarity of the
information to be collected; and
Minimize the burden of the collection of information on
those who are to respond, including through the use of appropriate
automated, electronic, mechanical, or other technological collection
techniques or other forms of information technology, e.g., permitting
electronic submissions of responses.
Background: The Methylene Chloride Standard and its information
collection requirements are designed to provide protection for
employees from adverse health effects associated with occupational
exposure to MC. The standard requires employers to monitor employee
exposure to MC and inform employees of monitoring results. If
monitoring results are above the 8-hour TWA PEL or the STEL, then
employers must also inform employees of the corrective action that will
be taken to reduce employee exposure to or below the 8-hour PEL or
STEL. Employers may also be required to provide medical surveillance to
employees who are or may be exposed to MC. Employers are also required
to provide information and training to employees on the following:
health effects of MC, specifics regarding use of MC in the workplace,
the contents of the standard, and means the employee can take to
protect themselves from overexposure to MC.
Current Actions: This notice requests public comment on the
paperwork requirements in the Methylene Chloride Final Standard. The
Agency previously sought clearance on three Methylene

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Chloride Notice of Proposed Rulemaking Information Collection Requests:
Shipyards, 1218-0177; Construction, 1218-0178; and General Industry,
1218-0179. Since the information requirements are identical for each
industry, the Agency has combined these three packages into one
entitled Methylene Chloride Sec. 1910.1052, OMB number 1218-0179.
Type of Review: Revision of a currently approved collection.
Agency: Occupational Safety and Health Administration.
Title: Methylene Chloride Sec. 1910.1052.
OMB Number: 1218-0179.
Agency Number: Methylene Chloride Docket Number H-71.
Recordkeeping: Employers must maintain employee medical records for
at least the duration of employment plus thirty years. Employee
exposure monitoring records must be maintained for at least 30 years.
Objective data, data showing that any materials in the workplace
containing MC will not release MC at levels which exceed the action
level or the STEL under foreseeable condition of exposures, must be
maintained as long as the employer is relying on the data in support of
the initial monitoring exemption.
Affected Public: Business or other for-profit, Federal government,
State and Local governments.
Total Respondents: 92,000.
Frequency: On Occasion.
Total Responses: Initial 719,948; Recurring 299,620.
Average Time per Response: 0.26 hour.
Estimated Total Burden Hours: Initial 188,728; Recurring 74,299.
Estimated Total Burden Cost: Initial $32,496,380; Recurring
$12,282,420.
Comments submitted in response to this notice will be summarized
and/or included in the request for the Office of Management and Budget
approval of the information collection request; they will also become a
matter of public record.

Federalism

This standard has been reviewed in accordance with Executive Order
12612, 52 FR 41685 (October 30, 1987), regarding Federalism. This Order
requires that agencies, to the extent possible, refrain from limiting
State policy options, consult with States prior to taking any actions
that would restrict State policy options, and take such actions only
when there is a clear constitutional authority and the presence of a
problem of national scope. The Order provides for preemption of State
law only if there is a clear Congressional intent for the Agency to do
so. Any such preemption is to be limited to the extent possible.
Section 18 of the Occupational Safety and Health Act (OSH Act),
expresses Congress' clear intent to preempt State laws with respect to
which Federal OSHA has promulgated occupational safety or health
standards. Under the OSH Act, a State can avoid preemption only if it
submits, and obtains Federal approval of, a plan for the development of
such standards and their enforcement. Occupational safety and health
standards developed by such State Plan-States must, among other things,
be at least as effective in providing safe and healthful employment and
places of employment as the Federal standards. Where such standards are
applicable to products distributed or used in interstate commerce, they
may not unduly burden commerce and must be justified by compelling
local conditions (See section 18(c)(2)).
The final MC standard is drafted so that employees in every State
will be protected by general, performance-oriented standards. States
with occupational safety and health plans approved under section 18 of
the OSH Act will be able to develop their own State standards to deal
with any special problems which might be encountered in a particular
state. Moreover, the performance nature of this standard, of and by
itself, allows for flexibility by States and employers to provide as
much leeway as possible using alternative means of compliance.
This final MC rule addresses a health problem related to
occupational exposure to MC which is national in scope.
Those States which have elected to participate under section 18 of
the OSH Act would not be preempted by this regulation and will be able
to deal with special, local conditions within the framework provided by
this performance-oriented standard while ensuring that their standards
are at least as effective as the Federal Standard.

State Plans

The 23 States and two territories with their own OSHA-approved
occupational safety and health plans must adopt a comparable standard
within six months of the publication of this final standard for
occupational exposure to methylene chloride or amend their existing
standards if it is not ``at least as effective'' as the final Federal
standard. The states and territories with occupational safety and
health state plans are: Alaska, Arizona, California, Connecticut (for
State and local government employees only), Hawaii, Indiana, Iowa,
Kentucky, Maryland, Michigan, Nevada, New Mexico, New York (for State
and local government employees only), North Carolina, Oregon, Puerto
Rico, South Carolina, Tennessee, Utah, Vermont, Virginia, the Virgin
Islands, Washington, and Wyoming. Until such time as a State standard
is promulgated, Federal OSHA will provide interim enforcement
assistance, as appropriate, in these states and territories.

Unfunded Mandates

The MC final rule has been reviewed in accordance with the Unfunded
Mandates Reform Act of 1995 (UMRA) (2 U.S.C. 1501 et seq.) and
Executive Order 12875. As discussed below in the Summary of the Final
Economic Analysis (FEA) (Section VIII of this document), OSHA estimates
that compliance with the revised MC standard will require the
expenditure of slightly more than $100 million each year by employers
in the private sector. Therefore, the MC final rule establishes a
federal private sector mandate and is a significant regulatory action,
within the meaning of Section 202 of UMRA (2 U.S.C. 1532). OSHA has
included this statement to address the anticipated effects of the MC
final rule pursuant to Section 202.
OSHA standards do not apply to state and local governments, except
in states that have voluntarily elected to adopt an OSHA State Plan.
Consequently, the MC standard does not meet the definition of a
``Federal intergovernmental mandate'' (Section 421(5) of UMRA (2 U.S.C.
658(5)). In addition, the Agency has concluded, based on review of the
rulemaking record, that few, if any, of the affected employers are
state, local and tribal governments. Further, OSHA has found that any
impact on such entities would be insignificant. In sum, the MC standard
does not impose unfunded mandates on state, local and tribal
governments.
The anticipated benefits and costs of this final standard are
addressed in the Summary of the FEA (Section VIII of this document),
below, and in the FEA [Ex. 129]. In addition, pursuant to Section 205
of the UMRA (2 U.S.C. 1535), having considered a reasonable number of
alternatives as outlined in this Preamble and in the FEA [Ex. 129], the
Agency has concluded that the final rule is the most cost-effective
alternative for implementation of OSHA's statutory objective of
reducing significant risk to the extent feasible. This is discussed at
length in the FEA [Ex. 129] and in the Summary and Explanation (Section
X of

[[Page 1496]]

this document) for the various provisions of the MC standard.

I. General

The preamble to the final rule on occupational exposure to
Methylene Chloride (MC) discusses the events leading to the final rule,
the physical and chemical properties of MC, the health effects of
exposure, the degree and significance of the risk presented by MC
exposure, the Final Economic Analysis and Regulatory Flexibility
Analysis, and the rationale behind the specific provisions set forth in
the final standard. The discussion follows this outline:

I. General
II. Pertinent Legal Authority
III. Events Leading to the Final Standard
IV. Chemical Identification
V. Health Effects
VI. Quantitative Risk Assessment
VII. Significance of Risk
VIII. Summary of the Final Economic Analysis
IX. Environmental Impact
X. Summary and Explanation of the Final Standard
A. Scope and Application
B. Definitions
C. Permissible Exposure Limits
D. Exposure Monitoring
E. Regulated Areas
F. Methods of Compliance
G. Respiratory Protection
H. Protective Clothing and Equipment
I. Hygiene Facilities
J. Medical Surveillance
K. Hazard Communication
L. Employee Information and Training
M. Recordkeeping
N. Dates
O. Appendices
XI. Authority and Signature
XII. Final Rule and Appendices
Appendix A: Substance Safety Data Sheet and Technical Guidelines for
Methylene Chloride
Appendix B: Medical Surveillance for Methylene Chloride
Appendix C: Questions and Answers--Methylene Chloride Control in
Furniture Stripping

II. Pertinent Legal Authority

The purpose of the Occupational Safety and Health Act, 29 U.S.C.
651 et seq. (``the Act'') is to ``assure so far as possible every
working man and woman in the nation safe and healthful working
conditions and to preserve our human resources.'' 29 U.S.C.
Sec. 651(b). To achieve this goal, Congress authorized the Secretary of
Labor to promulgate and enforce occupational safety and health
standards. U.S.C. Secs. 655(a) (authorizing summary adoption of
existing consensus and federal standards within two years of the Act's
enactment), 655(b) (authorizing promulgation of standards pursuant to
notice and comment), 654(b) (requiring employers to comply with OSHA
standards.)
A safety or health standard is a standard ``which requires
conditions, or the adoption or use of one or more practices, means,
methods, operations, or processes, reasonably necessary or appropriate
to provide safe or healthful employment or places of employment.'' 29
U.S.C. Sec. 652(8).
A standard is reasonably necessary or appropriate within the
meaning of Section 652(8) if it substantially reduces or eliminates
significant risk, and is economically feasible, technologically
feasible, cost effective, consistent with prior Agency action or
supported by a reasoned justification for departing from prior Agency
actions, supported by substantial evidence, and is better able to
effectuate the Act's purposes than any national consensus standard it
supersedes. See 58 FR 16612-16616 (March 30, 1993).
The Supreme Court has noted that a reasonable person would consider
a fatality risk of 1/1000 to be a significant risk, and would consider
a risk of one in one billion to be insignificant. Industrial Union
Department v. American Petroleum Institute, 448 U.S. 607, 646 (1980)
(the ``Benzene decision''). So a risk of 1/1000 (10-3) represents
the uppermost end of a million-fold range suggested by the Supreme
Court, somewhere below which the boundary of acceptable versus
unacceptable risk must fall. The Court further stated that ``while the
Agency must support its findings that a certain level of risk exists
with substantial evidence, we recognize that its determination that a
particular level of risk is significant will be based largely on policy
considerations.'' See, e.g., International Union, UAW v. Pendergrass,
878 F.2d 389 (D.C. Cir. 1989) (formaldehyde standard); Building and
Constr. Trades Department, AFL-CIO v. Brock, 838 F.2d 1258, 1265 (D.C.
Cir. 1988) (asbestos standard).
A standard is technologically feasible if the protective measures
it requires already exist, can be brought into existence with available
technology, or can be created with technology that can reasonably be
expected to be developed. American Textile Mfrs. Institute v. OSHA 452
U.S. 490, 513 (1981) (``ATMI ''), American Iron and Steel Institute v.
OSHA, 939 F.2d 975, 980 (D.C. Cir 1991) (``AISI '').
A standard is economically feasible if industry can absorb or pass
on the cost of compliance without threatening its long term
profitability or competitive structure. See ATMI, 452 U.S. at 530 n.
55; AISI, 939 F. 2d at 980.
A standard is cost effective if the protective measures it requires
are the least costly of the available alternatives that achieve the
same level of protection. ATMI, 453 U.S. at 514 n. 32; International
Union, UAW v. OSHA, 37 F. 3d 665, 668 (D.C. Cir. 1994) (``LOTO III '').
All standards must be highly protective. See 58 FR 16614-16615;
LOTO III, 37 F. 3d at 668. However, health standards must also meet the
``feasibility mandate'' of Section 6(b)(5) of the Act, 29 U.S.C.
655(b)(5). Section 6(b)(5) requires OSHA to select ``the most
protective standard consistent with feasibility'' that is needed to
reduce significant risk when regulating health hazards. ATMI, 452 U.S.
at 509.
Section 6(b)(5) also directs OSHA to base health standards on ``the
best available evidence,'' including research, demonstrations, and
experiments. 29 U.S.C. Sec. 655(b)(5). OSHA shall consider ``in
addition to the attainment of the highest degree of health and safety
protection * * * the latest scientific data * * * feasibility and
experience gained under this and other health and safety laws.'' Id.
Section 6(b)(7) of the Act authorizes OSHA to include among a
standard's requirements labeling, monitoring, medical testing and other
information gathering and transmittal provisions. 29 U.S.C.
Sec. 655(b)(7).

