**\[page 15526\]**

**DEPARTMENT OF LABOR**

**29 CFR Part 1910**

**Docket No. H-044**

**Occupational Exposure to 2-Methoxyethanol, 2-Ethoxyethanol and Their
Acetates (Glycol Ethers)**

**AGENCY:** Occupational Safety and Health Administration (OSHA), Labor

**ACTION:** Proposed rule and notice of hearing

**SUMMARY:** The Occupational Safety and Health Administration (OSHA)
proposes to amend its existing regulation for occupational exposure to
2-Methoxyethanol (2-ME), 2-Ethoxyethanol (2-EE) and their acetates
(2-MEA, 2-EEA) (\"Glycol Ethers\"), contained in 29 CFR 1910.1000 Table
Z-1, and to be codified as new section 29 CFR 1910.1031. The Assistant
Secretary has determined, based on a review and evaluation of studies
conducted on the health effects of these glycol ethers, that the current
permissible exposure limits (PELs) do not adequately protect employees
from significant risks of adverse health effects, specifically
reproductive and developmental health effects

To eliminate these significant risks of adverse health effects, OSHA is
proposing for general, maritime, agriculture and construction industries
to reduce the existing 8-hour time weighted average (TWA) PELs for 2-ME
and 2-MEA to 0.1 ppm and for 2-EE and 2-EEA to 0.5 ppm

OSHA proposes excursion limits (ELs) for these glycol ethers of five
times the proposed PELs. OSHA also proposes to set Action Levels (ALs)
for these glycol ethers of one-half the proposed PELs, measured as an
8-hour TWA, to encourage lower exposure for employees while reducing
administrative burdens on employers. In addition, OSHA proposes that no
employee shall be exposed to these glycol ethers through dermal contact

OSHA proposes to require certain ancillary provisions for employee
protection such as preferred methods to control exposure, employee
exposure monitoring, medical surveillance, recordkeeping, regulated
areas, emergency procedures, hazard communication, and personal
protective equipment

**DATES:** Written comments on the proposed standard must be postmarked
on or before June 7, 1993. Notices of Intention to Appear at the
informal public hearings on the proposed standard must be postmarked by
June 7, 1993. Parties who request more than 10 minutes for their
presentations at the informal public hearing and parties who submit
documentary evidence at the hearing must submit the full text of their
testimony and all documentary evidence no later than June 28, 1993. The
informal rulemaking hearing is scheduled to begin on July 20, 1993

**ADDRESSES:**Written comments should be submitted to the Docket
Officer, Docket No. H-044, Room N-2625, U.S. Department of Labor, 200
Constitution Avenue, N.W., Washington, DC 20210

Notices of Intention to Appear at the informal rulemaking hearing,
testimony, and documentary evidence are to be sent to Tom Hall, OSHA
Division of Consumer Affairs, Docket No. H-044, Room N-3662, U.S.
Department of Labor, 200 Constitution Avenue, N.W., Washington, DC 20210

**FOR FURTHER INFORMATION CONTACT:**Mr. James F. Foster, OSHA, U.S.
Department of Labor, Office of Public Affairs, Room N-3647, 200
Constitution Avenue, N.W., Washington , DC 20210. Telephone (202)
219-8151.

**SUPPLEMENTARY INFORMATION:**

**I. Introduction**

Table of Contents

I.  Introduction

II. Pertinent Legal Authority

III. History of the Regulation

IV. Chemical Identification, Production, and Use of Ethylene Glycol
    Ethers

V.  Health Effects

    A.  Introduction

    B.  Metabolism/Metabolic-Related Health Effects

    C.  Acute Toxicity

    D.  Background Discussion on Reproductive and Developmental
        Toxicology

    E.  Effects in Animals

        1.  Male Reproductive Effects

        2.  Maternal/Developmental Effects

        3.  Blood Effects

    F.  Adverse Effects in Humans

    G.  Mutagenicity

    H.  Conclusions

    I.  Health Effects of Other Glycol Ethers

VI. Risk Assessment

VII. Significance of Risk

VIII. Summary of the Regulatory Impact Analyses and Regulatory
      Flexibility Analysis

IX. Environmental Impact

X.  Summary and Explanation of the Proposed Standard

XI. Clearance of Information Collection Requirements

XII. Public Participation - Notice of Hearings

XIII. Authority and Signature

XIV. Proposed Standard and Appendices

A. Issues

Comment is requested on all relevant issues, including health effects,
risk assessment, technological and economic feasibility and provisions
that should be included in a final glycol ethers standard

OSHA is especially interested in answers, supported by evidence and
reasons, to the following questions

1\. Do OSHA\'s proposed TWA permissible exposure limits (PELs) of 0.1
ppm for 2-ME and 2-MEA and 0.5 ppm for 2-EE and 2-EEA adequately protect
employees from significant risk of adverse health effects? If not, what
TWA permissible exposure limits would be more appropriate or would more
adequately protect employees from health risks? Please provide data and
evidence to support your response

2\. In addition to the proposed TWA PELs and action levels, OSHA has
proposed Excursion Limits (ELs) of 0.5 ppm for 2-ME and 2-MEA and 2.5
ppm for 2-EE and 2-EEA. In the preamble to this proposal OSHA has also
explained the various reasons for establishing ELs for the glycol ethers
included in this proposal. OSHA requests comment on this provision.
Please provide data and evidence to support your response

3\. In addition to the PELs for airborne exposure to glycol ethers, OSHA
is also proposing that employers ensure that no employee is exposed to
glycol ethers through dermal contact. OSHA requests comment on this
provision. In particular:

a\. Are there methods to measure dermal exposure that could be routinely
used to monitor worker exposure to glycol ethers?

b\. For employers whose employees are exposed to glycol ethers, what
methods do you use to protect employees from dermal contact with glycol
ethers?

c\. What do these methods cost?

4\. OSHA has limited the scope of this proposal to the four glycol
ethers referred to OSHA by EPA. OSHA requests comment about whether the
proposed scope of this rulemaking is appropriate. OSHA also requests
comment about whether the scope of this proposed standard should be
expanded to cover other ethylene glycol ethers and/or other propylene
glycol ethers. Should there be separate rulemaking undertaken to cover
other glycol ethers not included in this proposal? If so, what data and
evidence are available to indicate that exposure to these other glycol
ethers present a risk to employees?

5\. In making its risk assessment, OSHA relied upon the NOEL-Uncertainty
Factor approach to describe and calculate the risks associated with
occupational exposure to glycol ethers. OSHA requests comment on whether
this approach is appropriate for making a risk assessment regarding
reproductive/developmental health effects

\[**page 15527\]**

a\. OSHA requests comment on whether there are more appropriate models
for describing or calculating the risks of adverse
reproductive/developmental effects among exposed workers. Are there
scientifically valid quantitative models that would be more appropriate
for assessing risk of reproductive/developmental health effects?

b\. OSHA has used an Uncertainty Factor of 100 to determine a level
below which humans are unlikely to experience significant risk of
adverse reproductive/developmental effects similar to those observed in
animals. Is an Uncertainty Factor of 100 appropriate in this
circumstance? Would an alternative Uncertainty Factor be more
appropriate? Please provide data and evidence to support your response.
(Please see Section VI of this section for more detailed questions on
risk assessment.)

6\. Paragraph (g) of the proposed standard would require that supplied
air respirators be used in those limited situations where the TWA and/or
EL permissible exposure limits are not capable of being achieved solely
by means of engineering and work practice controls. The requirement that
respiratory protection be limited to supplied air respiratory protection
is based on the fact that glycol ethers have poor warning properties at
the proposed PELs. OSHA requests comment on this provision. OSHA also
requests comment on the following:

a\. Would the proposed requirement of supplied air respirators provide
adequate protection or are there other kinds of respiratory protection
that would be more appropriate and provide more protection?

b\. Are there situations in which organic vapor cartridges or canisters
could be used to adequately reduce exposures to or below the PELs? Do
these other methods have adequate warning of potential breakthrough?
Please provide evidence to support your response

c\. Are there any end-of-service-life indicators for the glycol ethers
covered by this rulemaking?

d\. For those employers whose employees are exposed to glycol ethers,
what respiratory protection is provided to employees who are exposed
above the PELs? How and why was the particular type of respiratory
protection selected?

e\. What is the cost of the respiratory protection program?

7\. The proposed standard would require that employers provide
appropriate personal protective equipment (e.g. coveralls, gloves, eye
shields) to prevent exposure through dermal or eye contact in those
limited situations where elimination of such contact is not capable of
being achieved solely by means of engineering and work practice
controls. OSHA requests comment on this provision. OSHA also requests
information on the following:

a\. OSHA is aware that some exposures to glycol ethers may be
intermittent or of short duration. In these situations the breakthrough
time of protective clothing or gloves may not be exceeded during a
single use. OSHA requests comment on whether the clothing or gloves
should be allowed to be reused? If so, in what situations would reuse be
appropriate or to what situations should reuse be limited?

b\. For employers whose employees are exposed to glycol ethers, what
kind of personal protective equipment is provided and in what
situations? Please explain, based on the specific situation, how and why
use of such equipment was determined. Do employees reuse protective
clothing and gloves?

c\. For employers whose employees are exposed to glycol ethers, what is
the cost of the personal protective equipment that is provided?

8\. A number of provisions have been proposed to prevent exposure of
employees through off-gassing from and/or contact with glycol ethers
from contaminated personal protective equipment. OSHA requests
information on problems associated with off-gassing and/or contact in
the storage, handling, and disposal of contaminated equipment
(particularly at the action levels that have been proposed). Should
specific change rooms and showers be required?

9\. Specific clean-up procedures have not been required in the proposal.
OSHA requests information on whether specific procedures and practices
should be required and, if so, what procedures are necessary. Is
peroxide formation a problem with these compounds?

10\. Paragraph (d)(2) of the proposed standard provides that initial
exposure monitoring would be required for all employees who are or may
be exposed to glycol ethers. OSHA requests comment on this provision

a\. For employers whose employees are exposed to glycol ethers, please
describe your monitoring program and the basis for performing initial
monitoring

b\. What are the cost of your monitoring program?

11\. Monitoring would be permitted to be discontinued if initial
monitoring results show exposure levels to be below the action level and
at or below the excursion limits. Should the Agency require a second
sample, taken at least seven days later, to confirm the initial
monitoring results before permitting discontinuance of monitoring for
that employee, as has been required for discontinuance of periodic
monitoring?

12\. In the medical surveillance provisions of the proposed standard
OSHA has not proposed a requirement for any specific tests for the
detection of the early onset of adverse reproductive or developmental
effects. OSHA requests information about whether there are any medical
tests which can be routinely used to detect such effects? If so, what
are these tests and with what frequency should they be required? Please
provide data and evidence to support your response

13\. The medical surveillance provisions of the proposed standard would
require that counseling or tests, which are requested by the employee
and deemed appropriate by the examining physician, be made available to
employees exposed to glycol ethers who are having difficulty conceiving
a child or who have concerns about their ability to conceive a healthy
child. Are these requirements adequate and appropriate? If not, what
other provisions should be added? For those employers whose employees
are exposed to glycol ethers, OSHA also requests information on the
following:

a\. Is medical surveillance being provided to exposed employees?

b\. What exposure levels or other factors trigger medical surveillance?

c\. What tests and counseling are included in the medical surveillance
program?

d\. What provisions are included in the medical surveillance program to
address reproductive/developmental health effects resulting from
exposure to glycol ethers?

e\. What benefits have been achieved from the medical surveillance
program?

f\. What are the costs of the medical surveillance program?

14\. Under the recordkeeping provisions, OSHA proposes that medical
records be maintained for at least the duration of employment plus 30
years. Is this recordkeeping provision adequate? If not, what other
provisions would provide more protection and be more appropriate? For
those employers whose employees are exposed to glycol ethers, what is
the current policy regarding maintenance of medical records?

15\. Data and evidence presented to OSHA in response to the ANPR
indicate that a number of industry sectors are substituting away from
manufacture and use of the glycol ethers covered under

**\[page 15528\]**

this proposal.

The major substitutes are 2-Butoxyethanol, propylene glycol monomethyl
ether, propylene glycol monomethyl ether acetate and ethylene glycol
monopropyl ether. OSHA requests comment on the following:

a\. Where and how are these substitutes being used and to what degree
have substitutes replaced the glycol ethers covered by this proposal?

b\. What other substitutes are being used in place of the glycol ethers
covered by this proposal?

c\. What are the current employee exposure levels for the substitutes?

d\. Are there known hazards and health risks associated with these
substitutes?

e\. For employers who have substituted, wholly or partially, away from
the glycol ethers covered by this proposal, why was substitution
undertaken?

f\. What results, positive and negative, have been documented as a
result of substitution (e.g., changes in productivity and/or production
efficiency; changes in product quality; changes in employee absenteeism,
medical expenses, worker compensation payments, insurance premiums;
effects on compliance with environmental regulations)?

g\. What were the costs of substitution?

16\. For employers that currently manufacture or use glycol ethers
covered by this proposal, OSHA requests the following information
regarding substitution:

a\. Are there substitutes for glycol ethers available for your business?

b\. If you are planning to substitute, what plans and timeline do you
have for replacing glycol ethers with substitute chemicals?

c\. What percentage of production has been substituted and what
percentage still can be substituted away from glycol ethers? What
factors prevent complete substitution away from glycol ethers?

d\. What will be the projected costs of substitution?

17\. OSHA requests the following information from employers involved in
glycol ether operations:

a\. Job categories for each operation or process in which employees are
potentially exposed to glycol ethers

b\. The number of employees in each of those job categories

c\. A brief description of each of those operations, job categories and
production techniques

d\. A brief description of the engineering and work practice controls
associated with each of those operations

e\. Raw exposure data, annotated if possible, associated with the
operations described above

f\. The Standard Industrial Classification (SIC) codes of the
establishment(s)

18\. In each job category where employees are potentially exposed to
glycol ethers, please provide the following information regarding
employee exposure levels:

a\. The last two years of raw air monitoring results, annotated if
possible, expressed as an 8-hour time weighted average for all employees
who are exposed to glycol ethers and the dates of all raw air monitoring
data

b\. The duration and frequency of exposure for those employees

c\. The job tasks or duties being performed at the time of monitoring

d\. The engineering and work practice controls in place at the time of
monitoring

e\. The method of monitoring used to measure these exposures

f\. To the extent that representative sampling is used, clearly indicate
which employees within each job category were monitored, the
corresponding results and which employees were represented by the
sampling results. Please discuss your representative sampling strategy
and why representative sampling was used

19\. Please provide information on any job category and employee whose
exposure to glycol ethers is so varied, intermittent, or of such short
duration, etc., that the raw air monitoring data provided in response to
the previous question do not adequately portray the nature of the
exposures. Please explain your response and indicate peak levels,
duration and frequency of exposures for employees in those job
categories

20\. OSHA requests the following information regarding engineering and
work practice controls:

a\. For employers whose employees are exposed to glycol ethers, are the
proposed PELs currently being achieved in your facilities in most
operations most of the time by means of engineering and work practice
controls?

b\. In what operations are the proposed PELs being achieved most of the
time by means of engineering and work practice controls? What
engineering and work practice controls have been implemented in those
operations?

c\. For all operations in your facilities, what engineering and work
practice controls have been implemented?

d\. What additional engineering and work practice controls could be
implemented in each operation where exposure levels are currently above
the proposed PELs to further reduce exposure levels?

e\. When these additional controls are implemented, to what levels can
exposure levels be expected to be reduced?

f\. What are the costs and time needed to develop, install and/or
implement additional controls?

g\. Are there any processes or operations in which it is not reasonably
possible to implement engineering and work practice controls within six
months to one year to achieve the proposed PELs? If so, would allowing
additional time for employers to come into compliance with paragraph (f)
make compliance reasonably possible? How much time would be necessary?

21\. In operations where air exposure levels are above the proposed
PELs, to what extent can these operations and processes be automated and
enclosed or remotely controlled? To what extent can quality control
sampling be remotely controlled? Are there any restrictions on the use
of automated or remote control techniques?

22\. What are the benefits, other than reducing employee exposures to
glycol ethers, that can be derived from implementing engineering and
work practice controls (e.g., reduced exposure to other contaminants;
compliance with environmental regulations; increased productivity and/or
production efficiency; product improvement; reduced absenteeism;
reduction in medical expenses, insurance premiums and worker
compensation payments, etc.)?

23\. Are engineering control technologies that have proven effective in
industries not covered by this notice applicable or transferrable to the
chemicals covered by this proposal? Please explain and provide evidence
to support the nature and extent of compatibility or applicability

24\. OSHA requests information on whether there are any limited unique
conditions or job tasks in glycol ether manufacture or use where
engineering and work practice controls are not available or are not
capable of reducing exposure levels to or below the proposed PELs most
of the time. Please provide data and evidence to support your response

25\. In the Preliminary Regulatory Impact Analysis OSHA has estimated
benefits by extrapolating from the NOEL-Uncertainty Factor approach.
OSHA requests comment on its methodology in using the Uncertainty Factor
approach to project benefits. OSHA also requests comment on whether
there are alternative methods, either quantitative or qualitative, for
projecting benefits associated with a reduction in exposure to glycol
ethers

26\. In order to perform the economic feasibility analysis for the final
rule,

**\[page 15529\]**

OSHA requests employers and interested parties submit the following
information from the last five years on your company and/or industry
sector:

a\. Profits, sales and the percentage of each which are related to the
glycol ethers covered by this proposal

b\. Total annual volume and dollar value of production for your company
and/or industry sector. What percentages are related to the glycol
ethers covered by this proposal?

c\. Annual labor turnover rate of your company and/or industry sector
for jobs involving exposure to the glycol ethers covered by this
proposal

27\. For performing an economic feasibility analysis , OSHA also
requests the following:

a\. A financial and economic profile of your company and/or industry
sector

b\. A profile of your financial position in the market and your market
share in producing glycol ethers or producing products utilizing glycol
ethers

c\. The number of facilities in your industry sector

28\. What is the age, production capacity and estimated remaining life
of your plant and equipment?

29\. Will major renovation or reconstruction of your company be required
to bring air monitoring results into compliance with the proposed
standard? If so, please provide costs and time necessary for renovation
and/or reconstruction

30\. The Agency has prepared a draft Regulatory Flexibility Analysis
analyzing the impacts of the proposed standard on the small businesses
which OSHA believes may be affected. The following information is
requested for small businesses in addition to the information OSHA has
gathered

\(a\) What kinds of small businesses or organizations and how many of
them would be affected by regulating exposures?

\(b\) Which, if any, federal rules may duplicate, overlap, or conflict
with an OSHA regulation concerning glycol ethers?

\(c\) Will difficulties be encountered by small entities when attempting
to comply with requirements of the proposed standard? Can some of the
requirements be deleted or simplified for small entities, while still
achieving comparable protection for the health of employees of small
entities?

\(d\) What timetable would be appropriate to allow small entities
sufficient time to comply? 31. The National Environmental Policy Act
(NEPA) of 1969 (42 U.S.C. 4321 et seq.) requires that each Federal
agency consider the environmental impact of major actions significantly
affecting the quality of the human environment. Any person having
information, data or comments pertaining to possible environmental
impacts is invited to submit them along with accompanying documentation
to OSHA. Such impacts might include:

\(a\) Any positive or negative environmental effects that could result
should a standard be adopted;

\(b\) Beneficial or adverse relationships between the human environment
and productivity;

\(c\) Any irreversible commitments of natural resources which could be
involved should a standard be implemented; and

\(d\) Estimates of the degree of reduction of glycol ethers in the
environment by the proposed standard and alternatives

In particular, consideration should be given to the potential direct or
indirect impacts of any action, or alternative actions, on water and air
pollution, energy usage, solid waste disposal, or land use

B. Federalism

This proposed 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 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 Plan-States must, among other things, be at
least as effective as the Federal standards in providing safe and
healthful employment and places of employment

Since these materials are present in workplaces in every state of the
Union, the occupational hazard of glycol ethers is a national problem

The Federally proposed glycol ether standard is drafted so that
employees in every State would be protected by the standard. To the
extent that there are any State or regional peculiarities, States with
occupational safety and health plans approved under Section 18 of the
OSH Act would be able to develop their own State standards to deal with
any special problems

In short, there is a clear national problem related to occupational
safety and health for employees exposed to glycol ethers. Those States
which have elected to participate under Section 18 of the OSH Act would
not be preempted by this proposed regulation

State comments are invited on this proposal and will be fully considered
prior to promulgation of a final rule

C. State Plans Revisions

The 23 states and 2 territories which operate their own
Federally-approved occupational safety and health plans must adopt a
comparable standard within six months of the publication date of a final
standard. These States include: Alaska, Arizona, California, Connecticut
(for State and local government employees only), Hawaii, Indiana, Iowa,
Kentucky, Maryland, Michigan, Minnesota, Nevada, New Mexico, New York
(for State and local government employees only), North Carolina, Oregon,
Puerto Rico, South Carolina, Tennessee, Utah, Vermont, Virginia, Virgin
Islands, Washington, Wyoming. Until such time as a state or territorial
standard is promulgated, Federal OSHA will provide interim enforcement
assistance, as appropriate

II\. Pertinent Legal Authority

This proposed standard and the issuance of a final standard are
authorized primarily by sections 4(b)(2), 6(b), 8(c) and 8(g)(2) of the
Occupational Safety and Health Act of 1970 (the Act) (29 U.S.C.
653(b)(2), 655(b)., 657(c), 657(g)(2))

Section 6(b)(5) governs the issuance of occupational safety and health
standards dealing with toxic materials or harmful physical agents.
Section 6(b)(5) provides: The Secretary, in promulgating standards
dealing with toxic materials, or harmful physical agents under this
subsection, shall set the standard which most adequately assures, to the
extent feasible, on the basis of the best available evidence, that no
employee will suffer material impairment of health or functional
capacity even if such employee has regular exposure to the hazard dealt
with by such standard for the period of his working life. Development of
standards under this subsection shall be based upon research,
demonstrations, experiments, and such other

**\[page 15530\]**

information as may be appropriate. In addition to the attainment of the
highest degree of health and safety protection for the employee, other
considerations shall be the latest available scientific data in the
field, the feasibility of standards, and experience gained under this
and other health and safety laws

Section 3(8) of the Act defines an occupational safety and health
standard as : 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 and places of employment

Under section 6(b)(7) of the Act, standards must, where appropriate,
include provisions for labels or other appropriate forms of warning to
apprise employees of hazards, suitable protective equipment, exposure
control procedures, monitoring and measuring of employee exposure,
employee access to the results of monitoring, medical examinations or
other tests, at no cost to employees, to determine whether the health of
employees is adversely affected by such exposure, and training and
education. In addition, Section 8(c)(3) of the Act empowers the
Secretary to promulgate standards prescribing recordkeeping requirements
where necessary or appropriate for enforcement of the Act or for
developing information regarding the causes and prevention of
occupational accidents and illnesses

The Supreme Court has held that under the Act the Secretary, before
issuing a new standard, must determine that it is reasonably necessary
and appropriate to remedy a significant risk of material health
impairment. Industrial Union Department v. American Petroleum Institute,
448 U.S. 607, 642 (1980). The Court stated that \"before he can
promulgate any permanent health or safety standard, the Secretary is
required to make a threshold finding that a place of employment is
unsafe in the sense that significant risks are present and can be
eliminated or lessened by a change in practices.\" Id., at 642, 644, n.
49

The Court indicated, however, that the significant risk determination is
\"not a mathematical straightjacket.\" Id., at 655. \"OSHA is not
required to support its finding that a significant risk exists with
anything approaching scientific certainty.\" Id., at 656. Rather, the
Court stated that \"a reviewing court \[is\] to give OSHA some leeway
where its findings must be made of the frontiers of scientific
knowledge.\" Id., at 656. The Court also 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.\" Id., at 655- 56, n. 62

After OSHA has determined that a significant risk exists and that such a
risk can be reduced or eliminated, it must set a standard \"which most
adequately assures, to the extent feasible on the basis of the best
available evidence, that no employee will suffer material impairment of
health.\" (Section 6(b)(5)). The Supreme Court has interpreted this
section to mean that OSHA must enact the most protective standard
possible to eliminate a significant risk of material health impairment,
subject to the constraints of technological and economic feasibility.
American Textile Manufacturers Institute v. Donovan, 452 U.S. 490, 509
(1981). The Court held that \"cost-benefit analysis by OSHA is not
required by the statute because feasibility analysis is.\" Id

Section 4(b)(2) of the Act provides that standards issued under OSHA
apply to construction and maritime employment where the Secretary
determines these standards to be more effective than existing standards
which would otherwise apply to that employment. (OSHA has proposed the
addition of new paragraph (n) to 29 CFR 1910.19, which would apply the
proposed glycol ethers standard to construction and maritime employment,
in addition to its coverage of general industry)

Authority to issue this proposed standard is further supported by the
general rulemaking authority found in section 8(g) of the Act

Section 8(g)(2) empowers the Secretary to \"prescribe such rules and
regulations as he may deem necessary to carry out \[his\]
responsibilities under the Act.\" The Secretary\'s responsibilities
under the Act are defined largely by its enumerated purposes (section
2(b)), which include:

Encouraging employers and employees in their efforts to reduce the
number of occupational safety and health hazards at their places of
employment, and to stimulate employers and employees to institute new
and to perfect existing programs for providing safe and healthful
working conditions;

Building upon advances already made through employer and employee
initiative for providing safe and healthful working conditions;

Developing innovative methods, techniques, and approaches for dealing
with occupational safety and health problems;

Exploring ways to discover latent diseases, establishing causal
connections between diseases and work in environmental conditions;

Providing for the developing and promulgation of occupational safety and
health standards;

Providing for appropriate reporting procedures with respect to
occupational safety and health which procedures will help achieve the
objectives of this Act and accurately describe the nature of the
occupational safety and health problems;

Encouraging joint labor-management efforts to reduce injuries and
disease arising out of employment

Because the proposed glycol ethers standard is reasonably related to
these statutory goals and because the Agency\'s preliminary judgement is
that the evidence satisfies the statutory requirements and that the
proposed standard is feasible and substantially reduces significant risk
of adverse health effects, especially reproductive and developmental
health effects, the Secretary preliminarily finds that the proposed
standard is necessary and appropriate to carry out the Agency\'s
responsibilities under the Act

III\. History of the Regulation

OSHA\'s current Permissible Exposure Limits (PELs) for 2-ME, 2-MEA,
2-EE, and 2-EEA are 25 ppm, 25 ppm, 200 ppm, and 100 ppm, respectively.
All are time weighted averages (TWAs) for an 8-hour workshift (29 CFR
1910.1000, Table Z-1-A). In the Z-1-A Table, 2-ME, 2-MEA, 2-EE, and
2-EEA are listed under the names Methyl Cellosolve, Methyl Cellosolve
Acetate, 2-Ethoxyethanol, and 2-Ethoxyethanol Acetate, respectively. The
OSHA standards bear a skin notation, indicating the potential
contribution to the overall exposure by the cutaneous route, including
mucous membranes and eye, either by airborne or more particularly, by
direct contact with the substance

The current standards were adopted in 1971 pursuant to section 6(a) of
the Occupational Safety and Health Act of 1970 (29 U.S.C. 655). The
source of these standards was the American Conference of Governmental
Industrial Hygienists (ACGIH) and they are based primarily on blood,
kidney, liver and central nervous system toxicity

In the late 1970\'s, many studies began to be published regarding
adverse effects, including testicular atrophy, infertility,
fetotoxicity, and fetal malformations in laboratory animals exposed to
glycol ethers. In response to these findings, the ACGIH, in its notice
of Intended Changes (for 1982),

**\[page 15531\]**

proposed TWAs of 5 ppm for 2-ME, 2-EE and their acetates which were
subsequently adopted in 1984. Likewise, on May 2, 1983, NIOSH published
a Current Intelligence Bulletin recommending that 2-ME and 2-EE be
regarded in the workplace as having the potential to cause adverse
reproductive effects in male and female workers and embryotoxic effects,
including teratogenesis, in the offspring of the exposed pregnant
females and urged employers to reduce exposures to the lowest extent
possible (Ex. 5-001)

On January 24, 1984, EPA published an Advance Notice of Proposed
Rulemaking (ANPR) in which they announced their intention to regulate
2-ME, 2-EE and their acetates (49 FR 2921). EPA was concerned about the
toxicity of these chemicals due to evidence of human exposure to
concentrations above levels currently recommended by the ACGIH, and the
potential for significant numbers of individuals to become exposed.
After consideration of the record developed in connection with its ANPR,
EPA determined that the risks associated with exposure to 2-ME, 2-EE and
their acetates could be sufficiently reduced by action taken under the
OSH Act. Following these findings, EPA, in accordance with section 9(a)
of TSCA, on May 20, 1986, referred 2-ME, 2-EE and their acetates to OSHA
to give this Agency an opportunity to regulate the chemicals under the
OSH Act(51 FR 18488). EPA requested OSHA to determine whether the risks
described in the EPA report could be prevented or reduced to a
sufficient extent by action taken under the OSH Act. If such a
determination was made then OSHA was requested to issue a notice
declaring whether the manufacture and use described in the EPA report
presented the risk therein described. EPA requested OSHA to respond
within 180 days

On December 11, 1986, OSHA published a notice (51 FR 42257) responding
to the EPA referral report by making a preliminary determination that a
revised OSHA standard limiting occupational exposure to 2-ME, 2-EE and
their acetates could prevent or reduce the risks due to exposure to a
sufficient extent and that such a risk had been accurately described by
EPA in the report

On April 2, 1987, OSHA decided it would proceed with permanent
rulemaking to reduce exposure to 2-ME, 2-EE and their acetates and
published an ANPR (52 FR 10586). OSHA based its decision on the
determination that the existing standards did not adequately address the
adverse health effects associated with 2-ME, 2-EE and their acetates.
OSHA solicited information and comments regarding the hazards of
exposures to the chemicals, control methods for reducing these hazards
and the costs of controlling exposures

In September of 1991, NIOSH published a Criteria for a Recommended
Standard for Ethylene Glycol Monomethyl Ether, Ethylene Glycol Monoethyl
Ether, and Their Acetates (i.e., 2- ME, 2-EE and their acetates) (Ex.
5-154). In this document NIOSH recommended worker exposures to 2-ME and
its acetate, 2- MEA, be limited to 0.1 ppm as time weighted average for
up to 10 hours/day during a 40 hour workweek (10-hr TWA) and that worker
exposure to 2-EE and its acetate, 2-EEA, be limited to 0.5 ppm as a
10-hr TWA. NIOSH also recommended that dermal contact to 2-ME, 2-EE and
their acetates be prohibited. In addition to these recommended exposure
limits, NIOSH also recommended various industrial hygiene provisions
including exposure monitoring, medical monitoring, protective clothing
and equipment, engineering controls and work practices and hazard
communication. The provisions of this recommended standard were based
primarily on adverse reproductive, developmental and blood effects

IV\. Chemical Identification, Production and Use of Ethylene Glycol
Ethers

The chemicals, 2-Methoxyethanol (2-ME), 2-Methoxyethanol acetate
(2-MEA), 2-Ethoxyethanol (2-EE), and 2-Ethoxyethanol acetate (2-EEA) are
members of a class of chemicals known as ethylene glycol ethers which
are, in turn, members of a broader class of chemicals known as glycol
ethers. In this document the terms ethylene glycol ethers or glycol
ethers will refer only to 2-ME, 2-MEA, 2-EE and 2-EEA. The respective
Chemical Abstract Service (CAS) Registry numbers for the subject
ethylene glycol ethers are 109-86-4, 110-49-6, 110-80-5, 111-15-9. All
four compounds are colorless, flammable liquids which are compatible
with a broad range of resins and are miscible in both organic solvents
and water. They have relatively low vapor pressures, high boiling
points, low evaporation rates and high flash points. At room temperature
and atmospheric pressure, these compounds are highly reactive in the
presence of strong oxidizers; 2-MEA and 2-EEA are also highly reactive
in the presence of nitrates and strong acids. Decomposition products
during combustion include toxic gases and vapors such as carbon monoxide

2-ME, chemical formula CH(3) OCH(2)CH(2)OH, has a molecular weight of
76.1, a boiling point at 760mm Hg of 124 C, a vapor pressure at 20 C of
6mm Hg, a flash point of 42 C and possesses a mild non-residual odor.
2-MEA, chemical formula CH(3)COOCH(2)OCH(3), has a molecular weight of
118, a boiling point of 145 C , a vapor pressure of 2mm Hg, a flash
point of 44 C and possesses a mild ether-like odor. 2-EE, chemical
formula C(2)H(5)OCH(2)CH(2)OH, has a molecular weight of 90.1., a
boiling point of 135 C, a vapor pressure of 4mm Hg, a flash point of 49
C and possesses a sweetish odor with odor. 2-EEA has chemical formula
C(2)H(5)OCH(2)OCOCH(3), a molecular weight of 132, a boiling point of
156 C, a vapor pressure of 2mm Hg, a flash point of 47 C and possesses a
mild non-residual odor. The odor thresholds of these compounds are
discussed in the Respiratory Protection portion of this document