III. Events Leading to the Final Standard

The present OSHA standard for MC requires employers to ensure that
employee exposure does not exceed 500 ppm as an 8-hour TWA, 1000 ppm as
a ceiling concentration, and 2000 ppm as a maximum peak for a period
not to exceed five minutes in any two hours (29 CFR 1910.1000, Table Z-
2). This standard was adopted by OSHA in 1971 pursuant to section 6(a)
of the OSH Act, 29 U.S.C. 655, from an existing Walsh-Healey Federal
Standard. The source of this Walsh-Healey Standard [Ex. 7-1] was the
American National Standards Institute (ANSI) standard for acceptable
concentrations of MC (ANSI-Z37.23-1969), which was intended to protect
workers from injury to the neurological system including loss of
awareness and functional deficits linked to anesthetic and irritating
properties of MC which had been observed from excessive, acute or large
chronic exposures to MC in humans and experimental animals.
In 1946, the American Conference of Governmental Industrial
Hygienists (ACGIH) recommended a Threshold Limit Value (TLV) of 500 ppm
for MC [Ex. 2]. In 1975, the ACGIH lowered the

[[Page 1497]]

recommended TLV to 100 ppm [Ex. 7-11].
In March 1976, the National Institute for Occupational Safety and
Health (NIOSH) published ``Criteria for a recommended standard for
Methylene Chloride'' [Ex. 2], which recommended a reduction of
occupational exposures to MC to 75 ppm as an 8-hour TWA, and a lower
peak exposure not to exceed 500 ppm. Further exposure reduction based
on the ambient level of carbon monoxide was also recommended.
In February 1985, the National Toxicology Program (NTP) reported
the final results of animal studies indicating that MC is a potential
cancer causing agent [Ex. 7-8]. Subsequently, the U.S. Environmental
Protection Agency (EPA), upon receipt of the NTP studies, initiated a
risk assessment evaluation to determine whether or not MC presents an
unreasonable risk to human health or the environment and to determine
if regulatory actions are needed to eliminate or reduce exposures.
On May 14, 1985, EPA announced its determination that MC was a
probable human carcinogen. EPA classified MC as Group B2, in accordance
with its interim guidelines for cancer risk (49 FR 46294), and hence
announced the initiation of a 180-day priority review (50 FR 20126)
under section 4(f) of the Toxic Substances Control Act (TSCA). In
meeting its mandate under section 4(f) of TSCA to initiate a regulatory
action, on October 17, 1985, EPA published an Advance Notice of
Proposed Rulemaking (ANPR) (50 FR 42037) for the purpose of collecting
the necessary information required for initiating a rulemaking. In this
notice, EPA established December 16, 1985, as its deadline for
receiving comments.
On April 11, 1985, the U.S. Consumer Product Safety Commission
(CPSC) released its risk assessment findings for MC and began to
consider a regulatory action to ban MC containing products and to
develop a voluntary hazard communication program for consumers.
On December 18, 1985, the U.S. Food and Drug Administration (FDA)
published a proposal to ban the use of MC as an ingredient in aerosol
cosmetic products (50 FR 51551). This proposal was based on a risk
assessment that used the NTP animal data.
On July 19, 1985, Owen Bieber, President of International Union,
United Automobile, Aerospace and Agricultural Implement Workers of
America (UAW), petitioned OSHA to act expeditiously on reducing
workers' exposure to MC. Specifically, Mr. Bieber requested that OSHA:
(1) Publish a hazard alert; (2) issue an emergency temporary standard
(ETS); and (3) begin work on a new permanent standard for controlling
MC exposure. Subsequently, the following unions joined UAW in
petitioning OSHA to act on revising the current standard:

A. International Union, Allied Industrial Workers of America;
B. Glass, Pottery, Plastics and Allied Workers International Union;
C. United Furniture Workers of America;
D. The Newspaper Guild;
E. Communication Workers of America; and
F. United Steelworkers of America.

In March 1986, as a preliminary response to this petition, OSHA
issued ``Guidelines for Controlling Exposure to Methylene Chloride.''
That document, which was canceled by OSHA Notice ADM 8 (July 12, 1994),
provided information to employers and workers on risks of MC exposure
and methods for controlling such exposure [Ex. 8-11].
In April 1986, NIOSH published a Current Intelligence Bulletin #46
(CIB) on MC reflecting the findings of the NTP study [Ex. 8-26]. The
CIB concluded that MC should be regarded as a potential occupational
carcinogen and that exposure should be controlled to the lowest
feasible level.
On August 20, 1986, the CPSC issued a proposed rule [51 FR 29778]
``that would declare household products containing other than
contaminant levels of MC to be hazardous substances.'' The CPSC noted
the proposal was prompted by evidence that inhalation of MC vapor
increased the incidence of various malignant and benign tumors in rats
and mice. Accordingly, the Commission proposed to require that
household products which can expose consumers to MC vapor be treated as
hazardous substances and be labeled as provided by section 2(p)(1) of
the Federal Hazardous Substances Act (FHSA) (15 U.S.C. 1261(p)(1)). The
FHSA requires the use of labels which (1) indicate that exposure to a
product may present a cancer risk; (2) explain the factors (such as
level and duration of exposure) that control the degree of risk; and
(3) explain the precautions to be taken.
On November 17, 1986, OSHA denied the petition for an Emergency
Temporary Standard, but agreed that work on a permanent standard should
commence [Ex. 3A]. On November 24, 1986, OSHA announced, in an Advance
Notice of Proposed Rulemaking (ANPR) [51 FR 42257], that it was
considering revision of the occupational health standard for MC. The
Agency based this action on animal studies which indicated that the PEL
of 500 ppm did not provide adequate protection against potential cancer
risks and other adverse health effects. The ANPR summarized OSHA's
information regarding the production and use of MC, occupational
exposure to MC, and the potential adverse health effects associated
with MC exposure. In addition, the notice invited interested parties to
submit comments, recommendations, data, and information on a variety of
issues related to the regulation of MC. OSHA received 43 comments in
response to the ANPR. Those comments are discussed, as appropriate,
below.
On December 5, 1986, the FDA reopened the comment period for 30
days on the above-cited proposal to ban the use of MC in cosmetic
products [51 FR 43935]. The reopening enabled interested parties to
submit comments on studies received after the close of the initial
comment period regarding MC comparative pharmacokinetics, metabolism,
and genotoxicity.
On September 14, 1987, the CPSC issued a statement of
interpretation and enforcement policy, in lieu of continuing with
rulemaking, which expressed the Commission's determination that
consumer products containing MC and capable of exposing consumers to
significant amounts of MC may pose cancer risk to humans and,
therefore, are subject to the above- described hazardous substance
labeling requirements. The CPSC explicitly retained the option of
resuming the rulemaking if voluntary compliance with and enforcement of
the Commission's interpretation did not adequately induce firms to
label their products appropriately.
In 1988, based on the response to the ANPR, OSHA began contacting
small businesses and conducting a number of site visits, to develop a
clear understanding of how revisions to OSHA's MC standard would affect
small entities. For example, on April 27, 1989, OSHA participated in a
NIOSH conference on MC controls for the furniture stripping industry
(54 FR 11811, March 22, 1989) to learn how that industry, which is
dominated by small businesses, was dealing with MC exposure. That
conference focused on the progress of a NIOSH pilot program aimed at
developing affordable engineering controls for the furniture stripping
industry. OSHA continued to seek input from small businesses throughout
the MC rulemaking, as discussed below in the Preamble and in the Final
Economic Analysis [Ex. 129].
Also, in 1988, ACGIH officially lowered the TLV for MC to 50 ppm as
an 8-hour TWA. OSHA considered whether the TLV recommended by the

[[Page 1498]]

ACGIH would be an appropriate OSHA standard. The ACGIH is a
professional society devoted to administrative and technical aspects of
occupational and environmental health. Voting members of ACGIH are
scientists who work for government agencies or educational
institutions. Every year the ACGIH adopts new or revised TLVs for
several substances by a majority vote, not by consensus. OSHA has not
adopted the MC TLV (50 ppm) as the 8-hour TWA PEL because the Agency's
criteria for setting standards differ from those used by the ACGIH.
OSHA standards must eliminate significant risks to the extent feasible,
whereas the ACGIH sets limits under which it is believed that nearly
all workers may be repeatedly exposed day after day without adverse
health effects. Also, as evidenced by their ``Documentation of the
TLVs,'' the ACGIH does not perform quantitative risk assessments. This
difference between OSHA and ACGIH practice is critical because the
Supreme Court has required OSHA to perform quantitative risk
assessments when data permit, and to use these assessments to set
exposure limits.
On June 29, 1989, the FDA issued a final rule that banned the use
of MC in cosmetic products [54 FR 27328]. The Agency based its final
rule on scientific studies that showed inhalation of MC caused cancer
in laboratory animals. The FDA concluded, accordingly, ``that continued
use of MC in cosmetic products may pose a significant risk to human
health * * * '' The Agency considered comments and information
regarding the application of a physiologically-based pharmacokinetic
model to the prediction of human cancer risk. The FDA determined that
the risk assessment developed using animal studies should not be
changed to reflect the ``pharmacokinetic and metabolic data and
hypothesized GST metabolic mechanism of carcinogenicity.''
On August 8, 1990, the Consumer Product Safety Commission (CPSC)
issued a General Order (55 FR 32282) that required manufacturers,
importers, packagers and private labelers of consumer products
containing 1% or more of MC to report to the CPSC information on the
labeling and marketing of those products. The CPSC indicated that the
information obtained would aid the Commission in evaluating the CPSC's
policy concerning the labeling of MC-containing products as hazardous
substances, pursuant to the Federal Hazardous Substances Act.
On November 11, 1990, then-President Bush signed the Clean Air Act
Amendments (CAAA) of 1990. Title VI of the CAAA requires the phaseout
of ozone-depleting chemicals by the year 2000 (section 604) and
requires the EPA to determine which alternatives to ozone-depleting
chemicals are safe for use (section 612). MC was among the potential
substitutes studied by the EPA. In addition, section 112 of the CAAA
requires the EPA to address the residual risks of MC and other
specified Hazardous Air Pollutants (HAPs) by establishing Maximum
Achievable Control Technology (MACT) standards. In particular, section
112(d) requires EPA to promulgate National Emission Standards for
Hazardous Air Pollutants (NESHAP) (40 CFR part 63) over a 10-year
period. In addition, EPA regulates MC as a priority pollutant under the
Clean Water Act as amended (33 U.S.C. 1251, et seq.)
On February 12-13, 1991, EPA convened an international conference
on ``Reducing Risk in Paint Stripping'' that was well attended by
representatives of small businesses which use MC or its substitutes in
a wide range of operations. OSHA actively participated in the workgroup
and panel discussions to elicit information regarding the anticipated
impacts of a revised MC standard on paint stripping operations.
OSHA determined, based on animal and human data, that the existing
PELs for MC did not adequately protect employee health. Accordingly, on
November 7, 1991, OSHA issued a notice of proposed rulemaking (NPRM)
(56 FR 57036) to address the significant risks of MC-induced health
effects. The proposed rule required employers to reduce occupational
exposure to MC and to institute ancillary measures, such as employee
training and medical surveillance, for further protection of MC-exposed
workers. The provisions of the proposed rule are discussed in detail in
the Summary and Explanation, Section X, below. The Agency published a
correction notice on January 6, 1992 (57 FR 387). The NPRM solicited
comments on the proposed rule and raised 48 specific issues to elicit
information about MC health effects, use, and exposure controls, as
well as input regarding the appropriateness and impacts of particular
provisions. The written comment period, which ended on April 6, 1992,
produced 58 comments, including several hearing requests.
On February 11, 1992, then-President Bush announced an accelerated
phaseout schedule for ozone depleting substances and ordered the EPA to
accelerate its review of substitutes (such as MC) whose use would
reduce damage to the ozone layer.
On May 19, 1992, OSHA presented the MC proposal to the newly
reconstituted Advisory Committee on Construction Safety and Health
(ACCSH) for consultation. The Advisory Committee established a MC work
group to generate information and recommendations regarding MC use and
exposure in the construction industry.
In response to the hearing requests and to concerns raised by
commenters, the Agency issued a notice of informal public hearing (57
FR 24438, June 9, 1992), which scheduled hearings to start in
Washington, D.C. on September 16, 1992 and in San Francisco, California
on October 14, 1992. That notice also reopened the written comment
period until August 24, 1992. The hearing notice raised 16 issues,
based on the NPRM comments, which solicited input regarding the human
health risks of MC exposure and the impact of the proposed rule on MC
users. San Francisco was selected as a hearing site to facilitate
participation by small businesses, particularly foam blowers and
furniture refinishers, for whom attendance at the Washington, D.C.
hearing would have been economically burdensome.
On July 28, 1992, the MC work group's report was presented to the
ACCSH and was adopted as the Advisory Committee's recommendation to
OSHA. Based on the input from the ACCSH, OSHA issued a supplemental
hearing notice (57 FR 36964, August 17, 1992) which raised MC use,
exposure and control issues specific to the construction industry. The
supplemental notice extended the deadline for submission of comments
regarding the construction issues until September 22, 1992.
OSHA convened public hearings in Washington, D.C. on September 16-
24, 1992 and in San Francisco on October 14-16, 1992, with
Administrative Law Judge James Guill presiding. At the conclusion of
the hearings, Judge Guill set a post hearing period for the submission
of additional data, which ended on January 14, 1993, and for the
submission of additional briefs, arguments and summations, which ended
on March 15, 1993. The posthearing comment period elicited 35 comments.
On March 31, 1993, pursuant to section 112 of the CAAA, the EPA
issued a notice (58 FR 16808) requesting information on the anticipated
impacts of a National Emission Standard for Hazardous Air Pollutants
(NESHAP) for the halogenated solvent cleaning-vapor degreasing source
category. This notice characterized MC as the third most commonly used
halogenated solvent,

[[Page 1499]]

based on 1991 data. On November 29, 1993, the EPA issued a notice of
proposed rulemaking (58 FR 62566) describing MACT rules for the use of
MC and other HAPs in halogenated solvent cleaning-vapor degreasing
operations.
On March 11, 1994, OSHA reopened the rulemaking record for 45 days
(59 FR 11567) to receive public comment on reports related to
engineering controls for MC exposure in the furniture refinishing
industry, MC carcinogenicity, and the availability of water-based
substitutes for MC-based adhesives in the manufacture of flexible foam
products. In particular, OSHA solicited input regarding the extent to
which it was feasible for small businesses with furniture stripping
operations to comply with the proposed PELs using engineering controls
addressed in an OSHA contractor's report [Ex. 114]. The limited
reopening, which ended on April 25, 1994, elicited 29 comments.
OSHA has evaluated the impact of the final rule on the identified
application groups (except for farm equipment [Ex. 115-23], insofar as
this rulemaking does not address agricultural employment). The Agency's
analysis and conclusions are presented in the Final Economic Assessment
for this rulemaking [Ex.129], summarized in Section VIII, below.
On March 18, 1994, the EPA issued a final rule (59 FR 13044) which
addressed the use of MC as a substitute for ozone-depleting chemicals
being phased out under section 612 of the CAAA of 1990. The EPA has
found the use of MC to be acceptable in the production of flexible
polyurethane foam; polyurethane integral skin foams; metal cleaning;
electronics cleaning; precision cleaning; and adhesives, coatings and
inks. That Agency expressed concern regarding MC toxicity, stating
``methylene chloride use will be subject to future controls for
hazardous air pollutants under Title III section 112 of the CAA. In
addition, use of the compound must conform to all relevant workplace
safety standards * * * Use is also subject to waste disposal
requirements under RCRA (59 FR at 13088).'' The EPA also noted that it
is encouraging companies to decrease emissions of MC through the ``30/
50'' pollution prevention program, under which companies voluntarily
commit to reduce emissions 33 percent by the end of 1992 and 50 percent
by the end of 1995 (59 FR at 13093).
On April 21, 1994, the Department of Housing and Urban Development
(HUD) issued a notice (59 FR 19084) announcing that funds were
available for the removal of lead-based paint. That notice explicitly
provided that paint removal activities funded by HUD could not use
products containing MC.
On May 31, 1994, Judge Guill closed and certified the hearing
record for OSHA's MC rulemaking.
Pursuant to section 112(d) of the CAAA, the EPA has already
finalized NESHAP rulemakings that cover halogenated solvent cleaning
(59 FR 61801, December 4, 1994, 40 CFR part 63, subpart T), aerospace
manufacture and rework facilities (September 1, 1995, 40 CFR part 63,
subpart ) and wood furniture manufacturing (60 FR 62930, December 7,
1995, 40 CFR part 63, subpart JJ). MC-related NESHAP proceedings for
several industries (e.g., pharmaceuticals, flexible polyurethane foam,
polycarbonates and nylon 6 are currently underway.
Pursuant to its CAAA, CWA, RCRA and PPA mandates, EPA has proposed
effluent limitation guidelines for the pharmaceutical industry (60 FR
21592, May 2, 1995) which characterize MC as one of the most
significant priority pollutants to be addressed under the CWA. In
particular, EPA has addressed the use of stream stripping and
distillation technology to recover MC from wastewater for reuse or sale
for use in other industries. That Agency has also proposed requirements
for compliance monitoring of MC that, due to dilution with wastewater,
would be found at levels below current analytical limits of detection.
OSHA has attempted to consider the foreseeable impact of EPA action
on the use of MC because EPA-driven changes in such use would affect
the data on which OSHA relies to estimate the impact of this final
rule. In brief, while EPA action to reduce HAP exposure may encourage
employers to reduce or eliminate MC use, simultaneous EPA efforts to
reduce the emission of ozone-depleting chemicals may encourage
employers to maintain or increase MC use. Given the time frame for EPA
action and that Agency's need to coordinate proceedings that arise from
several statutory mandates, it is inappropriate to draw conclusions
regarding the impact of EPA regulatory action on the need for OSHA
action.
OSHA has also consulted with EPA to determine whether any potential
overlapping or conflicting requirements exist in OSHA's MC standard and
various EPA NESHAPs, and has committed to continue working with EPA on
future NESHAP compliance issues. OSHA discussed the MC regulation with
project officers for all recent, current and planned NESHAPs projects
and has determined that there are no overlapping or conflicting
requirements in the NESHAPs and OSHA's MC standard. Indeed, employers
can choose among a variety of means to comply which would not entail
any conflict in OSHA and EPA regulations.
In particular, OSHA conducted a thorough analysis of the EPA
Solvent Degreasing NESHAP. OSHA determined, and EPA agreed, that there
are no conflicting requirements in the two regulations. OSHA does not
require or recommend specific compliance strategies. One common method
of reducing worker exposure is local exhaust ventilation. In addition,
some of the alternative compliance strategies suggested in the EPA
solvent degreasing NESHAP include reducing room draft. OSHA has
determined that even if an employer chooses reducing room draft as its
compliance strategy for the EPA NESHAP, employers may use some local
exhaust ventilation to reduce worker MC exposures and still be in
compliance with both the OSHA MC standard and the EPA NESHAP. There are
also other combinations of compliance strategies that can be utilized
to comply with both regulations. OSHA plans further discussion of this
issue in its compliance assistance documents. The purpose of these
documents is to assist employers in selecting among the many
appropriate control strategies which satisfy requirements under both
OSHA and EPA regulations.
On October 25, 1995, OSHA reopened the rulemaking record (60 FR
54462) to obtain input regarding studies submitted by the Halogenated
Solvents Industry Alliance (HSIA) [Ex. 118-125] which address the use
of animal data to estimate human cancer risk from MC exposure. The
comments received on those studies [Exs. 126-1 through 126-37] are
discussed in relation to the Quantitative Risk Assessment (Section VI),
below.
The rulemaking record contains 129 exhibits, and 2717 pages of
hearing transcript. A wide range of employees, employers, union
representatives, trade associations, government agencies and other
interested parties contributed to the development of the rulemaking
record. The Agency appreciates these efforts to help OSHA develop a
record that provides a sound basis for the promulgation of this final
rule.
Throughout the ten years since OSHA initiated MC proceedings, the
Agency has sought and evaluated input regarding the anticipated impact
of a MC health standard on small entities. For example, Issue K of
OSHA's Advance Notice of Proposed

[[Page 1500]]

Rulemaking for MC (ANPRM) (51 FR 42257, November 24, 1986) solicited
comments, recommendations, data and information regarding the
anticipated impacts of a MC standard on small entities. Responses from
manufacturers of flexible polyurethane foam [Exs. 10-4 and 10-17] and
industrial paint removers [Ex. 10-7] indicated that rulemaking
regarding MC would affect small entities. Based on the response to the
ANPRM, OSHA initiated contacts with small businesses and conducted a
number of site visits, to develop a clear understanding of how
revisions to OSHA's MC standard would affect small entities.
Based on OSHA's contacts with small business and the response to
the ANPRM, the Preliminary Regulatory Impact Analysis (PRIA) for the MC
NPRM (56 FR 57036, November 7, 1991) considered small firms to be those
with fewer than 20 total employees. In addition, the PRIA estimated
that 45 percent of establishments using MC were ``small businesses.''
Issue 25 of the NPRM for MC stated that OSHA had analyzed the
impacts of the proposed rule on small businesses and had adapted the
standard to take into account the circumstances of small businesses,
where appropriate. The performance-oriented language covering the
demarcation of regulated areas (proposed paragraph (e)(4)) and the 30/
10 days of exposure thresholds for medical surveillance (proposed
paragraph (i)(1)(i)) reflected the Agency's determination to avoid
imposing unnecessary burdens on small entities. In addition, Issue 25
solicited information regarding anticipated small business impacts so
that OSHA could update the initial regulatory flexibility analysis
performed pursuant to 5 U.S.C. 604 of the Regulatory Flexibility Act.
Small businesses, particularly in the furniture refinishing [Exs.
19-1, 19-4, 19-6, 19-8, 19-10 and 19-11] and polyurethane foam blowing
industries [Ex. 19-3], expressed concern that the proposed rule would
impose excessive compliance burdens on their operations. Based in part
on these concerns, the Agency convened informal public hearings (57 FR
24438, June 9, 1992) in Washington, D.C. and San Francisco, CA. San
Francisco was selected as a hearing site to facilitate participation by
small businesses, particularly foam blowers and furniture refinishers,
for whom attendance at the Washington, D.C. hearing would have been
economically burdensome.
Hearing Notice Issue 8 solicited comments and testimony, with
supporting documentation, regarding the impact of the proposed rule on
small businesses, particularly in the furniture refinishing sector. A
significant number of small businesses participated in the Washington,
D.C. and San Francisco hearings, providing OSHA with useful testimony
and posthearing submissions. For example, Harold Markey of the Markey
Restoration Company proposed [Tr. 2660, 2672, 10/16/92] that
``furniture refinishing businesses be exempt from [25 ppm PEL] due to
the financial hardship that enforcement would cause.'' In addition, Mr.
Markey expressed appreciation for OSHA's efforts to facilitate his
participation in the hearing. As discussed above, OSHA subsequently
solicited (59 FR 11567, March 11, 1994) additional input regarding the
extent to which it was feasible for small businesses with furniture
stripping operations to comply with the proposed PELs using the
engineering controls addressed in an OSHA contractor's report [Ex.
114].
OSHA has had numerous contacts with furniture refinishers,
particularly with members of the National Association of Furniture
Refinishers and Refurbishers (NAFRR), the trade association for the
industry. In 1994, OSHA was represented at the NAFRR's annual
conference in Williamsburg, VA. The Agency has continued to provide
assistance to NAFRR members and other furniture refinishers regarding
appropriate industrial hygiene measures for workplaces where MC is
used. For example, OSHA has disseminated information about the
engineering controls developed by NIOSH for the furniture stripping
industry. OSHA will continue to strive for a cooperative relationship
with the small businesses affected by the MC final rule through careful
compliance with the Small Business Regulatory Enforcement Fairness Act
(SBREFA) (5 U.S.C. Chapter 8) and the Regulatory Flexibility Act (5
U.S.C. 601, et seq.), as amended. In addition, the Agency's ``Outreach
Program'' for the MC final rule will involve a commitment of
significant consultation and other resources by OSHA and other
concerned parties, building on the relationships established during the
rulemaking.
OSHA has developed a multifaceted outreach plan to provide
information and compliance assistance to the regulated community. In
particular, OSHA:

--Has developed a booklet which summarizes the provisions of the MC
standard;
--Has developed a compliance directive for the MC standard which
answers compliance-related questions about the MC standard;
--Is developing compliance guides directed at assisting small
businesses in complying with the MC standard, consistent with section
212 of the Small Business Regulatory Enforcement Fairness Act of 1996;
--Has recruited interested trade associations to assist in the
distribution of MC standard-related information, and the convening of
workshops to help small businesses understand available compliance
strategies;
--Has spoken to trade association meetings and distributed MC standard-
related materials;
--Has contacted manufacturers of MC to develop a strategy for inclusion
of OSHA MC-standard information in existing product stewardship
programs; and
--Is working with individuals interested in conducting workshops for
impacted industries, such as polyurethane foam manufacturers and
furniture refinishers, to train small businesses on compliance with
OSHA and EPA regulations.