Ethylene glycol ethers are produced by the ethoxylation of ethylene
oxide with preheated anhydrous alcohol. Methyl alcohol produces ethylene
glycol monomethyl ether (2-ME) and ethyl alcohol produces ethylene
glycol monoethyl ether (2-EE). The corresponding acetates, 2-MEA and
2-EEA, are produced by the esterification of 2-ME and 2-EE with acetic
acid

Due to their physical characteristics, ethylene glycol ethers are useful
in a wide variety of applications, particularly as solvents. In general,
these ethers are used extensively in the formulation of paints and
coatings, commercial printing inks, industrial solvents, and cleaners.
They are also used as chemical intermediates in the production of
plastisizers, as de-icing additives in jet fuels, and in electronics
manufacturing

After manufacture of glycol ethers for export (45% of total sales), the
utilization of these compounds as chemical intermediates accounts for
the largest percentage (24%) of their sales (PEI report, Ex. 5-164). For
example, the manufacture of 2-EEA is the largest single use of 2-EE
while 2-ME is used in the production of 2-MEA. Both 2-ME and 2-EE are
also used to produce a variety of plastisizers for use in such products
as 35 mm film, insulation for high voltage wires, and high flash
coatings

Another principal area of use (15% of total sales) of the four glycol
ethers is in the formulation of paints and coatings (e.g., primers,
varnishes, stains, etc.). These paints and coatings are utilized in
original equipment manufacture (OEM) of items such as automobiles and
trucks, machinery and equipment, metal cans,

**\[page 15532\]**

metal furniture and appliances, and in coil coatings. They are also
found in auto refinishing and maintenance painting formulations. In
addition, all four glycol ethers are used in a variety of special
coating applications ranging from fingernail polish to wood stains

The electronics industry employs glycol ethers in the manufacture of
semiconductors and circuit boards. Glycol ethers are a component of the
photoresist used in the photolithography of semiconductor circuit
designs in addition to being utilized in coating/lamination resins of
circuit boards. Products used in the marking, bonding, and labeling of
circuit boards may also contain ethylene glycol ethers

Substantial quantities of 2-ME are used as de-icing additive in jet
fuel. Since commercial jets have in-line de- icers, this market is
principally military. However, some general aviation jet fuel also
requires de-icing additive

Comparable to glycol ether\'s use in paint and coatings is their role as
solvents in the formulation of commercial printing inks, particularly
those used in silk screen, flexographic, and gravure printing. Ethylene
glycol ethers are also found in formulations used in textile dyeing and
printing. In addition to being a component of the ink itself, glycol
ethers are used in solvents and machinery cleaners for the commercial
printing industry

While the above uses account for the vast bulk of glycol ether
consumption, they have also been reported to be utilized in a number of
diverse cleaning solvents, as solvent in adhesive, in leather
dying/tanning, and in the manufacturing of pharmaceuticals

V. Health Effects

A. Introduction

The experimental studies in animals clearly demonstrate that 2-ME and
2-EE induce adverse reproductive, developmental and hematological
effects. Several species (e.g., rats, rabbits and mice) exposed through
several routes of exposure (e.g., oral, dermal, and inhalation) have
consistently shown similar effects after exposure to these ethylene
glycol ethers. Exposed males have exhibited testicular degeneration,
disrupted spermatogenesis and reduced fertility. Females exposed during
gestation have shown signs of maternal toxicity as well as increased
incidence of resorptions. Offspring from these exposed females have
exhibited a variety of teratogenic effects including cardiac, skeletal
and visceral malformations. In addition new born pups have exhibited
behavioral and neurochemical alterations. Adverse blood effects have
also been observed after exposure. These effects include decreases in
red blood cells, white blood cells, hemoglobin concentrations and
hematocrit

Although less extensive, the animal data has also shown that the
acetates, 2-MEA and 2-EEA, induce adverse reproductive and developmental
and hematological effects similar to those observed among their parent
glycol ethers. These studies confirm the findings of metabolic studies
which indicate that 2-ME, 2-EE and their acetates follow similar
metabolic pathways, producing similar metabolites, which are the active
agents most likely responsible for the observed effects

Consistent with these experimental results is human evidence of
reproductive and hematological effects. Workers exposed to 2-ME and 2-EE
have exhibited decreased sperm counts, testicular atrophy and decreased
red and white blood cell counts. Little data has been reported on the
reproductive, maternal or developmental effects for women exposed to
glycol ethers. However, the lack of data in this area may be due, in
most part, to the difficulty in conducting analyses for these types of
adverse effects. Although workers in some instances were exposed to
multiple substances, making it difficult to ascribe exposure to a
particular glycol ether to an observed effect, the human evidence is,
nevertheless, consistent with and supportive of the animal evidence
which indicates that these substances will induce adverse reproductive
and developmental effects

B. Metabolism/Metabolic-Related Health Effects

The ethylene glycol ethers, 2-ME and 2-EE, are metabolized to their
corresponding acetic acids, methoxyacetic acid (MAA) and ethoxyacetic
acid (EAA), by an alcohol dehydrogenase (ADH) mediated pathway. Animal
studies conducted with MAA have shown that it is the metabolite, rather
than the parent glycol ether, which is responsible for inducing adverse
reproductive and developmental effects. 2-MEA and 2-EEA are also
metabolized by the ADH pathway to MAA and EAA. Because these two
acetates are metabolized to the same primary metabolites as their
corresponding parent glycol ethers, it is assumed that they will induce
similar adverse reproductive and developmental effects. Studies in male
and female volunteers confirm that the ADH pathway is also the primary
route of metabolism in humans. However these studies also indicate that
the retention and biological half life of the active metabolite is
longer in humans than in animals

Miller et al. (Ex. 4-131) identified MAA as the primary metabolite of
2-ME by radiogas-chromatography/mass spectrometry analysis. The
investigators recovered 50-60% of the administered 14C from urine of
rats within 48 hours after a single oral dose of \[14C\] 2-ME. Expired
14CO2 was the only other significant route of elimination (12%). Thus,
urine was established as the major vehicle of elimination of 14C after a
single oral dose of \[14C\] 2-ME. Urine collected was then analyzed by
radiogas-chromatography/mass spectrometry. Analysis revealed the primary
component as methoxyacetic acid. Based on these findings Miller et al.
concluded that 2-ME is first oxidized to methoxyacetaldehyde by ADH and
then further oxidized to MAA by aldehyde dehydrogenase

Evidence also indicates that MAA is the ultimate toxin responsible for
the observed adverse reproductive and developmental effects. Brown et
al. (Ex. 4-102) gave single injections of 244 mg MAA/kg to pregnant rats
on days 8, 10, 12 or 14 of gestation. Exposure to MAA induced
significant increases in the incidence of embryo-fetal mortality,
decreases in fetal weight, and increases in structural malformations
(e.g., skeletal malformations, hydrocephalus and urogenital
abnormalities). Similarly Miller et al. (Ex. 4-133) found that the
administration of MAA daily for two weeks by gavage to rats resulted in
severe degeneration of testicular germinal epithelium and hematological
abnormalities. For example significant decreases in testicular weight
and in red blood cell counts were observed at 300 and 100 mg MAA/kg.
These toxicological effects were remarkably similar to those observed
following administration of 2-ME. The authors concluded that the adverse
health effects of 2-ME are probably the result of in vivo activation of
2-ME to MAA, and that MAA is the proximate toxin following
administration of 2-ME. The findings of Ritter et al. (Ex. 4-143),
Yonemoto (Ex. 4-192) and Foster et al. (Ex. 5-052) are consistent with
this view

In addition to their studies on the teratogenicity of MAA, Ritter al.
(Ex. 4-143) also investigated the effects of the co-administration of
2-ME and 4-Methylpyrazole. 4- Methylprazole(4-MP) is an inhibitor of
alcohol dehydrogenase(ADH) and thus may block metabolism occurring by an
ADH pathway. In this study it was observed

**\[page 15533\]**

that embryotoxicity (i.e., the number of dead, resorbed and malformed
fetuses) following co-administration of the two substance was 16.8%, as
compared to 100% for the same dose and the same route of 2-ME alone. The
observation that the co-administration of 4-MP provided significant
protection against the embryotoxic of 2-ME is consistent with the
hypothesis that metabolism of 2-ME occurs via the alcohol
dehydrogenase(ADH) pathway and that it is the primary metabolite that is
most likely the active agent in the induction of adverse effects

Similar findings have been reported by Sleet et al (Ex. 5-118). In this
study pregnant mice were exposed to either 2-ME (1.3 to 1.6 mmole/kg) or
MAA (1.1 to 1.7 mmole/kg) by gavage on day 11 of gestation. 2-ME and MAA
were found to be equally potent in producing significant increases in
the incidence of paw malformations (e.g., webbed, missing or additional
digits). The co-administration of 4-Methyl Pyrazole was found to reduce
the teratogenic potency of 2- ME. For example, the incidence of
malformations induced by 4.6 mmole/kg 2-ME was reduced from 94% to 59%
when 4-MP was administered at a dose of 0.12 mmole/kg. The incidence of
malformations was reduced to 0% when 4-MP was administered at a dose of
1.2 mmole/kg. These data further indicate the role of metabolism in
inducing teratogenic effects and strongly points to MAA as the active
agent

Similar to the metabolic studies on 2-ME, the evidence also indicates
that the primary metabolite of 2-EE is also an alkoxyacetic acid; in
this case ethoxyacetic acid (EAA). Cheever et al. (Ex. 5-089) gave
single oral doses of 230 mg 2-EE/kg body weight. The major metabolites
detected in the urine were EAA and N-ethoxyacetyl glycine. EAA was also
detected in the rat testes. The authors concluded that the most probable
route of metabolism was the oxidation of 2-EE through ADH to EAA with
some subsequent conjugation of EAA to glycine to form N-ethoxyacetyl
glycine

Similar to the findings in animal studies, experimental studies using
male and female volunteers, have shown alkoxyacetic acids to be the
primary metabolites in humans. In a series of experiments Groeseneken et
al. (Exs. 5-112, 5-113, and 5-114) exposed 10 male volunteers by
inhalation to 2.7, 5.4 or 10.8 ppm 2-EE for 4 hours, both at rest and
during physical exercise. Consistent with findings in animal studies,
EAA was found to be the major urinary metabolite. However the biological
half life in humans was found to be approximately 21-24 hours compared
to the biological half life of 8-12 hours reported in animals. It was
also observed that EAA excretion increased with increasing dose and/or
physical activity. Due to the long half life, the authors stated that
EAA will not be cleared from the urine by the next morning following
exposure and accumulation of the metabolite may be expected through
repetitive exposures. Thus EAA may build up in the body over the course
of the workweek

In a similar study Groeseneken et al. (Ex. 5-115) exposed 10 male
volunteers by inhalation to 2-EEA. Five volunteers were exposed at rest
to 2.6, 5.2 and 9.3 ppm 2- EEA and 5 were exposed to 5.2 ppm 2-EEA
during physical exercise. Again, EAA was detected as the major
metabolite with a biological half life of approximately 23 hours. It was
observed that the metabolism of 2-EEA followed the same time course as
2-EE (Ex. 5-112) and that for equivalent doses of 2-EE and 2-EEA,
equivalent amounts of EAA were excreted. The authors concluded that
2-EEA is first converted to 2-EE by esterases and then to EAA by an ADH
mediated pathway. Similarly it was found that EAA is not cleared from
urine by the next morning and thus may build up over the work week
following repetitive exposures

In field study of workers, Veulemans et al. (Ex. 5-114) studied the
urinary excretion of EAA for a group of 5 female silk screen operators
who were exposed, by inhalation, to mixtures of 2-EE and 2-EEA at
approximately 5.6 and 5 ppm, respectively. In this study the women were
monitored for 5 days during a normal production period. They were also
monitored during another 7 day period after a 12 day production stop.
Similar to the experimental studies among human volunteers, EAA was
detected in the urine as the major metabolite during the 5 days of
production and was also found to accumulate during the workweek. The
authors also reported that even after 12 days of non-exposure, traces of
EAA were still detectable in the urine. The authors stated that these
findings confirmed the earlier short term studies by Groeseneken (Exs.
5-112 and 5-115) and suggested that the biological half life of EAA may
even be greater than 24 hours. Moreover they added that from a
toxicological point of view, \"it would certainly warrant extra caution
in the extrapolation of experimental data from laboratory animals to
man, since comparable accumulation effects apparently are not found in
all species.\"

To further investigate the metabolic differences between rats and
humans, Groeseneken et al. (Ex. 5-137) compared the urinary excretion of
EEA in man and rat. In this study rats were orally exposed to 2-EE at
low doses comparable to the inhalation doses used on male volunteers in
previous experimental studies(Ex. 5-112). The authors stated that oral
doses were used in rats due to the lack of animal data necessary to
calculate respiratory uptake of 2- EE (e.g., 2-EE pulmonary retention
and respiratory minute volume). Data for calculating respiratory uptake
were available in human studies. It was assumed that metabolism was
independent of the route of administration. Groups of five rats were
exposed to single oral doses of 0.5 mg/kg, 1 mg/kg, 5 mg/kg, 10 mg/kg,
50 mg/kg or 100 mg/kg 2-EE. Exposure levels of 0.5 mg/kg and 1 mg/kg
were noted by the authors to be equivalent to human exposures of 5.4 ppm
or 10.8 ppm 2-EE used in the human experimental studies. After a
correction for body weight on urinary excretion, results from these
studies showed that, for humans, the maximal excretion rate of the
primary metabolite, EEA, declined at a slower rate (48 hours after
exposure) than in rats (12 hours after exposure) at equivalent doses. In
addition the half life for EEA in humans was calculated at 42 hours
compared to 7.2 hours for rats: almost 6 times higher for man. The
authors suggested that these findings could have important consequences
for the toxicity of 2-EE in man as the toxic properties of 2-EE have
been associated with the alkoxyacetic acid metabolite, EEA. Romer et al.
(Ex. 5-033) have also shown that the co-administration of ethanol with
2-ME and 2-EE prolonged the retention of 2-ME and 2-EE in the blood. In
this study rats were pretreated with ethanol and then exposed by
inhalation to 1600 ppm 2-ME or 420 ppm 2-EE or ip- administration to 5
ml/kg body weight 2-ME or 2-EE). In both cases it was observed that
degradation of 2-ME and 2-EE was almost completely inhibited when rats
were pretreated with ethanol. Only after the elimination of ethanol was
complete, did the blood levels of 2-ME and 2-EE begin to decrease. The
authors concluded that ethanol, which is also metabolized by the alcohol
dehydrogenase (ADH) pathway, must have a higher affinity for ADH enzymes
than 2-ME or 2-EE. Because of its higher affinity, ethanol is
preferentially metabolized. The authors suggested that blood levels of
2- ME and 2-EE may persist in workers who use 2-ME or 2-EE in
combination with alcoholic consumption. This persistence of 2-ME and
2-EE in the blood could result in an enhanced health risk.

**\[page 15534\]**

C. Acute Toxicity

The acute toxicity of ethylene glycol ethers have been shown in several
animal species (e.g., mice, rats, rabbits, guinea pigs and cats) by
various routes of administration (e.g., oral, injection, dermal and
inhalation). Smyth et al. (Ex. 5-138) examined the single dose toxicity
of a variety of compounds, including 2-ME, 2-EE, 2-MEA and 2-EEA. In
this study rats and guinea pigs were exposed through oral administration
to varying concentrations in order to determine the lethal dose (LD50)
of the various compounds. In rats, the LD50 identified for 2-ME, 2-MEA,
2-EE and 2-EEA were respectively 2460 mg/kg, 3920 mg/kg, 3000 mg/kg and
5100 mg/kg body weight. In guinea pigs the LD50\'s for these same 4
compounds were 0.95, 1.25, 1.4 and 1.91 mg/ kg body weight,
respectively. The authors noted that these compounds induced narcosis
but only at exposures at or above the LD50. Pathological examination
revealed the primary effect was kidney damage

Reviews of the data also report relatively high lethal doses (LD50) and
lethal concentrations (LC50) (Exs. 5-134, 5- 046 and 5-140). For
example, the LC50\'s observed in mice exposed for 7 hours to 2-EE and
2-ME were 1820 ppm and 1480 ppm, respectively. A LC50 of 7000 ppm was
observed among rats exposed to 2-MEA for 4 hours. For 2-EEA, a LC50 of
4000 ppm was reported for cats exposed from 4 to 6 hours. In most cases
deaths were attributed to lung and kidney damage. Pathological
examination revealed lung edema, slight liver damage and marked kidney
injury. Prior to death animals exhibited difficulty in breathing,
sleepiness, weakness and loss of muscular coordination

Little evidence is available on acute toxicity in humans. Most of the
available evidence is limited to case studies of accidental poisonings
where glycol ethers have been ingested (Ex. 5-134, pp.21-24). For
example, two men hospitalized after drinking 100 ml of 2-ME, exhibited
signs of confusion, disorientation, and progressive muscular weakness.
They also suffered from hyperventilation, tachycardia and moderate renal
failure. Similarly a woman who drank 40 ml of 2-EE exhibited renal
failure and adverse central nervous system effects (e.g., vertigo and
unconsciousness). Other effects observed among humans after acute
exposures include irritation of the eyes and mucous membranes including
the respiratory system

D. Background Discussion On Reproductive And Developmental Toxicity

Reproductive and developmental effects are the primary health concerns
associated with exposure to ethylene glycol ethers. The term
reproductive effects refers to effects on the male and female
reproductive systems and the term developmental effects refers to
effects on the developing organism. Various terms have been used in the
field of reproductive and developmental toxicology, many of which are
ambiguous and open to different interpretations. In order to provide
guidance and assistance in assessing reproductive and developmental
risks, the EPA has published proposed guidelines on assessing female and
male reproductive toxicity (Exs. 5-122 and 5-123) and developmental
toxicity (Exs. 5-106, 5-153). These guidelines discuss many of the
critical issues in reproductive and developmental toxicology. Much of
the terminology in the following discussion is adopted and modified from
the EPA guidelines

Male reproductive toxicity is generally defined as the occurrence of
adverse effects on the male reproductive system that may result from
exposure to chemical, biological, or physical agents

The toxicity may be expressed as alterations to the male reproductive
organs and/or related endocrine system. For example toxic exposures may
interfere with spermatogenesis (the production of sperm), resulting in
adverse effects in number, morphology (e.g., size and shape), or
function (e.g., motility) of sperm. These effects in turn may adversely
affect fertility. The process of spermatogenesis is a cyclical process
marked by distinct stages that may be sensitive to toxic agents. In this
process germ cells (spermatogonia) differentiate into primary
spermatocytes then to secondary spermatocytes, to spermatids and finally
into spermatozoa

Men produce sperm continually from puberty throughout life and thus the
risk of disrupted spermatogenesis is of concern for the entire adult
life of a man. Reproductive toxicity may also include dysfunction in
sexual behavior or processes which are integral to reproductive success

Female reproductive toxicity is generally defined as the occurrence of
adverse effects on the female reproductive system that may result from
exposure to chemical, biological, or physical agents

This toxicity includes adverse effects in sexual behavior, onset of
puberty, ovulation, menstrual cycling, fertility, gestation,
parturition, lactation, or premature reproductive senescence(the loss of
reproductive capability associated with aging)

Developmental toxicity is defined as adverse effects on the developing
organism that may result from exposure prior to conception (either
parent), during prenatal development, or postnatally to the time of
sexual maturation. Developmental effects induced by exposures prior to
conception may occur, for example, when mutations are chemically induced
in sperm. If the mutated sperm fertilizes an egg, adverse developmental
effects may be manifested in developing fetuses. Mutations may also be
induced in the eggs. Such effects are often referred to as dominant
lethal effects

The major manifestations of developmental toxicity include: (1) death of
the developing organism, (2) structural abnormality, (3) altered growth,
and (4) functional deficiency. Structural abnormalities include
malformations and variations. As stated in the EPA Guidelines, a
malformation is usually defined as a permanent structural change that
may adversely affect survival, development, or function. These types of
effects are often referred to as teratogenic effects. The term variation
is used to indicate a divergence or a change in structure which is
beyond the range of what is generally considered to be normal
development. This divergence may not adversely affect survival, or
health. However as noted by EPA in its guidelines, distinguishing
between variations and malformations is difficult since there exists a
continuum of responses from the normal to the extreme deviant. There is
no generally accepted classification of malformations and variations.
Other terminology that is often used, but no better defined, includes
anomalies, deformations, and aberrations

Altered growth is an alteration in offspring organ or body weight or
size. Altered growth can be induced at any stage of development, may be
reversible, or may result in a permanent change

Functional deficiency includes alterations in the functional competence
of an organ or a variety of organ systems. This functional deficiency
may be expressed as behavioral abnormalities. Such effects may often not
be apparent at birth but may instead be noted during postnatal
development. Similarly, exposure during development may lead to adverse
reproductive functioning. For example, a female\'s entire complement of
oocytes (eggs) are formed during gestation, as opposed to males who
produce spermatocytes

**\[page 15535\]**

continually throughout their adult life. Thus toxic insults during
gestation may adversely effect oogenesis (the formation of eggs) .
However because structural and functional maturity of eggs does not
occur until puberty, adverse effects may not be manifested until females
reach reproductive maturity

One of the critical phases in development, is the period of gestation
referred to as organogenesis. During this phase of gestation, embryonic
cells migrate and associate into tissues and organ rudiments and
establish the basic organizational patterns of organ systems. Because
this is a period marked by rapid cell proliferation and organ
development it is vulnerable to the induction of structural defects. It
is generally assumed that a single exposure, of sufficient dose, during
such critical periods of development, may be sufficient to produce an
adverse developmental effect. Thus repeated exposures may not be
necessary to induce developmental toxicity. However developing organisms
are also known to have the capacity to compensate for or to repair
certain amounts of damage at the cellular, tissue or organ level. Thus
it is also generally assumed that there may be thresholds for
developmental toxins

The level of concern for a developmental toxic effect is related to
several issues, including the relative toxicity of an agent to the
offspring versus the adult animal and the long-term consequences of
findings in the fetus or neonate. The developing organism is dependent
on the maternal animal to provide nutrients and to maintain a protective
environment in which the conceptus can grow and develop

Thus any agent which adversely affects the maternal animal may have the
potential to adversely affect the offspring. However it is often
difficult to differentiate between effects which are a result of stress
to the maternal animal and effects which are solely a result of the
sensitivity of the developing organism. Those agents which produce
developmental toxicity at a dose that is not toxic to the maternal
animal are of the greatest concern because the developing organism
appears to be more sensitive than the adult. The adult/developmental
toxicity ratio (A/D Ratio) was introduced to account or describe the
differential susceptibility between the maternal animal and the
developing organism (Exs. 4-147 and 5-106). This ratio is calculated by
dividing the Lowest Observed Effect Level (LOEL) in the maternal animal
by the LOEL observed for the developing organism. A/D ratios greater
than 1 suggest that the developing organism is more sensitive to a
chemical insult than the mother and is therefore of greater concern.
However, there is no consensus on the predictive value of the A/D ratio
(Exs. 5-098 and 5-099). One reason is that the A/D ratio can be
influenced by the design of the underlying bioassay (e.g., the spacing
of doses chosen for study). Secondly, the maternal-developmental
relationship may be misrepresented if insensitive developmental
endpoints are compared to sensitive maternal endpoints or vice-versa. In
these cases the power of the experimental study may influence the level
at which an effect is observed and thus influence the calculation of the
A/D ratio. Thus, developmental effects which are produced only at
maternally toxic doses cannot be discounted as being secondary to
maternal toxicity. Current information is inadequate to assume that
developmental effects at maternally toxic doses result only from the
maternal toxicity. Rather, when the lowest observed effect level is the
same for the adult and the developing organism, it may simply indicate
that both are sensitive to that dose level. Moreover, the maternal
effects may be reversible while effects on the offspring may be
permanent. These are important considerations for agents to which humans
may be exposed at minimally toxic levels in the workplace

Most of the evidence on the reproductive and developmental toxicity of
the four subject glycol ethers, as will be discussed later, is limited
to data from experimental studies in mice, rats and rabbits. This, in
major part, is due to the difficulty in conducting epidemiological
analyses to detect adverse reproductive and/or developmental outcomes.
For example, many outcomes such as early embryonic loss, spontaneous
abortions, or reproductive capacity of offspring are not easily observed
in humans. Epidemiological analysis is also complicated by the fact
that, because there is a wide spectrum of inter- related effects,
different types of effects may occur at different exposure levels. Thus
multiple endpoints may result from a single toxicant. Some reproductive
outcomes are rare and thus a large number of births are required to give
the study enough power to detect a possible effect. For example, it has
been estimated that to detect a two fold increase in spontaneous
abortions a sample size of 322 pregnancies (161 exposed and 161
controls) would be required (Ex. 5-135, p. 167). More rare outcomes such
as severe mental retardation, neural tube defects and chromosomal
abnormalities would require samples sizes of 1819, 8986 and 17,907 live
births respectively, to detect a two fold increase. Large populations of
workers would be required to observe this many pregnancies or live
births. Adequate sample sizes may be difficult to obtain due to factors
such as marital status, education, age, use of birth control or prior
reproductive history. These factors may affect couples\' ability or
attempts to have children and thus affect the number of outcomes
available for study

Because adequate human data are rarely available for reproductive or
developmental outcomes, animal studies have been used and are generally
considered to be useful in the prediction of reproductive/developmental
toxicity for humans. A basic tenet of toxicology is that if an agent
produces adverse effects in experimental animals, this agent may pose
potential hazards to humans. This tenet is supported by reviews of
studies in both humans and experimental animals on the reproductive
effects of selected agents which have shown parallels among the adverse
effect observed in animal experiments and effects reported in humans
(Exs. 4-103, p. 96 and 5-135, pp. 169-170). For example, disturbances in
estrous cycles in rats were observed after exposure to benzene and
menstrual disorders were reported among humans exposed to benzene. DBCP
induced testicular atrophy and decreased fertility in rats and has also
been associated with similar effects in men. EDB has caused sterility in
rats and reduced fertility in men. Similar concordance of effects have
been observed with other agents such as carbon disulfide, arsenic, lead,
alcohol and vinyl chloride

While there are parallels in observed effects between experimental
animals and humans, it is not necessarily assumed that there is site
concordance of effects seen in animals and effects potentially occurring
in humans. That is, effects observed in experimental animals may not
exactly be the same as those which may occur in humans. For example
within the period of organogenesis, different organ systems may form at
different times. In addition an individual organ system may have a
narrow time span when it is vulnerable. Furthermore, the time during
organogenesis when a particular organ system develops may vary across
species. Therefore, exposures occurring in different developing systems
or even in similar systems, but at different times, may result in
different types of adverse developmental effects. Thus although a
particular adverse effect may not be observed in humans,

**\[page 15536\]**

the presence of the effect in experimental animals indicates the
potential of an agent to perturb development and therefore is an outcome
of concern for human development

E. Effects In Animals

Experimental studies in rats, rabbits, mice and monkeys through
inhalation, dermal and oral exposure, have shown clearly and
consistently that 2-ME, 2-EE and their acetates cause adverse
hematologic, reproductive and developmental effects. These effects
include decreased white and red blood cell counts, decreased hemoglobin
concentrations, decreased fertility, decreased sperm count, decreased
testes size and weight, early embryonic death, fetal malformations,
delayed development and behavioral and neurochemical alterations

1\. Male Reproductive Toxicity

a\. 2-ME. 2-ME was shown to induce testicular degeneration in rats by
Rao et al.(Ex. 4-142). In this study male rats were exposed, by
inhalation, to 0, 30, 100 or 300 ppm 2-ME, 6 hours/day for 13 weeks.
These rats were then bred with unexposed females to evaluate male
reproductive function and dominant lethality. Dominant lethal tests are
conducted to detect mutagenic effects in the spermatogenic process which
may lead to fetal effects on the embryo/fetus. Male rats exposed to 300
ppm exhibited significant decreases in testes size and atrophy of the
seminiferous tubules. Only 4 of 20 unexposed females mated to this group
of exposed males were successfully inseminated and all 4 pregnancies
ended in resorptions. The authors stated that at 300 ppm there was a
complete suppression of fertility which they attributed to an
interference in spermatogenesis. No significant decreases in fertility
were reported for males exposed to 100 or 30 ppm 2-ME. Because no
litters were produced in the 300 ppm exposure group, the authors stated
that dominant lethality could not be assessed. However the authors did
not address the issue as to whether the resorptions observed in the 300
ppm group may have been a possible dominant lethal effect. Among the
litters from rats exposed to 30 and 100 ppm there were no significant
increases in pre- implantation loss or resorption rate compared to
controls. The authors thus concluded that there was no dominant lethal
effect from exposure at these doses. The authors did note that there was
a significant increase in the resorption rate at 30 ppm . However
because this effect was not observed at 100 ppm, it was not considered
to be treatment related. Thus the NOEL for this study was identified as
100 ppm

In this same study by Rao et al., male rats exposed at 300 ppm were
additionally bred with unexposed females 13 and 19 weeks after exposure
was terminated. Fifty percent of the males sired litters with viable
implantations. Rats bred 13 weeks post exposure had regained 55%
fertility. Rats bred 19 weeks post exposure had regained 50% fertility.
These results suggest that adverse effects on fertility may be partially
reversible after exposure is stopped. However these results also
indicate that recovery may not be complete as 50% of the exposed males
still showed signs of reduced fertility

Testicular degeneration was also observed in a study by Miller et al.
(Ex. 5-023, see also Ex. 4-045) where both rats and rabbits were exposed
to 0, 30, 100, or 300 ppm 2-ME for 6 hours/day, 5 days/week for 13
weeks. Rats exposed to 300 ppm exhibited significant decreases in testes
weight as a result of degeneration of the germinal epithelium of the
seminiferous tubules. The authors reported that rats exposed to 300 ppm
showed reduced numbers of spermatozoa and degenerating spermatozoa in
the epididymis. However the authors did not state whether these were
significant reductions. No treatment related effects were observed among
rats exposed to 30 or 100 ppm 2-ME. A more sensitive response was
observed among the exposed rabbits which exhibited testicular effects at
300, 100 and 30 ppm. All male rabbits exposed to 300 ppm had small and
flaccid testes. Significant but less severe decreases in testes size
were observed in rabbits exposed at 100 and 30 ppm. Histological
examination of the rabbits revealed that the testicular effects were
related to atrophy of the seminiferous tubules. The effects observed in
rabbits at 30 ppm were questioned by the authors as they noted that only
a small percentage of the animals (1 of 5 rabbits) were effected and
rabbits exposed to 30 ppm in a subsequent study (Ex. 5-057) showed no
adverse testicular response

2-ME has also been shown to induce adverse testicular effects in shorter
term tests. In an inhalation study by Doe et al.(Ex. 4-111) male rats
were exposed to 100 or 300 ppm 2-ME, 6 hours/day for 10 consecutive
days. Adverse testicular effects were only observed among rats exposed
at 300 ppm. In these animals the testes were significantly decreased in
both size and weight. Histological examination of the testes revealed
atrophy of the seminiferous tubules and degeneration of the primary
spermatocytes. No significant adverse effects were observed among rats
exposed at 100 ppm, and thus this level was identified as the NOEL

Similarly adverse effects were produced in a short term (9-day)
inhalation test conducted by Miller et al. (Ex. 4- 132). Male rats and
mice were exposed 6 hours/day to 0, 100, 300 or 1000 ppm 2-ME. Severe
testicular degeneration was observed in both rats and mice exposed at
1000 ppm. Histopathological examination revealed a degeneration and
necrosis of all spermatogenic elements as well as a cessation of
spermatogenesis. Similar but less severe testicular effects were
observed in the 300 ppm exposure groups. However theese effects were not
statistically significantly different from control groups. No treatment
related changes were observed in the 100 ppm exposed animals

2-ME also induces adverse testicular effects when administered orally.
For example, Nagano et al. (Ex. 4-135) exposed male mice to 62.5, 125,
250, 500, 1000, or 2000 mg 2-ME/kg body weight, 5 days a week for 5
weeks. In the high dose group 4 out of 5 mice died before examination.
Significant decreases in testes weight were observed for the 1000, 500,
and 250 mg/kg dose groups as a result of seminiferous tubule atrophy.
The authors noted that the degree of changes in atrophy were related to
increases in dosage thus implying the presence of a dose-response
relationship. For example histopathological examination showed that at
1000 mg/kg no germ cells were present. At 500 mg/kg only small numbers
of spermatozoa, spermatocytes and spermatids were present