All 50 states and the territories covered by the OSH Act provide
free consultation services for small businesses to assist them in
achieving compliance with OSHA standards. Those services are funded by
federal OSHA but supplied by the states in state plan states and by
private contractors in other areas. Those consultation services will
provide free assistance for small business so it will be easier to come
into compliance with the MC standard.
OSHA will also set up Cooperative Assessment Programs (CAP's) for
individual employers to assist them in achieving compliance in a
reasonable manner. In a CAP, an OSHA industrial hygienist works with
the employer and employee representatives, to determine a reasonable
number of cost-effective engineering controls and work practices to
bring the employer into compliance. A reasonable schedule is determined
for the implementation of those controls. Good faith efforts to
implement a CAP are generally considered to be in compliance with the
provisions of the standard. OSHA has had success in implementing CAP's
for the arsenic, lead and other standards. Employers have found that
working with OSHA or CAP's has led to cost effective compliance with
OSHA standards.

IV. Chemical Identification

Methylene chloride (MC), also called dichloromethane (DCM)
[Chemical Abstracts Service Registry Number 75-09-2] is a halogenated
aliphatic hydrocarbon with a chemical formula of CH2Cl2, a
molecular weight of 84.9, a

[[Page 1501]]

boiling point of 39.8 deg.C (104 deg.F) at 760 mm Hg, a specific
gravity of 1.3, a vapor density of 2.9 and a vapor pressure of 350 mm
Hg at 20 deg.C (68 deg.F). Concentration of MC in saturated air at
25 deg.C reaches 550,000 ppm. MC has low water solubility (1.3 gm per
100 gm of water at 20 deg.C), an extensive oil and fat solubility, and
a low flammability potential. It is used as a flame suppressant in
solvent mixtures (lower explosive limit of 12% and upper explosive
limit of 19%). It is a colorless volatile liquid with a chloroform-like
odor and its odor threshold varies between 100 and 300 ppm. Contact
with strong oxidizers, caustics and active metal powder may cause
explosions and fires. Decomposition products during combustion or fire
include phosgene, hydrogen chloride and carbon monoxide.

V. Health Effects

A. Introduction

The toxicology of MC is summarized below. A more detailed review of
MC toxicology can be found in the NPRM [56 FR 57036].

B. Absorption and Disposition of Methylene Chloride

Inhalation is the most significant route of entry for MC in
occupational settings. The quantity of MC taken into the body depends
on the concentration of MC in inspired air, the breathing rate, the
duration of exposure to MC, and the solubility of MC in blood and
tissues. Because MC is volatile, inhalation exposures to MC can be
quite high, especially in poorly ventilated spaces.
Dermal absorption of MC is a slow process relative to inhalation.
In the NPRM, OSHA described the rate of skin absorption of pure MC as
insignificant relative to inhalation. In contrast, Mr. Harvey Clewell,
in comments prepared for the U.S. Navy [Ex. 19-59], stated that
substantial occupational exposure could occur through the dermal route
when the employee is exposed to high concentrations of MC vapor and
protective clothing is not worn [Ex. 19-59]. Mr. Clewell provided a
physiologically-based pharmacokinetic (PBPK) model to describe the
potential absorption through skin exposed to high vapor concentrations
of MC. Where the employee is protected from inhalation exposure by use
of an air-supplied respirator and the skin (exposed surface area = two
hands) is unprotected in high MC-vapor concentrations, the primary
route of exposure in this case will be dermal exposure. Mr. Clewell has
determined that sufficient MC may be absorbed by the dermal route over
an 8-hour shift to give an internal concentration which would exceed
that experienced by workers exposed to MC through inhalation of 25 ppm
for 8 hours.
In the NPRM, OSHA also indicated that the burning sensation
associated with dermal exposure to liquid MC would likely lead
employers and employees to limit skin absorption. However, exposure to
high concentrations of vapor may not be associated with a burning
sensation, and there is evidence in the record [Tr. 2468-70, 10/15/92]
to suggest that employees are exposed to liquid MC without protective
clothing. OSHA believes that dermal exposure to liquid and high vapor
concentrations of MC should be limited to the extent feasible to
protect the employee from overexposure. For this reason, in this
standard OSHA has required that employers provide personal protective
clothing and equipment appropriate to the hazard. For example, if an
employee will be at risk of hand contact with liquid MC, impermeable
gloves must be provided.

C. Metabolism of MC

Once MC is absorbed into the body, it is widely distributed in the
body fluids and in various tissues. The uptake and elimination of MC
has been well described in human and animal studies [Exs. 7-156, 7-157,
7-174].
The carcinogenic mechanism of action for MC has not been clearly
established. Although it has not been proven whether MC is carcinogenic
through a genotoxic or non-genotoxic mechanism, current evidence
supports the hypothesis that MC is a genotoxic carcinogen. Genotoxic
carcinogens typically are reactive compounds or metabolized to reactive
compounds. MC is unreactive in the body until it is metabolized.
Therefore, many investigators believe that one or more of the
metabolites of MC, and not MC itself, is the ultimate carcinogen.
It has been established by Kubic and Anders [Ex. 7-167] and Ahmed
and Anders [Ex. 7-25] that MC is metabolized by rat liver enzymes in
vitro by two distinct pathways. The first pathway is the mixed function
oxidase system (MFO pathway) associated with the microsomal cell
fraction and the second is the glutathione dependent pathway localized
primarily in the cytoplasm and mediated by glutathione-S-transferase
(GST pathway). The metabolism of MC is illustrated in Figure 1.

BILLING CODE 4510-26-P

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[GRAPHIC] [TIFF OMITTED] TR10JA97.000

BILLING CODE 4510-26-C

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The MFO pathway metabolizes MC via a cytochrome-P450 dependent
oxidative dehalogenation [Ex. 7-167] which produces formyl chloride.
The formyl chloride decomposes to give chloride ion and carbon
monoxide. It has been postulated that if the MFO pathway contributes to
the carcinogenicity of MC, it is through the production of the reactive
compound, formyl chloride. The end product of the MFO pathway, carbon
monoxide, can be detected in the blood and breath of humans and animals
exposed to MC, and has been used as a surrogate measure of MC exposure
in humans.
The GST pathway metabolizes MC to formaldehyde and chloride ions
via a postulated S-chloromethylglutathione conjugate [Ex. 7-25].
Formaldehyde is further metabolized to carbon dioxide in mammalian
systems. Potential reactive metabolites in this pathway are the S-
chloromethylglutathione conjugate and formaldehyde (known to react with
protein, RNA and DNA).
Animal data indicate that the MFO pathway is saturated at ambient
concentrations less than 500 ppm, while the GST pathway remains linear
throughout the exposure levels examined [Exs. 7-161, 7-171]. Saturation
of the MFO pathway in humans has been estimated to occur at a level
which is within the range of the animal data (estimates range from 200
to 1000 ppm MC) [Exs. 7-114, 7-115, 8-32]. The GST pathway is not
thought to be saturated for any of the species investigated at doses up
to 4000 ppm.

D. Carcinogenicity

The evidence for the carcinogenicity of MC has been derived from
mutagenicity studies, animal bioassays and human epidemiological
studies. OSHA analyzed data from each of these sources in determining
that MC is carcinogenic to test animals and a potential occupational
carcinogen. The evidence that OSHA evaluated in making this
determination is summarized below. Additional evidence pertaining to
the hazard identification of MC is discussed in the Quantitative Risk
Assessment, Section VI, below.
1. Mutagenicity Studies
Mutagenicity and genotoxicity studies are useful in describing the
possible carcinogenic mechanism of action of MC. Evidence for the
interaction of MC or MC metabolites with DNA (producing mutations or
toxicity) is consistent with a genotoxic mechanism for the carcinogenic
action of MC, rather than a non-genotoxic action (i.e., by acting as a
promoter, increasing cell turnover). The EPA reviewed the literature on
the mutagenic potential of MC in their ``Health Assessment Document for
Dichloromethane (Methylene Chloride)'' (HAD) [Ex. 4-5] and studies
conducted by ECETOC in the ``Technical Analysis of New Methods and Data
Regarding Dichloromethane Hazard Assessments'' [Ex. 7-129].
As described in the MC Notice of Proposed Rulemaking (56 FR 57036),
the documentation of positive responses in the production of mutations
in bacteria, yeast and Drosophila, chromosomal aberrations in CHO cells
and sister chromatid exchanges (SCE) in CHO and V79 cells and equivocal
responses in other systems indicated the potential genotoxicity of MC.
A paper submitted to the record by Dr. Trevor Green [Ex. L-107],
for the Halogenated Solvents Industry Alliance (HSIA), investigated the
role of metabolites of the GST pathway in the bacterial mutagenicity of
MC. The authors of this study found that in glutathione-deficient
strains of Salmonella typhimurium there was approximately a two-fold
decrease in mutations. Mutation rates returned to normal when bacteria
were supplemented with exogenous glutathione. They also investigated
whether individual metabolites in the GST pathway were likely to be
responsible for mutagenesis. Experiments in S. typhimurium strains were
consistent with the S-chloromethylglutathione conjugate as the
mutagenic moiety. Experiments in Escherichia coli strains implicated
formaldehyde as the active mutagen. Overall, these results support the
hypothesis that MC may act as a genotoxic carcinogen, but the ultimate
reactive species still remains to be identified.
Dillon et al. [Ex. 21-89] also conducted experiments on the
mechanism of MC mutagenicity in bacterial cells, using wild type and
glutathione-deficient Salmonella typhimurium TA100. Dose-related
increases in mutagenicity were observed with and without metabolic
(cytosolic or microsomal) activation. The authors characterized the
mutagenicity as marginally highest in the presence of cytosol at the
highest MC concentrations. The glutathione-deficient strain was
slightly less responsive to MC-induced mutation than the wild type. In
contrast to the study by Green, Dillon et al. found that MC
mutagenicity was not appreciably enhance by the addition of microsomal
or cytosolic liver fractions or exogenous glutathione. They concluded
that it was not clear to what extent, if any, glutathione was involved
in MC mutagenicity, and noted that ``* * * the residual glutathione
present in the glutathione-deficient strain may have been sufficient to
facilitate the mutagenic responses observed.''
The differing results in these studies suggest that the exact
mechanism of MC mutagenicity, even in bacterial cells, has not been
determined with certainty. However, OSHA has concluded that the
evidence that MC is genotoxic is compelling. Additional studies
supporting classification of MC as a genotoxin were submitted to the
Agency in late 1995 and are discussed in the Quantitative Risk
Assessment, Section VI, below.
2. Animal Studies
The evidence for the carcinogenicity of MC has been derived
primarily from data obtained in chronic toxicity studies in rodents.
Table V-1 contains a summary of the major bioassays. These bioassays
have been conducted in three rodent species (rat, mouse and hamster)
using two routes of administration (oral and inhalation) and a wide
range of doses (from 5 mg/kg/d, oral to 4000 ppm inhaled for 6 hr/d, 5
d/wk).
The National Toxicology Program conducted two 2-year inhalation
bioassays [Ex. 7-8] using B6C3F1 mice and Fischer 344 rats. In the NTP
mouse study [Ex. 7-8], groups of 50 male and 50 female B6C3F1 mice were
exposed to 0, 2000 or 4000 ppm MC, 6 hr/day, 5 d/wk for 102 weeks. All
animals were necropsied and examined histopathologically.
Treated male and female mice had increased incidences of alveolar
or bronchiolar adenomas and carcinomas as compared with control
animals. In addition, there was an increased number of lung tumors per
tumor-bearing animal (multiplicity of tumors) with increasing dose of
MC.
In the liver, the toxic effects of MC were expressed as cytologic
degeneration in male and female mice which was not present in the
controls. An increased incidence of hepatocellular adenomas and
carcinomas (combined) was observed in male mice. The incidence of
hepatocellular carcinomas in male mice was statistically significantly
increased at 4000 ppm. Female mice also experienced dose-related
increases in the incidences of hepatocellular adenomas and carcinomas.
An increased multiplicity of liver tumors was also found in both male
and female mice.

[[Page 1504]]

Table V-1.--Methylene Chloride Lifetime Bioassays
----------------------------------------------------------------------------------------------------------------
Route and dosing Dosage (No. of
Reference Species/strain schedule animals) Comments
----------------------------------------------------------------------------------------------------------------
NTP (1985).................... B6C3F1 mouse.... Inhalation 6 hr/ 0, 2000, 4000 ppm (50 Lung and liver tumors
day, 5 days/ mice/ sex/dose). both sexes, both
week. doses.
Serota (NCA) (1986)........... B6C3F1 mouse.... Daily in water.. 0 (125M, 100F), 60 No tumors observed.
(200M, 100F), 125
(100M, 50F), 185
(100M, 50F), and 250
(125M, 50F) mg/kg/d.
NTP (1985).................... Fischer 344 rat. Inhalation 6 hr/ 0, 1000, 2000 and Mammary and
day, 5 days/ 4000 ppm (50 rats/ integumentary
week. sex/dose). fibromas and
fibrosarcomas in
both sexes.
Burek (DOW) (1980)............ Sprague-Dawley Inhalation 6 hr/ 0, 500, 1500 and 3500 Malignant salivary
rat. day, 5 days/ ppm (95 rats/sex/ gland tumors at 3500
week. dose). ppm, dose-related
increase in mammary
tumors.
Nitschke (DOW) (1982)......... Sprague-Dawley Inhalation 6 hr/ 0, 50, 200 and 500 No tumors observed.
rat. day, 5 days/ ppm (70 rats/ sex/
week. dose.
Serota (NCA) (1986)........... Fischer 344 rat. Daily in water.. 0, 5, 50, 125 and 250 No tumors observed.
mg/kg/d (135/sex at
0, 85/sex/dose).
Burek (DOW) (1980)............ Syrian Golden Inhalation 6 hr/ 0, 500, 1500, 3500 No tumors observed.
hamster. day, 5 days/ ppm (90 hamsters/sex/
week. dose).
----------------------------------------------------------------------------------------------------------------

The dose-related increase in the incidence of lung and liver tumors
in mice, and the increased multiplicity of these tumors, present the
strongest evidence for the carcinogenicity of MC. NTP concluded that,
based on the evidence from these lung and liver tumors, there was clear
evidence of the carcinogenicity of MC in both male and female mice.
In a second two-year bioassay, the NTP examined the effects of
inhalation of MC at 0, 1000, 2000 and 4000 ppm in F344 rats [Ex. 7-8].
Body weights of all exposure groups were comparable. The highest dose
female rats experienced reduced survival after 100 weeks of exposure.
The incidence of mammary tumors in the high dose group in both
sexes was statistically significantly higher than in control animals
(concurrent and historical). The incidence of mammary fibroadenomas
alone and the combined incidence of fibroadenomas and adenomas in male
and female rats occurred with statistically significant positive
trends. When subcutaneous fibromas or sarcomas in the male rat, which
were believed to have originated in the mammary chain, were included in
comparisons, differences between control and exposed animals were even
greater.
MC-exposed male and female rats also showed increased incidence of
liver effects, characterized by hemosiderosis, hepatocytomegaly,
cytoplasmic vacuolization and necrosis. Neoplastic nodules alone and
combined incidence of neoplastic nodules and hepatocellular carcinomas
in female rats occurred with significant positive trends by the life
table test. Pair-wise comparisons did not indicate statistically
significant effects at any one dose. Although this is suggestive of a
carcinogenic response in the female rat liver, NTP did not use this
response in their determination of the carcinogenicity of MC.
NTP based its determination of the carcinogenicity of MC in the rat
on the mammary tumor incidence data. NTP has concluded that the
increased incidences of mammary gland tumors in the female rats
provided clear evidence of carcinogenicity and, in the male rats, some
evidence of carcinogenicity.
The Dow Chemical Company [Ex. 7-151] conducted experiments in which
Sprague-Dawley rats and Syrian Golden hamsters were exposed to 0, 50,
1500 or 3500 ppm MC, 6 hr/d, 5 d/wk for 2 years. A dose-related
statistically-significant increase in the number of mammary tumors per
tumor-bearing female rat was observed. These results support the NTP
findings of increased mammary tumors in F344 rats. The background
mammary tumor response in the Sprague-Dawley rat is higher than in F344
rats, so a quantitative analysis of risk is easier to perform on the
data from the NTP study.
A statistically significant increase in male rat salivary tumors
was also observed in this study, although the authors believed that
this response should be discounted because of the presence of
sialodacryoadenitis virus in the rats. OSHA believes that the presence
of this virus in the rats would complicate the interpretation of the
data, and so has relied on the NTP studies for its quantitative risk
assessments.
No statistically significant excess incidence of tumors was
observed in either sex of hamsters at any exposure level. This suggests
that hamsters are less sensitive to the carcinogenic effects of MC than
either mice or rats. Metabolism data gathered in hamsters indicate that
hamsters have less capability to metabolize MC by the GST pathway than
rats or hamsters (or humans). This correlation between lack of GST
metabolism capacity and lack of tumor response supports the hypothesis
that GST metabolism is important in MC carcinogenesis and also
indicates that it would not be protective to use the hamster response
to MC as the basis for a carcinogenic risk assessment.
A second inhalation study in Sprague-Dawley rats conducted by
investigators at Dow Chemical [Ex. 7-173], with exposures up to 500
ppm, showed an increase in the number of mammary tumors per tumor-
bearing animal in female rats at the highest dose level only. This
study extended the finding of excess mammary tumors in rats to the 500
ppm level. However, because of the high background rates of mammary
tumors in Sprague-Dawley rats, the NTP study showed a clearer dose-
response relationship between MC exposure and incidence of mammary
tumors.
In a study conducted for the National Coffee Association [Ex. 7-
180], no statistically significant increased incidence of tumors was
observed in B6C3F1 mice or F344 rats exposed to up to 250 mg/kg/d MC in
drinking water. These studies used the drinking water route of exposure
instead of inhalation and exposed animals to lower doses (on an mg/kg/d
basis) than the NTP and high-dose Dow studies. These factors most
likely accounted for the lack of a positive tumor response. The NCA
studies were used by Reitz et al. in the development of the
physiologically-

[[Page 1505]]

based pharmacokinetic models for MC. Specifically, these studies helped
to determine that the lack of tumor development was consistent with
model predictions of the amount of GST metabolites in lung and liver of
mice and that the MFO pathway was most likely not primarily responsible
for the mouse tumor response.
The Agency believes that the NTP studies show the clearest evidence
of a carcinogenic effect of MC and has used these studies as the basis
of its risk assessment for the following reasons: (1) The studies were
well conducted and underwent extensive peer review. (2) The inhalation
route of exposure was used, which is the most appropriate route for
extrapolation to occupational exposures. (3) Dose-related,
statistically significant increases in tumor incidence were observed in
both sexes in mice and in female rats. OSHA believes that because of
the clear tumor response, and quality of the studies, the NTP studies
provide the best data for quantitative cancer risk assessment. OSHA
concludes from these studies that MC causes cancer in two species of
test animals by the inhalation route, and that a clear dose-response
has been demonstrated.
3. Epidemiological Studies
Epidemiological studies of occupational exposure to MC have been
conducted in the manufacturing of triacetate fibers, photographic film
production, and the manufacturing of paint and varnish. Those studies
were reviewed by OSHA in the preamble to the proposed rule [56 FR
57075] and are summarized and updated in this document. In addition, an
epidemiological study of MC exposure and astrocytic brain cancer is
reviewed in this text.
a. Studies of triacetate fiber production workers. Ott et al. [Ex.
7-76] performed a retrospective cohort study using a cellulose
diacetate and triacetate plant in Rock Hill, South Carolina to examine
the effects of MC on a working population. In particular, Ott et al.
evaluated the effects that were possibly mediated through the
metabolism of MC to carboxyhemoglobin. Employees at this plant had MC
exposures close to OSHA's time weighted average (TWA) permissible
exposure limit (PEL) of 500 ppm. Ott et al. used workers in a plant in
Narrows, Virginia as a comparison population because it had operations
similar to those at the Rock Hill plant, but did not use MC. In this
study, Ott et al. compared the number of deaths within the exposed
cohort with the United States population and the Narrows, Virginia
referent group. Ott et al. observed that the overall mortality of the
cohort was comparable to that of the age, sex, and race-matched U.S.
population. Comparing exposed and referent cohorts, statistical
differences in risk were observed in white men for ``all causes'' (risk
ratio=2.2, p-3.68=0.025. On the
other hand, if MC had no effect on liver and biliary cancer mortality,
Lanes et al. estimated that the probability of observing zero deaths
would have been 0.527 (e-0.64). Lanes et al. used the likelihood
ratio (0.527/0.025=21.08) to compare these two hypotheses. The authors
concluded that the null hypothesis that the SMR=1.0 was 21 times more
probable than the hypothesis that the SMR=5.75.
Because of the small number of cases involved and the instability
of the numbers generated in this type of statistical analysis, OSHA
believes that this study, overall, is suggestive (but not definitive)
of an association between occupational exposure to MC and elevation of
human cancer risk. Furthermore, the Agency has determined that the
study results are not inconsistent with the results of the NTP cancer
bioassay.
Hoechst-Celanese [Ex. 19-65, pp. 6-8; Ex. 19-19] was concerned that
OSHA considered the incidence of biliary cancer as evidence of a
positive effect. They argued that the reported excess in biliary tract
cancer did not support the conclusion that MC exposure is associated
with an increased risk of cancer. Specifically, they noted that,

(1) Biliary cancers have not been reported in any of the animal
cancer studies of MC; (2) no statistically significant increase in
biliary cancers was seen in the Cumberland study (described below);
(3) no statistically significant excess in biliary cancers was
reported in the Kodak studies (described below); (4) It was unlikely
that MC could have been responsible for the biliary tract cancer
observed in one employee who had been exposed to MC for less than
one year; and (5) the Rock Hill study did not control for other
chemical exposures.

Comments by the Halogenated Solvents Industry Alliance (HSIA) [Ex. 19-
45, p. 47] were in accord with those of Hoechst-Celanese.
Dr. Shy, on behalf of Kodak, asserted [Tr. 1303, 9/22/92; Ex. 91F]
that MC exposure failed to meet Bradford Hill's criteria for causality
(e.g., biological plausibility, dose-response, and consistency) for
producing biliary tract cancer. Dr. Shy acknowledged that animal
bioassays have demonstrated liver tumors from MC exposure, but he noted
that there is no evidence in humans that liver and biliary tract
cancers have the same etiology. Furthermore, Dr. Shy argued that,
(1) the results from the Lanes study is not supported by in vitro
or pharmacokinetic studies.
(2) a dose-response relationship could not be determined from the
Lanes study because there were no direct measurements of worker
exposure to MC.
(3) the observed association between MC exposure and liver/biliary
cancer was an isolated finding and the existence of a causal
relationship could not be concluded.
(4) the excess biliary tract cancer in the Lanes study was not
consistent with the other three epidemiological studies (Hearne, 1987,
1990, 1992; Hearne, 1992; Gibbs, 1992).
Dr. Shy did recognize that there was a strong association between
MC exposure and biliary tract cancer in the Lanes study (SMR=20).
Moreover, the 20 year time interval between first exposure and death
from biliary tract cancer provided evidence that ``exposure preceded
cancer with an appropriate interval for induction of the tumor [Ex.
91F].''
OSHA disagrees with the conclusions reached by Dr. Shy. The Agency
believes that the risks of biliary cancer observed in these studies is
consistent with risks derived from its pharmacokinetic analysis (see
the Quantitative Risk Assessment, Section VI). Since the occupational
exposures in these studies are likely to have been among the highest in
any of the epidemiologic cohorts, there is no evidence that the
increased biliary/liver cancer result is inconsistent with other
reported epidemiological findings. Regarding the biological
plausibility, the Agency notes that human biliary cells appear to
contain high concentrations of the mRNA for GST (the enzyme many
investigators believe to be responsible for MC-induced carcinogenesis)
[Exs. 124 and 124A]. Although this requires more investigation to
determine if there is a direct relationship, OSHA believes there is a
plausible mechanistic argument for MC causality in human biliary tract
cancers. The Agency agrees with Dr. Shy, however, that the lack of
dose-response data and the small number of cases in this cohort limit
the strength of conclusions that can be drawn from this study. After
weighing these considerations, the Agency has determined that there is
suggestive evidence of a causal role for MC in these cases of biliary
cancer.
Gibbs et al. conducted a study of another cellulose acetate and
triacetate fibers plant in Cumberland, Maryland [Ex. 54] to evaluate
the possible relationship between MC exposure and biliary/liver cancer.
This plant, which ceased to operate in 1982, had operations similar to
the plant in Rock Hill, and it was assumed to have had similar MC
exposure levels as well. However, exposure measurements were not
submitted for the Cumberland plant and it is unknown whether the
Cumberland employees experienced the same exposures as their Rock Hill
counterparts.
The Gibbs study investigated the mortality of 3,211 workers who
were employed at this plant on or after January 1970. There were 2,187
men and 1,024 women in the cohort. Most of the workers in the cohort
were hired prior to 1979 (2,566 total). The study population was
divided into three subcohorts based on their estimated exposure to MC:
1) 834 men and 146 women in the ``high exposure'' group (estimated to
be 350-700 ppm), 2) 1095 men and 832 women in the ``low but never high
exposure'' group (estimated to be 50-100 ppm), and 3) 256 men and 46
women in the ``no exposure'' group. This cohort was followed through
December 1989. The observed mortality was compared to expected death
rates for Allegany County, Maryland (where the plant was located and
where most of the cohort deaths occurred), the State of Maryland, and
the United States.
The author of this study believed that the county rates were the
most appropriate to use because the city of Cumberland is located in a
rural area of Maryland and the state rates may have been influenced by
rates in large urban areas such as Baltimore. In addition, local rates
tend to adjust for social, economic, ethnic, and cultural factors which
may be related to disease risk, access to medical care, etc. However,
if the fiber plant was the major employer in this rural area, then
county rates may reflect the cohort's mortality rather than the
background risk, in which case, state rates or U.S. population rates
would be more appropriate. The overall mortality rate for the high MC-
exposed group was below the expected rates for Allegany County,
Maryland, and the U.S. population.
As in the Rock Hill study, mortality from biliary tract cancer was
observed in the Cumberland study, although no statistically significant
elevated incidence of biliary cancer was found (two cases of biliary
tract cancer were observed). In the high exposure group, there was one
death (1.24 expected with Allegany rates (SMR=80.5) and 1.42 expected
with Maryland rates (SMR=70.4)). In the low MC-exposed group, there was
also one death from biliary/liver cancer. For the high MC-