Similar effects were observed by Foster et al.(Ex. 4- 119) where male
rats were exposed orally to 50, 100, 250 or 500 mg 2-ME/kg body weight
for 11 days. A significant degeneration of the testes was observed in
the 100, 250 and 500 mg/kg dose groups. A single dose exposure to 100
mg/kg 2-ME resulted in testicular damage within 24 hours of exposure. In
this study meiotic cells of the testes were identified as the primary
site of testicular damage. Primary spermatocytes were damaged initially.
Prolonged exposure damaged late spermatocytes and led to a depletion of
the spermatid population. Results of this study indicated that
testicular damage may be partially reversible. After exposure was
stopped, testes weight returned to control values and spermatogenesis
resumed. However some animals exposed at high doses still exhibited a
small proportion of atrophied seminiferous tubules. Thus the authors
concluded that prolonged

**\[page 15537\]**

high exposure may prevent total recovery of testicular function

Adverse effects in spermatogenesis and mating performance were observed
in short term tests conducted by Chapin (Ex. 5-007). In the first phase
of this study male rats were exposed to 0, 50, 100 or 200 mg 2-ME/kg
body weight for 5 days and then mated with untreated females for 8
weeks. Significant decreases in the percentage of pregnancies and the
number of live fetuses were observed among females mated with males from
the 200 and 100 mg/kg dose groups. No significant effects were observed
among females mated with 50 mg/kg dosed males. Females mated to rats
exposed at 200 mg/kg exhibited an increase in the incidence of
resorptions but only at weeks 5 and 6. No increases in resorption rates
were observed among any other group

Significant increases in preimplantation losses were observed among
females mated with males exposed to 200 and 100 mg/kg. The authors noted
that the decrease in litter size is a possible indication of a dominant
lethal effect. However because there was no significant increase in the
number of dead fetuses and only a slightly significant increase in
resorptions at weeks 5 and 6 of the high dose group, the authors stated
that the decrease in litter size was probably due to decreased number of
viable sperm number rather than a dominant lethal effect. The authors
added that this conclusion is supported by the evidence of pre-
implantation loss as well as by the findings of others researchers
(e.g., Rao et al., Ex. 4-142)

In the second phase of this study by Chapin, additional groups of male
rats were exposed similar to rats in the first phase of the study but
this time were not allowed to mate. Rats exposed at 100 and 200 mg/kg
showed significant sperm count reductions throughout the study. In
addition, these groups showed significant decreases in the percentage of
motile sperm and increases in the frequency of abnormal sperm
morphology. A reduction in sperm counts was observed in the 50 mg/kg
group at week 5 only. In this group sperm motility was unaffected. The
findings of this study also indicated that as dose increased, different
types of testicular cells were affected. For example, at 100 mg/kg only
spermatocytes were affected, while at 200 mg/kg the later stage
spermatids and spermatogonia were effected

In a subsequent study using a similar protocol, Chapin et al.(Ex. 5-006)
examined testicular recovery from 2-ME treatment. Again male rats were
exposed orally to 0, 50, 100, or 200 mg 2-ME/kg body weight for 5 days
and followed for 8 weeks. Rats exposed to 200 and 100 mg 2-ME/kg
exhibited significant signs of testicular damage including abnormal
sperm morphology, delayed spermatogenesis, and cell death. All animals
exposed to 200 mg 2-ME/kg showed significant signs of testicular
toxicity during the first week of observation. These animals exhibited
widespread death of all stages of spermatocytes and abnormal sperm
morphology. By weeks 5-8, 50% of the tubules appeared normal for the 200
mg/kg exposed groups. Cell death and abnormal sperm morphology were also
observed at 100 mg/kg. Similarly by week 8 a 50% recovery was noted. In
the 50 mg/kg exposure group, changes in morphology were not noted until
week 4. By week 8 no treatment related changes were observed

Similar findings have been reported in more recent studies by Anderson
et al.(Ex. 5-100). Male mice and rats were exposed to single doses of 0,
500, 750, 1000 or 1500 mg 2-ME/kg body weight. Selected groups were
additionally mated to untreated females to examine dominant lethality.
As in earlier studies increasing doses resulted in increased levels of
testicular damage. In the rat, testes weight and sperm counts were
significantly reduced at all dose levels. Abnormal sperm morphology was
also observed among treated rats. In mice, significant decreases in
testes weight and sperm count were observed in the 750 mg/kg group at
week 3 and in the 500 and 1000 mg/kg groups at week 4. In the dominant
lethal studies female rats mated to exposed males, exhibited a
significant reduction in the number of implants. No statically
significant increase in the incidence of abnormalities in offspring or
any other signs of dominant lethality were observed among the rat
offspring. In the mice, no significant decreases in fertility or signs
of dominant lethality were observed

b\. 2-MEA

Evidence strongly indicates that 2-MEA will induce adverse reproductive
effects similar to its parent glycol ether 2-ME. As was discussed in the
section on metabolism, MAA is thought to be the primary metabolite of
2-MEA. Metabolic studies indicate that the adverse reproductive effects
of 2-ME are mediated by its primary metabolite methoxyacetic acid (MAA).
Therefore it is likely that equal doses of 2-MEA would induce adverse
reproductive effects similar to 2-ME, as these two compounds appear to
follow similar metabolic pathways

The metabolic data are supported by the findings of testicular
degeneration in mice by Nagano et al. (Ex. 4- 135). In this study, male
mice were orally exposed to 62.5, 125, 250, 500, 1000, or 2000 mg
2-MEA/kg body weight, 5 days/week for 5 weeks. Significant decreases in
testicular weight were observed only in the 500 mg/kg dose group.
Converting this dosage to mmole/kg the authors noted that on an
equimolar basis 2-ME and 2-MEA resulted in similar effects

c\. 2-EE

Like 2-ME, 2-EE has also been shown to cause male reproductive toxicity
in laboratory animals although 2-EE has not been tested as extensively.
For example, Barbee and Terrill et al. (Exs. 5-084 and 4-108) exposed
male rats and rabbits by inhalation to 25, 100 or 400 ppm of 2-EE, 6
hours/day, 5 days a week, for 13 weeks. In rats the only significant
effects observed were decreased pituitary weights at 400 ppm.
Pathological examination of these organs did not reveal any lesion
indicative of a treatment related effect. Thus the authors concluded
that the increased pituitary weight was not likely to be a treatment
related effect. Rabbits exhibited a significant decrease in testes
weight when exposed to 400 ppm. Based on the pathological analyses this
decreased weight was attributed, by the authors, to the degeneration of
the seminiferous tubules. No adverse effects were observed at 100 or 25
ppm. From these findings the NOEL for reproductive effects in male rats
was identified as 400 ppm while the NOEL for reproductive effects in
male rabbits was 100 ppm

2-EE also induces testicular degeneration after oral exposure. For
example, Nagano et al. (Ex. 4-135) exposed male mice to 500, 1000, 2000,
or 4000 mg 2-EE/kg body weight, 5 days/week over a 5 week period. At
4000 mg 2- EE/kg, all animals died before examination. Significant
decreases in testes weights were observed in the 1000 and 2000 mg/kg
exposure groups. Histopathological examinations revealed dosage related
degrees of seminiferous atrophy among groups exhibiting a significant
reduction in testes weight. For example, at 500 mg/kg no significant
effects on the testes were observed. At 1000 mg/kg there were
significant reductions in the testes weight and a corresponding decrease
in the number of spermatozoa, spermatids and spermatocytes. At 2000
mg/kg there were also a significant decrease in testes weight with a
corresponding decreae in spermatozoa and spermatids had completely
vanished

Similar effects were observed in short term oral studies by Foster et
al. (Ex. 4-119). In this study male rats were exposed to 250, 500 or
1000 mg 2-EE /kg body weight for 11 days. Significant decreases in
testes weight were

**\[page 15538\]**

observed at 500 and 1000 mg/kg after the 11th day of exposure. The
authors noted that rats appeared to be slightly more sensitive than
mice. Histological examination of the testes revealed spermatocyte
degeneration of the primary and secondary spermatocytes. No significant
testicular abnormalities were observed at 250 mg/kg. The NOEL was
identified as 250 mg/kg body weight

d\. 2-EEA

As in the case of 2-MEA, evidence strongly indicates that 2-EEA will
induce adverse reproductive effects similar to 2-EE. As discussed
earlier, metabolic studies indicate that ethoxyacetic acid (EAA) is the
primary metabolite of both 2-EE and 2-EEA and thus 2-EEA is likely to
produce similar effects to those of 2-EE. This evidence is supported by
the studies of Nagano et al. (Ex. 4-135) who exposed male mice to 500,
1000, 2000, or 4000 mg 2-EEA/kg body weight, 5 days/week, for 5 weeks.
Significant decreases in testicular weight were observed in mice exposed
to 1000, 2000 and 4000 mg/kg 2-EEA. Histopathological examinations
revealed dose related changes in seminiferous tubule atrophy. For
example at 200 and 100 mg/kg the exposed groups exhibited a significant
reduction in testes weight and a corresponding reduction in the number
of spermatozoa, spermatids and spermatocytes. At 400 mg/kg there was
also a significant reduction in testes weight but at this dose the
spermatozoa and spermatids had completely vanished. Conversion of dosage
to mmole/kg revealed that equimolar doses of 2-EE and 2-EEA induced
similar effects. Thus the authors concluded that these results suggest
that a glycol ether and its corresponding acetate have similar toxic
potential

In summary, the evidence clearly shows that 2-ME, 2-EE and their
acetates induce adverse male reproductive effects. Both through
inhalation and oral exposure of these compounds, several animal species
have exhibited infertility and testicular degeneration. 2.
Maternal/Developmental Effects

2-ME and 2-EE and their acetates also induce adverse developmental and
maternal effects. Rats, mice, rabbits and monkeys after oral and dermal
exposures to these compounds have exhibited adverse effects including
decreased maternal weight gain, increased lengths of gestation,
increased resorptions, fetal malformations and delayed development

a\. 2-ME

Hanley et al. (Exs. 4-120, 4-106, and 4-042a) studied the effects of
inhaled 2-ME on fetal development in rats, mice and rabbits. Pregnant
rats were exposed to 0, 3, 10, or 50 ppm 2-ME for 6 hours/day on days 6
through 15 of gestation. Pregnant mice were exposed to 0, 10 or 50 ppm
for 6 hours/day on days 6 through 15 of gestation. Pregnant rabbits were
exposed to 0, 3, 10, or 50 ppm for 6 hours/day on days 6 through 18 of
gestation. Female rats exposed to 50 ppm exhibited a significant
decrease in maternal body weight gain. No other signs of maternal
toxicity for any other test doses were noted. A significant decreased in
maternal body weight gain was also observed in mice but again only at 50
ppm. The only statistically significant dose-related developmental
effects in rats were an increased incidence of lumbar spurs and delayed
ossification after exposure to 50 ppm 2-ME. In mice the only significant
dose related developmental effects observed were increased incidence of
lumbar spurs and unilateral testicular hypoplasia at 50 ppm. No
statistically significant effects were observed at 10 or 3 ppm in mice.
Rabbits however exhibited a more sensitive response to 2-ME exposure. At
50 ppm significant decreases in maternal body weight gain and increases
in maternal liver weight were observed. At 50 ppm rabbits had a
significant increase in the incidence of resorptions. Fetuses from this
group exhibited a significant decrease in mean fetal body weight and a
significant increase in the incidence of malformations of all organ
systems (e.g., joint contracture, shortness and absence of digits,
ventricular septal defects of the heart, missing paw bones and rib
malformations). Despite the strong effect observed at 50 ppm, there was
no statistically significant increased incidence of malformations at 10
or 3 ppm for rabbits. However a statistically significant increase in
resorption rate was observed at 10 ppm. The authors of the study however
dismissed this effect stating that the observed increase was a result of
an unusually low concurrent control value for resorptions. The authors
stated that the observed increase at 10 ppm was within the range
observed among historical controls

Similar results were observed by Doe et al. (Ex. 4-111). In this study
pregnant rats were exposed by inhalation to 0, 100 or 300 ppm 2-ME for 6
hours/day on days 6 through 17 gestation. Rats exposed to 300 ppm
exhibited a significant decrease in maternal body weight gains and
failed to produce any litters. Nine of the 20 rats exposed to 100 ppm
2-ME produced litters, but the gestation period was significantly
increased over controls. Exposure to 100 ppm also induced a significant
reduction in the total numbers of pups, the proportion of pups live at
birth and the proportion of pups surviving to day 3 postpartum. The
authors stated that all pups from the 100 ppm group were normal
externally, but no further examination of the pups was performed to
determine whether or not there was any other evidence of a developmental
effect. Because statistically significant effects were observed at both
of the tested doses a NOEL was not established in this study

Inhalation studies by Nelson et al.(Ex. 4-136) examined the behavioral
and neurochemical effects in offspring after parental exposure to 2-ME.
In these studies both male and female rats were exposed to 25 ppm 2-ME.
Twenty-five ppm was chosen as a test level as this dose represented the
current allowable limit of exposure under the OSHA standards. Male rats
were exposed for 7 hours/day, 7 days/week, for 5 weeks. These rats were
then mated with untreated females which were allowed to deliver their
young. Separate groups of pregnant rats were exposed 7 hours/day on days
7 through 13 or days 14 through 20 gestation and were also allowed to
deliver their young. Behavioral testing to evaluate central nervous
system effects (i.e motor, sensory and cognitive functions) were
conducted on offspring from both groups of rats and the brains from
selected offspring were analyzed for neurochemical levels (e.g.,
dopamine, acetylcholine, and norepinephrine). The only statistically
significant effect in behavior observed was the difference in avoidance
conditioning in offspring from female rats exposed on days 7-13
gestation. In the neurochemical analyses offspring from both the
paternally and maternally exposed rats exhibited significant
neurochemical deviations particularly in the brainstem and cerebrum.
These results indicate that both paternal and maternal exposure may
result in teratogenic effects on the offspring. However only one dose
was used in this study and thus no conclusions about dose-response
effects or NOEL\'s can be drawn

Studies have shown that oral exposure to 2-ME also induces adverse
developmental effects. Nagano et al. (Ex. 5-026) orally exposed pregnant
mice to 31.25, 62.5, 125, 250, 500 or 1000 mg 2-ME/kg body weight on
days 7 through 14 gestation. A significant increase in the incidence of
dead fetuses was observed among mice exposed to 250, 500 and 1000 mg/kg
2-ME. There were also significant reductions in fetal weight among
fetuses from the 125 and 250 mg/kg dosed groups. At 250 mg/kg

**\[page 15539\]**

there was a significant increase in the incidence of gross
malformations, including exencephaly, umbilical hernia and abnormal
fingers. Increased skeletal malformations including fused ribs, fused
vertebrae, spina bifida, syndactly (fused fingers), oligodactly (absence
of fingers), and polydactly (extra fingers) were observed after exposure
to 62.5, 125, and 250 mg/kg. Delayed ossification was observed in
fetuses from all dose levels. Thus in this study a NOEL was not
established

Similarly, Toraason et al.(Ex. 5-042) exposed pregnant rats by gavage to
0, 25, 50, or 100 mg 2-ME/kg body weight on days 7 through 13 gestation.
At day 20 of gestation fetuses were removed for electrocardiographic
(EKG) analysis and later examined for physical defects. The EKG
evaluation involved measuring rhythm variations of the heart, the
presence or absence of peaks produced by EKG output (i.e., R, QRS, QT
and R-R peaks). All fetuses were resorbed at 100 mg/kg 2-ME and thus no
EKG analysis was possible at this dose. There was a significant increase
in the number of fetuses with abnormal QRS\'s from both the 25 and 50
mg/kg exposure groups. At these doses no other EKG characteristics were
significantly affected by 2-ME exposure. The most prevelant
cardiovascular defect, ventricular septal defect and ductus arteriosis,
was observed in fetuses from the 50 mg/kg exposure group. However the
authors concluded that the abnormal QRS\'s did not appear to be related
to the cardiovascular malformation. For example the authors noted that
four fetuses with abnormal QRS\'s had heart defects but 4 fetuses
without heart malformations also had abnormal QRS\'s. The authors
attributed the abnormal QRS\'s to a delay in conduction. Nevertheless
the results of this study indicate that 2-ME exposure may adversely
effect fetal heart function

Adverse developmental effects of 2-ME have also recently been reported
in non-human primates. Scott et al.(Ex. 5-125) exposed pregnant monkeys
by gavage to 0, 12, 24 or 36 mg/kg body weight, on days 20 to 45 of
gestation. Signs of maternal toxicity including a reduction in maternal
body weight and loss of appetite were observed at all dose levels. At
the highest dose (36 mg/kg) all pregnancies ended in abortion. Three of
10 pregnancies were also aborted in the 24 mg/kg dose group and 3 of 13
pregnancies were aborted in the 12 mg/kg dose group. Fetuses were
removed on day 100 of gestation and examined for abnormalities. No
malformations were observed among any of the fetuses surviving to day
100 of gestation

b\. 2-MEA

The studies discussed above clearly show that 2-ME induces adverse
maternal and developmental effects. As discussed earlier, metabolic data
indicate that the toxicity of 2-ME is mediated by its primary
metabolite, methoxyacetic acid (MAA). MAA is also the primary metabolite
of 2-MEA and thus it is likely that 2-MEA will induce similar adverse
effects to 2-ME

c\. 2-EE

Similar to 2-ME, 2-EE has also induced adverse developmental effects.
Doe and Tinston et al. (Exs. 5-071, 4-038, 4-039 and 4-105) exposed
pregnant rats, by inhalation, to 0, 10, 50 or 250 ppm 2-EE for 7
hours/day on days 6 through 15 gestation. Pregnant rabbits were exposed
to 0, 10, 50 or 175 ppm 2-EE for 7 hours/day on days 6 through 18
gestation. No adverse maternal effects were observed among either
exposed rats or rabbits. Among rats, exposure to 250 ppm induced a
significant increase in late interuterine death and a decrease in fetal
growth. Fetuses from the 250 ppm group exhibited significant increases
in skeletal defects, (e.g., partial and/or nonossification of the skull
and the thoracic and lumbar vertebrae) and increases in sternebrae
abnormalities. No significant adverse effects were observed in the 50 or
10 ppm exposed groups. In the high dose rabbits (175 ppm) there were no
significant increases in late interuterine death or decreases in fetal
growth. The only statistically significant effect observed at this dose
was an increased number of fetuses with extra ribs. As neither species
showed any significant adverse effects at 50 ppm, the authors stated
that a clear no effect level of 50 ppm for 2- EE was identified in this
study

Similar findings were reported by Andrew et al. (Exs. 4-065 and 5-069)
who exposed pregnant rabbits by inhalation to 0, 160, or 615 ppm 2-EE
for 7 hours/day on days 1-18 gestation. Rabbits exposed to 615 ppm
exhibited maternal toxicity including severe anorexia, reduced weight
gain and an increased incidence of maternal mortality (5 of 19 died).
Rabbits exposed to 160 ppm exhibited significant reductions in food
consumption and maternal body weight gain. All litters, from the
surviving does, in the 615 ppm exposure group, were resorbed.
Resorptions were also significantly increased in the 160 ppm exposure
group. In addition there was a significant reduction in the number of
live fetuses. Fetuses from the 160 ppm group exhibited a significant
increase in malformations including cardiovascular effects (e.g., fused
aorta and pulmonary artery), renal effects (e.g., fused kidneys) and
skeletal effects (e.g., extra and malformed ribs)

In the Andrew study, female rats were also exposed to 2-EE by inhalation
to 0, 150, or 650 ppm for 7 hours/day, 5 days/week for a 3 week
pregestational period followed by exposure to 0, 200 or 760 ppm 2-EE
during days 1-19 gestation. Pregestational exposure had no effect on
maternal toxicity or the establishment of pregnancy. Significant
decreases in liver weights and kidney weights were observed in the rats
exposed to 760 ppm during gestation. All litters in the 760 ppm exposure
group were resorbed. The number of resorptions was not increased in the
200 ppm exposure group. However exposure to 200 ppm during gestation
significantly increased the incidence of cardiovascular malformations,
and skeletal defects (e.g., extra ribs and vertebrae, and reduced
skeletal ossification) in the pups

Nelson et al.(Ex. 4-138) examined developmental effects in the behavior
of offspring from rats exposed to 2-EE. Pregnant rats were exposed by
inhalation to 100 ppm 2-EE, 7 hours/day on days 7-13 or days 14-20 of
gestation. Behavioral tests were subsequently conducted on offspring
from the control and exposed groups to evaluate CNS function (e.g.,
motor, sensory and cognitive functions). Selected offspring were also
used for neurochemical analyses (e.g., acetylcholine, norepinephrine and
dopamine levels). The only evidence of any maternal toxicity was a
significant increase in the duration of pregnancy compared to controls.
Offspring from rats exposed on days 7-13 of gestation exhibited impaired
performance in the rotorod and open field test and marginal superiority
in the avoidance conditioning test. Offspring from the 14- 20 gestation
day exposure group had impaired performance in the running wheel and
avoidance conditioning tests. Neurochemical analyses revealed that in
both the 7-13 and 14-20 day exposure groups, whole brain samples from
offspring showed significantly decreased levels of norepinephrine. In
the 7- 13 day groups the cerebrum and cerebellum had significant
elevations in acetylcholine and dopamine. Thus the results of this study
indicate that at 100 ppm 2-EE can induce behavioral and neurochemical
alterations. Because only one dose was tested the study was not able to
evaluate any potential dose-response trend or identify a NOEL

2-EE has also induced adverse developmental effects after dermal
exposure. Hardin et al. (Ex. 4-121) applied 0.25 ml or 0.50 ml 2-EE

**\[page 15540\]**

dermally four times daily to pregnant rats on days 7-16 gestation. Rats
exposed to 0.50 ml 2-EE exhibited ataxia (loss of muscular coordination)
and reduced body weight gain during the later days of exposure. No other
significant signs of maternal toxicity were noted. All fetuses from the
0.50 ml exposure group were resorbed. There was also a significant
increase in the numbers of resorptions in the 0.25 ml exposure group.
The 0.25 ml group also exhibited significantly increased incidence of
cardiovascular malformations and skeletal defects (e.g., incomplete
ossification, extra and malformed ribs and vertebrae). The results of
this study indicate that skin exposure is a significant route of
exposure for inducing teratogenic effects

d\. 2-EEA

Inhalation, dermal and oral studies have clearly shown a teratogenic
response from exposure to 2-EE. As discussed earlier, metabolic studies
also indicate that it is the primary metabolite, EAA, which is likely to
be the active agent. EAA is also the primary metabolite of 2-EEA and
thus it is likely that 2-EEA will induce teratogenic effects similar to
2-EE. Several inhalation studies support these conclusions. For example,
Nelson et al. (Ex. 5-091) exposed pregnant rats by inhalation to 0, 130,
390, or 600 ppm 2- EEA, 7 hours/day, on days 7-15 gestation. At 600 ppm
rats exhibited a significant decrease in maternal body weight. However
the authors attributed this reduction in maternal weight at high dose to
be due to resorptions. They thus concluded that no significant signs of
maternal toxicity were observed. All fetuses from the 600 ppm group were
resorbed. Resorptions were also significantly increased in the 390 ppm
exposure group. Fetuses from both the 390 and 130 ppm exposure groups
exhibited significant decreases in weight, as well as significant
increases in visceral malformations (e.g., septal defects of the heart
and umbilical hernia) and skeletal defects (e.g., wavy and fused ribs).
A NOEL was not established for this study

Adverse effects were also reported by Doe et al. (Ex. 5-071) who exposed
pregnant rabbits to 0, 25, 100 or 400 ppm 2-EEA for 6 hours/day on days
6 through 18 of gestation. Maternal toxicity was only observed among the
400 ppm exposed rabbits. In this group rabbits exhibited significant
decreases in maternal body weight gain and food consumption. Mean live
fetal weights were significantly reduced for fetuses from both the 400
and 100 ppm exposure groups. Fetuses from the 400 ppm exposure group
exhibited significant increases in visceral defects (e.g., opaque/empty
gall bladders, reduced/pale spleens) and skeletal defects (e.g.,
retarded ossification). Fetuses from the 100 ppm group also showed a
significantly increased incidence of partial ossification. The only
significant effect observed among fetuses from the low dose exposure
group (25 ppm) was an extra center of ossification above the 1st
sternebra. However because significant skeletal defects were observed
only at 400 and 25 ppm the authors concluded that the effects at 25 ppm
were probably not dose related and thus the NOEL for this study was 25
ppm

More recent investigations by Tyl et al. (Ex. 5-124) have further
confirmed the teratogenic potential of 2-EEA. In this inhalation study
pregnant rabbits and rats were exposed to 0, 50, 100, 200 or 300 ppm
2-EEA, 6 hours/day for days 6-15 (rats) or days 6-18 (rabbits) of
gestation. Rabbits exhibited significant decreases in maternal weight
gain at 300, 200 and 100 ppm 2-EEA. After exposure to 300 and 200 ppm
rabbits also exhibited significant decreases in gravid uterine weight
and increases in absolute liver weight. Rats exposed to 2-EEA exhibited
a significant decrease in maternal weight gain and food consumption at
300 and 200 ppm. A significant decrease in absolute liver weight was
observed in rats at 100, 200 and 300 ppm. A significantly increased
incidence of nonviable implantations was observed at 300 and 200 ppm in
rabbits and at 300 ppm in rats. Rabbits also exhibited a significant
increase in the incidence of resorptions after exposure to 300 ppm.
Significant reductions in fetal body weight per litter were observed
only among rats exposed to 300 and 200 ppm 2-EEA. Examinations of rabbit
fetuses revealed a significant increase in the incidence of skeletal,
cardiovascular and renal effects at 300 and 200 ppm. Similarly rats
exhibited significant increases in malformations (e.g., cardiovascular,
renal and skeletal effects) at both 200 and 300 ppm. No signs of
maternal or fetal toxicity were observed at 50 ppm for either species
and thus this exposure dose was identified as the NOEL for this study

Similar to findings in dermal studies on 2-EE, studies on 2-EEA have
also shown that dermal exposure induces teratogenic effects similar to
those observed in inhalation studies. Hardin et al. (Ex. 5-073) dermally
exposed pregnant rats to 0.35 ml 2-EEA, twice daily for days 7 through
16 of gestation. Dermal exposure induced significant decreases in
maternal body weight gain, significant increases in the incidence of
dead implants per litter and significant increases in the frequency of
resorbed litters. Fetal examination revealed a significant increase in
the incidence of cardiovascular and skeletal defects (e.g., reduced
ossification and mishaped vertebrae). Thus the findings of this study
further demonstrate the teratogenic potential of 2-EEA. In addition
these findings indicate that dermal exposure may be a significant route
of exposure

3\. Blood Effects

In addition to adverse reproductive and developmental effects, the
animal studies provide evidence that 2-ME, 2-EE and their acetates also
induce adverse hematological effects. Various studies in rats, rabbits
and mice by both inhalation and oral exposure have demonstrated exposure
related decreases in various blood parameters including white blood cell
counts (WBC), hemoglobin concentration (HGB), platelet count and red
blood cell count (RBC)

a\. 2-ME and 2-MEA

Miller et al. (Ex. 4-132) exposed rats and mice to 0, 100, 300 or 1000
ppm 2-ME, 6 hours/day for 9 days. At 1000 ppm both male and female rats
exhibited significant decreases in WBCs, RBCs, HGB and packed cell
volume. Male mice showed similar significant effects at 1000 ppm while
female mice showed a significant decrease in WBC only at 1000 ppm. WBC
was also decreased at 300 ppm for male rats and at 100 ppm for female
rats

In a similar study, Doe et al. (Ex. 4-111) exposed male rats to 0, 100
or 300 ppm 2-ME, 6 hours/day for 10 consecutive days. Exposures at 300
ppm resulted in significant reductions in whole blood count, red blood
cell count, hemoglobin concentration, hematocrit and mean cell
hemoglobin. No significant blood effects were observed among rats
exposed to 100 ppm

Thirteen week inhalation studies by Miller et al. (Ex. 5-023) support
the authors\' earlier findings (Ex. 4-132) of adverse blood effects. In
this study rats and rabbits were exposed to 0, 30, 100 or 300 ppm 2-ME
for 6 hours/day, 5 days/week for 13 weeks. Both rats and rabbits, male
and female, exposed to 300 ppm 2-ME exhibited significant decreases in
WBC, platelet counts, packed cell volume, and HGB. Rabbits exposed to
300 ppm also showed a significant decrease in RBC. No adverse effects in
blood were observed at 100 or 30 ppm 2-ME for rats or rabbits

Similarly, Hanley et al. (Ex. 4-120) exposed pregnant rats, rabbits and
mice to 0, 3, 10 or 50 ppm 2-ME for 6 hours/day on days 6-15, 6-18 and
6-15

**\[page 15541\]**

respectively. Rats exhibited a significant decrease in HGB and packed
cell volume at all dose levels and a significant decrease in RBC at 50
ppm only. Neither mice nor rabbits showed any significant dose related
blood effects

Oral studies in mice by Nagano et al. (Exs. 5-026 and 4-135) have
observed significant decreases in WBC after high dose exposure. Pregnant
mice exposed during days 7-14 gestation to 31.25, 62.5, 125, 250, 500 or
1000 mg 2-ME/kg body weight showed significantly decreased WBCs at 1000
mg/kg (5-026). Male mice exposed at 12.5, 125, 250 500, 1000 or 2000
mg/kg over a five week period also exhibited significant decreases in
WBC at 500 mg/kg and above (Ex. 4- 135). Nagano et al. also exposed male
mice to 2-MEA, resulting in a significant decrease in WBC at 1000 mg/kg.
The authors noted that when expressed in equimolar doses, the
dose-effect levels are similar for 2-ME and 2-MEA. No other studies have
investigated the hematological effects of 2-MEA

b\. 2-EE

Barbee et al.(Ex. 5-084) exposed male and female, rats and rabbits, to
0, 25, 100 or 400 ppm 2-EE, 6 hours/day for 5 days/week for 13 weeks.
Adverse blood effects were only observed among male and female rabbits
exposed at 400 ppm. These rabbits exhibited a significant decrease in
HGB, hematocrit and RBC

In their teratology studies Doe et al. (Ex. 5-071) exposed pregnant rats
to 0, 10, 50 or 250 ppm 2-EE, 6 hours/day on days 6-15 gestation and
rabbits to 0, 10, 50 or 175 ppm 2-EE, 6 hours/day on days 6-18
gestation. Rats exposed to 250 ppm exhibited a decrease in HGB,
hematocrit and RBC. It is not stated clearly as to whether or not these
effects were statistically significant. No treatment related effects
were observed at 50 or 10 ppm. No adverse blood effects were observed at
any of the test doses for rabbits

Nagano et al. (Ex. 4-135) exposed male mice to 500, 1000, 2000 or 4000
mg 2-EE/kg body weight 5 days/week for 5 weeks. Significant decreases in
WBC were observed in the 2000 and 4000 mg/kg exposure groups

c\. 2-EEA

Tyl et al. (Ex. 5-124) exposed pregnant rats and rabbits to 0, 50, 100,
200 or 300 ppm 2-EEA 6 hours/day on days 6-15 and days 6-18 gestation,
respectively. Rabbits showed significant decreases in platelet counts at
200 and 300 ppm. Rats also had decreased platelet counts at 200 and 300
ppm. In addition rats exhibited a significant increase in WBC at 200 and
300 ppm and a decrease in RBC at 100, 200, and 300 ppm exposure. Barbee
et al. (Ex. 5-071) also exposed pregnant rabbits to 2-EEA at doses of 0,
25, 100 or 400 ppm. The only statistically significant effect observed
was a decrease in HGB at 400 ppm. Oral studies by Nagano (Ex. 4-135)
exposed mice to 500, 1000, 2000, or 4000 mg 2- EEA/kg body weight. The
only significant effect in this study was a decrease in packed cell
volume in mice exposed at 4000 mg/kg

F. Adverse Health Effects In Humans

Workers exposed to 2-ME and 2-EE have exhibited adverse effects on the
hematologic and male reproductive systems. Blood effects among exposed
workers include bone marrow injury, reduced red and white blood cell
counts and anemia. The major reproductive effect observed among exposed
workers is reduced sperm count. OSHA is unaware of any female
reproductive or developmental toxicity data among workers exposed to
glycol ethers. OSHA believes however that the lack of data in this area
is due in major part, to the difficulty in structuring and conducting
analyses to detect these types of adverse effects. Thus, although the
human data are limited, there is positive evidence among exposed workers
and this evidence supports the strong body of evidence observed in
experimental animals