[[Page 1507]]

exposed subcohort, Gibbs et al. estimated SMRs of 80.4, 70.3, and 75.1
when comparisons were made with Allegany County, Maryland, and U.S.
rates, respectively. In the low MC-exposed subcohort, the SMRs using
Allegany and Maryland rates were 75.4 and 76.4, respectively. This
cohort should be followed for a longer period of time to help clarify
the suggested association between MC exposure and biliary cancer
observed in the Rock Hill cohort.
Statistically significant excess mortality was also observed from
prostate, uterine, and cervical cancers, although these also
represented small numbers of cases: 13, 2, and 1, respectively.
The excess of prostate cancer in the Gibbs et al. study suggested
an exposure-response relationship (3 deaths in no MC-exposure group, 9
in low MC-exposure group, and 13 in high MC-exposure group). According
to Gibbs et al. and Shy [Tr. 1303, 9/22/92; Exs. 19-64, 91F], this
response may have been related to other chemical exposures
(occupational or non- occupational). In support of this hypothesis, no
other epidemiological or animal studies of MC exposure have suggested a
relationship between prostate cancer and MC. Hoechst-Celanese [Ex. 19-
65, pp. 10-12; Ex. 91D, p. 12] cautioned OSHA not to overinterpret the
excess of prostate cancer in the Cumberland study for the following
reasons:

(1) of all the epidemiological studies, only the Cumberland
study has shown an excess of prostate cancer; (2) of the thirteen
high subcohort men who died of prostate cancer, twelve worked in the
extrusion area of the Cumberland plant before methylene chloride was
used as a solvent in cellulose triacetate fiber production. Thus,
these men may have had longer exposure to other chemicals; (3) the
study did not control for other personal risk factors; (4) Gibbs
reported an increased incidence of prostate cancer elsewhere in the
textile industry; and (5) the large number of statistical tests may
have increased the probability of finding the death rate of a
specific cause to be elevated or depressed.

OSHA believes that the increased risk of prostate cancer should be
noted as a possible positive effect of MC exposure on cancer risk,
particularly considering the exposure-response relationship. However,
because of potential confounding factors and lack of corroborating
findings in other studies, OSHA believes this is suggestive rather than
conclusive evidence of a human carcinogenic effect.
b. Studies of film production workers.
In their original study of film production workers, Friedlander et al.
[Ex. 4-27] conducted both a proportionate mortality study and a
retrospective mortality cohort study to determine if workers exposed to
MC experienced an increased risk for specific causes of mortality. The
cohort in these studies consisted of workers who worked in any
department in film production that used MC as its primary solvent for
approximately thirty years. The cohort was followed through 1976.
Proportionate mortality analysis for those workers ever employed in
the study area versus a comparison group of workers in other Kodak Park
departments produced a proportionate mortality ratio (PMR) of 143.88
for liver (intrahepatic ducts-primary) cancer. For ischemic heart
disease, Friedlander et al. calculated a PMR of 94.74. No statistically
significant differences were observed at p 0.05.
For the cohort mortality study, Friedlander et al. used rates from
the 1964-70 hourly males age group exposed to MC in the film department
and the other Kodak Park departments for internal comparison. Mortality
rates for New York State, excluding New York City, males age group were
used for external comparisons.
Forty-five deaths from circulatory diseases were observed in the
MC-exposed cohort versus 38.5 expected in the Kodak Park referent
group. Also, 6 deaths from respiratory diseases were reported in the
MC-exposed group versus 3.2 expected for the Kodak Park comparison
group. No liver deaths were observed in this cohort. Thirty-three
deaths from ischemic heart disease were observed in this cohort
compared with 28.7 expected in the Kodak Park population. None of these
observed differences in mortality reached statistical significance.
Hearne et al. conducted several updates to the cohort study
involving MC exposure and mortality among workers in film production
areas at the Kodak plant in Rochester, New York [Exs. 7-122, 7-163, 49
A-1]. In the first update, the study cohort was followed through 1983.
Two referent groups were utilized in this study: the general population
of upstate New York men, excluding New York City, and Kodak Park
employees.
No statistically significant findings were observed for any cause
of death. However, Hearne et al. did find a relatively large number (8
observed) of pancreatic cancer deaths compared with the New York State
(3.2 expected) and Kodak (3.1 expected) populations. This observation
did not achieve statistical significance and a dose-response
relationship was not observed when Hearne et al. considered latency and
dose.
Hearne et al. then updated this study through 1988 [Ex. 7-163] and
1990 [Ex. 49 A-2]. In the 1988 update, nonsignificant deficits in
observed-expected ratios for lung and liver cancer were found. Also,
overall mortality from 1964 to 1988 was significantly less than in both
referent groups. Since 1986, the number of pancreatic cancer deaths
remained the same. As before, dose-response analysis showed no
statistically significant pattern when latency or dose were considered.
The 1990 update showed that deaths due to liver cancer, lung
cancer, and ischemic heart disease were below the expected numbers in
both referent groups. Also, no additional pancreatic cancer deaths were
observed in this second update. Since the start of the follow-up,
Hearne et al. observed 8 deaths from pancreatic cancer compared with
4.5 expected (SMR = 1.78, p = 0.17).
Hearne et al. [Ex. 49 A-1] conducted a second Kodak cohort study
involving workers in cellulose triacetate preparation and film base
manufacturing between 1946 and 1970. Hearne et al. addressed the
potential selection bias in the 1964-70 Kodak cohort by including only
workers exposed primarily to MC after it was introduced in these areas
and making the study more complete by adding workers in the Dope
Department, which prepares the viscous cellulose triacetate mixture
used in the film base coating, and the Distilling Department, which
redistills and reblends solvents recovered from the coating operations.
The 1,311 men in the cohort were followed through 1990. An
occupational control group could not be formed because death rates for
Kodak employees before 1964 were unavailable. Instead, male residents
of upstate New York living outside of the five New York City counties
were used.
Hearne et al. combined exposures by job and time period with
occupational history information to produce a career exposure estimate
for each individual in the study for dose-response analyses. The mean
career individual exposure was approximately 40 ppm for 17 years and
the average interval between first exposure and end of follow-up was
about 32 years.
Total mortality for this cohort was 22% below the expected
mortality (statistically significant). Circulatory diseases and
ischemic heart disease mortality were also statistically significantly
below expectation. For lung cancer there were 22 deaths (28.7 expected)
and for liver/biliary cancer

[[Page 1508]]

there was one death (1.5 expected). Hearne et al. found that the number
of pancreatic cancer deaths observed (4) was similar to the expected
number (4.4). In this cohort, the number of observed deaths was greater
than expected for diseases of the colon/rectum (13 observed v. 10.8
expected), brain (5 v. 2.3), and for leukemia (7 v. 3.4), but were not
statistically significant.
Hearne et al. concluded that the findings in the 1964-70 cohort
were consistent with the 1946-70 cohort: mortality from all causes,
cancer (including lung and liver malignancies), and ischemic heart
disease was lower than expected. Also, since the number of observed
pancreatic cancer deaths in this cohort was similar to the expected
number, Hearne et al. believed that this provided further evidence that
the earlier finding of an excess of pancreatic cancer in the 1964-70
cohort was due to chance or to factors other than MC exposure.
Kodak [Tr. 1287-88, 9/22/92] also investigated the risk of adverse
health effects during active occupational exposure to MC, as suggested
by NIOSH [Tr. 970, 9/21/92]. Using person-years of active employment
only in their analysis, Hearne observed 27 deaths (36 were expected in
the internal Kodak reference group) from ischemic heart disease in the
1964-70 Kodak cohort; in the 1946-70 cohort, Kodak recorded 33 deaths
compared with 43 expected in the New York State comparison population.
NIOSH testified [Tr. 877-83, 9/21/92] that the healthy worker
effect (HWE) could have obscured any excess mortality from ischemic
heart disease caused by MC exposure. NIOSH has stated that the HWE may
be particularly strong for cardiovascular diseases.
The HWE is likely to be less of a factor when occupational
comparison groups are used. Kodak's use of the Kodak Park employees as
a comparison group should reduce the HWE in its studies. However, there
are two potential problems with using occupational comparison groups in
this instance:
(1) Cancer rates are more stable in larger populations, so
comparison with state and national rates may be more appropriate.
(2) Due to the volume of MC used in the Kodak plant, the
occupational comparison group may be exposed to air- or water-borne
environmental concentrations of MC which could obscure the impact of
occupational exposure to MC on cancer incidence.
c. Study of workers in paint and varnish manufacturing. The NPCA
submitted to the record an epidemiological study of employees who
worked for at least one year in the manufacture of paint or varnish
[Ex. 10-29B]. OSHA's review of this study was published in the proposed
rule [56 FR 57077]. Although no statistically significant excess of
mortality was reported, OSHA noted that there were 4 pancreatic cancers
(1.93 expected) and 15 cancers of digestive organs and peritoneum
(10.66 expected) among MC-exposed workers.
d. Astrocytic brain cancer among workers in electronic equipment
production and repair. In its March 11, 1994 Notice of Limited
Reopening of the Rulemaking Record, OSHA solicited comments on a case-
control study submitted to the Agency by the National Cancer Institute
(NCI) [Exs. 112 and 113].
Heineman et al. conducted a case-control study to examine the
potential association between brain cancer and exposure to organic
solvents as a group and six chlorinated aliphatic hydrocarbons (CAHs)
including MC. Cases were defined as white males who died from brain or
other central nervous system tumors in southern Louisiana, northern New
Jersey, and Philadelphia, Pennsylvania. Controls were randomly selected
from death certificates and included white males who died of causes
other than brain tumors, cerebrovascular diseases, epilepsy, suicide,
and homicide. Controls were frequency-matched to cases by age, year of
death, and geographic area.
Four-digit Standard Industrial Classification (SIC) and 4-digit
Standard Occupational Classification (SOC) codes were employed to code
occupational histories of study subjects. These codes linked work
histories to job-exposure matrices which ``characterized likely
exposure to the six CAHs and to organic solvents'' [Ex. 112]. Gomez et
al. [Ex. 112] used an algorithm to assign estimates of probability and
intensity of exposure to each industry/occupation combination in
subjects' work histories. As noted by Gomez et al., these estimates
were based on ``occupation alone, industry alone, or both occupation
and industry, depending on the specificity of the exposure environment
that could be inferred from the occupational (SOC) code.''
The following surrogate measures of dose, for each substance, were
used to summarize ``likely'' exposure histories for each study subject:
duration of employment in occupation/industry combinations considered
exposed, a cumulative exposure score, and ``average'' intensity of
exposure. Odds ratios were calculated for exposure intensity categories
to refrain from using weights. These categories did not include
duration in jobs with lower intensity for subjects with high or medium
intensity jobs. In their statistical analyses, Heineman et al.
controlled for age, geographic area, and employment in electronics-
related occupations/industries.
Astrocytic brain cancer was not found to be associated with
``ever'' being exposed to organic solvents as a group or to any of the
six CAHs examined in this study. However, as probability of exposure to
organic solvents as a group, and MC in particular, increased, the risk
of brain cancer increased (chi-squared statistics for trend for organic
solvents and MC were 1.93 and 2.29 (p2.
Cardiovascular stress has been observed after exposure to CO, so it is
reasonable to suspect that similar health effects would be observed
after exposure to MC (and metabolism to CO) [Ex. 7-73, 4-33].
Carbon monoxide successfully competes with oxygen and blocks the oxygen
binding site on hemoglobin, producing carboxyhemoglobin (COHb) and
reducing delivery of oxygen to the tissues. This reduces the oxygen
supply to the heart itself, which can result in myocardial infarction
(heart attack) [Ex. 4-33].
Generally, humans have a baseline level of COHb of less than 1%
COHb due to the endogenous production of CO from normal metabolic
processes. The measured level of COHb in the general non-smoking
population is from 1% to 3% because of direct exposure to CO from
combustion sources such as automobiles, etc. In smokers, COHb generally
ranges from 2% to 10% because of the additional CO exposure during
smoking. CO generated from exposure to MC would be additive to the COHb
burden already experienced by an individual from direct exposure to CO.
The cardiac health effects anticipated from exposure to MC itself or CO
as the result of metabolism of MC are described below.
a. Animal studies. There is no evidence from animal studies in the
MC rulemaking record that MC has a direct toxic effect on cardiac
tissue. After lethal doses of MC, death has been primarily attributed
to CNS and respiratory depression [Exs. 7-27, 7-28]. Also, chronic
studies (in which COHb levels have been maintained at 10% and higher)
[Exs. 7-3, 7-8, 7-14, 7-130, 7-151] have not shown direct
cardiotoxicity.
Chlorinated solvents have been shown to sensitize the cardiac
tissue to epinephrine- induced fatal cardiac arrhythmias [Ex. 7-226].
However, MC is less effective in sensitizing cardiac