1\. 2-ME

Ohi and Wegman (Ex. 4-139) reported on two workers in a textile printing
plant who developed clinical manifestations of encephalopathy (brain
disease) after the acetone that was usually used in a hand cleaning
operation had been substituted with 2-ME. Protective gloves were not
worn. In addition to the neurological symptoms of encephalopathy, both
workers had evidence of bone marrow injury. One had pancytopenia
(reduction in the numbers of all of the formed elements of the blood).
Air samples collected during the washing operation averaged 8 ppm.
Although no estimate was made of the magnitude of skin absorption,
exposure was characterized as being \"predominantly dermal.\" Thus
dermal exposure may have played a significant part in the observed
effects. The authors noted that blood counts returned to normal after
removal from exposure indicating that blood effects may be reversible

Cohen (Ex. 5-049) presented a case report of subjective central nervous
system complaints and asymptomatic hematopoietic effects following
inhalation and skin exposure to 2-ME in a microfilm coating and mixing
operator. The worker\'s job in this case report entailed mixing
chemicals, often while standing directly over open 1500 gallon kettles
which contained 33% 2-ME. 2-ME was also used in the manual cleaning of
the kettles, usually done without gloves. Breathing zone exposures
revealed time-weighted average 2-ME levels of 18.2 ppm to 57.8 ppm
(average being approximately 35 ppm). Small quantities of methylethyl
ketone (MEK) (1-5 ppm) were present. During a periodic examination less
than a year after starting his job, it was found that the blood indices
of this 32-year old worker, which had previously been normal, dropped.
His white blood cell (WBC) count, red blood cell (RBC) count,
hemoglobin, hematocrit, and platlets were all found to have fallen to
abnormally low levels. The worker also noted an increase in sleep time,
increase in weight, decrease in appetite, increased fatigue, and
feelings of apathy. When the worker was removed from skin and inhalation
exposure to 2-ME, all hematologic parameters returned to normal

Cook et al. (Ex. 5-002) conducted a cross-sectional study among male
manufacturing and processing employees, 40 with potential exposure to
2-ME, to determine if anemia, leukopenia (reduction in number of white
blood cells), or sterility were present and, if so, if they were more
prevalent among the exposed workers. Manufacturing of 2-ME was by a
continuous enclosed process. In a separate packaging and distribution
facility, 2-ME was loaded into drums, tank cars, or rail cars. Drums
were filled automatically, but there was manual capping. TWA air samples
of 2-ME collected in the packaging and distribution facility in 1980
indicated personal exposures of 5 to 9 ppm 2-ME and area concentrations
of 4 to 20 ppm. However, because of the potential for skin contact and
absorption, continued use of protective gloves was recommended to avoid
skin contact during sampling and maintenance. Workers exposed to 2-ME
were also potentially exposed to 2-EE, polyols and polyoxypropylene
glycols, brake fluids, butylene oxide, and polyglycols. Complete blood
counts (CBC), hormone levels \[i.e., Luteinizing hormone (LH), Follicle
Stimulating hormone (FSH), testosterone\], length and width of testis,
and sperm counts were evaluated for frequencies of abnormal outcomes and
percentage differences of grouped means in workers exposed to 2-ME and
in the unexposed workers. Hematologic variables in 40 exposed and 25
controls were compared to determine prevalence of anemia and/or
leukopenia. Clinical fertility indices for a subgroup of 15 (6

**\[page 15542\]**

exposed, 9 control) were supplemented by medical history and responses
to the question: \"Looking back, do you feel you have had any trouble
having children?\"

Study results indicated little difference between exposed and controls.
The only difference between means that approached statistical
significance was testicular width (p=.08); however, testicular length
was also diminished among the total exposed (p=.19). The authors
acknowledged a variety of chemical exposures for both study groups. They
also suggested the likelihood of interobserver bias, given that one
physician consistently measured lower values and examined appreciably
more exposed individuals than controls

2\. 2-EE

In 1984 NIOSH conducted a Health Hazard Evaluation of possible
reproductive effects among male workers exposed to 2-EE at Precision
Castparts Corporation (Ex. 5-003). 2-EE was used as a binder in the
preparation of ceramic shells used to cast precision metal parts from
wax molds. Approximately 80 male workers engaged in this process were
potentially exposed to 2-EE. Full shift breathing zone airborne
exposures ranged from non-detectable to 23.8 ppm. Because of the
potential for skin exposure to 2-EE, urine measurements of ethoxyacetic
acid (EAA), a metabolite of 2- EE, were also determined

Urine excretion of EAA ranged from non-detectable to 163 ug/g
creatinine. Blood samples analyzed for 2-EE concentrations did not
reveal any detectable levels of 2-EE

In this study NIOSH also conducted a cross-sectional evaluation of semen
quality (sperm concentration, pH, volume, viability, motility, velocity
and morphology) among 37 men exposed to 2-EE in this plant. The
evaluation included a comparison group of 38 unexposed men from
elsewhere in the plant. A questionnaire to determine personal habits,
medical and work histories and a brief examination of the genital tract,
including measurements of testicular size, were also administered

The average sperm count per ejaculate among the 2-EE exposed workers was
significantly lower than that of the unexposed group (113 v. 154 million
sperm per ejaculate; (p \< 0.05). For exposed workers, this difference
was statistically highly significant (p \< 0.001). The two groups did
not differ significantly with respect to other semen characteristics or
testicular size. Consideration of the other factors (e.g., abstinence,
sample age, subject\'s age, tobacco, alcohol, and caffeine use, history
of urogenital disorders, fever, and other illness) which affect semen
quality did not alter these results. However the authors noted that the
average sperm concentrations of both groups were lower than the average
for other occupational populations studied by NIOSH. Historical control
sperm concentration is 70 million/ml. In the present study the mean
sperm concentration of the unexposed group was 60 million/ml and that of
the exposed group was 48 million/ml

NIOSH concluded that there was a possible effect of 2- EE on sperm count
among these workers, and recommended limiting exposure to 2-EE to the
fullest extent feasible, given the known testicular toxicity in animals

In the first of three related papers Sparer, Welch, McManus and Cullen
(Ex. 5-103) characterized exposure to ethylene glycol ethers in a group
of shipyard painters. Painters employed at the shipyard worked in four
crews: shop crew, interior crew, tank crew, and exterior crew. The shop
crew worked in the paint shop where they formulated and mixed paints and
issued respirators. The majority of men in the shop crew had worked on
other crews in the past. Interior, exterior, and tank crews worked on
the boats. Assignment of a painter to a crew depended on the stage of
completion of the boat. Painters may have been assigned to one crew and
worked overtime on another. In any given month a painter may have worked
on the interior, exterior, and tank crews

Much of the painting performed by the interior crews was by brush
application. Tanks were primarily spray painted, and air-supplied
respirators were always worn during this operation. Half-face filter
respirators with organic vapor cartridges and paint filters were worn by
painters whenever they sprayed on interior jobs and were available, but
seemed to be optional, for those doing brush painting

One hundred and two air samples from thirty-six painters were analyzed
for 2-EE, and 2-ME. 2-EE was detected in 90 samples, 2-ME in 81. For
2-ME the mean was 0.8 +/- 1.0 ppm; median 0.44 ppm and the range 0-5.6
ppm. The mean value for 2-EE was 2.6 +/- 4.2 ppm; the median 1.2; the
range 0 - 21.5 ppm. The mean air exposure of the interior crew was 2.6
+/- 4.2 ppm for 2-EE and 0.8 +/- 1.0 ppm for 2-ME. Visible paint on the
painters indicated that 60% of the men sampled had skin contact.
Painters who were using paints without ethylene glycol ethers, or not
painting at all, still had exposure to these solvents as demonstrated by
air sampling

Sparer and Welch et al. stated that although these sampling observations
do serve to help characterize the exposure of these painters to ethylene
glycol ethers, several factors suggest that these measurements may
underestimate exposure. A NIOSH investigation of 2-EE exposures reported
variable results in recovering analyte from field samples that are
shipped to an analytical laboratory and stored for extended periods.
Recovery was found to be between 60% and 100% (Ex. 5-003). The painters
also reported that, perhaps because of the sampling in progress, work on
the study days was much slower than usual. This may have resulted in
measured values lower than usual levels

Welch et al. (Ex. 5-104) conducted semen, hematologic, and fertility
studies for the entire study population, 94 painters and 55 nonexposed
controls. The workers supplied information on demographic
characteristics, medical conditions, personal habits, and reproductive
history and underwent a physical examination. The questionnaire elicited
basic demographic information and information about medical conditions
and personal habits that have been reported to effect semen parameters,
including smoking, alcohol consumption, caffeine consumption,
medications, radiotherapy or chemotherapy, recent febrile illness, past
history of mumps, and genitourinary conditions. Each participant was
asked about his work history and hobbies. He was asked if he and his
wife ever had difficulty conceiving a child, whether he ever saw a
physician for this problem, and the physician\'s diagnosis

A sample of blood was obtained for a complete blood count (CBC), and for
determination for serum follicular stimulating hormone (FSH),
luteinizing hormone (LH) and testosterone. Urine samples were obtained
from each painter at the beginning and end of each sampling period.
These samples were frozen and transported to the NIOSH laboratories for
analysis for the alkoxyacetic acid metabolites of 2-ME and 2-EE

Semen samples were collected from 73 of the painters and 40 controls to
determine whether 2-EE and 2-ME affects the reproductive potential of
exposed men. Semen samples were analyzed for pH, volume, turbidity,
liquidity , viability, sperm density and count per ejaculate, motility,
morphology and morphometry

The proportion of men with a sperm density\< 20 million/cc was higher in
the exposed group than in the unexposed group, 13.5% (10 painters) vs.
5% (2 controls) (p=0.12). The authors noted

**\[page 15543\]**

that the proportion found in the controls, 5%, was in agreement with
population surveys of sperm density. When oligospermia (deficiency in
number of sperm) is defined as a sperm count per ejaculate\< 100
million, 33% (24 painters) and 20% (18 controls) were oligospermic
(p=0.20). The rate of oligospermia was analyzed separately for smokers
and non-smokers. Among the non-smokers, the exposed group had a higher
rate of oligospermia (p=0.05). When smoking was controlled, the odds
ratio calculated for a decreased count per ejaculate among the painters
was 1.85, with a 95% confidence interval of 0.6 - 5.6

Because of the regular rotation of painters from one job to another at
the shipyard, the painters could not be classified into dose groups.
Because of the cyclical nature of spermatogenesis the authors stated
that exposure from two to six months prior to semen analysis was likely
to have produced an effect at the time of the study, and it was not
possible to determine each man\'s job and exposure at that time.
Therefore, the researchers assumed that all the painters had the same
exposure

Painters were also exposed to two other substances that have been
reported in the past to affect semen quality, lead and epichlorohydrin.
Lead is known to cause a depression of sperm count

The mean lead levels of the 45 men who had been monitored for lead were
mostly below 20 ug/deciliter(dl), and the highest single level in any
individual was 40 ug/dl. The authors stated that this level of lead
exposure has not been documented to cause a depressed count.
Epichlorohydrin was not detected in air sampling during the study

The authors thus concluded that exposure to the ethylene glycol ethers
2-EE and 2-ME lowered sperm count in this group of painters. The authors
pointed out that this finding is consistent with the effect seen in
animal studies. Studies in several species show that these glycol ethers
cause loss of germinal epithelium and testicular atrophy. Cellular
studies show that this effect occurs by inhibition of cell division in
the early pachytene stage of spermatogenesis, an effect that would be
expected to result in a decreased count rather than an effect on
motility or morphology

Welch and Cullen (Ex. 5-102) undertook a cross- sectional clinical
appraisal of a sample of painters and unexposed workers to evaluate the
relationship between measurements of peripheral blood of the workers and
ethylene glycol ether exposure. The study of hematologic function
included : a complete blood count, a manual differential count of 200
cells, and a manual platelet count. In addition, each subject\'s past
medical record from the employer\'s medical department was requested,
including routine blood counts and whole blood levels. Complete records
were obtained for two-thirds of the subjects

The authors reported that the only other compounds known to be toxic to
bone marrow or circulating blood cells that painters at the shipyard
were exposed to, in addition to ethylene glycol ethers, were lead and
benzene. Lead exposure was limited to abrasive blasting operations; the
highest lead level detected during brushing or cleaning operations was
10 ug/m3. Sampled levels during blasting were as high as 11 mg/m3.
Painters engaged in blasting use air-supplied respirators and their
blood lead was routinely monitored. Forty-five of 94 painters were
categorized by the employer as \"lead exposed\" and were participating
in the routine blood testing; only nine of the forty-five men had a mean
lead level greater than 15 ug/dl, and only two had a mean greater than
20 ug/dl, with the highest at 30 ug/dl. The highest single value was 40
ug/dl

Paints or cleaning solutions containing more than 1% benzene have not
been used in the shipyard sine 1977. Ten air samples for benzene were
obtained by NIOSH during the 1978 survey; levels of 0.08 to 0.53 mg/m3
were detectable in eight samples. None of the bulk samples of paints or
cleaning solutions in the current industrial hygiene survey revealed any
benzene. Mean hemoglobin levels did not differ between the painters
(15.43 g/dl + 1.09 S.D.) and controls (15.67 g/dl + 0.84); p=0.14 in a
two-tailed test. Additionally, there were no statistically significant
correlations between hemoglobin and cumulative exposure measured as
years painting at the shipyard

The hemoglobin data were rank ordered and analyzed by the Wilcoxon rank
order test. There was no significant difference in rank for the entire
group. However, when only those study subjects in the lowest quartile
for hemoglobin were included in the analysis, the majority of low values
were in painters (p=0.028)

Using an a priori standard for anemia in working age adult males of less
than 14 grams hemoglobin/dl blood, nine of the 147 subjects with
adequately coded data were below this cutoff; all nine were painters.
The past medical records of the shipyard for the anemic painters were
reviewed; complete medical records were available on 7 of the 9. Normal
hemoglobins were noted on hire in four of the seven anemic men with
available records. In a fifth, the initial hemoglobin of 13.8 g/dl had
dropped steadily to 12 at the time of the study. For the two men for
whom there were no preemployment blood counts, their hemoglobins were
compared to those of the respondents of the National Health and
Nutrition Examination Survey of the same age, sex, and race, and found
to be less than the 10th percentile. In the remaining two, hemoglobins
were 13.1 and 13.7 g/dl on hire, comparable to those found during the
study. After eliminating these two, whose values did not change since
first employed, the rate of anemia is significantly different between
painters and controls (p= 0.04). Two of the anemic painters also had an
abnormal semen analysis; one was oligospermic, and one was
azoospermic(lack of sperm)

Total polymorphonuclear leukocyte (PMN) count was calculated by
multiplying the total white count by the percentage PMNs in the
differential count. The mean values did not differ significantly between
the two groups (painters, 4,602 cell/ul + 2,041 S.D.; controls,4,650 +
1,771). A lower limit of 1,800 cells/ul was used to define \"normal\"
and \"abnormal\" groups of painters and controls. The lowest total
counts were found among painters; five, or 3.4% of the painters had
values below 1,800 cell/ul, whereas none of the controls had such low
levels (p=0.07)

The authors concluded that the differences in hematologic values seen
between the groups of painters and the unexposed controls is significant
and that preexisting host factors or rates of participation are not able
to explain their results. Welch and Cullen concluded that an analysis of
other exposures demonstrates that the difference is attributable to
ethylene glycol ethers. They added that the absence of a significant
effect on the group as a whole and the inability to detect a
dose-response pattern, make strong conclusions unwarranted. The authors
called for further research on hematologic effects of these compounds in
human populations

In summary, although limited in part by confounding exposures to other
solvents, data among workers exposed to 2-ME and 2-EE have exhibited
anemia, reduced white and red blood cell counts, bone marrow injury and
reduced sperm counts. In some cases these effects were observed at
levels which were reportedly below those of the current permissible
exposure limits for 2-ME and 2-EE. These findings support the strong
body of experimental animal evidence, which show, in

**\[page 15544\]**

several species, that 2-ME and 2-EE induce adverse hematologic,
reproductive and developmental effects

G. Mutagenicity

Studies in general indicate a lack of mutagenic potential for 2-ME and
2-EE. Mutagenicity is the ability to induce genetic mutation, i.e., a
change in the genetic material. Mutations may give rise to developmental
effects in cases where the genetic material of the egg or the sperm has
been changed such as to induce abnormal development in the fetus.
(Mutations may also give rise to cancer. However, there are substances
which may be carcinogenic which are not mutagenic. The carcinogenicity
of these glycol ethers has not been tested.)

2-ME and 2-EE have been tested in various tests including Ames tests,
unscheduled DNA synthesis(UDS) assays in human embryo fibroblasts,
sister chromatid exchange (SCE) tests in hamster ovary cells, cytogenic
analyses in rat bone marrow cells, dominant lethal tests in rats, sperm
abnormality tests in mice and sex linked recessive (SLR) tests in fruit
flies. (Exs. 5-022, 5-056 and 5-076)

Neither 2-ME nor 2-EE induced effects in either the Ames test or UDS
assays. 2-EE did induce chromosomal abnormalities in SCE tests. The
authors stated that the positive findings in 2-EE are in contrast to the
general negative findings in most mutagenic assays. Thus the authors
concluded that it may be premature to classify these substances as
mutagenic. In the SLR assays 2-EE was found to be negative while
inconsistent results were observed for 2-ME. Positive results were
observed for 2-ME in the sperm abnormality and dominant lethal tests.
For example, 2-ME induced abnormal sperm head morphology and a reduction
in male rat fertility. While the dominant lethal test showed a decrease
in male fertility, the authors raised the possibility that the reduction
in fertility could also be attributed to reduced sperm number rather
than a dominant mutation

Thus, the majority of the available data indicates that 2-ME and 2-EE
lack mutagenic potential. However the presence of positive findings
raise the possibility that these substances may have some weak mutagenic
potential. No mutagenicity testing has been conducted with 2-MEA or
2-EEA, but the metabolic data discussed earlier suggest that all four
compounds are metabolized by similar pathways and are thus likely to
induce similar effects. Thus the results observed for 2-ME and 2-EE are
predictive of mutagenic potential in their respective acetates

H. Conclusions

Health effects data from experimental animal studies clearly and
consistently show that 2-ME, 2-EE and their acetates produce dose
related adverse hematologic, reproductive and developmental effects.
These effects include testicular damage, reduced fertility, maternal
toxicity, early embryonic death, external, skeletal and visceral
malformations, delayed development, and adverse effects on the blood

Evidence also indicates that both inhalation and dermal exposures are
significant routes of exposure for glycol ethers and the induction of
adverse effects. In addition persons occupationally exposed to 2-ME and
2-EE through inhalation and dermal exposures have exhibited adverse
reproductive and hematologic effects. Although not as extensive, in
major part due to methodological limitations, the human data are
nevertheless highly consistent with and supportive of the strong body of
data in experimental animals showing adverse hematologic, reproductive
and developmental effects

I. Other Glycol Ethers

Past research on the health effects of glycol ether compounds has
primarily been concentrated on 2-ME and 2-EE as these two compounds and
their acetates have represented a major percentage of the industrial use
of glycol ethers

Although less extensive there is also research on other glycol ether
compounds. Much of the concentration in this area has been on
substitutes for 2-ME and 2-EE such as 2- Butoxyethanol and the propylene
glycol ethers (e.g., propylene glycol monomethyl ether and its acetate)

1\. 2-Butoxyethanol (2-BE)

In a series of experiments Carpenter et al (Ex. 5-146) exposed various
animal species (e.g., rats, guinea pigs and mice) to 2-BE by inhalation.
Groups of rats and guinea pigs were exposed for 7 hours/day, 5 days/week
for 30 days at doses of 54, 107, 203, 314 or 432 ppm (rats) and doses of
54, 107, 203 376, or 494 ppm (guinea pigs). Significant increases in
osmotic fragility in red blood cells was observed in rats at doses of
107 ppm 2-BE and higher. Osmotic fragility was also observed at 54 ppm
when doses were administered daily for 30 days. No statistically
significant evidence of osmotic fragility was observed among the guinea
pigs at any of the doses tested. Mice were exposed to exposed 7
hours/day for 30, 60 or 90 days to 100, 200 or 400 ppm. No controls were
included. Osmotic fragility was observed at all doses tested

Hematologic analyses were also conducted by Tyl et al.(Ex. 4-152) on
pregnant rats and rabbits exposed to 2-BE by inhalation. Rabbits and
rats were exposed to 0, 25, 50, 100 or 200 ppm 2-BE on days 6-18
(rabbits) and days 6-15 (rats) of gestation. Red blood cell counts,
hemoglobin and hematocrit were analyzed in blood samples from both
pregnant rats and rabbits. In rats osmotic fragility of red blood cells
were not detected at any of the tested doses. However, significant
reductions in red blood cell count and mean corpuscular hemoglobin
concentration were observed at both 200 and 100 ppm. Mean cell volume
and hemoglobin were significantly increased at 200 and 100 ppm. The only
significantly treatment related effects observed among rabbits were
increases in hemoglobin content and hematocrit at 100 ppm. However these
same blood effects were not observed at 200 ppm

Dodd et al. (Ex. 5-050) performed acute, 9-day and 13 week inhalation
studies in rats to investigate the toxicity of 2-BE. In the acute study
rats were exposed for 4 hours to target concentrations of 200, 500 and
850 ppm 2-BE. The acute 4 hour LC50 was 486 ppm for males and 450 ppm
for females. Rats exposed to 500 and 850 ppm exhibited loss of
coordination. Post mortem examinations of these animals revealed red
stained urine and kidney damage. Rats exposed to 200 ppm appeared
normal. In the 9-day study rats were exposed 6 hours/day to 0, 25, 100
and 250 ppm 2-BE. At 250 ppm rats exhibited significant decreases in red
blood cell count and hemoglobin concentration. SSignificant effects in
the blood were also observed among rats in the 100 ppm exposure group.
However the authors stated that the effects were less profound. No
statistically significant adverse hematological effects were observed
among the rats exposed to 25 ppm. In the 13 week study, rats were
exposed to 0, 5, 25 or 75 ppm 2-BE, 6 hours/day, 5 days a week for 13
weeks. At 75 ppm female rats exhibited significant decreases in red
blood cell count and hemoglobin concentration and increases in mean
corpuscular hemaglobin after 6 weeks of exposure. However by the end of
the study these decreases had either lessened or returned to controls
levels. Male rats exposed at 75 ppm showed a significant decrease only
in red blood cell count. No other dose related effects were observed
among male or female rats. In particular there were no alterations in
testes weight among males exposed to 2-BE, nor were any lesions observed

**\[page 15545\]**

which would have been indicative of a testicular effect.

A similar lack of testicular effect after exposure to 2-BE was noted by
Nagano et al. (Ex. 4-135). In this study mice were orally exposed to
500, 1000, or 2000 mg/kg body weight of 2-BE, 5 days/week for 5 weeks.
Animals exposed at 2000 mg/kg died. Decreases in red blood cell count
were observed among both the 1000 and 500 mg/kg exposure groups. However
males at 100 and 500 mg/kg 2-BE did not exhibit any statistically
changes in testicular weight. This observation was in contrast to
results from this same study which showed marked testicular degeneration
after exposure to 2-ME, 2-EE and their acetates

Doe (Ex. 4-112) studied the testicular effects of single high dose
exposures to 2-BE, in addition to examining the effects of 2-ME and
2-EE. Rats were exposed for 3 hours to single high doses of 2-BE (800
ppm), 2-ME (7500 ppm), or 2-EE (3500 ppm) and then were followed for 14
days. 2-ME and 2-EE significantly induced testicular atrophy however no
significant reduction in testes weight were seen among the 2-BE exposed
rats

Similar comparative analyses were performed by Foster et al (Ex. 5-052).
However in this study the metabolites of 2-BE, 2-ME and 2-EE were
administered rather than the parent glycol ethers. Male rats were
exposed by gavage to single oral doses of butoxyacetic acid (0, 174, 434
or 868 mg/kg), methoxyacetic acid (0, 118, 296, or 595 mg/kg) or
ethoxyacetic acid (0, 137, 342, or 684 mg/kg). No statistically
significant evidence of testicular toxicity was observed at any of the
test doses for butoxyacetic acid whereas both methoxy- and ethoxyacetic
acid were found to significantly decrease testicular weight (at all
doses for 2-ME and at high doses only for 2-EE). As a part of this same
study in vitro testicular cell cultures were exposed to the above
metabolites to investigate the effects on testicular germ cells. Adverse
effects in spermatocytes were observed after administration of methoxy-
and ethoxyacetic acids. For example, MAA and EAA produced an enhancement
of germ cell loss from Sertoli cell cultures. In contrast no specific
effects such as those that were observed after administration of
butoxyacetic acid

The developmental effects of 2-BE were studied by Tyl et al (Ex. 4-152).
Pregnant rats and rabbits were exposed to either 0, 25, 50 100 or 200
ppm 2-BE for 6 hours/day on days 6-15 (rats) or days 6-18 (rabbits) of
gestation. Signs of maternal toxicity were observed in rats at 100 and
200 ppm (e.g., significant reductions in body weight, food consumption
and absolute and relative organ weights). A significant increase in the
number of resorbed litters, a significant decrease in the number of
viable implantation per litter and a significant reduction in skeletal
ossification were also observed after exposure to 200 ppm 2- BE. No
significant increases in the incidence of malformations were observed at
any doses among the rats

In rabbits, increases in resorptions and reduced body weight gain were
observed at 200 ppm however these effects were not statistically
significant. Significant reductions in the number of viable implants
were observed at 200 ppm. No evidence of statistically significantly
increased incidences of malformations were found among any of the
exposed rabbits. The authors concluded that 2-BE induced maternal and
fetotoxic effects but not teratogenic effects

No significant increases in maternal or developmental effects of 2-BE
were observed by Nelson et al (Ex. 5-091). In this study pregnant rats
were exposed to 0, 150, or 200 ppm 2-BE for 7 hours/day on days 7-15
gestation. These levels were chosen as earlier findings reported death
at doses from 250 to 500 ppm 2-BE. The only significant adverse effect
observed was \"slight\" hematuria among the maternal animals after the
first day of exposure. Otherwise, no other significant maternal or
developmental adverse effects were observed. Effects examined included
resorptions, fetal weights and incidence of malformations. These
findings are in contrast to results of this same study in which 2-ME and
2-EE were shown to induce adverse maternal and developmental effects

Dermal application of 2-BE has also shown a similar lack of maternal or
developmental effect. Hardin et al (Ex. 5-073) exposed pregnant rats by
dermal application to 0.35 mL 2-BE, four times daily on days 9-13 of
gestation. Deaths occurred through the third and seventh days of
exposure. Only one of the 11 rats treated survived. Therefore, tests
were repeated at 0.12 mL, four times daily. No significant adverse
maternal or developmental effects were observed at this exposure dose

In the recent final Air Contaminants standard (54 FR 2332) OSHA revised
the Permissible Exposure Limit (PEL) for 2-BE from 50 ppm to 25 ppm.
OSHA concluded that, \[T\]he former PEL of 50 ppm was insufficiently
protective against the risk of 2-butoxyethanol\'s irritant,
hematological, and other potential systemic effects, which constitute
material health impairments. The limit of 25 ppm included in the final
rule will reduce this significant risk to a level below that at which
these toxic effects have been observed in animals and humans. This lower
limit will also prevent the discomfort experienced by workers at
exposure levels of 40 ppm. (Air Contaminants Final Rule, 54 FR 2554)

In 1990 NIOSH published a Criteria Document for 2-BE and its acetate,
2-BEA (Ex. 5-145). NIOSH reported that data from animals indicate that
2-BE and 2-BEA do not cause adverse reproductive or development effects.
However they report that the animal evidence shows that these substances
do induce marked adverse effects on the blood. Based on the adverse
blood effects observed in animals, NIOSH recommended occupational
exposure limits of 5 ppm for both 2-BE and 2-BEA

2\. Propylene Glycol Ethers

The production of propylene glycol ethers is analogous to that of
ethylene glycol ethers. Ethylene glycol ethers are made by reacting
ethylene oxide and the appropriate alcohol. Propylene glycol ethers are
produced by reacting propylene oxide with the appropriate alcohol. As
such the propylene and ethylene glycol ethers are structurally
analogous. For example, ethylene glycol monomethyl ether (2-ME) is
structurally very similar to propylene glycol monomethyl ether. However
despite some structural similarities, differences in toxicities have
been observed between the two general types of compounds

For example, in a series of experimental studies Hanley et al. (Exs.
5-068 and 4-120) compared the developmental effects of 2-ME and
propylene glycol monomethyl ether (2- PGME). In studies on 2-ME (Ex.
4-120) rats and rabbits were exposed to 0, 3, 10, or 50 ppm 2-ME, 6
hours/day on days 6- 15 and days 6-18 of gestation respectively. In
rabbits, exposure at 50 ppm 2-ME resulted in a significant decrease in
maternal body weight gain, a significant increase in resorption rates
and significant increases in major malformations. Increased resorption
rates were also observed at 10 ppm compared to concurrent controls, but
because the resorption rates were not statistically different from
historical control values, the authors did not consider the effects to
be dose related. Rats did not show any signs of maternal toxicity after
exposure to 50 ppm. However fetuses from this exposure group exhibited a
significant increase in the incidence in lumbar spurs and delayed
ossification. Neither rats nor rabbits had any other significant adverse
effects at 10 or 3 ppm. In comparison,

**\[page 15546\]**

Hanley et al.( Ex. 5-068) exposed rats and rabbits to 0, 500, 1500 or
300 ppm 2-PGME to similar periods of gestation for 6 hours/day. At 3000
ppm both rats and rabbits exhibited maternal effects including central
nervous system depression and a significant decrease in body weight
gain. No significant maternal effects were observed at 1500 or 500 ppm
for either species. Neither rats nor rabbits exhibited any significant
increase in resorption rates or major malformations at any of the dose
levels tested. It was noted by the authors that a significant increase
in malformations among rat fetuses at 3000 ppm was observed compared to
concurrent controls. However this increase was similar to historical
control values and thus was not considered to be dose related. The only
significant effect observed, delayed sternebral ossification, was
observed at 3000 ppm in rats. This result was interpreted by the authors
to be an indication of slight fetotoxicity

Miller et al. (Ex. 5-088) also compared the toxicities of 2-ME and
2-PGME in rats and rabbits. Rats and rabbits were exposed to 0, 30, 100
or 300 ppm 2-ME or 0, 300, 1000 or 5000 ppm 2-PGME, 6 hours/day for 13
weeks. Exposure to 300 ppm 2-ME induced testicular degeneration,
decreased sperm count, decreased white blood cell counts and decreased
hemoglobin concentrations. No significant effects were observed among
the 100 or 30 ppm exposure groups. In contrast, no significant effects
on testes weight or blood were observed among rats or rabbits exposed to
2-PGME at any dose tested. The authors attributed the difference in
toxicity to differences in metabolism. The authors noted that 2-ME is a
primary alcohol and has been shown to be metabolized by an alcohol
dehydrogenase mediated pathway to methoxyacetic acid. In addition
methoxyacetic acid is considered to be the active metabolite in the
induction of reproductive and developmental toxicity. In contrast, 2-
PGME is a secondary alcohol and is metabolized by microsomal enzymes to
propylene glycol. The authors concluded that this difference in
metabolism is most likely to be responsible for the differing toxicities
of 2-ME and 2-PGME

However Miller et al. (Ex. 5-093) have also noted that there are two
isomeric forms of 2-PGME; the alpha isomer (which is a secondary
alcohol) and the beta isomer (which is a primary alcohol). Because of
their differences in structure the two isomers are metabolized
differently. The alpha isomer is metabolized by microsomal enzymes to
propylene glycol and the beta isomer is metabolized by the
alcohol/aldehyde dehydrogenase pathway to 2-methoxypropionic acid. The
beta isomer follows a metabolic pathway similar to that of the ethylene
glycol ethers, 2-ME and 2-EE, which are also primary alcohol glycol
ethers. Thus it was postulated that the beta isomer may have toxic
properties different from its alpha isomer and may possibly be more
similar to ethylene glycol ethers. These conclusions are supported by
studies by Merkle et al. (Ex. 5-092) on the pure beta isomer of 2-PGME
Acetate. In this study pregnant rats were exposed to 0, 110, 550 or 2700
ppm 2-PGME Acetate and pregnant rabbits were exposed to 0, 36, 145 or
550 ppm 2-PGME Acetate. In rats, exposure to 2700 ppm resulted in a
significant increase in the number of litters with skeletal anomalies
(e.g., dumbbell shaped notches of the thoracic vertebrae). A slight, but
significant, decrease in fetal body weight was also noted at 2700 ppm.
No significant effects were observed at the lower test doses. Rabbits
however showed a more sensitive response. At 550 ppm, all fetuses
exhibited severe malformations (e.g., heart defects and anomalies of the
paw and sternum). No significant increases in malformations were
observed at other tested doses. It was concluded from these results that
the beta isomer of the 2-PGME Acetate has teratogenic potential. By
analogy, the beta isomer of its parent glycol ether, 2-PGME was also
considered to have teratogenic potential