[[Page 1513]]

tissue than other chlorinated analogues. MC caused sensitization of
cardiac tissues only at doses well above doses which produce a narcotic
effect. This finding indicates that compliance with an 8-hour TWA of 25
ppm MC would likely be sufficient to protect against such
sensitization.
b. Human studies. The metabolism of MC to CO and measurement of
COHb in human subjects exposed to MC were described in detail in the
NPRM. In summary, it was found that exercising increased MC uptake and,
subsequently, increased blood COHb levels compared to that of sedentary
individuals [Ex. 7-222]. In addition, COHb levels due to smoking were
found to be additive to the COHb produced by MC metabolism. Taken
together, these results suggested that smokers or individuals engaged
in physical exertion (as in a workplace) may be at increased risk from
CO- induced toxicity from MC exposure. This risk may be especially
elevated in individuals with silent or symptomatic cardiac disease who
may be susceptible to very small increases in COHb because of an
already impaired blood supply to the heart. Many American workers have
silent or symptomatic heart disease. This increased OSHA's concern for
the potential cardiac effects of MC and its metabolites.
Elevated COHb has been measured in humans experimentally and
occupationally exposed to MC [Exs. 7-4, 7-5-R0327, 7-102, 7-115, 7-157,
7-159, 7-169, 7-174, 7-176]. The effects of elevated COHb are primarily
increased risk of myocardial infarction, especially in susceptible
individuals. Atkins and Baker [Ex. 7-198] described two cases of
myocardial infarction in workers subsequent to CO exposure. COHb was
measured at 30% and 24% in these individuals, which is much higher than
normal general population levels of COHb. Humans exposed to MC would
not be expected to experience COHb at those levels unless the exposure
to MC was extremely high (greater than 500 ppm).
In a laboratory study of humans with coronary artery disease,
subjects were exposed to CO and observed for cardiac health effects
during exercise. In subjects with 3 to 10% COHb, decreased exercise
tolerance and increased anginal pain were observed [Ex. 7-198]. In an
epidemiological study submitted to OSHA by NIOSH during the MC public
hearings, the investigators observed a statistically significant excess
of ischemic heart disease mortality among tunnel workers when compared
with rates for the New York City population [Ex. 23-18]. This increase
in mortality is supported by clinical findings. Allred et al. [Ex. 23-
18] observed that elevation of COHb from 0.6% to as low as 2% decreased
time to myocardial ischemia and anginal pain during laboratory tests.
OSHA believes that these studies, taken together, suggest that small
increases in COHb can adversely affect persons with compromised cardiac
health. The results observed in the tunnel workers are particularly
relevant because they show an increased risk in a working population.
NIOSH used these studies to support its recommendation that the COHb
effects of MC be carefully considered in the MC rulemaking [Tr. 881-2,
9/21/92]. OSHA agreed with NIOSH that the effects observed at low
levels of COHb are cause for concern about the risks of MC metabolism
to CO.
In the NPRM, OSHA also reviewed case reports in which individuals
exposed to MC experienced myocardial infarctions [Exs. 7-102, 7-73].
These case reports suggested that exposure to MC increased cardiac
stress, although it was not determined whether this was a direct effect
of MC or as the result of metabolism of MC to CO. OSHA believes that
these case studies support the hypothesis that CO generated through
metabolism of MC would have the same adverse health effects as direct
CO exposure.
Two epidemiological studies (in film coating and fiber production
workers) [Exs. 7-75, 7-76, 7-122, 7-163] examined cardiac mortality due
to occupational exposure to MC. Ott [Ex. 7-76] compared mortality from
a plant in South Carolina that used MC to a reference plant in
Virginia. An increased risk ratio for ischemic heart disease (risk
ratio = 3.1) was observed in the MC-exposed workers compared to the
reference population.
This approach controls for the healthy worker effect by comparing
two working populations, and excess risk was demonstrated. The authors
believed that the apparent excess risk was due to geographical
variability in the incidence of ischemic heart disease. The population
from the reference plant was found to have an unusually low death rate
due to ischemic heart disease in comparison to the general population
rate.
In an update of the study [Ex. 7-75], the ischemic heart disease
rate in the exposed population was compared to that in the surrounding
York County, S.C. population instead of a reference plant. No
difference in ischemic heart disease rates was detected between exposed
workers and controls, although this approach would not control for the
healthy worker effect. The SMR was 0.94 (32 observed, 34.2 expected).
NIOSH disagreed with the conclusion of the authors of this study,
and indicated that the studies summarized above would be cause for
concern regarding the cardiac effects of MC. NIOSH suggested that the
raw data from the epidemiological studies of cellulose acetate film
production workers and the studies of workers in cellulose acetate
fiber manufacture be reviewed for cardiac mortality occurring during
the period of occupational exposure for the workers. OSHA is concerned
about the potential CO effects from metabolism of MC and will continue
to monitor the scientific literature on this topic. However, the Agency
is setting the exposure limits based on cancer and CNS effects and has
not reached final conclusions on this issue.
3. Hepatic Toxicity
Chlorinated hydrocarbons as a class, such as carbon tetrachloride
and chloroform, are toxic to the liver. In general, chlorinated
hydrocarbons cause cytotoxicity (cell death) in rodent livers.
Therefore, there was suspicion that the liver would also be a target
organ for MC (a chlorinated hydrocarbon) toxicity. OSHA evaluated the
available literature on the hepatic effects of MC in animal and human
studies.
a. Animal studies. Studies of the effects of MC exposure on the
rodent liver have not demonstrated significant acute liver toxicity,
even at lethal or near-lethal doses. As summarized in the NPRM, Kutob
et al. [Ex. 7-27] and Klaassen et al. [Ex. 7-28] conducted experiments
on halogenated methanes and hepatotoxicity. MC was determined to be the
least hepatotoxic of the halogenated methanes examined. The only injury
described was a mild inflammatory response associated with lethal MC
concentrations. These studies demonstrated that liver was not the
primary target organ for the acute toxicity of MC.
Weinstein et al. [Ex. 7-181] examined the hepatic effects of MC on
female mice who were continuously exposed for up to 7 days to MC
concentrations of up to 5000 ppm. Mild, nonlethal injury to the livers
was noted, characterized by balloon degeneration of the rough
endoplasmic reticulum (RER), transient severe triglyceride accumulation
(fatty liver), partial inhibition of protein synthesis and breakdown of
polysomes into individual ribosomes. The injury is similar to a mild
form of carbon tetrachloride toxicity (a structural analog of MC) and
suggests that although the toxicity due to MC is not as severe as that
produced by carbon tetrachloride, the mechanism of toxicity may be
similar.

[[Page 1514]]

In subchronic experiments more severe effects were observed in the
liver after continuous exposure. MacEwen et al. [Ex. 7-14] studied the
effects of continuous exposure of mice, rats, dogs and rhesus monkeys
to 1000 and 5000 ppm MC for up to 14 weeks. Fatty liver, icterus,
elevated SGPT and ICDH were reported in dogs at both concentrations.
These effects appeared at 6-7 weeks of exposure to 1000 ppm MC and at 3
weeks of exposure to 5000 ppm. Monkeys were less sensitive to hepatic
injury, and showed no changes in liver enzymes and only mild to
moderate liver changes at 5000 ppm MC. No liver alterations were
detectable in monkeys exposed to 1000 ppm MC. Mice and rats developed
liver toxicity at both exposure levels, characterized by increased
hemosiderin pigment, cytoplasmic vacuolization, nuclear degeneration
and changes in cellular organization.
Hepatic effects associated with chronic MC exposure were observed
in lifetime cancer bioassays in three rodent species: rats, mice and
hamsters. In studies conducted by the NTP and Dow Chemical Co., rats
were exposed to inhalation concentrations of MC from 50 ppm to 4000 ppm
6 hours per day, 5 days per week [Exs. 7-8, 7-151, 7-173]. Hepatic
effects were observed after exposure to MC concentrations as low as 500
ppm. These effects were characterized by increased fatty liver,
cytoplasmic vacuolization and an increased number of multinucleated
hepatocytes. At higher doses (greater than 1500 ppm), increased numbers
of altered foci and hepatocellular necrosis became apparent.
Serota et al. [Ex. 7-180] administered 5 to 250 mg MC/kg body
weight to rats in drinking water. Hepatic toxicity similar to that
observed in the inhalation studies was reported at doses from 50 to 250
mg/kg.
In mice, the chronic hepatic effects of MC were investigated in two
bioassays: NTP [Ex. 7-8] and Serota et al. [Ex. 7-179]. In the NTP
study, mice were exposed by inhalation to 2000 or 4000 ppm MC.
Cytologic degeneration was observed in both male and female mice and
increased incidences of hepatocellular adenomas and carcinomas were
found at both concentrations. The carcinogenic effects of MC are
described in greater detail above, in the discussion of MC
carcinogenicity.
In a drinking water study, Serota et al. found that mice exposed to
50 to 250 mg/kg/d MC had dose-related increases in the fat content of
the liver (a sign of liver toxicity). Although some proliferative
hepatocellular lesions were identified in this study, they were
distributed across all exposure groups. Hepatocellular tumor incidences
were not elevated above historical control incidences.
In the hamster, Burek et al. [Ex. 7-151] found minimal treatment-
related changes in the livers of the MC-exposed animals after exposure
to 500, 1500 or 3500 ppm MC. A dose-related increase in hemosiderin was
found in male hamsters at 6 months and at 3500 ppm at 12 months. No
other changes in liver physiology were reported.
OSHA believes that these studies demonstrate that the rodent liver
is not sensitive to acute affects of MC, but that chronic exposure to
MC caused toxic effects in rat and mouse liver and cancer in mouse
liver. These studies appear to have been well conducted and the
differences in toxicity observed across studies were likely due to
differences in dose or route of exposure. The hamsters appeared to be
insensitive to liver toxicity. OSHA believes that this is most likely
due to inherent species differences in response to toxicants.
b. Human studies. OSHA evaluated epidemiological studies and case
reports to determine the extent of hepatic effects detected after
exposure of humans to MC. Liver toxicity was measured as alterations in
the blood levels of any of several normal liver enzymes in these
studies.
i. Epidemiological studies. In a cross-sectional analysis of the
health of workers in an acetate fiber production plant in which workers
were exposed to 140 to 475 ppm MC, Ott et al. [Ex. 4-33c] reported
statistically significant increases in serum bilirubin and alanine
aminotransferase (ALT) (also known as serum glutamic pyruvic
transaminase (SGPT)) when compared with a reference group of industrial
workers. The elevation in bilirubin levels showed a dose-response
relationship, but the ALT levels were not associated with MC exposure.
The authors felt that the increase in ALT in MC-exposed workers could
not be attributed to MC because a dose-response relationship was not
demonstrated and, therefore, the increase in ALT between the exposed
and reference populations could be disregarded as a sign of liver
toxicity. The authors concluded that although bilirubin elevation may
be interpreted as a sign of liver toxicity, this interpretation was not
supported by alterations in other liver parameters. OSHA feels that ALT
cannot be disregarded as unrelated to MC exposure based on the lack of
dose response within the exposure group. The high variability of this
parameter and the low numbers of individuals within certain exposure
subgroups (e.g., 10 men exposed at 280 ppm), make a dose-response
relationship more difficult to demonstrate. Any mistake made in the
characterization in an exposure group would result in obscuring the
dose-response relationship. Although the evidence is not unequivocal,
OSHA believes that the elevated bilirubin coupled with the elevated ALT
values indicate suggestive evidence of a hepatotoxic response to MC
exposure in this worker population.
In an update to the study described above, Cohen et al. [Ex. 7-75]
found 4 cases of liver/biliary duct cancer in workers with more than 10
years of exposure to MC and after 20 years from first hire. Further
description of this study can be found in the discussion of MC
carcinogenicity, above.
In an English translation of a 1968 Czechoslovakian study, Kuzelova
et al. [Ex. 7-26] found no liver enzyme abnormalities in workers
exposed to MC concentrations from 29 ppm to 4899 ppm for up to two
years. In contrast, in an English translation of a German study which
focussed on neurological changes due to MC exposure, Hanke et al. [Ex.
7-195] observed pathological liver function tests and hepatomegaly
(enlarged liver) in 4 of 14 floor tile setters examined. These workers
were chronically exposed to MC at concentrations as high as 400 to 5300
ppm. The average tenure of employment of these workers was 7.7 years.
The authors of the Hanke study noted that although MC with its
impurities could be responsible for the liver damage, the evidence was
not conclusive. OSHA has determined that there is insufficient evidence
from the Kuzelova and Hanke studies to conclude that MC causes chronic
human hepatotoxic effects.
ii. Case reports. In addition to the cross-sectional analyses of
worker morbidity described above [Exs. 4-33c and 7-26], the
relationship of MC exposure and hepatotoxicity has been studied by
analysis of case reports. Welch [Ex. 7-73] collected 144 case reports
of clinical disease reported subsequent to occupational MC exposure.
Quantitative exposure estimates for individuals were unreliable, but
the presence of MC in the work environment was ascertained for each
employee. The most prevalent findings in these case reports were CNS
symptoms, upper respiratory syndrome and alterations in liver enzymes.
The patterns of alteration in liver enzymes were not consistent among
individuals, but may be suggestive of a MC-associated hepatotoxic
effect. One case of hepatitis of unknown etiology was identified. The
case physician believed