While the beta isomers of the propylene glycol ethers appear to have
teratogenic potential Miller et al. (Ex. 5- 093) also note in their
metabolic study that the commercial product of 2-PGME is usually a
mixture of the two isomers, with the alpha isomer accounting for up to
95% of the mixture. In its comment on the ANPR, the ARCO Chemical
Company, a primary producer of propylene glycol ethers, has also stated
that 2-PGME and its acetate routinely contain less than 2% of the beta
isomer (Ex. 7-19). These types of commercial products were used by
Miller et al. (Ex. 5-088) and Hanley et al. (Ex. 5-068) in their
reproductive and developmental studies and were shown to have a low
degree of biological activity in comparison to ethylene glycol ethers

3\. Ethylene Glycol Monopropyl Ether (EGPE)

Katz et al. (Ex. 5-085) conducted a series of acute and subchronic
toxicity tests on EGPE and its acetate EGPEA in rats. In single dose
oral studies rats were exposed to 1090, 2180, 4360, 8720 mg/kg
(EGPE&EGPEA) or 17,470 mg/kg (EGPEA only). The LD50 of EGPE and EGPEA
were observed to be 3089 and 9456 mg/kg, respectively. Prior to death
animals exhibited weakness, anorexia and hemoglobinuria. In single
inhalation dose studies rats were exposed to target concentrations of 0,
250, 100 or 200 ppm EGPE and 0, 250, 500 or 100 pp, EGPEA. No lethality
was observed at any dose, therefore the LC50 was concluded to be greater
than 2132 ppm for EGPE and greater than 934 ppm for EGPEA. In six week
oral studies male rats were exposed to 0, 195, 390, 780 or 1560 mg/kg
body weight EGPE or 0, 1097, 2193, or 4386 mg/kg EGPEA. Adverse blood
effects (e.g., significant decreases in hemoglobin concentration and
significant increases in platelet counts and nucleated red blood cells)
were observed for both compounds at all dose levels. However, only rats
exposed to EGPEA at 4386 mg/kg exhibited significant decreases in
testicular weight. Pathological examinations revealed atrophy of the
seminiferous tubules and degenerated sperm. In the two week inhalation
studies both male and female rats were exposed for 6 hours/day to either
0, 100, 200, 400, 800 ppm EGPE or 0, 100, 200, 400 or 800 ppm EGPEA.
Slight, but significant changes in red blood cells (e.g., decreased
count, and increased corpuscular volume) were observed at 800 and 400
ppm for both compounds. Hemoglobinuria was observed in males and females
at 800 ppm EGPE and males only at 400 ppm. Both males(4 out of 5) and
females(5 out of 5) exhibited hemoglobinuria after exposure to 400 and
200 ppm EGPEA. A significant increase in spleen weights were observed at
800 and 400 ppm for both compounds. No significant changes in testicular
weight were observed for either compound. Based on these results the
authors concluded that the NOELs in this study were 200 ppm for EGPE and
100 EGPEA

Krasavage and Katz (Ex. 5-070) studied the developmental toxicity of
EGPEA. In this study pregnant rats were exposed to 100, 200, 400 or 800
ppm EGPEA, 6 hours/day on days 6-15 gestation. Exposure to 800 and 400
ppm resulted in decreases in mean maternal body weight, feed intake, and
red blood cell counts. Exposure at 800 ppm also resulted in a
significant increase in the incidence in resorptions and a significant
reduction in mean fetal body weight. No significant increases in
theincidence of major malformations were observed among fetuses exposed
up to 800 ppm. The authors stated that a significant increases in the
incidence of minor skeletal effects (e.g., wavy,

**\[page 15547\]**

knobby, fused and partially ossified ribs and decreased ossification of
the skull) were observed at 800 and 400 ppm. A significant increase in
rudimentary ribs was observed in the 200, 400 and 800 ppm exposure
groups. The authors concluded that adverse fetal effects occur after
exposure to EGPEA. However they stated that these effects occurred only
after doses which were overtly toxic to the maternal animal (i.e., 800
and 400 ppm)

4\. Di-Ethylene Glycol Monomethyl Ether (DEGME)

In inhalation studies by Miller et al. (Ex.5-058) male and female rats
were exposed to 0, 30, 100 or 216 ppm DEGME, 6 hours/day, five days/week
for 13 weeks. No dose related significant effects were observed among
the male or female animals for any of the doses tested. Based on the
lack of effects the authors concluded that DEGME is unlikely to present
the same degree of hazard as its structural homolog 2-ME

The teratogenic potential of DEGME was examined by Scortichini et al.
(Ex. 5-060). In this study pregnant rabbits were exposed by dermal
application to 0, 50, 250 or 750 mg/kg day of DEGME on days 6-18
gestation. Rabbits exposed at 750 mg/kg exhibited a significant decrease
in maternal weight gain and red blood cell counts. No statistically
significant maternal effects were observed at 250 or 50 mg/kg/day. The
authors noted an increase in resorptions at 750 mg/kg/day, although this
effect was not statistically significantly different from controls. In
addition no statistically significant increases in major malformations
were observed at any of the doses tested. A significant increase in
minor skeletal defects such as forelimb flexure, fused ribs, delayed
ossification, forked ribs and cervical spurs were observed among litters
from rabbits exposed to 250 and 750 mg/kg DEGME. The authors considered
these to be significant signs of fetotoxicity rather than teratogenicity
and suggested that these types of fetal defects might be associated with
maternal toxicity

5\. Ethylene Glycol Monophenyl Ether (2-Phenoxyethanol)

Scortichini et al (Ex. 5-059) have also examined the teratogenic
potential of 2-Phenoxyethanol. Pregnant rabbits were dermally exposed to
0, 300, 600 or 1000 mg/kg/day of 2- Phenoxyethanol on days 6-18
gestation. Nine of 25 rabbits died after exposure to 1000 mg/kg/day and
5 of 25 rabbits died after exposure to 600 mg/kg/day. Death was
attributed to intravascular hemolysis. The animals surviving in these
groups showed no statistically significant treatment related effects. In
addition no statistically significant signs of maternal toxicity were
observed after exposure to 300 mg/kg/day. Among fetuses examined, there
were no statically significant increases in the incidence of external,
visceral or skeletal malformations at 300 or 600 mg/kg/day. (Fetal
observations were not available at 1000 mg/kg/day due to the high
lethality at 1000 mg/kg. Animals were sacrificed with no further
observations. In addition, no other reproductive parameters such as
resorptions or fetal body measurements were adversely affected at 600 or
300 mg/kg/day. Based on these results the authors concluded that doses
up to 600 mg/kg/day produced no significant signs of developmental
toxicity

6\. Conclusions

The available data for other glycol ether compounds suggests that there
are differential toxicities between the longer chain glycol ethers and
shorter chain glycol ethers such as 2-ME, 2-EE and their acetates. For
example, in the case of 2-butoxyethanol, there were observations of
adverse hematological effects but no observations of adverse
reproductive or developmental effects. Similarly for propylene glycol
ethers there was little evidence of any reproductive or developmental
toxicity except in the case of the beta isomeric forms of these
compounds. There are scattered reports on other ethylene glycol ether
compounds showing adverse hematological effects and, in some cases,
slight evidence of testicular effects and minor skeletal defects. In
some studies the authors have suggested that defects observed in some of
the fetuses may be due to maternal toxicity rather than a direct effect
on the conceptus. However, as discussed earlier, developmental effects
observed at maternally toxic doses do not necessarily imply that the
developmental effects are secondary to maternal effects

In general, the toxicities of these compounds appear less potent than
those of shorter chain glycol ethers. The results from toxicity tests on
other glycol ethers strongly contrast with the evidence observed after
exposures to 2-ME and 2-EE. The evidence on 2-ME and 2-EE clearly and
consistently show reduced sperm count, decreased fertility, testicular
degeneration, early fetal death, major external, visceral and skeletal
malformations, delayed development and functional deficiency. These
effects have been observed in several species and through various routes
of exposure. The totality and consistency of the evidence on 2-ME, 2-EE
and their acetates in experimental animals, clearly indicate that these
agents are potential reproductive and developmental toxins in humans.
However, OSHA reiterates that past research primarily concentrated on
2-ME, 2-EE and their acetates. The lack of evidence on other glycol
ethers may be due, in part, because less research has been conducted on
these compounds. Thus, OSHA requests data and analyses on other glycol
ethers and their potential reproductive and developmental toxicity

VI\. Preliminary Risk Assessment

A. Introduction

The United States Supreme Court, in the \"benzene\" decision, Industrial
Union Department, AFL-CIO v. American Petroleum Institute, 448 U.S. 607
(1980), has ruled that the OSH Act requires that, prior to the issuance
of a new standard, a determination must be made, based on substantial
evidence in the record considered as a whole, that there is a
significant risk of health impairment at existing permissible exposure
limits and that issuance of a new standard will significantly reduce or
eliminate that risk. The Court stated that \"before he can promulgate
any permanent health or safety standard, the Secretary is required to
make a threshold finding that a place of employment is unsafe in the
sense that significant risks are present and can be eliminated or
lessened by a change in practices.\" 448 U.S. 642. The Court also stated
\"that the Act does limit the Secretary\'s power to require the
elimination of significant risks.\" 448 U.S. 644

Although the Court in the \"cotton dust\" case, American Textile
Manufacturers Institute v. Donovan, 452 U.S. 490 (1981), rejected the
use of cost-benefit analysis in setting OSHA standards, it reaffirmed
its previous position in \"benzene\" that a risk assessment is not only
appropriate, but also required to identify significant health risk to
workers and to determine if a proposed standard will achieve a reduction
in that risk. Although the Court did not require OSHA to perform a
quantitative risk assessment in every case, the Court implied, and OSHA
as a matter of policy agrees, that assessments should be put into
quantitative terms to the extent possible

The extent to which a risk assessment may be put in quantitative terms
is limited in the case of glycol ethers. This is not because there are
no data suitable for assessing the risk. On the contrary, there are a
number of well conducted rodent bioassays which clearly demonstrate the
adverse health effects

**\[page 15548\]**

associated with exposure to glycol ethers (see the discussion of health
effects above). The problem lies in the fact that there is not a
quantitative model for extrapolating the risk of developmental and
reproductive effects either from high doses to low doses or across
species, that is generally accepted in the scientific community.
Therefore, unlike other risk assessments which OSHA has prepared in the
past, this risk assessment will be far more qualitative than
quantitative and will closely follow the guidelines of the Environmental
Protection Agency for assessing the risks of suspect developmental and
reproductive toxicants (Ex. 5-153) to determine those levels of
occupational exposure to the glycol ethers below which significant risk
of adverse health outcomes is unlikely. This approach, which is
described in detail in the following sections, is one that has been
generally accepted in both the scientific and regulatory communities and
is generally accepted as the best methodology for assessing the risks
associated with reproductive and developmental toxins

Risk assessment is a process in which scientific judgments are made
concerning the potential for toxicity to occur in humans. Because human
data are often not available, the risk assessment process often requires
the use of models to extrapolate experimental data to humans. These
models may be quantitative or qualitative. Quantitative models generally
involve mathematical descriptions of dose-response relationships which
allow one to calculate numerical estimates of potential risk for a given
exposure. Qualitative models, on the other hand, rely more on narrative
descriptions of dose-response relationships to describe the likelihood
of an adverse effect for a given exposure. However both approaches are
based on scientific judgments and scientifically based assumptions about
dose response relationships and the predictive value of experimental
data

The scientific and regulatory communities have chosen a preference for
quantitative models especially in the case of carcinogens. However the
scientific and regulatory communities also consider qualitative models
as an acceptable means of extrapolating animal data to humans. The No
Observed Effect Level-Uncertainty Factor (NOEL-UF) approach, described
herein, is such a qualitative model

As a matter of policy, OSHA has chosen to use the NOEL- UF approach in
describing the risks associated with exposure to glycol ethers. OSHA has
chosen to use this qualitative approach because it is the most generally
well accepted approach for assessing the risks from reproductive and
developmental toxins. OSHA\'s decision to use the NOEL-UF approach is
based on agreement in the scientific community that this approach is the
best methodology currently available for assessing reproductive health
risks. This approach, in addition to its general acceptance in the
scientific community, is also the methodology that has been consistently
used by both EPA and FDA to assess reproductive health risks in their
rulemaking procedures. As such it represents the best evidence available
to OSHA for making its risk determinations. However while this is a
policy choice it should be kept in mind that OSHA\'s decision to use the
NOEL-UF approach is a scientifically informed choice that is supported
by scientific expertise and judgment. The selection of the NOEL-UF
approach, as well as the steps involved in the process (e.g., the
selection of the size of uncertainty factors to extrapolate from animals
to humans) are choices based on underlying scientific data and
assumptions to account for certain basic scientific uncertainties and
are not choices borne solely from a public health perspective to provide
a safe workplace in the face of scientific uncertainty

B. Assessing the Risk of Developmental and Reproductive Effects

Most OSHA risk assessments have focused on the risk of cancer from
occupational exposure to toxic substances. In the case of carcinogen
risk assessment, mathematical models are fit to dose-response data, and
the fitted models are used to make predictions of risk at a variety of
doses. Although there are a number of mathematical models available to
fit to carcinogen dose-response data, within the risk assessment
community in general, and the regulatory community in particular, a
consensus exists as to which are the \"best\" models

In the case of non-carcinogen risk assessment, no such generally
accepted mathematical models exist for predicting risks. The traditional
approach to assessing the risk of non-cancer effects has been first to
make a qualitative determination that a toxic substance poses a risk of
inducing an adverse effect and then to determine the level of exposure
below which that adverse effect is unlikely to be induced in humans
using an uncertainty or safety factor approach

This approach is relatively simple. It is most often applied to
experimental (animal) data, but it can be applied to epidemiological
data when such data are available. The first step in this approach is to
determine whether an effect occurs in each exposure group at a rate
which is statistically significantly elevated over the rate at which the
effect occurs in the unexposed or control group. The highest exposure
level which does not induce the effect at a statistically significantly
elevated rate is called the no observed effect level or NOEL. In its
most recent guidelines (Ex. 5-153), the EPA uses the term NOAEL or no
observed adverse effect level instead of NOEL, to make clear that
effects being considered are of toxicological significance. For purposes
of this document, NOEL is synonomous with NOAEL. The lowest exposure
level which does induce the effect at a statistically significantly
elevated rate is called the lowest observed effect level or LOEL. (EPA
also refers to this level as the LOAEL or Lowest Observed Adverse Effect
Level. Again, for purposes of this document, LOEL and LOAEL are
synonomous.) In this approach the NOEL is usually the value of interest,
but a substance may induce an effect at a statistically significantly
elevated rate at each exposure level under study. In that case, the LOEL
becomes the value of interest. Determination of the NOEL and/or the LOEL
is the purpose of this first step

The next step in this approach is to divide the NOEL or, in the absence
of a NOEL, the LOEL by an uncertainty factor. Choice of the uncertainty
factor will depend, in part, upon whether one uses the NOEL or the LOEL,
and this is discussed at greater length below. The value NOEL

Uncertainty Factor is termed the \"acceptable daily intake\" or ADI and
is considered to represent the level of exposure at which humans are
unlikely to experience an adverse effect. (OSHA notes that for purposes
of this document, the ADI is not to be interpreted as a regulatory
limit, but rather as a health-based level upon which regulatory
considerations can be referenced.)

Although this approach requires only two steps, each step introduces
uncertainty as to whether the final ADI estimate does indeed represent
an exposure level below which an adverse effect is unlikely to be
induced. Implicit in the uncertainty factor approach is the assumption
that there is a threshold level of exposure below which a toxic

**\[page 15549\]**

response will not be induced, and the NOEL is an estimate of that
threshold. There is debate, however, as to whether non-cancer effects,
in particular developmental effects, are indeed threshold phenomena.
Brent, for example, has argued that teratogenesis \"is by and large a
threshold phenomena, which means that the vast majority of teratogenic
agents have a \'no effect\' dose.\" (Ex.5-126). He cites thalidomide as
an example of a developmental toxin which if administered at 50 mg
during the critical gestation period can effect a majority of embryos
but which will have no effect on the development of embryos administered
at 0.5 mg during the same period

Others, however, maintain that not all developmental toxins have a
threshold. Gaylor et al argue that \"if a chemical produces a
malformation by different mechanism than spontaneous malformations, then
there is a possibility for a threshold dose. However, if a chemical
produces a malformation by augmenting or accelerating an already
existing mechanism that produces spontaneous malformations, then no
population threshold can exist\" (Ex. 5-128). Rodricks et al maintain
that \"in cases in which the mechanisms of toxic or carcinogenic action
are not understood, it is not possible to establish or reject the
threshold hypothesis or no-threshold hypothesis, at least with the
degree of certainty usually sought in scientific proof. There are
numerous reasons to believe that thresholds must exist . . ., but
generalization to all agents and all effects is not possible\" (Ex.
5-130)

In its comments in response to OSHA\'s Advance Notice of Proposed
Rulemaking (ANPR), the Chemical Manufacturer\'s Association (CMA) argues
that acceptance of the existence of thresholds is central to evaluating
reproductive and developmental risk (Ex. 7-17). CMA bases its position
in part on the \"demonstrated regenerative, repair and regulation
abilities of an embryo and fetus.\" In addition, CMA notes that fetuses
are protected by maternal placenta and the metabolic processes of the
pregnant female that break down, excrete, store, or otherwise inactivate
chemicals before they can damage the embryo. CMA concludes that \"to
make appropriate decisions about potential human reproductive risks,
OSHA must focus its attention on studies that determine the threshold
below which adverse effects on the adult or the conceptus will not
occur\" (Ex. 7-17)

While OSHA believes it is likely that most chemically- induced
developmental effects have a threshold, it would seem that CMA is
confusing the finding of a NOEL in an animal bioassay with the certainty
a threshold exists. As noted by Rodricks et al, the existence of a NOEL
from experimental data is consistent with the hypothesis of a threshold
but is not sufficient to prove it (Ex. 5-130). Furthermore, if a
threshold does exist, there is little reason to believe that the NOEL is
indeed the threshold as CMA implies. The exposure level at which no
effect is observed is not only a function of the potency of the
substance under test but also a function of the experimental design of a
study. For example, an exposure level which is not tested cannot be a
NOEL. If a researcher tests a substance at 10, 25, and 50 ppm, then the
NOEL can only be 10, 25, or 50 ppm. As noted by Rodricks et al,
\"\[f\]or practical reasons, only a few doses can be used in
experimental studies. While these doses may fall above and below the
true threshold doses, it is only by chance that any will precisely match
the true threshold doses (and this chance is very small).\"

The exposure level found to be the NOEL in a study, (and the exposure
level found to be the LOEL in a study), will depend not only upon the
exposure levels chosen by a researcher but also upon the numbers of
animals in each exposure group. This is because exposure group size is
an important factor in determining whether an observed excess of an
effect is statistically significant. For example, suppose an experiment
is run, and an effect is found to occur in 20% of the animals in the
unexposed group. If there are 15 animals in each exposure group, then
60% of the animals exposed at some level X, (9 out of 15), must
experience the effect in order to find that level X is the LOEL (i.e.
60% is the lowest rate at which the effect can occur in order to be
statistically significantly elevated at the p=0.05 level over the 20%
rate in the unexposed animals using a Fisher\'s Exact Test). If level X
induces the effect in only 8 of the 15 exposed animals, then the rate
for the effect in this exposure group will not be statistically
significant

If, in the example above, the number of animals in each exposure group
were larger, then the proportion of exposed animals which must
experience the effect to achieve statistical significance over the 20%
rate in the unexposed group decreases. Thus, if there were 30 animals in
each exposure group, then only 43.3% of the animals exposed to some
level Y, (13 out of 30), must experience the effect in order to find
that level Y is the LOEL. If there were 1000 animals in each exposure
group, then only 23.2% of the animals exposed to some level Z, (232 out
of 1000), must experience the effect in order to find that level Z is
the LOEL

It is clear from this example that the exposure levels determined to be
the NOEL and LOEL will depend on study group size. The \"true\" NOEL may
be lower than the NOEL determined for a particular study, but the study
may not be sensitive enough to detect it. Few studies employ 1000
animals per group in their study design, and thus the direction of
uncertainty due to sample size is towards overestimating the NOEL and
LOEL; a response rate which is statistically significant for a small
number of study animals will always be statistically significant for any
larger number of animals

Because small exposure group size and therefore lack of statistical
power can lead to the erroneous conclusion that exposure induces no
effect, the NOEL is not taken by itself to represent the \"acceptable
daily intake\" (ADI). Instead, the NOEL is adjusted by an uncertainty
factor not only to account for uncertainties associated with the
experimental design but also to account for uncertainties associated
with extrapolation across species (i.e. from experimental animals to
humans) and to account for the variability of responses within a human
population (i.e. intra-species variability)

In their chapter on risk assessment for effects other than cancer,
Rodricks et al provide a brief history of the origins of the uncertainty
factor (Ex. 5-130). Referring to uncertainty factors as safety factors,
these authors write:

The safety factor approach was originated by Lehman and Fitzhugh of the
FDA who indicated that variability in sensitivity to chemicals
(expressed as differences in dose causing similar responses) across
several species was usually in the range of two or threefold and did not
appear to exceed tenfold. They also indicated that the variability among
extensively outbred individuals and individuals of all ages and degrees
of susceptibility (e.g., persons in the general population) appeared
also to be less than one order of magnitude. They consequently founded
the 100-fold safety factor as a general method of dealing with the
uncertainties of extrapolation. This incorporated a factor of 10 when
extrapolating from animals to humans and an additional factor of 10 to
account for differential sensitivities within the human population. When
this 100-fold safety factor is applied to the highest experimental
animal NOEL, it is considered to approximate a NOEL for humans in the
general population, and becomes the ADI.

**\[page 15550\]**

Since the concept of uncertainty factors was first introduced, it has
been modified to derive an ADI from data of varying quality. For
example, the FDA has expanded the original 100-fold uncertainty factor
approach. When a NOEL is derived from subchronic animal data but that
NOEL has been identified in two species, then the FDA recommends an
uncertainty factor of 1000. Here, the additional factor of 10 is needed
to account for the added uncertainty in estimating a chronic ADI from
subchronic data. When a NOEL is derived from subchronic animal data but
that NOEL has been identified in only one species, FDA recommends an
uncertainty factor of 2000. The additional two-fold factor is intended
to account for possible interspecies differences (Ex. 5-130)

If a NOEL can not be identified from study data, that is, if the lowest
exposure level used in a study induces an effect at a rate statistically
significantly greater than observed among the unexposed group, then the
uncertainty factor is applied to the LOEL instead of the NOEL to derive
the ADI. As with the NOEL, the uncertainty factor applied to the LOEL is
used to account for the uncertainties and variability described above,
but EPA recommends that an additional uncertainty factor, usually
between one and 10, be used to account for the fact that no NOEL was
identified from the data (Ex. 5-131)

Although the selection of uncertainty factors in the multiples of ten
may appear to be arbitrary, there is some experimental support for their
selection, and this is discussed at some length in an article by Dourson
and Stara (Ex. 4-113). (The scientific basis underlying the selection
and use of uncertainty factors is further discussed in OSHA Exhibit
5-155.) In addition, these choices of uncertainty factors as well as the
entire uncertainty factor approach for non-cancer health effects have
been adopted by a number of governmental agencies and international
organizations including the U.S. Environmental Protection Agency (EPA),
the U.S., Food and Drug Administration (FDA), the Joint Food and
Agricultural Organization of the World Health Organization (FAO/WHO),
and the National Academy of Sciences (NAS). The uncertainty factor
approach for regulating occupational exposure to glycol ethers is
supported by many of the commentors responding to OSHA\'s ANPR including
CMA (Ex. 7-17), DOW Chemical (Ex. 7-21), and Du Pont (Ex. 7-28), among
others, although not all agree on the value of the uncertainty factor
which should be used

As CMA points out in its comments, the uncertainty factor approach \"has
been well established for regulating reproductive risks\" (Ex. 7-17). As
noted above, the ADI represents an exposure level below which an adverse
effect is unlikely, and confidence that the ADI is an exposure level
below which an adverse effect is unlikely will depend, to a large
extent, upon the quality of the data from which it is derived. If we
know something of the mechanism which induces an effect and if we know
that that mechanism is activated when exposure exceeds some threshold
level, then our confidence that an adverse effect is unlikely at
exposures levels at or below the ADI increases further

C. Assessment of the Developmental Risk from Exposures to Glycol Ethers

1\. Introduction

According to the EPA Guidelines for Developmental Toxicity Risk
Assessment (Ex. 5-153), the major manifestations of developmental
toxicity include 1) death of the developing organism; 2) malformations;
3) altered growth, and 4) functional deficiency. The studies used by
OSHA for its assessment of developmental risk from glycol ethers
employed a protocol exposing fetuses in utero during organogenesis, the
phase of gestation during which the major organ systems develop. The
pregnant dams were sacrificed at the end of this gestational phase and
prior to giving birth. Each of the unborn fetuses was then examined.
Under this protocol the endpoints of interest in these studies are the
first three of the outcomes listed above

The endpoint \"death of the developing organism\" includes resorptions
and intra-uterine deaths. Pre- implantation loss is not a measure of
developmental toxicity in these studies because the pregnant females
were not exposed to any glycol ether until after implantation had
occurred

A malformation is usually defined as a permanent structural change that
may adversely affect survival, development, or function. A malformation
is different than a variation which is usually defined as a divergence
beyond the usual range of structural constitution that may not adversely
affect survival or health. It is not always possible, however, to
distinguish between variations and malformations because, as noted by
EPA in its Guidelines, \"there exists a continuum of responses from the
normal to extreme deviant.\" Furthermore, there is no generally accepted
classification of malformations. Other terminology which is also used
includes anomalies, deformations, and aberrations, but, as EPA points
out, these terms are no better defined. Nonetheless, these effects
indicate toxicity to the developing organism when associated with
exposure to a chemical

Altered growth is defined by EPA as an alteration in offspring organ or
body weight or size. This endpoint may be reversible or may result in a
permanent change

As noted by the Interagency Regulatory Liaison Group (IRLG) in its
Workshop on Reproductive Toxicity Risk Assessment, \"the developmental
toxicity endpoints encountered in experimental animals do not and should
not be expected necessarily to mimic those observed in humans exposed to
the same toxicant\" and \"the specific agent-related endpoints in humans
are not always reproduced in experimental animals\" (Ex. 5-018). All
substances known to cause developmental effects in humans, however, have
also been found to induce developmental effects in animals with the
exception of the coumarin anticoagulants which have not been studied
extensively in animals (Ex. 4-147). Schardein has compared the effects
of all \"known or possible\" teratogens in humans with the teratogenic
responses observed in laboratory animals exposed to these substances
(Ex. 4-147). Each of the developmental toxicants he looked at induced
some developmental effect in at least one animal species, but only one
class of substances, androgenic hormones, induced the same effect as
observed in humans in each species which experienced an effect.
Androgenic hormones have been tested in fourteen species, and only one
species tested, sheep, experienced no effect

The more common result in cross-species testing of developmental
toxicants can be found in the case of thalidomide which was found to
induce limb defects (i.e. missing limbs) in humans. In laboratory
animals, the drug was found to induce developmental effects in seventeen
species, but an effect concordant to the effect observed in humans was
observed in only nine species. Furthermore, eight of these nine species,
the rhesus monkey, the marmoset, the baboon, the bonnet monkey, the
crab-eating monkey, the green monkey, the Japanese monkey, and the
stump-tailed monkey, are not the usual animals used in animal bioassays.
The rabbit was the sole rodent species to exhibit an effect concordant
to the effect observed in humans (Ex. 4-147)

The IRLG has noted that there is \"no evidence that any particular
species or

**\[page 15551\]**

strain more consistently predicts human susceptibility to animal
teratogens than any other species or strain \"(Ex. 5-018). This is borne
out by Schardein (Ex. 4-147). He found that the rabbit, which
experienced an effect from thalidomide concordant to the effect induced
humans, experienced no adverse developmental effects from alcohol or
diethylstilbestrol (DES), both known to cause birth defects in humans.
The mouse experienced effects concordant to those in humans for a number
of substances including alcohol, diethylstilbestrol, and antithyroid
compounds, but neither aminopterin nor streptomycin, substances found to
induce developmental effects in humans, induced any developmental
effects in this species. Rats experienced adverse developmental effects
from exposure to most of the toxicants considered by Schardein, (rats,
and mice were the most commonly used animals in tests of the toxicants
considered by Schardein), but the effects were concordant with those in
humans in only little more than half the substances and at least one
substance considered by Schardein, trimethadione, induced no effect in
this species

The response to a developmental toxicant in animal bioassay can be
measured in a number of ways. One of these is the number of fetuses
affected per number of fetuses exposed. This shall be referred to as the
\"fetus measure of response\". While this measure gives some indication
of the potency of a developmental toxicant, it treats each fetus
independently of all other fetuses thereby ignoring the \"litter
effect\". The litter effect is the tendency for littermates to respond
more like each other than like animals from different litters.
Furthermore, the fetus measure cannot distinguish between the case where
all litters have one or two affected fetuses and the case where all
affected fetuses are from only one or two litters, although these two
scenarios have different implications for the potency of a developmental
toxicant

An alternative measure of response is number of litters with at least
one affected fetus per total number of litters exposed, referred to as
the \"litter measure of response\". This measure treats the litters as
the experimental unit because, as noted by EPA in its Guidelines, it is
the maternal animal and not the conceptus which is treated during
gestation (Ex. 5-153). This is the measure of response favored by EPA
for evaluating the potency of a developmental toxicant. The drawback to
this measure, however, is that it gives equal weight to a litter with
one affected fetus as it gives to a litter with all affected fetuses

In addition to both of these measures, a third measure which OSHA has
considered for evaluating response in animals exposed to developmental
toxicants is average number of fetuses affected per affected litter.
This shall be referred to as the \"fetus/litter measure of response\".
This measure provides a compliment to the fetus measure of response and
the litter measure of response, for, whereas the former indicates only
the number of fetuses affected and the latter indicates only the number
of litters affected, the fetus/litter measure provides an indication of
how severe an effect may be within an affected litter. For example, a
fetus/litter value of 1.0 would indicate that only one fetus was
affected in each of the affected litters. A fetus/litter value of 2.0
would indicate that on average, two fetuses were affected in each of the
litters with affected fetuses. Comparison of fetus/litter values across
exposure groups would allow one to determine whether more fetuses were
affected in each affected litter as dose increases. The limitation of
this measure, however, is that unlike the other two measures discussed
above, the fetus/litter measure of response has utility only as a
descriptive measure and can not be used for statistical inference
because the statistical distribution of this measure is unknown

2\. Choice of Data

a\. 2-ME

OSHA has identified three well conducted animal bioassays for 2-ME which
are suitable for assessing the risk of developmental effects from
occupational exposure to this glycol ether and for determining the
acceptable daily intake or ADI. (As noted earlier for purposed of this
document,the ADI is not a regulatory limit but rather a health-based
level which describes the level at which humans are unlikely to exhibit
effects similar to those obseved in experimental data.) These studies
were chosen because in each of these studies, exposure levels were
documented, the routes of exposure were the same as is found in most
occupational settings (i.e. inhalation), concurrent controls were used,
two or more exposure levels of the test substance were employed,
statistically significant excesses of developmental

**\[page 15552\]**

effects were observed in exposed groups, and individual litter data were
available

Hanley and associates of the Dow Chemical Company conducted three animal
inhalation bioassays for 2-ME using female rats, rabbits, and mice (Exs.
4-042a and 4-106). Groups of 30 to 31 bred Fisher 344 rats and 20 to 30
bred New Zealand white rabbits were exposed to 2-ME at levels of 3, 10,
or 50 ppm. Groups of 30 to 32 bred CF-1 mice were exposed to 2-ME at
levels of 10 or 50 ppm. The test article was supplied by Dow and was
99.96% pure. Thirty bred rats, 30 bred rabbits, and 31 bred mice served
as controls

The female rats were bred one to one with male rats of the same strain.
The female mice were bred two to one with male mice of the same strain
(two females to one male), and the rabbits were bred through artificial
insemination. Animals were randomly assigned to exposure groups.
Exposure occurred six hours per day through the organogenesis phase of
gestation: from day 6 through day 15 of gestation for rats and mice and
from day 6 through day 18 gestation for rabbits. All animals were given
food and water ad libitum except during periods of exposure and were
observed daily throughout the experimental period for indications of
toxicity and adverse effects of treatment

Animals found dead or moribund during the course of the study were
submitted for gross pathological examination. Surviving mice were
sacrificed on day 18 of gestation, surviving rats were sacrificed on day
21 of gestation, and surviving rabbits were sacrificed on day 29 of
gestation. Caesarean sections and examinations were preformed on all
animals to determine: (1) the number and position of fetuses in utero;
(2) the number of live and dead fetuses; (3) the number and position of
resorption sites; (4) the sex, and body weight, and crown-rump length of
each fetus; and (5) any gross external alternations. In addition, the
rats and the rabbits were examined for number of corpora lutea. The
uteri of apparently non-pregnant animals were stained and examined for
evidence of implantation sites to determine whether pregnancy had
occurred. One half of each litter was dissected and examined for soft
tissue alternations. All fetuses were examined for skeletal alternations

b\. 2-EE

OSHA has identified two well conducted animal inhalation bioassays for
2-EE which are suitable for assessing the risk of developmental effects
from occupational exposure to this glycol ether and for determining the
acceptable daily intake or ADI. As with 2- ME, both of these studies
were chosen because in each, exposure levels were documented, the routes
of exposure were the same as is found in most occupational settings
(i.e. inhalation), concurrent controls were used, two or more exposure
levels of the test substance were employed, statistically significant
excesses of developmental effects were observed in exposed groups, and
individual litter data were available

Tinston, Doe and associates of Imperial Chemical Industries PLC
conducted two animal inhalation studies for 2-EE using rats and rabbits
(Exs. 4-038 and 4-039; see also Ex. 5-071). These studies were sponsored
by the Chemical Manufacturer\'s Association (CMA) and followed a
protocol similar to the one used by Hanley et al. Groups of 24 bred rats
of the Alpk/AP (Wistar-derived) strain were exposed to 2-EE at levels of
10, 50, or 250 ppm. Groups of 24 bred Dutch rabbits were exposed to 2-EE
at levels of 10, 50, and 175 ppm. The test article was supplied by
Imperial Chemical Industries and was more than 99% pure. Twenty-four
bred rats and 24 bred rabbits served as controls

The female rats were bred one to one with male rats of the same strain,
and female rabbits were bred with 2 male rabbits of the same strain.
Animals were randomly assigned to exposure groups. Exposure occurred six
hours per day throughout the organogenesis phase of gestation: from day
6 through day 15 of gestation for the rats and from day 6 through day 18
of gestation for the rabbits. All animals were given food and water ad
libitum except during periods of exposure and were observed daily for
their clinical condition

Terminal sacrifice of the animals occurred on day 21 of gestation for
the rats and day 29 of gestation for the rabbits. After sacrifice, the
number of corpora lutea in each animal\'s ovaries was counted. The
uterus of each animal was cut open and the number of implantations as
well as the number of early and late intra-uterine deaths was
determined. An intra-uterine death was judged to be late if fetal
tissues were distinguishable. Each fetus which had not died in utero was
removed from the uterus. These fetuses were weighed and examined for
gross defects. Half of the rat fetuses and all of the rabbit fetuses
were examined for skeletal defects. All fetuses of both species were
examined for external and visceral defects

3\. Bioassay Results

a\. 2-ME

In measuring the incidence of effects of 2-ME in fetal rats, rabbits,
and mice, Hanley et al grouped the effects into three categories:
external alterations, soft tissue alterations, and skeletal alterations.
Each of these categories of defects was subdivided further into major
defects and minor defects. The study authors provided no explanation as
to the criteria used to subdivide these categories, and one must assume
it was professional judgement (Exs. 4-047 and 4-106)

Table VI-A presents the incidence of developmental effects in fetal rats
exposed to 2-ME. Incidence is reported using each of the measures of
response discussed above (i.e. fetus, litter and fetus/litter). The only
effects presented in this discussion are those which occurred in any
exposed group at a rate statistically significantly greater than the
rate in the unexposed group at the p=0.05 level using either the fetus
measure of response or the litter measure of response. Statistical
significance was determined using Fisher\'s Exact Test

  --------------- -------------- ----------- ----------- ----------- -----------
  Table VI-A                                                         

  Incidence of                                                       
  Developmental                                                      
  Effects                                                            

  Observed in                                                        
  Fisher 344 Rats                                                    

  Exposed to 2-ME                                                    
  Days 6 through                                                     
  15 of Gestation                                                    
  (1)                                                                

  MINOR SKELETAL                                                     
  ALTERATIONS                                                        

  \--                            Control     3 ppm       10 ppm      50 ppm

                  Fetus (2)      4/287       3/283       6/293       19/307(3)

  Delayed                                                            

  Ossification    Litters (4)    4/29        3/28        5/28        13/30(5)

  of Centra                                                          

                  Fetus/Litter   1.00        1.00        1.20        1.46
                  (6)                                                

                  Fetus          18/287      13/283      20/293      57/307(3)

  Rib Spurs       Litters        12/29       10/28       13/28       26/30(3)

                  Fetus/Litter   1.50        1.30        1.54        2.19

                  Fetus          125/287     131/293     97/307(3)   
                                 142/283                             

  Delayed                                                            

  Ossification    28/29          27/28       27/28       28/30       
  Litters                                                            

  of Sternebrae                                                      

  Fetus/Litter    4.46           5.26        4.85        3.40        
  --------------- -------------- ----------- ----------- ----------- -----------

1 - Data from Hanley et al, Ex. 4-042a.

2 - Incidence is number of fetuses affected divided by the total number
of fetuses

3 - Significantly different than controls at the p\< .01 level

4 - Incidence is number of litters with at least one fetus affected

5 - Significantly different than controls at the p\< .05 level

6 - Average number of affected fetuses per affected litter

Delayed ossification of the centra and rib spurs are the two
developmental effects which occurred at a rate statistically
significantly greater in an exposed group than in the controls. Both of
these effects were classified as minor skeletal alterations. Both
effects were elevated for the 50 ppm group only, but incidence was
significant at the p=0.012 level or lower regardless of measure of
response, and the fetus/litter measure of response increases with dose.
Delayed ossification of the sternebra was significantly reduced for the
50 ppm group when measured using the fetus measure of response, but it
was not significant using the litter measure of response and the
fetus/litter measure does not show a dose related trend. The authors
attribute the observed deficit of delayed ossification of the sternebra
to normal variation and not to exposure to 2-ME

Table VI-B presents the incidence of developmental effects in fetal
rabbits exposed to 2-ME. The same measures of incidence presented for
the rats are presented for the rabbits,and the same statistical criteria
were used for inclusion of an effect in the table

**\[page 15553\]**

  ----------------- ----------------- ----------- ----------- ------------ -----------
  Table VI-B                                                               

  Incidence of                                                             
  Developmental                                                            
  Effects Observed                                                         
  in New Zealand                                                           

  White Rabbits                                                            
  Exposed to 2-ME                                                          
  Days 6 through 18                                                        
  of Gestation (1)                                                         

                                                                           

                                      Control     3 ppm       10 ppm       50 ppm

                                                                           

  Resorptions:                        7/180       14/186      23/210(3)    46/191(3)
  Fetus(2)                                                                 

                    Litters(4)        5/23        10/24       14/24(5)     16/24(3)

                    Fetus/Litter(6)   1.40        1.40        1.64         2.88

  MAJOR EXTERNAL                                                           
  ALTERATIONS(7)                                                           

  Arthrogryposis:                                                          

                    Fetus             0/173       1/172       0/187        54/145(3)

                    Litters           0/23        1/23        0/24         15/22(3)

                    Fetus/Litter      0.00        1.00        0.00         3.60

  Anonychia:                                                               

                    Fetus             0/173       0/172       0/187        14/145(3)

                    Litters           0/23        0/23        0/24         6/22(3)

                    Fetus/Litter      0.00        0.00        0.00         2.33

  Brachydactyly:                                                           

                    Fetus             0/173       0/172       0/187        6/145(3)

                    Litters           0/23        0/23        0/24         4/22(5)

                    Fetus/Litter      0.00        0.00        0.00         1.50

  Ectrodactyly:                                                            

                    Fetus             0/173       0/172       0/187        6/145(3)

                    Litters           0/23        0/23        0/24         4/22(5)

                    Fetus/Litter      0.00        0.00        0.00         1.50

  Omphalocele:                                                             

                    Fetus             0/173       0/172       0/187        5/145(5)

                    Litters           0/23        0/23        0/24         2/22

                    Fetus/Litter      0.00        0.00        0.00         2.50

  Thinning of                                                              
  Adominal Wall:                                                           

                    Fetus             0/173       0/172       0/187        6/145(3)

                    Litters           0/23        0/23        0/24         3/22

                    Fetus/Litter      0.00        0.00        0.00         2.00

  Kinky Tail:                                                              

                    Fetus             0/173       0/172       0/187        4/145(5)

                    Litters           0/23        0/23        0/24         4/22(5)

                    Fetus/Litter      0.00        0.00        0.00         1.00

  MINOR EXTERNAL                                                           
  ALTERATIONS                                                              

  Misalignment of                                                          
  Palatine Rugae:                                                          

                    Fetus             0/173       0/174       0/187        27/145(3)

                    Litters           0/23        0/23        0/24         11/22(3)

                    Fetus/Litter      0.00        0.00        0.00         2.45

  Narrowed tip of                                                          
  Tail:                                                                    

                    Fetus             0/173       0/172       0/187        6/145(3)

                    Litters           0/23        0/23        0/24         6/22(3)

                    Fetus/Litter      0.00        0.00        0.00         1.00

  MAJOR SOFT TISSUE                                                        
  ALTERATIONS f                                                            

  Coarctation of                                                           
  the Aortic Arch:                                                         

                    Fetus             0/95        0/93        0/101        13/80(3)

                    Litters           0/23        0/23        0/24         6/22(3)

                    Fetus/Litter      0.00        0.00        0.00         2.17

  Ventricular                                                              
  Septal Defect:                                                           

                    Fetus             0/95        0/93        0/101        34/80(3)

                    Litters           0/23        0/23        0/24         15/22(3)

                    Fetus/Litter      0.00        0.00        0.00         2.27

  Hypoplastic                                                              
  Spleen:                                                                  

                    Fetus             0/95        0/93        0/101        25/80(3)

                    Litters           0/23        0/23        0/24         13/22(3)

                    Fetus/Litter      0.00        0.00        0.00         1.92

  Dilated Renal                                                            
  Pelvis:                                                                  

                    Fetus             0/95        1/93        1/101        28/80(3)

                    Litters           0/23        1/23        1/24         14/22(3)

                    Fetus/Litter      0.00        1.00        1.00         2.00

  Patent Ductus                                                            
  Arteriosis:                                                              

                    Fetus             0/95        1/93        0/101        5/80(5)

                    Litters           0/23        1/23        0/24         4/22(5)

                    Fetus/Litter      0.00        1.00        0.00         1.25

  Hypoplastic Gall                                                         
  Bladder:                                                                 

                    Fetus             0/95        0/93        0/101        4/80(5)

                    Litters           0/23        0/23        0/24         4/22(5)

                    Fetus/Litter      0.00        0.00        0.00         1.00

  Pale Spleen:                                                             

                    Fetus             4/95        2/93        1/101        30/80(3)

  **\[page                                                                 
  15554\]**                                                                

                    Litters           1/23        1/23        1/24         16/22(3)

                    Fetus/Litter      4.00        2.00        1.00         1.88

  Dilated Ureter:                                                          

                    Fetus             0/95        0/93        0/101        7/80(3)

                    Litters           0/23        0/23        0/24         6/22(3)

                    Fetus/Litter      0.00        0.00        0.00         1.17

  Convoluted                                                               
  Ureter:                                                                  

                    Fetus             3/95        2/93        0/101        12/80(3)

                    Litters           2/23        2/23        0/24         8/22(5)

                    Fetus/Litter      1.50        1.00        0.00         1.50

  Paroavarian Cyst:                                                        

                    Fetus g           0/48        1/47        1/53         9/40(3)

                    Litters h         0/23        1/21        1/24         8/22(3)

                    Fetus/Litter      0.00        1.00        1.00         1.13

  Testicular Cyst:                                                         

                    Fetus g           0/47        0/46        0/48         5/40(5)

                    Litters i         0/22        0/23        0/23         3/22

                    Fetus/Litter      0.00        1.00        1.00         1.13

  Shortened Nasals,                                                        
  Maxillae and                                                             
  Mandibles:                                                               

                    Fetus             0/173       0/172       0/187        6/145(3)

                    Litters           0/23        0/23        0/24         1/22

                    Fetus/Litter      0.00        0.00        0.00         6.00

  MAJOR SKELETAL                                                           
  ALTERATIONS e                                                            

  Missing                                                                  
  Palange(s):                                                              

                    Fetus             0/173       0/172       0/187        7/145(3)

                    Litters           0/23        0/23        0/24         4/22(5)

                    Fetus/Litter      0.00        0.00        0.00         1.75

  Missing                                                                  
  Metacarpal(s):                                                           

                    Fetus             0/173       0/172       0/187        4/145(5)

                    Litters           0/23        0/23        0/24         2/22

                    Fetus/Litter      0.00        0.00        0.00         2.00

  Missing                                                                  
  Metatarsal(s):                                                           

                    Fetus             0/173       0/172       0/187        9/145(3)

                    Litters           0/23        0/23        0/24         4/22(5)

                    Fetus/Litter      0.00        0.00        0.00         2.25

  Shortened Ribs:                                                          

                    Fetus             0/173       0/172       0/187        4/145(5)

                    Litters           0/23        0/23        0/24         2/22

                    Fetus/Litter      0.00        0.00        0.00         2.00

  Enlarged                                                                 
  Interparietals:                                                          

                    Fetus             0/173       0/172       0/187        5/145(5)

                    Litters           0/23        0/23        0/24         1/22

                    Fetus/Litter      0.00        0.00        0.00         5.00

  Delayed                                                                  
  Ossification of                                                          
  the Hyoid:                                                               

                    Fetus             1/173       2/172       2/187        14/145(3)

                    Litters           1/23        2/23        2/24         8/22(3)

                    Fetus/Litter      1.00        1.00        1.00         1.75

  Delayed                                                                  
  Ossification of                                                          
  the Tarsals(s):                                                          

                    Fetus             0/173       3/172       1/187        17/145(3)

                    Litters           0/23        3/23        1/24         8/22(3)

                    Fetus/Litter      0.00        1.00        1.00         2.13

  Extra Lumbar                                                             
  Ribs:                                                                    

                    Fetus             0/173       0/172       0/187        13/145(3)

                    Litters           0/23        0/23        0/24         7/22(3)

                    Fetus/Litter      0.00        0.00        0.00         1.86

  Shortened Lumbar                                                         
  Ribs:                                                                    

                    Fetus             0/173       0/172       0/187        4/145(5)

                    Litters           0/23        0/23        0/24         2/22

                    Fetus/Litter      0.00        0.00        0.00         1.86

  Delayed                                                                  
  Ossification of                                                          
  the Centra:                                                              

                    Fetus             4/173       2/172       0/187        11/145(5)

                    Litters           4/23        2/23        0/24 (5)     
                                                              8/22         

                    Fetus/Litter      1.00        1.00        0.00         1.38

  Delayed                                                                  
  Ossification of                                                          
  the Sternebrae:                                                          

                    Fetus             82/173      93/172      123/187(3)   
                                                              127/145(3)   

                    Litters           23/23       23/23       24/24        22/22

                    Fetus/Litter      3.57        4.04        5.13         5.77

  Fused Sternebrae:                                                        

                    Fetus             3/173       2/172       0/187        11/145(5)

                    Litters           3/23        2/23        0/24         8/22

  **\[page                                                                 
  15555\]**                                                                

                    Fetus/Litter      3.57        4.04        5.13         1.33

  Sternebrae -                                                             
  Extra Site of                                                            
  Ossification:                                                            

                    Fetus             0/173       0/172       0/187        4/145(5)

                    Litters           0/23        0/23        0/24         3/22

                    Fetus/Litter      3.57        4.04        5.13         1.33
  ----------------- ----------------- ----------- ----------- ------------ -----------

1 -Data from Hanley et al, Ex. 4-042a\
2 -Incidence is number of fetuses affected divided by the total number
of fetuses\
3 -Significantly different than controls at the p\< .01 level.\
4 -Incidence is number of litters with at least one fetus affected\
5 -Significantly different than controls at the p\< .05 level.\
6 -Average number of affected fetuses per affected litter.\
7 -Denominator (i.e. the number of animals at risk) is adjusted for
resorptions\
8 -Only a portion of fetuses in each exposure group were examined for
soft tissue alterations.\
9 -Denominator not specified by study authors. Number of fetuses at risk
estimated by applying male/female ratio for each exposure group to
number of fetuses examined for soft tissue alterations\
10 - Denominator is number of litters with at least one female fetus.\
11 - Denominator is number of litters with at least on male fetus.

Incidence of resorptions was statistically significantly increased using
both the fetus and the litter measures of response for the 10 ppm and
the 50 ppm group. The fetus/litter measure of incidence shows a dose
related increase. The study authors note that although resorptions are
significantly elevated for the 10 ppm group, the observed rate for
fetuses (11%) and for litters (58%) are comparable to the historical
incidence of resorptions observed in other studies in the same
laboratory (7% to 15% for fetuses and 38% to 74% for litters). They
attribute the finding of statistical significance of resorptions in this
exposure group to the unusually low control group incidence of
resorptions (4% for fetuses and 22% for litters) and not to exposure

Major external alterations in rabbits occurred at a significant excess
in the 50 ppm group only. Incidence of arthrogryposis (abnormal flexure
of the forelimbs), anonychia (absence of nails), brachydactyly (short
digits), ectrodactyly (absence of part or all of a digit), and kinky
tail occurred at a statistically significantly elevated rate for both
the fetus measure of response and the litter measure of response.
Incidence of omphalocele (protrusion of the intestines through the
abdominal wall), and thinning of the abdominal wall was significant for
fetuses but not for litters

As with the major external alterations, the minor external alterations,
misalignment of the palatine rugae and narrowed tip of tail, occurred at
a significant excess only in the 50 ppm group. Both were statistically
significant using both the fetus and the litter measure of response

What is most striking about these data is that every external alteration
observed, major or minor, was observed only in the 50 ppm group except
for one fetus in the 3 ppm group observed with arthrogryposis. The
almost total absence of background incidence of these effects reduces
the uncertainty as to whether the response in the 50 ppm group could be
attributed to chance variation rather than exposure to 2-ME

While all the fetal rabbits were examined for external alterations, only
half were examined for soft tissue alterations. Thus, the study had less
power to detect this type of developmental effect. Nonetheless, a large
number of soft tissue alterations were observed at a significant excess
in 50 ppm group. Incidence of these effects was not significantly
elevated over controls in any other exposure group. The major soft
tissue alterations were coarctation of the aortic arch, ventricular
septal defect, hypoplastic spleen, and dilated renal pelvis, and
incidence of these effects in the 50 ppm group were statistically
significant using both the fetus and the litter measure of response at
the p=0.009 level or lower. All but one minor soft tissue alteration
occurred at a statistically significant rate in the 50 ppm group using
both measures of response

These alterations were patent ductus arteriosis, hypoplastic gall
bladder, pale spleen, dilated ureter, convoluted ureter, and parovarian
cysts. Testicular cysts were statistically significant in male fetal
rabbits in the 50 ppm group using the fetus measure but not using the
litter measure. Here again, the almost total absence of any of these
effects in the control group, the 3 ppm group, or the 10 ppm group lends
further support to 2-ME as the cause for these effects in the 50 ppm
group

All fetuses were examined for skeletal alterations, yet incidence of all
but two of these alterations was significantly elevated in the 50 ppm
group only. The major skeletal alterations which occurred at a
significantly elevated rate in this group using both measures of
response were missing phalanges and missing metatarsal; the minor
skeletal alterations were delayed ossification of the hyoid, delayed
ossification of the tarsals, and extra lumbar ribs. Incidence of
shortened nasals, maxillae and mandibles and shortened ribs, both major
external alterations, were significantly elevated in the 50 ppm group
also but only when measured in fetuses. Likewise, incidence of enlarged
interparietals, shortened lumbar ribs, delayed ossification of the
centra, fused sternebra, and extra site of sternebra ossification, all
minor external alterations, were significantly elevated in the 50 ppm
group but again, only for the fetus measure of response. There was a
statistically significant deficit of delayed ossification of the centra
in litters in the 10 ppm group, this most likely is attributable to
chance variation and not to exposure. Delayed ossification of the
sternebra was significantly elevated over controls in fetuses in the 10
ppm and the 50 ppm exposure groups, but the incidence of this effect
measured in litters at both exposure levels was the same (100%) as in
the control and 3 ppm exposure group

Exposure to 2-ME did not have as strong an effect in fetal mice as it
did in fetal rabbits. Table VI-C presents the results of the mouse
bioassay. Criteria for inclusion of an effect in the table in the same
as was used for both rats and rabbits. Only one effect, extra lumbar
ribs, a minor skeletal alteration, was significantly elevated using both
the fetus and the litter measure of response, and this was in the 50 ppm
group.

**\[page 15556\]**

Incidences of resorption, hypoplastic testicle, and extra site of
sternebra ossification in the 50 ppm group were significantly elevated
over controls but only in fetuses and not in litters. Incidence of
testicular hemorrhage and delayed ossification of the sternebra was
significantly elevated over controls in the 10 ppm group and the 50 ppm
using the fetus measure of response, but incidence of these effects was
not significant when response was measured in litters

  --------------- -------------- ----------- ----------- --------------------- ----
  Table VI-C                                                                   

  Incidence of                                                                 
  Developmental                                                                
  Effects                                                                      

  Observed in                                                                  
  CF-1 Mice                                                                    

  Exposed to 2-ME                                                              
  days 6 through                                                               
  15 of Gestation                                                              
  (1)                                                                          

                                                                               

                                 Control     10 ppm      50 ppm                

                                                                               

  Resorptions:                                                                 

                  Fetus b        25/342      25/285      35/286(3)             

                  Litters c      16/26       14/23       18/24                 

                  Fetus/Litter d 1.56        1.79        1.94                  

                  MINOR SOFT                                                   
                  TISSUE                                                       
                  ALTERATIONS e                                                

  Hypoplastic                                                                  
  Testicle:                                                                    

                  Fetus f        2/86        3/64        8/66(3)               

                  Litters g      2/26        3/23        6/22                  

                  Fetus/Litter   1.00        1.00        1.33                  

  Testicular                                                                   
  Hemorrhage:                                                                  

                  Fetus f        2/86        3/64        8/66(3)               

                  Litters g      2/26        3/23        6/22                  

                  Fetus/Litter   1.00        1.00        1.33                  

                  MINOR SKELETAL                                               
                  ALTERATIONS h                                                

  Extra Lumbar                                                                 
  Rib:                                                                         

                  Fetus          48/317      49/260      82/251(10)            

                  Litters        14/26       14/23       21/24(3)              

                  Fetus/Litter   3.43        3.50        3.90                  

  Delayed                                                                      
  Ossification of                                                              
  the Sternebrae:                                                              

                  Fetus          76/317      43/260 (3)  77/251(3)             

                  Litters        18/26       13/23       21/24                 

                  Fetus/Litter   3.43        3.50        3.90                  

  Sternebrae -                                                                 
  Extra Site of                                                                
  Ossification:                                                                

                  Fetus          21/317      9/260       8/251(3)              

                  Litters        9/26        6/23        4/24                  

                  Fetus/Litter   3.43        3.50        3.90                  
  --------------- -------------- ----------- ----------- --------------------- ----

\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_

1 - Data from Hanley et al, Ex. 4-106. 2 - Incidence is number of
fetuses affected divided by the total number of fetuses

3 - Significantly different than controls at the p\< .05 level. 4 -
Incidence is number of litters with at least one fetus affected

5 - Average number of affected fetuses per affected litter. 6 - Only a
portion of fetuses in each exposure group were examined for soft tissue
alterations

7 - Denominator not specified by study authors. Number of fetuses at
risk estimated by applying male/female ratio for each exposure group to
number of fetuses examined for soft tissue alterations

8 - Denominator is number of litters with at least on male fetus. 9 -
Denominator (i.e. the number of animals at risk) is adjusted for
resorptions

10 - Significantly different than controls at the p\< .01 level

b\. 2-EE

In their studies of the developmental effects of 2-EE on fetal rats and
fetal rabbits, Tinston, Doe et al, (Exs. 4-038 and 4-039; see also Ex.
5-071), classified effects differently than Hanley et al. Abnormalities
which were deemed either rare or lethal or both were classified as major
external and visceral defects or major skeletal defects while those
defects which were judged to be small changes that would not normally
impair survival and that occur at a moderate to low frequency in the
strain were classified as minor external and visceral defects or minor
skeletal defects. A third classification, variant, was used to describe
those defects which are common in the species and are not normally
deleterious

Another difference between the 2-EE bioassays and the 2-ME bioassays is
that the investigators in the 2-EE bioassays considered much more
specific effects than did the investigators in the 2-ME bioassays. For
example, Tinston et al looked at the degree of ossification (i.e.
partially ossified or not ossified) of each centrum and sternebra in
each fetus examined. Thus, the study authors report the incidence of
partial ossification of the first sternebra, partial ossification of the
second sternebra, and so forth. In the 2-ME bioassays, on the other
hand, Hanley et al grouped any ossification defect of any sternebra into
the category \"delayed ossification of the sternebra\" and any
ossification defect of any centrum into the category \"delayed
ossification of the centra.\" The different approaches for measuring the
incidence of effects have implications for the inferences which can be
drawn from analysis of the study results, and these implications will be
discussed in the next section

Table VI-D presents the incidence of developmental effects in fetal rats
exposed to 2-EE. As with the results from the 2-ME bioassays, incidence
is reported using the fetus, litter, and fetus/litter measures of
response, and only those effects which occurred in any exposed group at
a statistically significantly greater rate than in control using either
the fetus or the litter measure of response are included.

**\[page 15557\]**

Again, statistical significance was determined using Fisher\'s Exact
Test with a critical value of p=0.05.