[[Page 1515]]

that the hepatitis was secondary to solvent exposure. The solvents to
which this employee was exposed included xylene and methylethyl ketone
as well as MC. OSHA believes that the confounding solvent exposures in
the hepatitis case and the unknown exposure histories of the
individuals with altered liver enzymes limit the interpretation of
these studies. OSHA has determined that these case reports provide
insufficient evidence to conclude that MC was the causative agent in
these cases.
Analysis of cases of fatal and near-fatal human exposures [Exs. 7-
18, 7-19] indicated no apparent acute alterations of liver function.
Acute concentrations of MC which caused narcosis and even death were
not associated with changes in liver enzymes.
OSHA concludes that limited evidence supports the hypothesis that
MC causes human hepatotoxicity, based on the data in the Ott study. The
remaining studies and case reports do not provide clear evidence of a
causative role of MC in hepatotoxicity. The Agency has set the exposure
limits based on cancer and CNS effects and has not reached final
conclusions on this issue.
4. Reproductive Toxicity
There are only limited data available regarding the potential
adverse teratogenic or reproductive effects due to MC exposure.
Teratogenicity studies have been conducted in rats and mice and limited
epidemiology and case reports have been described for humans.
a. Animal studies. A study [Ex. 4-5] using chicken embryos
indicated that MC disrupts embryogenesis in a dose-related manner.
Since the application of MC to the air space of chicken embryos is not
comparable to MC administration to animals with a placenta, the
exposure effect seen in the chick embryos can only be considered as
suggestive evidence that an effect may also occur in mammalian systems.
The teratogenicity of inhaled MC has also been studied in rats and
mice [Exs. 7-20, 7-21, 7-22]. In 1975, Schwetz et al. [Ex. 7-21]
conducted a study on Swiss Webster mice. Mice were exposed to 1250 ppm
MC for 7 hours/day, on days 6-15 of gestation. On day 18 of gestation,
Caesarian sectioning of dams was performed. A statistically significant
increase in mean maternal body weight (11-15%) was observed in dams
exposed to 1250 ppm MC; however, food consumption was not measured. The
only effect on fetal development associated with MC exposure was a
statistically significant increase in the number of fetuses which
contained a single extra center of ossification in the sternum. The
incidence of gross anomalies observed in the MC-exposed fetuses was not
significantly different from that in the control litters. Maternal COHb
level during exposure reached 12.6%; however, 24 hours after the last
exposure, COHb had returned to control levels.
In the same study by Schwetz et al. [Ex. 7-21], Sprague-Dawley rats
were exposed to 1250 ppm MC via inhalation for 7 hours daily on days 6-
15 of gestation. No MC-associated effects were observed in food
consumption or maternal body weight. Among litters from MC-exposed
dams, the incidence of lumbar ribs or spurs was significantly decreased
when compared to controls, while the incidence of delayed ossification
of sternebrae was significantly increased compared to controls. No
increased incidence of gross anomalies were observed in the fetuses
from exposed rats compared to fetuses from control litters. No MC-
associated effects were observed on the average number of implantation
sites per litter, litter size, the incidence of fetal resorptions,
fetal sex ratios or fetal body measurements, in the 19 litters that
were evaluated. As observed in the MC-exposed mice, there was
significant elevation of the COHb level in the dams, but the level
returned to control values within 24 hours of cessation of exposure.
In 1980, Hardin and Manson [Ex. 7-22] evaluated the effect of MC
exposure in Long-Evans rats after inhalation of 4500 ppm for 6 hours/
day, 7 days/week prior to and during gestation. Four exposure groups
were described. The first group was exposed to MC for 12 to 14 days
prior to gestation and during the first 17 days of pregnancy. The
second group was exposed to MC only during the 12 to 14 days prior to
gestation. The third group was exposed to MC only during the first 17
days of pregnancy. The fourth group (control group) was exposed only to
filtered air. The purpose of this study was to test whether MC exposure
prior to and/or during gestation was more detrimental to reproductive
outcome in female rats than exposure during gestation alone.
In rats exposed to MC during gestation, there were signs of
maternal toxicity, characterized by a statistically significant
increase in maternal liver weights. The only fetal MC effects observed
were statistically significant decreases in mean fetal body weights. No
significantly increased incidence of skeletal or soft tissue anomalies
was observed in the offspring.
In 1980, Bornschein et al. [Ex. 7-224] tested some of the offspring
of the Long-Evans rats from Hardin and Manson's study described above.
All four treatment groups were used to assess the postnatal toxicity of
MC exposure at 4500 ppm. The general activity measurements of groups of
5-day old pups showed no exposure-related effects. At 10-days of age,
however, significant MC-associated effects were observed in both sexes
in the general activity test. These effects were still apparent in male
rats at 150-days of age. This study showed that maternal exposure to MC
prior to and/or during pregnancy altered the manner in which the
offspring react and adapt to novel test environments at up to 150-days
of age. These effects suggest that MC exposure prior to, or during
pregnancy may influence the processes of orientation, reactivity, and/
or behavioral habituation. No changes in growth rate, long-term food
and water consumption, wheel running activity or avoidance learning
were reported.
OSHA concluded from the animal studies that maternal exposure to
high concentrations of MC during pregnancy may have some adverse
effects on the offspring, in particular with regard to behavioral
effects. The Agency has set the exposure limits based on cancer and CNS
effects and has not reached final conclusions on this issue.
b. Human studies. Limited data have been collected on the
reproductive effects of MC in male workers. In a study reported in the
Occupational Safety and Health Reporter [Ex. 7-43], a greater risk of
male sterility was found in male workers exposed to MC. In 1988, Kelly
[Ex. 7-165] reported 4 cases of oligospermia in MC-exposed workers.
This study was described in detail in the NPRM. Although the study
provided some evidence of an effect of MC on male fertility, the
observations were based on a small number of cases and OSHA believes
that more research is necessary before causative conclusions can be
drawn about the human male reproductive toxicity of MC.
The reproductive and developmental effects due to MC exposure in
female workers have also been studied. According to information
reported in an English translation of an abstract of a Russian article
by Vozovaya et al. [Ex. 7-16], detectable levels of MC were found in
the blood, milk, embryonal, fetal and placental tissues of nursing
women exposed to MC in a rubber product plant. No other information was
provided in the abstract. In a study by Taskinen et al. [Ex. 7-199],
increased rates of spontaneous abortions were observed in female
pharmaceutical

[[Page 1516]]

workers exposed to MC. Exposure data were not reported in this study
and it is unclear what confounding factors or other chemical exposures
were present. OSHA believes that more research is necessary in order to
evaluate the potential effect of MC on pregnancy outcomes, and so has
not reached a conclusion on this issue.
Carbon monoxide has well known adverse reproductive effects in
humans. Since MC is metabolized to CO, OSHA was concerned about the
adverse reproductive effects of CO as a metabolite of MC. The EPA has
reviewed the literature on the effects of maternal CO exposure on the
development of the fetus in the Air Quality Criteria for Carbon
Monoxide [Ex. 7-201]. Very high maternal CO exposures have resulted in
fetal or infant death or severe neurological impairment of the
offspring. CO reduces the amount of oxygen available to the tissues.
The developing fetus is very sensitive to these effects. According to
Fechter et al. [Ex. 7-200], low levels of CO exposure in animals have
been shown to adversely affect the fetus, producing CNS damage or
reduced fetal growth. These effects suggest that the fetus may be
especially sensitive to the toxic effects of MC through its metabolism
to CO.
As described above, OSHA is sufficiently concerned about the
potential for reproductive health effects of carbon monoxide as a
result of MC metabolism that it has decided to continue to gather
information and revisit this issue, if warranted.

F. Conclusion

OSHA's determination that MC is a potential occupational carcinogen
was based primarily on the positive findings of chronic inhalation
bioassays in rodents. MC is carcinogenic to mice of both sexes,
producing lung and liver neoplasms. In rats, MC produced dose-related
increases in mammary tumors and increases in the number of tumors per
tumor-bearing rat. The evidence in rodents is supported by
epidemiologic findings from cellulose triacetate fiber production
workers and a case-control study of individuals with astrocytic brain
cancer. The study of fiber production workers suggests an association
between liver and biliary cancer and long term (greater than 10 years)
exposure to MC. The case-control study indicates an association between
risk of astrocytic brain cancer and occupational exposure to MC. This
evidence is further supported by the findings of genotoxic activity of
MC in bacterial and mammalian cell systems. OSHA has set the 8-hour TWA
PEL of 25 ppm primarily to protect employees from the risk of cancer
due to MC exposure in the workplace.
CNS depression has been demonstrated in humans and animals at
relatively low inhalation concentrations of MC. The CNS depression
observed in those studies was relatively mild, although the effects
occurred at concentrations in the range of the STEL of 125 ppm. OSHA
believes that the STEL will be protective against CNS depression for
most employees exposed to MC most of the time, but the Agency is
sufficiently concerned about the potential for CNS health effects at
concentrations below the STEL and have decided to continue to gather
information and revisit this issue, if warranted.

VI. Quantitative Risk Assessment

Summary

After examining all the available data, both animal and human, and
both quantitative and qualitative, OSHA has concluded that MC is a
multi-species, multi-site carcinogen in various rodent species, and is
likely to be so in humans, and that it most probably acts via one or
more genotoxic metabolite(s). The evidence for this conclusion is quite
strong: there exist several positive bioassays with low background
incidence and dose-related increases; there is an unusually large
amount of mechanistic information; and there are several positive
epidemiological studies and no negative epidemiological studies of
sufficient power to rule out the animal-based potency estimates.
Furthermore, OSHA has conducted a quantitative risk assessment
based on the highest-quality animal tumor data, constructing a state-
of-the-art physiologically-based pharmacokinetic (PBPK) model
incorporating rodent and human metabolic information. That analysis
shows a final estimate of risk of 3.62 deaths per 1000 workers
occupationally exposed to 25 ppm MC for a working lifetime. [An
alternative analysis, which incorporated all of the data used in the
main analysis plus the assumption that human enzymes are even less
active to MC (as compared to mice) than that predicted by the main
analysis, gave a risk estimate of 1.23 deaths per 1000]. Both estimates
are clearly well above any plausible upper boundary of the
``significant risk'' range defi

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Source: Frix Law Library, https://www.frixlaw.com/law-library/documents/fr%3A97-198. Public record. Not legal advice.