+----------+-----------+----------+----------+----------+-----------+
| Table    |           |          |          |          |           |
| VI-D     |           |          |          |          |           |
+----------+-----------+----------+----------+----------+-----------+
| I        |           |          |          |          |           |
| ncidence |           |          |          |          |           |
| of       |           |          |          |          |           |
| Devel    |           |          |          |          |           |
| opmental |           |          |          |          |           |
| Effects  |           |          |          |          |           |
+----------+-----------+----------+----------+----------+-----------+
| Observed |           |          |          |          |           |
| in       |           |          |          |          |           |
| Wistar   |           |          |          |          |           |
| Rats     |           |          |          |          |           |
+----------+-----------+----------+----------+----------+-----------+
| Exposed  |           |          |          |          |           |
| to 2-EE  |           |          |          |          |           |
| days 6   |           |          |          |          |           |
| through  |           |          |          |          |           |
| 15 of    |           |          |          |          |           |
| G        |           |          |          |          |           |
| estation |           |          |          |          |           |
| (a)      |           |          |          |          |           |
+----------+-----------+----------+----------+----------+-----------+
|          |           |          |          |          |           |
+----------+-----------+----------+----------+----------+-----------+
|          |           | Control  | 10 ppm   | 50 ppm   | 250 ppm   |
+----------+-----------+----------+----------+----------+-----------+
|          |           |          |          |          |           |
+----------+-----------+----------+----------+----------+-----------+
| All      |           |          |          |          |           |
| Intra    |           |          |          |          |           |
| -uterine |           |          |          |          |           |
| Deaths:  |           |          |          |          |           |
+----------+-----------+----------+----------+----------+-----------+
|          | Fetus (b) | 16/297   | 22/277   | 12/261   | 32/266    |
|          |           |          |          |          | \*\*      |
+----------+-----------+----------+----------+----------+-----------+
|          | Litters   | 12/23    | 15/24    | 10/22    | 12/21     |
|          | (c)       |          |          |          |           |
+----------+-----------+----------+----------+----------+-----------+
|          | Fet       | 1.33     | 1.47     | 1.20     | 2.67      |
|          | us/Litter |          |          |          |           |
|          | (d)       |          |          |          |           |
+----------+-----------+----------+----------+----------+-----------+
| Late     |           |          |          |          |           |
| Intra    |           |          |          |          |           |
| -uterine |           |          |          |          |           |
| Deaths:  |           |          |          |          |           |
+----------+-----------+----------+----------+----------+-----------+
|          | Fetus (e) | 3/284    | 3/258    | 2/251    | 17/251    |
|          |           |          |          |          | \*\*      |
+----------+-----------+----------+----------+----------+-----------+
|          | Litters   | 2/23     | 2/24     | 2/22     | 7/21 \*   |
+----------+-----------+----------+----------+----------+-----------+
|          | Fet       | 1.50     | 1.50     | 1.00     | 2.43      |
|          | us/Litter |          |          |          |           |
+----------+-----------+----------+----------+----------+-----------+
| MINOR    |           |          |          |          |           |
| SKELETAL |           |          |          |          |           |
| A        |           |          |          |          |           |
| NOMALIES |           |          |          |          |           |
| (f)      |           |          |          |          |           |
+----------+-----------+----------+----------+----------+-----------+
| Skull -  |           |          |          |          |           |
| P        |           |          |          |          |           |
| artially |           |          |          |          |           |
| Ossified |           |          |          |          |           |
| F        |           |          |          |          |           |
| rontals: |           |          |          |          |           |
+----------+-----------+----------+----------+----------+-----------+
|          | Fetus     | 1/147    | 0/131    | 4/129    | 14/122    |
|          |           |          |          |          | \*\*      |
+----------+-----------+----------+----------+----------+-----------+
|          | Litters   | 1/23     | 0/24     | 4/22     | 7/21 \*   |
+----------+-----------+----------+----------+----------+-----------+
|          | Fet       | 1.00     | 0.00     | 1.00     | 2.00      |
|          | us/Litter |          |          |          |           |
+----------+-----------+----------+----------+----------+-----------+
| Skull -  |           |          |          |          |           |
| P        |           |          |          |          |           |
| artially |           |          |          |          |           |
| Ossified |           |          |          |          |           |
| P        |           |          |          |          |           |
| arietal: |           |          |          |          |           |
+----------+-----------+----------+----------+----------+-----------+
|          | Fetus     | 10/147   | 1/131    | 15/129   | 35/122    |
|          |           |          | \*\*     |          | \*\*      |
+----------+-----------+----------+----------+----------+-----------+
|          | Litters   | 6/23     | 1/24 \*  | 8/22     | 17/21     |
|          |           |          |          |          | \*\*      |
+----------+-----------+----------+----------+----------+-----------+
|          | Fet       | 1.67     | 1.00     | 1.88     | 2.06      |
|          | us/Litter |          |          |          |           |
+----------+-----------+----------+----------+----------+-----------+
| Skull -  |           |          |          |          |           |
| P        |           |          |          |          |           |
| artially |           |          |          |          |           |
| Ossified |           |          |          |          |           |
| Interp   |           |          |          |          |           |
| arietal: |           |          |          |          |           |
+----------+-----------+----------+----------+----------+-----------+
|          | Fetus     | 26/147   | 3/131    | 24/129   | 40/122    |
|          |           |          | \*\*     |          | \*\*      |
+----------+-----------+----------+----------+----------+-----------+
|          | Litters   | 10/23    | 3/24 \*  | 12/22    | 17/21 \*  |
+----------+-----------+----------+----------+----------+-----------+
|          | Fet       | 2.60     | 1.00     | 2.00     | 2.35      |
|          | us/Litter |          |          |          |           |
+----------+-----------+----------+----------+----------+-----------+
| Skull -  |           |          |          |          |           |
| Odontoid |           |          |          |          |           |
| Not      |           |          |          |          |           |
| O        |           |          |          |          |           |
| ssified: |           |          |          |          |           |
+----------+-----------+----------+----------+----------+-----------+
|          | Fetus     | 26/147   | 19/131   | 32/129   | 93/122    |
|          |           |          |          |          | \*\*      |
+----------+-----------+----------+----------+----------+-----------+
|          | Litters   | 13/23    | 10/24    | 16/22    | 20/21     |
|          |           |          |          |          | \*\*      |
+----------+-----------+----------+----------+----------+-----------+
|          | Fet       | 2.00     | 1.90     | 2.00     | 4.65      |
|          | us/Litter |          |          |          |           |
+----------+-----------+----------+----------+----------+-----------+
| Cervical |           |          |          |          |           |
| centrum  |           |          |          |          |           |
| \# 3 Not |           |          |          |          |           |
| O        |           |          |          |          |           |
| ssified: |           |          |          |          |           |
+----------+-----------+----------+----------+----------+-----------+
|          | Fetus     | 14/147   | 21/131   | 25/129   | 115/122   |
|          |           |          |          | \*       | \*\*      |
+----------+-----------+----------+----------+----------+-----------+
|          | Litters   | 6/23     | 9/24     | 12/22 \* | 21/21     |
|          |           |          |          |          | \*\*      |
+----------+-----------+----------+----------+----------+-----------+
|          | Fet       | 2.33     | 2.33     | 2.08     | 5.48      |
|          | us/Litter |          |          |          |           |
+----------+-----------+----------+----------+----------+-----------+
| Cervical |           |          |          |          |           |
| Centrum  |           |          |          |          |           |
| \# 4 Not |           |          |          |          |           |
| O        |           |          |          |          |           |
| ssified: |           |          |          |          |           |
+----------+-----------+----------+----------+----------+-----------+
|          | Fetus     | 10/147   | 7/131    | 16/129   | 109/122   |
|          |           |          |          |          | \*\*      |
+----------+-----------+----------+----------+----------+-----------+
|          | Litters   | 5/23     | 4/24     | 11/22 \* | 21/21     |
|          |           |          |          |          | \*\*      |
+----------+-----------+----------+----------+----------+-----------+
|          | Fet       | 2.00     | 1.75     | 1.45     | 5.19      |
|          | us/Litter |          |          |          |           |
+----------+-----------+----------+----------+----------+-----------+
| Cervical |           |          |          |          |           |
| Centrum  |           |          |          |          |           |
| #5 Not   |           |          |          |          |           |
| O        |           |          |          |          |           |
| ssified: |           |          |          |          |           |
+----------+-----------+----------+----------+----------+-----------+
|          | Fetus     | 2/147    | 5/131    | 9/129 \* | 98/122    |
|          |           |          |          |          | \*\*      |
+----------+-----------+----------+----------+----------+-----------+
|          | Litters   | 1/23     | 3/24     | 6/22 \*  | 21/21     |
|          |           |          |          |          | \*\*      |
+----------+-----------+----------+----------+----------+-----------+
|          | Fet       | 2.00     | 1.67     | 1.50     | 4.67      |
|          | us/Litter |          |          |          |           |
+----------+-----------+----------+----------+----------+-----------+
| Cervical |           |          |          |          |           |
| Centrum  |           |          |          |          |           |
| #6 Not   |           |          |          |          |           |
| O        |           |          |          |          |           |
| ssified: |           |          |          |          |           |
+----------+-----------+----------+----------+----------+-----------+
|          | Fetus     | 1/147    | 2/131    | 6/129 \* | 84/122    |
|          |           |          |          |          | \*\*      |
+----------+-----------+----------+----------+----------+-----------+
|          | Litters   | 1/23     | 2/24     | 4/22     | 20/21     |
|          |           |          |          |          | \*\*      |
+----------+-----------+----------+----------+----------+-----------+
|          | Fet       | 1.00     | 1.00     | 1.50     | 4.20      |
|          | us/Litter |          |          |          |           |
+----------+-----------+----------+----------+----------+-----------+
| Cervical |           |          |          |          |           |
| Centrum  |           |          |          |          |           |
| #7 Not   |           |          |          |          |           |
| O        |           |          |          |          |           |
| ssified: |           |          |          |          |           |
+----------+-----------+----------+----------+----------+-----------+
|          | Fetus     | 0/147    | 0/131    | 2/129    | 26/122    |
|          |           |          |          |          | \*\*      |
+----------+-----------+----------+----------+----------+-----------+
|          | Litters   | 0/23     | 0/24     | 2/22     | 10/21     |
|          |           |          |          |          | \*\*      |
+----------+-----------+----------+----------+----------+-----------+
|          | Fet       | 0.00     | 0.00     | 1.00     | 2.60      |
|          | us/Litter |          |          |          |           |
+----------+-----------+----------+----------+----------+-----------+
| Thoracic |           |          |          |          |           |
| Centrum  |           |          |          |          |           |
| #8       |           |          |          |          |           |
| P        |           |          |          |          |           |
| artially |           |          |          |          |           |
| O        |           |          |          |          |           |
| ssified: |           |          |          |          |           |
+----------+-----------+----------+----------+----------+-----------+
|          | Fetus     | 0/147    | 0/131    | 0/129    | 6/122     |
|          |           |          |          |          | \*\*      |
+----------+-----------+----------+----------+----------+-----------+
|          | Litters   | 0/23     | 0/24     | 0/22     | 6/21 \*\* |
+----------+-----------+----------+----------+----------+-----------+
|          | Fet       | 0.00     | 0.00     | 0.00     | 1.00      |
|          | us/Litter |          |          |          |           |
+----------+-----------+----------+----------+----------+-----------+
| Thoracic |           |          |          |          |           |
| Centrum  |           |          |          |          |           |
| #9       |           |          |          |          |           |
| P        |           |          |          |          |           |
| artially |           |          |          |          |           |
| O        |           |          |          |          |           |
| ssified: |           |          |          |          |           |
+----------+-----------+----------+----------+----------+-----------+
|          | Fetus     | 0/147    | 1/131    | 0/129    | 7/122     |
|          |           |          |          |          | \*\*      |
+----------+-----------+----------+----------+----------+-----------+
|          | Litters   | 0/23     | 1/24     | 0/22     | 5/21 \*   |
+----------+-----------+----------+----------+----------+-----------+
|          | Fet       | 0.00     | 1.00     | 0.00     | 1.40      |
|          | us/Litter |          |          |          |           |
+----------+-----------+----------+----------+----------+-----------+
| Thoracic |           |          |          |          |           |
| Centrum  |           |          |          |          |           |
| #10      |           |          |          |          |           |
| P        |           |          |          |          |           |
| artially |           |          |          |          |           |
| O        |           |          |          |          |           |
| ssified: |           |          |          |          |           |
+----------+-----------+----------+----------+----------+-----------+
|          | Fetus     | 0/147    | 0/131    | 0/129    | 18/122    |
|          |           |          |          |          | \*\*      |
+----------+-----------+----------+----------+----------+-----------+
|          | Litters   | 0/23     | 0/24     | 0/22     | 12/21     |
|          |           |          |          |          | \*\*      |
+----------+-----------+----------+----------+----------+-----------+
|          | Fet       | 0.00     | 0.00     | 0.00     | 1.50      |
|          | us/Litter |          |          |          |           |
+----------+-----------+----------+----------+----------+-----------+
| Thoracic |           |          |          |          |           |
| Centrum  |           |          |          |          |           |
| #11      |           |          |          |          |           |
| P        |           |          |          |          |           |
| artially |           |          |          |          |           |
| O        |           |          |          |          |           |
| ssified: |           |          |          |          |           |
+----------+-----------+----------+----------+----------+-----------+
|          | Fetus     | 5/147    | 0/131    | 1/129    | 19/122    |
|          |           |          |          |          | \*\*      |
+----------+-----------+----------+----------+----------+-----------+
|          | Litters   | 5/23     | 0/24     | 1/22     | 10/21     |
+----------+-----------+----------+----------+----------+-----------+
|          | Fet       | 1.00     | 0.00     | 1.00     | 1.90      |
|          | us/Litter |          |          |          |           |
+----------+-----------+----------+----------+----------+-----------+
| Thoracic |           |          |          |          |           |
| Centrum  |           |          |          |          |           |
| #12      |           |          |          |          |           |
| P        |           |          |          |          |           |
| artially |           |          |          |          |           |
| O        |           |          |          |          |           |
| ssified: |           |          |          |          |           |
+----------+-----------+----------+----------+----------+-----------+
|          | Fetus     | 2/147    | 1/131    | 4/129    | 17/122    |
|          |           |          |          |          | \*\*      |
+----------+-----------+----------+----------+----------+-----------+
|          | Litters   | 2/23     | 1/24     | 4/22     | 10/21     |
|          |           |          |          |          | \*\*      |
+----------+-----------+----------+----------+----------+-----------+
|          | Fet       | 1.00     | 1.00     | 1.00     | 1.70      |
|          | us/Litter |          |          |          |           |
+----------+-----------+----------+----------+----------+-----------+
| **\[page |           |          |          |          |           |
| 1        |           |          |          |          |           |
| 5558\]** |           |          |          |          |           |
|          |           |          |          |          |           |
| Thoracic |           |          |          |          |           |
| Centrum  |           |          |          |          |           |
| #13      |           |          |          |          |           |
| P        |           |          |          |          |           |
| artially |           |          |          |          |           |
| O        |           |          |          |          |           |
| ssified: |           |          |          |          |           |
+----------+-----------+----------+----------+----------+-----------+
|          | Fetus     | 1/147    | 2/131    | 3/129    | 12/122    |
|          |           |          |          |          | \*\*      |
+----------+-----------+----------+----------+----------+-----------+
|          | Litters   | 1/23     | 2/24     | 3/22     | 8/21 \*\* |
+----------+-----------+----------+----------+----------+-----------+
|          | Fet       | 1.00     | 1.00     | 1.00     | 1.50      |
|          | us/Litter |          |          |          |           |
+----------+-----------+----------+----------+----------+-----------+
| Lumbar   |           |          |          |          |           |
| Centrum  |           |          |          |          |           |
| #1       |           |          |          |          |           |
| P        |           |          |          |          |           |
| artially |           |          |          |          |           |
| O        |           |          |          |          |           |
| ssified: |           |          |          |          |           |
+----------+-----------+----------+----------+----------+-----------+
|          | Fetus     | 0/147    | 0/131    | 1/129    | 9/122     |
|          |           |          |          |          | \*\*      |
+----------+-----------+----------+----------+----------+-----------+
|          | Litters   | 0/23     | 0/24     | 1/22     | 6/21 \*\* |
+----------+-----------+----------+----------+----------+-----------+
|          | Fet       | 0.00     | 0.00     | 1.00     | 1.50      |
|          | us/Litter |          |          |          |           |
+----------+-----------+----------+----------+----------+-----------+
| Lumbar   |           |          |          |          |           |
| Traverse |           |          |          |          |           |
| Process  |           |          |          |          |           |
| P        |           |          |          |          |           |
| artially |           |          |          |          |           |
| Os       |           |          |          |          |           |
| sified - |           |          |          |          |           |
| 4th      |           |          |          |          |           |
| Right:   |           |          |          |          |           |
+----------+-----------+----------+----------+----------+-----------+
|          | Fetus     | 0/147    | 5/131    | 1/129    | 6/122     |
|          |           |          |          |          | \*\*      |
+----------+-----------+----------+----------+----------+-----------+
|          | Litters   | 0/23     | 5/24     | 1/22     | 5/21 \*   |
+----------+-----------+----------+----------+----------+-----------+
|          | Fet       | 0.00     | 1.00     | 1.00     | 1.20      |
|          | us/Litter |          |          |          |           |
+----------+-----------+----------+----------+----------+-----------+
| Lumbar   |           |          |          |          |           |
| Traverse |           |          |          |          |           |
| Process  |           |          |          |          |           |
| P        |           |          |          |          |           |
| artially |           |          |          |          |           |
| Os       |           |          |          |          |           |
| sified - |           |          |          |          |           |
| 4th      |           |          |          |          |           |
| Both:    |           |          |          |          |           |
+----------+-----------+----------+----------+----------+-----------+
|          | Fetus     | 0/147    | 3/131    | 0/129    | 4/122 \*  |
+----------+-----------+----------+----------+----------+-----------+
|          | Litters   | 0/23     | 2/24     | 0/22     | 3/21      |
+----------+-----------+----------+----------+----------+-----------+
|          | Fet       | 0.00     | 1.50     | 0.00     | 1.33      |
|          | us/Litter |          |          |          |           |
+----------+-----------+----------+----------+----------+-----------+
| S        |           |          |          |          |           |
| ternebra |           |          |          |          |           |
| #1       |           |          |          |          |           |
| P        |           |          |          |          |           |
| artially |           |          |          |          |           |
| O        |           |          |          |          |           |
| ssified: |           |          |          |          |           |
+----------+-----------+----------+----------+----------+-----------+
|          | Fetus     | 4/147    | 2/131    | 4/129    | 35/122    |
|          |           |          |          |          | \*\*      |
+----------+-----------+----------+----------+----------+-----------+
|          | Litters   | 3/23     | 2/24     | 4/22     | 14/21     |
|          |           |          |          |          | \*\*      |
+----------+-----------+----------+----------+----------+-----------+
|          | Fet       | 1.33     | 1.00     | 1.00     | 2.50      |
|          | us/Litter |          |          |          |           |
+----------+-----------+----------+----------+----------+-----------+
| S        |           |          |          |          |           |
| ternebra |           |          |          |          |           |
| #2       |           |          |          |          |           |
| P        |           |          |          |          |           |
| artially |           |          |          |          |           |
| O        |           |          |          |          |           |
| ssified: |           |          |          |          |           |
+----------+-----------+----------+----------+----------+-----------+
|          | Fetus     | 1/147    | 2/131    | 6/129 \* | 10/122    |
|          |           |          |          |          | \*\*      |
+----------+-----------+----------+----------+----------+-----------+
|          | Litters   | 1/23     | 2/24     | 5/22     | 7/21 \*   |
+----------+-----------+----------+----------+----------+-----------+
|          | Fet       | 1.00     | 1.00     | 1.20     | 1.43      |
|          | us/Litter |          |          |          |           |
+----------+-----------+----------+----------+----------+-----------+
| SKELETAL |           |          |          |          |           |
| VARIANTS |           |          |          |          |           |
+----------+-----------+----------+----------+----------+-----------+
| S        |           |          |          |          |           |
| ternebra |           |          |          |          |           |
| #6       |           |          |          |          |           |
| P        |           |          |          |          |           |
| artially |           |          |          |          |           |
| O        |           |          |          |          |           |
| ssified: |           |          |          |          |           |
+----------+-----------+----------+----------+----------+-----------+
|          | Fetus     | 0/147    | 0/131    | 1/129    | 8/122     |
|          |           |          |          |          | \*\*      |
+----------+-----------+----------+----------+----------+-----------+
|          | Litters   | 0/23     | 0/24     | 1/22     | 3/21      |
+----------+-----------+----------+----------+----------+-----------+
|          | Fet       | 0.00     | 0.00     | 1.00     | 2.67      |
|          | us/Litter |          |          |          |           |
+----------+-----------+----------+----------+----------+-----------+
| S        |           |          |          |          |           |
| ternebra |           |          |          |          |           |
| #4       |           |          |          |          |           |
| Mis      |           |          |          |          |           |
| aligned: |           |          |          |          |           |
+----------+-----------+----------+----------+----------+-----------+
|          | Fetus     | 1/147    | 0/131    | 4/129    | 6/122 \*  |
+----------+-----------+----------+----------+----------+-----------+
|          | Litters   | 1/23     | 0/24     | 4/22     | 5/21      |
+----------+-----------+----------+----------+----------+-----------+
|          | Fet       | 1.00     | 0.00     | 1.00     | 1.20      |
|          | us/Litter |          |          |          |           |
+----------+-----------+----------+----------+----------+-----------+
| S        |           |          |          |          |           |
| ternebra |           |          |          |          |           |
| #5       |           |          |          |          |           |
| Mis      |           |          |          |          |           |
| aligned: |           |          |          |          |           |
+----------+-----------+----------+----------+----------+-----------+
|          | Fetus     | 1/147    | 0/131    | 2/129    | 6/122 \*  |
+----------+-----------+----------+----------+----------+-----------+
|          | Litters   | 1/23     | 0/24     | 2/22     | 4/21      |
+----------+-----------+----------+----------+----------+-----------+
|          | Fet       | 1.00     | 0.00     | 1.00     | 1.50      |
|          | us/Litter |          |          |          |           |
+----------+-----------+----------+----------+----------+-----------+
| S        |           |          |          |          |           |
| ternebra |           |          |          |          |           |
| #1       |           |          |          |          |           |
| Bi       |           |          |          |          |           |
| partite: |           |          |          |          |           |
+----------+-----------+----------+----------+----------+-----------+
|          | Fetus     | 0/147    | 0/131    | 0/129    | 9/122     |
|          |           |          |          |          | \*\*      |
+----------+-----------+----------+----------+----------+-----------+
|          | Litters   | 0/23     | 0/24     | 0/22     | 8/21 \*\* |
+----------+-----------+----------+----------+----------+-----------+
|          | Fet       | 0.00     | 0.00     | 0.00     | 1.13      |
|          | us/Litter |          |          |          |           |
+----------+-----------+----------+----------+----------+-----------+
| Skull -  |           |          |          |          |           |
| P        |           |          |          |          |           |
| artially |           |          |          |          |           |
| Ossified |           |          |          |          |           |
| Occ      |           |          |          |          |           |
| ipitals: |           |          |          |          |           |
+----------+-----------+----------+----------+----------+-----------+
|          | Fetus     | 141/147  | 113/131  | 124/129  | 122/122   |
|          |           |          |          |          | \*        |
+----------+-----------+----------+----------+----------+-----------+
|          | Litters   | 23/23    | 23/24    | 22/22    | 21/21     |
+----------+-----------+----------+----------+----------+-----------+
|          | Fet       | 6.13     | 4.91     | 5.64     | 5.81      |
|          | us/Litter |          |          |          |           |
+----------+-----------+----------+----------+----------+-----------+
| cervical |           |          |          |          |           |
| Centrum  |           |          |          |          |           |
| #1 Not   |           |          |          |          |           |
| O        |           |          |          |          |           |
| ssified: |           |          |          |          |           |
+----------+-----------+----------+----------+----------+-----------+
|          | Fetus     | 28/147   | 40/131   | 48/129   | 94/122    |
|          |           |          | \*       | \*\*     | \*\*      |
+----------+-----------+----------+----------+----------+-----------+
|          | Litters   | 13/23    | 15/24    | 17/22    | 21/21     |
|          |           |          |          |          | \*\*      |
+----------+-----------+----------+----------+----------+-----------+
|          | Fet       | 2.15     | 2.67     | 2.82     | 4.48      |
|          | us/Litter |          |          |          |           |
+----------+-----------+----------+----------+----------+-----------+
| Cervical |           |          |          |          |           |
| Centrum  |           |          |          |          |           |
| #2 Not   |           |          |          |          |           |
| O        |           |          |          |          |           |
| ssified: |           |          |          |          |           |
+----------+-----------+----------+----------+----------+-----------+
|          | Fetus     | 52/147   | 63/131   | 80/129   | 118/122   |
|          |           |          | \*       | \*\*     | \*\*      |
+----------+-----------+----------+----------+----------+-----------+
|          | Litters   | 17/23    | 22/24    | 21/22    | 21/21 \*  |
+----------+-----------+----------+----------+----------+-----------+
|          | Fet       | 3.06     | 2.86     | 3.81     | 5.62      |
|          | us/Litter |          |          |          |           |
+----------+-----------+----------+----------+----------+-----------+
| Extra    |           |          |          |          |           |
| (14th)   |           |          |          |          |           |
| Rib -    |           |          |          |          |           |
| Un       |           |          |          |          |           |
| ilateral |           |          |          |          |           |
| Left     |           |          |          |          |           |
| Short:   |           |          |          |          |           |
+----------+-----------+----------+----------+----------+-----------+
|          | Fetus     | 5/147    | 7/131    | 4/129    | 15/122    |
|          |           |          |          |          | \*\*      |
+----------+-----------+----------+----------+----------+-----------+
|          | Litters   | 5/23     | 7/24     | 3/22     | 8/21      |
+----------+-----------+----------+----------+----------+-----------+
|          | Fet       | 1.00     | 1.00     | 1.33     | 1.88      |
|          | us/Litter |          |          |          |           |
+----------+-----------+----------+----------+----------+-----------+
| Extra    |           |          |          |          |           |
| (14th)   |           |          |          |          |           |
| B        |           |          |          |          |           |
| ilateral |           |          |          |          |           |
| Short:   |           |          |          |          |           |
+----------+-----------+----------+----------+----------+-----------+
|          | Fetus     | 14/147   | 12/131   | 33/129   | 7         |
|          |           |          |          | \*\*     | 5/122\*\* |
+----------+-----------+----------+----------+----------+-----------+
|          | Litters   | 10/23    | 6/24     | 15/22    | 18/21     |
|          |           |          |          |          | \*\*      |
+----------+-----------+----------+----------+----------+-----------+
|          | Fet       | 1.40     | 2.00     | 2.22     | 4.17      |
|          | us/Litter |          |          |          |           |
+----------+-----------+----------+----------+----------+-----------+
| Pelvic   |           |          |          |          |           |
| Girdle   |           |          |          |          |           |
| Moved    |           |          |          |          |           |
| Poste    |           |          |          |          |           |
| riorly - |           |          |          |          |           |
| 27       |           |          |          |          |           |
| Pr       |           |          |          |          |           |
| e-Sacral |           |          |          |          |           |
| V        |           |          |          |          |           |
| ertebrae |           |          |          |          |           |
| (g):     |           |          |          |          |           |
+----------+-----------+----------+----------+----------+-----------+
|          | Fetus     | 1/147    | 3/131    | 2/129    | 15/122    |
|          |           |          |          |          | \*\*      |
+----------+-----------+----------+----------+----------+-----------+
|          | Litters   | 1/23     | 2/24     | 2/22     | 7/21 \*   |
+----------+-----------+----------+----------+----------+-----------+
|          | Fet       | 1.00     | 1.50     | 1.00     | 2.14      |
|          | us/Litter |          |          |          |           |
+----------+-----------+----------+----------+----------+-----------+
| Both     |           |          |          |          |           |
| C        |           |          |          |          |           |
| alcaneum |           |          |          |          |           |
| Not      |           |          |          |          |           |
| O        |           |          |          |          |           |
| ssified: |           |          |          |          |           |
+----------+-----------+----------+----------+----------+-----------+
|          | Fetus     | 136/147  | 115/131  | 119/129  | 122/122   |
|          |           |          |          |          | \*\*      |
+----------+-----------+----------+----------+----------+-----------+
|          | Litters   | 23/23    | 24/24    | 22/22    | 21/21     |
+----------+-----------+----------+----------+----------+-----------+
|          | Fet       | 5.91     | 4.79     | 5.41     | 5.81      |
|          | us/Litter |          |          |          |           |
+----------+-----------+----------+----------+----------+-----------+
| **\[page |           |          |          |          |           |
| 15       |           |          |          |          |           |
| 559\]**\ |           |          |          |          |           |
| \        |           |          |          |          |           |
| MINOR    |           |          |          |          |           |
| EXTERNAL |           |          |          |          |           |
| AND      |           |          |          |          |           |
| VISCERAL |           |          |          |          |           |
| DEFECTS  |           |          |          |          |           |
| ^10^     |           |          |          |          |           |
+----------+-----------+----------+----------+----------+-----------+
| Renal    |           |          |          |          |           |
| Pelvic   |           |          |          |          |           |
| D        |           |          |          |          |           |
| ilation: |           |          |          |          |           |
+----------+-----------+----------+----------+----------+-----------+
|          | Fetus     | 19/281   | 25/255   | 22/249   | 30/234 \* |
+----------+-----------+----------+----------+----------+-----------+
|          | Litters   | 12/23    | 14/24    | 12/22    | 18/21 \*  |
+----------+-----------+----------+----------+----------+-----------+
|          | Fet       | 1.58     | 1.79     | 1.83     | 1.67      |
|          | us/Litter |          |          |          |           |
+----------+-----------+----------+----------+----------+-----------+
| Hydr     |           |          |          |          |           |
| oureter: |           |          |          |          |           |
+----------+-----------+----------+----------+----------+-----------+
|          | Fetus     | 13/281   | 6/255    | 4/249 \* | 10/234    |
+----------+-----------+----------+----------+----------+-----------+
|          | Litters   | 5/23     | 6/24     | 3/22     | 5/21      |
+----------+-----------+----------+----------+----------+-----------+
|          | Fet       | 2.60     | 1.00     | 1.33     | 2.00      |
|          | us/Litter |          |          |          |           |
+----------+-----------+----------+----------+----------+-----------+
| Limb     |           |          |          |          |           |
| Malr     |           |          |          |          |           |
| otation: |           |          |          |          |           |
+----------+-----------+----------+----------+----------+-----------+
|          | Fetus     | 0/281    | 9/255    | 2/249    | 3/234     |
|          |           |          | \*\*     |          |           |
+----------+-----------+----------+----------+----------+-----------+
|          | Litters   | 0/23     | 4/24     | 1/22     | 2/21      |
+----------+-----------+----------+----------+----------+-----------+
|          | Fet       | 0.00     | 2.25     | 2.00     | 1.50      |
|          | us/Litter |          |          |          |           |
+----------+-----------+----------+----------+----------+-----------+
|          |           |          |          |          |           |
+----------+-----------+----------+----------+----------+-----------+

a -Data from Tinston, Doe et al, Exs. 4-038.See also Ex. 5-071\
b -Incidence is number of fetuses affected divided by the total number
of fetuses\
c -Incidence is number of litters with at least one fetus affected\
d -Average number of affected fetuses per affected litter\
e -Denominator (i.e. the number of animals at risk) is adjusted for
early intra-uterine deaths\
f -Only a portion of fetuses in each exposure group were examined for
soft tissue alterations\
g -This skeletal defect was not classified as either a minor skeltal
anomalie or a skeletal variant\
h -Denominator (i.e. the number of animals at risk) is adjusted for all
intra-uterine deaths\
\* -Significantly different than controls at the p \<.05 level\
\*\* - Significantly different than controls at the p \<.01 level

A significant excess of late intra-uterine deaths occurred in the 250
ppm group using both the fetus and the litter measures of response, but
when combined with early intra-uterine deaths (i.e. all intra-uterine
deaths) the effect is significant for the 250 ppm group in fetuses only.
Early intra-uterine deaths considered separately were not found to be
related to exposure

Most of the minor skeletal defects which occurred at a significantly
elevated rate were also in the 250 ppm group. The effects which are
significant using both measures of response were partially ossified
frontals, partially ossified parietals, partially ossified
interparietals, odontoid not ossified, third, fourth, fifth, sixth, and
seventh cervical centra not ossified, eighth ninth, tenth, eleventh,
twelfth, and thirteenth thoracic centra partially ossified, first lumbar
centrum partially ossified, fourth right lumbar traverse process
partially ossified, and first and second sternebrae partially ossified.
One minor skeletal defect, fourth right lumbar traverse process
partially ossified, was significant for fetuses in the 250 ppm group but
not for litters

Two minor skeletal defects were significant for the 50 ppm group using
both measures of response: third cervical centrum not ossified and fifth
cervical centrum not ossified. The minor skeletal defects of unossified
sixth cervical centrum and partially ossified second sternebra shows a
significant excess in this exposure group but only for fetuses. The
incidence of unossified fourth cervical centrum was significantly
elevated over controls in the 50 ppm group for litters but not for
fetuses

Two minor skeletal defects showed a significant deficit of occurrence in
the 10 ppm group. Using both the fetus and the litter measure of
response, study results show that fetal rats exposed to 10 ppm of 2-EE
were significantly less likely to experience partially ossified
parietals or partially ossified interparietals than were controls. The
study authors offer no explanation for this, but given the large number
of effects for which each fetus was examined, the statistical
significance of this deficit can easily be attributed to chance
variation

A number of skeletal variants were observed to be associated with
exposure in fetal rats. Those which were found to be statistically
significantly elevated over controls using both the fetus and the litter
measures of response, bipartite first sternebra, unossified first
cervical centrum, and extra (14th) rib - bilateral short, were found
only in the 250 ppm group. Interestingly, incidence of unossified first
and second cervical centra were also significantly elevated in the 10
ppm group and the 50 ppm group when measured in fetuses but not when
measured in litters. The fetus/litter measure shows a dose-related trend
for ossified first cervical centrum but not for unossified second
cervical centrum. The effect extra (14th) rib - bilateral short showed a
showed a significant excess in 50 ppm fetuses but not in 50 ppm litters

There were an additional number of skeletal variants which were
statistically significant in the 250 ppm group but only when response
was measured in fetuses. These effects were partially ossified sixth
sternebra, misaligned fifth sternebra, partially ossified occipital and
extra (14th) rib - unilateral (left) short, and although these effects
were not significant when measured in litters, when measured in fetuses
these effects were significant at the P=0.035 level or lower

Three minor external and visceral defects were found to be statistically
significant. Renal pelvic dilation occurred at a significantly elevated
rate in fetuses and in litters in the 250 ppm group. Incidence of
hydroureter was significantly reduced in the 50 ppm fetuses but in no
other group of fetuses and in no group of litters. Incidence of limb
malrotation was significantly elevated in the 10 ppm group of fetuses
but in no other group of fetuses and in no groups of litters

There were two skeletal defects which occurred at a statistically
significant rate in the 250 ppm group which were not classified.
\"Pelvic girdle moved posteriorly (27 pre-sacral vertebrae)\" was not
categorized as either a major or minor skeletal defect or as a variant.
This effect was significant in both fetuses and litters. Likewise,
\"both calcaneum not ossified\" was not classified as either a major or
minor skeletal defect or as a variant. This effect was significant only
in fetuses in the 250 ppm group.

**\[page 15560\]**

The incidence of developmental effects in fetal rabbits exposed to 2-EE
are presented in Table VI-E. As for fetal rats, three measures of
response are presented, and the same statistical criteria were used for
inclusion of an effect in the table

  --------------- -------------- ----------- ----------- ----------- -----------
  Table VI-E                                                         

  Incidence of                                                       
  Developmental                                                      
  Effects                                                            

  Observed in                                                        
  Dutch Rabbits                                                      

  Exposed to 2-EE                                                    
  days 6 through                                                     
  18 of Gestation                                                    
  (a)                                                                

                                                                     

  MINOR SKELETAL                                                     
  DEFECTS (b)                                                        

                                                                     

                                 Control     10 ppm      50 ppm      175 ppm

                                                                     

  Skull -                                                            
  Partially                                                          
  Ossified Hyoid:                                                    

                  Fetus (c)      15/136      32/138 \*\* 12/96       28/134 \*

                  Litters (d)    8/21        9/20        5/16        11/22

                  Fetus/Litter   1.88        3.56        2.40        2.55
                  (e)                                                

  27 Pre-sacral                                                      
  Vertebrae:                                                         

                  Fetus          3/136       7/138       5/96        31/134 \*\*

                  Litters        3/21        4/20        2/16        10/22 \*

                  Fetus/Litter   1.00        1.75        2.50        3.10

  6th Sternebra                                                      
  Partially                                                          
  Ossified:                                                          

                  Fetus          2/136       1/138       2/96        8/134 \*

                  Litters        2/21        1/20        2/16        6/22

                  Fetus/Litter   1.00        1.00        1.00        1.33

  5th Sternebra                                                      
  Not Ossified:                                                      

                  Fetus          9/136       20/138 \*   9/96        13/134

                  Litters        5/21        7/20        6/16        5/22

                  Fetus/Litter   1.80        2.86        1.00        2.00

  Pelvic Girdle -                                                    
  Pubes Not                                                          
  Ossified:                                                          

                  Fetus          0/136       1/138       1/96        7/134 \*

                  Litters        0/21        1/20        1/16        4/22

                  Fetus/Litter   0.00        1.00        1.00        1.75

  Extra (13th)                                                       
  Rib -                                                              
  Unilateral                                                         
  Short:                                                             

                  Fetus          3/136       7/138       7/96        15/134 \*\*

                  Litters        3/21        6/20        7/16        10/22 \*

                  Fetus/Litter   1.00        1.17        1.00        1.50

  Extra (13th                                                        
  Rib - Bilateral                                                    
  Normal:                                                            

                  Fetus          10/136      17/138      7/96        38/134 \*\*

                  Litters        5/21        7/20        3/16        13/22 \*

                  Fetus/Litter   2.00        2.43        2.33        2.92

  Extra (13th)                                                       
  Rib - Bilateral                                                    
  One Normal One                                                     
  Short:                                                             

                  Fetus          4/136       5/138       6/96        16/134 \*\*

                  Litters        4/21        4/20        4/16        9/22

                  Fetus/Litter   1.00        1.25        1.50        1.78

  5th Sternebra                                                      
  Partially                                                          
  Ossified:                                                          

                  Fetus          53/136      61/138      45/96       53/134

                  Litters        14/21       20/20 \*\*  14/16       18/22

                  Fetus/Litter   3.79        3.05        3.21        2.94

                                                                     
  --------------- -------------- ----------- ----------- ----------- -----------

a - Data from Tinston, Doe et al, Exs. 4-039. See also Ex. 5-071\
b - Only a portion of fetuses in each exposure group were examined for
soft tissue alterations\
c - Incidence is number of fetuses affected divided by the total number
of fetuses\
d - Incidence is number of litters with at least one fetus affected\
e - Average number of affected fetuses per affected litter\
\* - Significantly different than controls at the p\< .05 level\
\*\* - Significantly different than controls at the p\< .01 level

Only one skeletal defect, 27 pre-sacral vertebrae, which Tinston et al
classified as minor in rabbits, was statistically significant in fetuses
and litters and this was in the 175 ppm group. Three minor skeletal
defects, partially ossified hyoid, partially ossified sixth sternebra,
and unossified pubes, were significant in fetuses in the 175 ppm group
but not in litters. The defect partially ossified hyoid occurred at a
significantly elevated rate in 10 ppm fetuses but was not significant in
this group when measured in litters. The same result was seen for the
defect unossified fifth sternebra which was significant in fetuses in
the 10 ppm group but not in litters and not in any other exposure group

The 175 ppm group had statistically significant excess of two skeletal
variants when measured in fetuses and in litters: extra (13th) rib -
unilateral short and extra (13th) rib - bilateral normal. The skeletal
variant extra (13th) rib - one normal and one short was significantly
elevated in fetuses in the 175 ppm group but was not significant in
litters

One skeletal variant was significantly elevated in the 10 ppm group.
This variant was partially ossified fifth sternebra. Incidence was
significant only when measured in litters but not when measured in
fetuses and was not significant for any other exposure group using any
measure of response. Incidence of partially ossified fifth sternebra
does not show a dose-related trend using the fetus/litter measure of
response, and the study authors attribute the observed excess to
coincidence because similar increases in this variant were not observed
in the 50 and 175 ppm groups.

**\[page 15561\]**

4\. Derivation of the No Observed Effect Level

a\. 2-ME

In reviewing Table VI-A, VI-B, and VI-C, it is clear that almost all
effects which occurred in an exposed group at rates statistically
significantly elevated over controls occurred in the highest dose group,
the 50 ppm 2-ME dose group, in each species. Only one effect,
resorptions, was statistically significant in litters at a dose below 50
ppm, but, as noted by the study authors, the rate of resorptions in
exposed rabbits fell well within the range of historical controls

It is apparent from these data that 10 ppm is the no observed effect
level (NOEL) in each of the species studied by Hanley et al despite the
varying sensitivity of each of the species to 2-ME

Still, the question arises as to how the incidence of effects can or
should be combined to arrive at a measure of overall response

Intuitively, one would have greater confidence in a NOEL derived from an
overall measure of response rather than one derived from specific
effects which may be statistically significant due to chance alone

OSHA proposes that an overall measure of the incidence of developmental
effects be arrived at by pooling the incidence of effects which occurred
at a statistically significant excess in any exposed group when measured
in litters. The Agency has chosen litters as the most appropriate unit
of measure for a number of reasons. First, as noted above, it is the
pregnant female that is exposed to the test substance, therefore it is
her litter which is the affected unit. Because dose is administered to
the fetus through the pregnant dam, the dose each fetus receives is
unknown and may depend upon the individual sensitivity of the mother
animal to the test substance. Furthermore, the dose the fetus does
receive may be affected by the number of littermates in utereo

Another reason for prefering the litter as the unit of measure is that
fetuses in a litter are more likely to respond like each other than like
fetuses from other litter (i.e. the litter effect). Therefore, if an
effect is observed in some number of fetuses, but all affected fetuses
come from only one or two litters, then it is possible to attribute the
effect to exposure when in fact it is due to variation among the mother
animals

The use of litters as the unit of measure in studies of developmental
effects in animals is recommended by the EPA in its Guidelines (Ex.
5-153), and this unit of measure enjoys wide support in the literature
(see, for example, Ex. 5-018)

OSHA\'s decision to include in an overall measure of response only those
effects which are statistically significant when considered individually
is based on its belief that by so restricting inclusion of an effect in
an overall measure one obtains a more accurate measure of overall
response. Inclusion of effects which are not dose related and are
attributable solely to chance dilutes the overall measure of the potency
of a developmental toxicant

This position is easily illustrated. Hanley et al counted all the rabbit
litters in the control and exposed groups which had at least one fetus
with any major malformation. The incidence of major malformations was
found to be 6/23 in controls (26%), 4/23 in the 3 ppm group (17%), 3/24
in the 10 ppm group (13%) and 20/22 in the 50 ppm group (91%). If only
those major malformations which were statistically significant in
exposed litters had been included, the overall incidence of major
malformations would have been 0/23 in the control group (0%), 2/23 in
the 3 ppm group (13%) 1/24 in the 10 ppm group (4%) and 20/22 in the 50
ppm group (91%). While the NOEL is 10 ppm regardless of how the overall
incidence of major malformations is measured, the effect attributable to
exposure at 50 ppm is clearer and starker when those major malformations
attributable to chance are excluded

Tables VI-F, VI-G, and VI-H present the overall incidence of
developmental effects in rats, rabbits, and mice, respectively. For
rabbits, resorptions were not included in the overall measure of
response because the rate for all three exposure groups (42% to 67%) was
well within the historical range reported by Hanley et al (mean 55%,
range 38% to 74%) and only the rate of resorption among controls (22%)
was outside of that range. The tables clearly indicate that 2-ME induces
developmental effects in all three species at 50 ppm and that the NOEL
for all three species in these studies is 10 ppm

  ----------------- ----------- ----------- ----------- ----------- -----------
  Table VI-F                                                        

  Overall Incidence                                                 
  of Developmental                                                  
  Effects                                                           

  Observed in                                                       
  Litters of Fisher                                                 
  344 Rats                                                          

  Exposed to 2-ME                                                   
  Days 6 through 15                                                 
  of Gestation (a)                                                  

                                                                    

                                Control     3 ppm       10 ppm      50 ppm

                                                                    

  Minor Skeletal                                                    
  Alterations(b):                                                   

                    Litters     14/29       12/28       16/28       27/30 \*\*

                                                                    
  ----------------- ----------- ----------- ----------- ----------- -----------

a - Data from Hanley et al, Ex. 4-042a\
b - The numerator is the number of litters with at least one fetus
presenting either delayed ossification of centra or rib spurs; the
denominator is the number of litters at risk\
\*\* - Significantly different than controls at the p \< .01 level

+----------+-----------+-----------+----------+----------+-----------+
| Table    |           |           |          |          |           |
| VI-G     |           |           |          |          |           |
+----------+-----------+-----------+----------+----------+-----------+
| Overall  |           |           |          |          |           |
| I        |           |           |          |          |           |
| ncidence |           |           |          |          |           |
| of       |           |           |          |          |           |
| Devel    |           |           |          |          |           |
| opmental |           |           |          |          |           |
| Effects  |           |           |          |          |           |
+----------+-----------+-----------+----------+----------+-----------+
| Observed |           |           |          |          |           |
| in       |           |           |          |          |           |
| Litters  |           |           |          |          |           |
| of New   |           |           |          |          |           |
| Zealand  |           |           |          |          |           |
| White    |           |           |          |          |           |
| Rabbits  |           |           |          |          |           |
+----------+-----------+-----------+----------+----------+-----------+
| Exposed  |           |           |          |          |           |
| to 2-ME  |           |           |          |          |           |
| Days 6   |           |           |          |          |           |
| through  |           |           |          |          |           |
| 15 of    |           |           |          |          |           |
| G        |           |           |          |          |           |
| estation |           |           |          |          |           |
| (a)      |           |           |          |          |           |
+----------+-----------+-----------+----------+----------+-----------+
|          |           |           |          |          |           |
+----------+-----------+-----------+----------+----------+-----------+
|          |           | Control   | 3 ppm    | 10 ppm   | 50 ppm    |
+----------+-----------+-----------+----------+----------+-----------+
|          |           |           |          |          |           |
+----------+-----------+-----------+----------+----------+-----------+
| Major    |           |           |          |          |           |
| External |           |           |          |          |           |
| Altera   |           |           |          |          |           |
| tions(b) |           |           |          |          |           |
+----------+-----------+-----------+----------+----------+-----------+
|          | Litters   | 0/23      | 1/23     | 0/24     | 16/22     |
|          |           |           |          |          | \*\*      |
+----------+-----------+-----------+----------+----------+-----------+
| Minor    |           |           |          |          |           |
| External |           |           |          |          |           |
| Altera   |           |           |          |          |           |
| tions(c) |           |           |          |          |           |
+----------+-----------+-----------+----------+----------+-----------+
|          | Litters   | 0/23      | 0/23     | 0/24     | 15/22     |
|          |           |           |          |          | \*\*      |
+----------+-----------+-----------+----------+----------+-----------+
| Major    |           |           |          |          |           |
| Soft     |           |           |          |          |           |
| Tissue   |           |           |          |          |           |
| Altera   |           |           |          |          |           |
| tions(d) |           |           |          |          |           |
+----------+-----------+-----------+----------+----------+-----------+
|          | Litters   | 0/23      | 1/23     | 1/24     | 20/22     |
|          |           |           |          |          | \*\*      |
+----------+-----------+-----------+----------+----------+-----------+
| Minor    |           |           |          |          |           |
| Soft     |           |           |          |          |           |
| Tissue   |           |           |          |          |           |
| Altera   |           |           |          |          |           |
| tions(e) |           |           |          |          |           |
+----------+-----------+-----------+----------+----------+-----------+
|          | Litters   | 3/23      | 5/23     | 2/22     | 18/22     |
|          |           |           |          |          | \*\*      |
+----------+-----------+-----------+----------+----------+-----------+
| Major    |           |           |          |          |           |
| Skeletal |           |           |          |          |           |
| Altera   |           |           |          |          |           |
| tions(f) |           |           |          |          |           |
+----------+-----------+-----------+----------+----------+-----------+
|          | Litters   | 0/23      | 0/23     | 0/24     | 5/22 \*   |
+----------+-----------+-----------+----------+----------+-----------+
| **\[page |           |           |          |          |           |
| 1        |           |           |          |          |           |
| 5562**\] |           |           |          |          |           |
|          |           |           |          |          |           |
| Minor    |           |           |          |          |           |
| Skeletal |           |           |          |          |           |
| Altera   |           |           |          |          |           |
| tions(g) |           |           |          |          |           |
+----------+-----------+-----------+----------+----------+-----------+
|          | Litters   | 1/23      | 4/23     | 2/24     | 13/22     |
|          |           |           |          |          | \*\*      |
+----------+-----------+-----------+----------+----------+-----------+
| Any      |           |           |          |          |           |
| Major    |           |           |          |          |           |
| Altera   |           |           |          |          |           |
| tions(h) |           |           |          |          |           |
+----------+-----------+-----------+----------+----------+-----------+
|          | Litters   | 0/23      | 2/23     | 1/24     | 20/22     |
|          |           |           |          |          | \*\*      |
+----------+-----------+-----------+----------+----------+-----------+
| Any      |           |           |          |          |           |
| Minor    |           |           |          |          |           |
| Altera   |           |           |          |          |           |
| tions(i) |           |           |          |          |           |
+----------+-----------+-----------+----------+----------+-----------+
|          | Litters   | 4/23      | 7/23     | 4/24     | 20/22     |
|          |           |           |          |          | \*\*      |
+----------+-----------+-----------+----------+----------+-----------+
| Any      |           |           |          |          |           |
| Altera   |           |           |          |          |           |
| tions(j) |           |           |          |          |           |
+----------+-----------+-----------+----------+----------+-----------+
|          | Litters   | 4/23      | 7/23     | 5/24     | 20/22     |
|          |           |           |          |          | \*\*      |
+----------+-----------+-----------+----------+----------+-----------+
|          |           |           |          |          |           |
+----------+-----------+-----------+----------+----------+-----------+

a - Data from Hanley et al, Ex. 4-042a\
b - The numerator is the number of litters with at least one fetus
presenting any of the following major external alterations:
arthrogryposis, anonychia, brachydactyly, ectrodactyly, or kinky tail;
the denominator is the number of litters at risk\
c - The numerator is the number of litters with at least one fetus
presenting any of the following minor external alterations: misalignment
of the palatine rugae or narrowed tip of tail; the denominator is the
number of litters at risk\
d - The numerator is the number of litters with at least one fetus
presenting any of the following major soft tissue alterations:
coarctation of the aortic arch, ventricular septal defect, hypoplastic
spleen, or dilated renal pelvis; the denominator is the number of
litters at risk\
e - The numerator is the number of litters with at least one fetus
presenting any of the following minor soft tissue alterations: patent
ductus arteriosis, hypoplastic gall bladder, pale spleen, dilated
ureter, convoluted ureter, or parovarian cyst; the denominator is the
number of litters at risk\
f - The numerator is the number of litters with at least one fetus
presenting any of the following major skeletal alterations: missing
phalange or missing metatarsal; the denominator is the number of litters
at risk\
g - The numerator is the number of litters with at least one fetus
presenting any of the following minor skeletal alterations: delayed
ossification of the hyoid, delayed ossification of the tarsal, or extra
lumbar ribs; the denominator is the number of litters at risk\
h - The numerator is the number of litters with at least one fetus
presenting any major external alterations, any major soft tissue
alteration or any major skeletal alterations listed above; the
denominator is the number of litters at risk\
i - The numerator is the number of litters with at least one fetus
presenting any minor external alterations, any minor soft tissue
alteration or any minor skeletal alterations listed above; the
denominator is the number of litters at risk\
j - The numerator is the number of litters with at least one fetus
presenting any major or minor external alterations, soft tissue
alteration or skeletal alterations listed above; the denominator is the
number of litters at risk\
\* - Significantly different than controls at the p \< .05 level\
\*\* - Significantly different than controls at the p \< .01 level

  ---------------- ----------- ----------- ----------- ----------- -----------
  Table VI-H                                                       

  Overall                                                          
  Incidence of                                                     
  Developmental                                                    
  Effects                                                          

  Observed in                                                      
  Litters of CF-1                                                  
  mice                                                             

  Exposed to 2-ME                                                  
  days 6 through                                                   
  15 of Gestation                                                  
  (a)                                                              

                                                                   

                                           Control     10 ppm      50 ppm

                                                                   

  Minor Skeletal                                                   
  Alterations(b)                                                   

                               Litters     14/26       14/23       21/24 \*

                                                                   
  ---------------- ----------- ----------- ----------- ----------- -----------

a - Data from Hanley et al, Ex. 4-106\
b - The numerator is the number of litters with at least one fetus
presenting extra lumbar ribs; the denominator is the number of litters
at risk\
\* - Significantly different than controls at the p\< .05 level

In its comments to OSHA\'s ANPR, Du Pont states that it is \"appropriate
to look at all adverse effects, but not to accumulate these effects into
one endpoint\" (Ex. 7-28). OSHA seeks additional information on how the
approach suggested by Du Pont could be used for quantitative risk
assessment. Specifically, it is unclear how different NOELs for
different endpoints from the same study would be treated. In addition,
OSHA seeks comment on whether adverse developmental effects should be
combined, and if so, how this should be done

Given that the NOEL for 2-ME has been derived from animal studies, OSHA
believes that an uncertainty factor of 100 is appropriate for derivation
of the acceptable daily intake (ADI) i.e. the dose at which humans are
unlikely to exhibit effects similar to those observed in animals. An
uncertainty factor of 100 provides a factor of 10 for inter- species
variability and a factor of 10 for intra-species variability (i.e.
individual human sensitivity to 2-ME). Therefore, based on the studies
of Hanley et al, OSHA estimates the ADI to be 10 ppm/100 or 0.1 ppm.
That is, at 0.1 ppm of 2-ME, humans are unlikey to exhibit effects
similar to those observed in animals

b\. 2-EE

Table VI-D and VI-E show clearly that exposure to 2-EE had an effect on
developing animals although the results of the 2-EE bioassay are not as
strong as those from the 2-ME bioassay. While most of the developmental
effects observed in the 2-EE bioassay were observed in the high dose
groups for both rats and rabbits (250 ppm and 175 ppm respectively),
there were statistically significant effects in the 50 ppm group of rats
and the 10 ppm group of rabbits. Thus, determination of the NOEL for
2-EE is more difficult than for 2-ME

Table VI-I presents the overall incidence of developmental effects in
fetal rats exposed to 2-EE. Only those effects which were statistically
significant when measured in litters are included in the overall measure
of incidence.

\[page 15563\]

  --------------- ----------- ----------- ----------- ----------- -----------
  Table VI-I                                                      

  Overall                                                         
  Incidence of                                                    
  Developmental                                                   
  Effects                                                         

  Observed in                                                     
  Litters of                                                      
  Wistar Rats                                                     

  Exposed to 2-EE                                                 
  Days 6 through                                                  
  15 of Gestation                                                 
  (a)                                                             

                                                                  

                              Control     10 ppm      50 ppm      250 ppm

                                                                  

  Late                                                            
  Intra-Uterine                                                   
  Deaths (b)                                                      

                  Litters     2/23        2/24        2/22        7/21 \*

  Minor Skeletal                                                  
  Defects (c)                                                     

                  Litters     17/23       21/24       20/22       21/21 \*

  Skeletal                                                        
  Variants (d)                                                    

                  Litters     20/23       23/24       22/22       21/21

  Minor External                                                  
  and Visceral                                                    
  Defects (a)                                                     

                  Litters     12/23       14/24       12/22       18/21 \*

  Unclassified                                                    
  Defects (f)                                                     

                  Litters     1/23        2/24        2/22        7/21 \*

  Any Death,                                                      
  Defect or                                                       
  Variant (g)                                                     

                  Litters     23/23       23/24       22/22       21/21

                                                                  
  --------------- ----------- ----------- ----------- ----------- -----------

a - Data from Tinston, Doe et al, Ex. 4-038a\
b - The numerator is the number of litters with at least one late
intra-uterine death; the denominator is the number of litters at risk\
c - The numerator is the number of litters with at least one fetus
presenting any of the following minor skeletal defects: frontal
partially ossified, parietal partially ossified, interparietal partially
ossified, odontoid not ossified, third, fourth, fifth, sixth or seventh
cervical centrum not ossified, eighth, ninth, tenth, twelfth, or
thirteenth thoracic centrum partially ossified, first lumbar centrum
partially ossified, fourth right lumbar traverse process partially
ossified, or first or second sternebra partially ossified; the
denominator is the number of litters at risk\
d - The numerator is the number of litters with at least one fetus
presenting any of the following skeletal variants: first sternebra
bipartite, first or second cervical centrum not ossified, or extra
(14th) rib bilaterally short; the denominator is the number of litters
at risk\
e - The numerator is the number of litters with at least one fetus
presenting renal pelvic dilation; the denominator is the number of
litters at risk\
f - The numerator is the number of litters with at least one fetus
presenting a posteriorly moved pelvic girdle (27 pre-sacral vertebrae);
the denominator is the number of litters at risk. The defect \"pelvic
girdle moved posteriorly\" was not classified as a major or minor
external and visceral defect, a major or minor skeletal defect, or a
skeletal defect. Thus it is \"unclassified.\"\
g - The numerator is the number of litters with at least one fetus dying
late in utero or presenting any minor skeletal defect, skeletal variant,
minor external or visceral defect, or unclassified defect listed above;
the denominator is the number of litters at risk\
\* - Significantly different than controls at the p\< .05 level

The surprising result in table VI-I is that when all the effects are
combined, it would appear that 2-EE has no effect on developing rats
despite the fact that there is a significant excess of late
intra-uterine deaths in the 250 ppm group, a significant excess of minor
skeletal defects in the 250 ppm group, and a significant excess of
external and visceral defects in the 250 ppm group. Furthermore, Table
VI-D shows that there were twenty-four effects that were significantly
elevated in the 250 ppm group in both litters and fetuses

The reason the overall incidence of effects in fetal rats exposed to
2-EE is not significant is that the study authors looked at the
developmental effects in such minute detail. While this results in there
being a large number of effects which are statistically significant in
the 250 ppm group when each effect is considered individually, when
combined the incidence of these effects in the other exposure groups
dilutes the association between dose and response

Examination of the data reveals that the incidence of non-ossification
of the cervical centra is one effect which is diluting the overall
dose-response relationship. When ossification of each of the seven
cervical centra is considered individually, it is clear that exposure to
250 ppm of 2-EE in fetal rats results in non-ossification of each of the
centrum. Incidence of non-ossification of each of the centrum in the 250
ppm group is statistically significant at the p=.014 level or lower. If
all the centra were combined into a category \"delayed ossification of
the cervical centra\", however, this effect would not be statistically
significant when measured in litters. The litter incidence of delayed
ossification of any cervical centrum is 19/23 in control (83%), 23/24 in
the 10 ppm group (96%), 21/22 in the 50 ppm group (95%), and 21/21 in
the 250 ppm group (100%). Thus, when each centrum is considered
individually, there is clearly a dose-related effect at the 250 ppm
level, but when the centra are considered together, this effect
disappears. Because of the high background incidence of the effect and
the small number of litters in each group, the overall incidence of
developmental effects in the 250 ppm group appears to be unrelated to
dose

OSHA does not believe that there is no developmental effect on fetal
rats exposed to 2-EE. When the incidence of late intra-uterine deaths is
considered, when the overall incidence of minor skeletal defects is
considered and when the overall incidence of minor external and visceral
defects are considered, it is clear that exposure to 250 ppm of 2-EE
results in detrimental effects on the developing fetus. No such effect
is seen at 50 ppm or lower, and therefore OSHA concludes that the NOEL
for 2-EE is 50 ppm in rats

The results presented in Table VI-J demonstrate that 50 ppm is also the
NOEL for fetal rabbits exposed to 2-EE. The overall incidence of
developmental effects is statistically significant for the 175 ppm group
at the p=0.004 level. This indicates that exposure below the 250 ppm
level, the level observed to have an adverse effect on developing rats,
can have an adverse effect on developing rabbits

Although fewer effects were observed in the rabbit at 175 ppm than in
the rat at 250 ppm, dose-related adverse effects were nonetheless
induced at the 175 ppm level.

  --------------- ----------- ----------- ----------- ----------- -----------
  Table VI-J                                                      

  Overall                                                         
  Incidence of                                                    
  Developmental                                                   
  Effects                                                         

  Observed in                                                     
  Litters of                                                      
  Dutch Rabbits                                                   

  Exposed to 2-EE                                                 
  Days 6 through                                                  
  18 of Gestation                                                 
  (a)                                                             

                                                                  

                              Control     10 ppm      50 ppm      175 ppm

                                                                  

  Minor Skeletal                                                  
  Defects (b)                                                     

                  Litters     3/21        4/20        2/16        10/22 \*

  **\[page                                                        
  15564\]**                                                       

  Skeletal                                                        
  Variants (c)                                                    

                  Litters     7/21        10/20       9/16        18/22 \*\*

  Any Defect or                                                   
  Variant (d)                                                     

                   Litters    8/21        11/20       9/16        18/22 \*\*

                                                                  
  --------------- ----------- ----------- ----------- ----------- -----------

a - Data from Tinston, Doe et al, Ex. 4-039a\
b - The numerator is the number of litters with at least one fetus
presenting 27 pre-sacral vertebrae; the denominator is the number of
litters at risk\
c - The numerator is the number of litters with at least one fetus
presenting an extra (13th) rib unilaterally short or bilaterally normal;
the denominator is the number of litters at risk\
d - The numerator is the number of litters with at least one fetus
presenting any minor skeletal defect or skeletal variant listed above;
the denominator is the number of litters at risk\
\* - Significantly different than controls at the p\< .05 level\
\*\* - Significantly different than controls at the p\< .01 level

Given, as with 2-ME, that the NOEL for 2-EE has been derived from animal
studies, OSHA believes that an uncertainty factor of 100 is again
appropriate for derivation of the ADI. As with 2-ME, an uncertainty
factor of 100 provides a factor of 10 for inter-species variability and
a factor of 10 for intra-species variability. Therefore, based on the
studies by Tinston et al, OSHA estimates the ADI to be 50 ppm/100 or 0.5
ppm. That is, at 0.5 ppm of 2-EE, humans are unlikely to exhibit adverse
effects similar to those observed in animals

5\. Alternative Uncertainty Factors

As discussed in a previous section, an ADI (i.e the levels at ewhich
humans are unlikely to exhibit effects similar to those observed in
humans) is derived by dividing a NOEL by an uncertainty factor. To
derive ADIs for glycol ethers, OSHA has used an uncertainty factor of
100; a factor of ten to account for inter-species variability and a
factor of 10 to account for intra-species variability. Several of the
commentors who responded to OSHA\'s ANPR for glycol ethers advocated use
of a lower uncertainty factor (see, for example, Kodak, Ex. 7-16, and Du
Pont, Ex. 7-28). In its comments, CMA argues that an uncertainty factor
well below 100 should be used to arrive at new PELs (Ex. 7-17). While
CMA presents a number of reasons for its position, OSHA does not find
any of its reasons sufficiently compelling to depart from the
traditional uncertainty factor for derivation of ADIs across species.
What follows here is a brief description of each of the arguments
presented by CMA and OSHA\'s response to these arguments

To begin, CMA states that lower safety factors are appropriate with high
quality animal studies. OSHA agrees that the Hanley et al studies and
the Tinston et al studies are high quality studies, but the Agency does
not see how the quality of these studies reduces either inter-species
variability or intra-species variability. Both types of variability are
issues in determining a \"safe\" occupational exposure level from animal
data even when such studies are of high quality

CMA argues that lower safety factors are appropriate when NOELs have
been established in more than one species. CMA notes that not only have
NOELs been established for a number of species but the NOELs and the
observed effects have also been quite similar across species

While OSHA agrees that one has greater confidence in a NOEL determined
in more than one species, the Agency is concerned the CMA has confused
the finding of the same NOEL in more than one species with the finding
of the same threshold in more than one species. The exposure levels
employed by Hanley et al and by Tinston et al were almost identical in
each of the species tested. In the case of 2- ME, for example, rats and
rabbits were exposed at identical exposure levels and mice were exposed
to two of the three same levels. Given this similarity of exposure, it
is not surprising that the same NOEL was identified in all three
species. One cannot conclude from this, however, that the exposure
threshold for developmental effects is the same in all three species.
Based on the data from the Hanley et al bioassays, for example, one
cannot reject a hypothesis that the \"true\" NOELs might be 40 ppm for
mice, 25 ppm for rats, and 10 ppm for rabbits. The exposure levels
employed do not allow one to reject this hypothesis, thus one cannot
conclude there is no inter-species variability for 2-ME. The same is
true for 2-EE. In addition, the small number of animals used in each of
these bioassays, (no study used more than 30 animals in each exposure
group and most used less), limited the power of these bioassays to
detect lower NOELs. For these reasons, OSHA cannot support the use of a
lower safety factor on these grounds as advocated by CMA

In addition, OSHA does not agree that the effects observed across
species exposed to the same glycol ethers were quite as similar as CMA
maintains. In the case of 2- ME, the only effects observed to occur at a
statistically significantly greater rate in the high dose groups of rats
and mice were minor skeletal defects. In high dose rabbits, however, the
effects were far and away more severe including major external
alterations, major soft tissue alterations, and major skeletal
alterations. In the case of 2-EE, it is difficult to compare effects
across species because of differences in exposure levels used for the
high dose group

CMA\`s third reason for advocating an uncertainty factor well below 100
is that data on inter-species metabolism and pharmacokinetics can be
employed to justify this. As discussed in the Health Effects section of
this preamble, the evidence indicates that the four glycol ethers of
interest here are most likely metabolized via the alcohol dehydrogenase
(ADH) pathway in both animals and humans. Although all species seem to
share the same metabolic pathway, however, there is also evidence that
the species do not metabolize glycol ethers at the same rate.
Groeseneken et al found that the biological half-life of 2-EE in humans
was 21 to 24 hours compared to the biological half-life of 8 to 12 hours
reported in animals (Exs. 5-112, 5-113, and 5- 114). This finding led
the study authors to conclude that the metabolites of 2-EE will not be
cleared from the urine by the next morning following exposure and
accumulation of the metabolites may be expected through repetitive
exposures. In a study of 2-EEA in humans, Groesenken et al found

**\[page 15565\]**

similar results (Ex. 5-115), and these results were confirmed in study
of female silk screen operators exposed to 2-EE and 2-EEA by Veulemans
et al (Ex. 5-114). The finding of a longer biological half-life for 2-EE
and 2-EEA in humans prompted Veulemans et al to note that \"it would
certainly warrant extra caution in the extrapolation of experimental
data from laboratory animals to man, since comparable accumulation
effects apparently are not found in all species.\" Although 2-EE and
2-EEA are the only glycol ethers which have been studied in humans,
these findings raise enough questions about the similarities of the
metabolism and pharmacokinetics of glycol ethers across species to deter
the Agency from reducing the uncertainty factor used based on the
similarity of the pharmacokinetics and metabolism of glycol ethers
across species

CMA\'s fourth argument is that when dose is expressed in the correct
units using the correct cross-species scaling factor, then a lower
uncertainty factor can be used. OSHA intends to discuss this issue later
in this section in its review of the risk assessment performed by
Environ et al (Ex. 4-016f). The Agency does agree with CMA that
uncertainty is reduced when dose is expressed in the correct units, but
the Agency is not as confident as CMA regarding what are the correct
units

CMA\'s final argument for supporting a lower uncertainty factor is that
lower uncertainty factors should be used because exposure is
occupational. In an appendix to CMA\'s comments, E.M. Johnson argues
that the 10-fold factor for intra-species variability can be reduced
when the exposed population is less diverse than the total population as
in the case of workers who tend to be healthier and more homogeneous
than the general population (Ex. 7-17, Appendix A)

OSHA cannot agree with this position for a number of reasons. First of
all, while it is plausible that a woman who is a worker may be healthier
than a woman who is not a worker, CMA presents no evidence that the
\"healthy worker effect\" is conferred upon the developing fetus.
Furthermore, a fetus has two parents who contribute to its genetic
identity, and there is no reason to assume that the father of a fetus of
a working mother is also a \"healthy worker\". Finally, although
\"healthy workers\" may constitute a homogeneous population, it does not
follow that their offspring will constitute a homogenous population,
healthy or otherwise

Although OSHA\'s approach of using an uncertainty factor of 100 may
appear conservative, OSHA believes that the uncertainties associated
with deriving an ADI for occupational exposure to glycol ethers require
the use of this factor. Some of the uncertainties stem from the
qualitative nature of the uncertainty factor approach as outlined
earlier in this risk assessment (e.g. the unlikelihood that an exposure
level used in a bioassay will be the \"true\" threshold, varying
susceptibilities across species, etc.). Other uncertainties stem
specifically from the data available for assessing the risk from glycol
ethers as noted above (e.g. similar exposure levels used across species,
possible differences in metabolism and pharmacokinetics across species,
etc.). For these reasons, OSHA has used an uncertainty factor of 100.
The Agency seeks comment on its choice of uncertainty factor and its
justification for this choice. The Agency seeks detailed reasons for
either accepting or rejecting the choice of a 100-fold uncertainty
factor and any data available to support the position

D . Assessment of the Reproductive Risk from Exposure to Glycol Ethers

1\. Introduction

The Interagency Regulatory Liaison Group, (IRLG), describes reproductive
toxicity as dealing with \"the effects of toxicants on adult
reproductive function and development of the offspring which may be
produced by alteration of a wide range of processes in either the female
or the male.\" As noted by the IRLG, these processes include \"those
associated with the primary and accessory sexual organs and with
fertilization, as well as those which impact more indirectly on normal
reproductive function; e.g., neuroendocrine control, general
physiological and psychological health, and nutrition.\" The IRLG
continues, \"\[f\]ollowing fertilization, processes associated
specifically with pregnancy are also vulnerable; e.g., implantation,
placental formation and function, conceptal development, and parturation
and lactation\" (Ex. 5-018)

In its Proposed Guidelines for Assessing Male Reproductive Risk (Ex.
5-123), the EPA identifies a number of measures which may be evaluated
to assess the reproductive effects of exposure of males to a potential
reproductive toxicant. In animals, these include body weight; weight and
histopathology of the testes, epididymides, seminal vesicles, prostate,
and pituitary gland; mating ratio and pregnancy ratio; and pregnancy
outcomes such as litter size, pre- and post-implantation loss, the ratio
of live to dead pups, sex ratios, malformations, birth and postnatal
weights, and survival. Supplemental end points of male reproductive
toxicity may be identified through sperm and endocrine evaluations. EPA
points out that while these measures are useful for evaluating
reproductive risk in humans as well as animals, many of these measures
such as early fetal loss, reproductive capacity of the offspring, and
the invasive measures of reproductive function are not easily observed
in humans

The most feasible measures used in studies of reproductive effects in
human males are semen evaluations, indirect measures of
fertility/infertility, and certain pregnancy outcomes such as fetal
loss, birth weight, sex ratio, congenital malformations, postnatal
function, and neonatal growth and survival

The measures recommended by EPA for evaluation to determine reproductive
effects in female laboratory animals include capacity to conceive;
length of time required for conception; alterations in the onset of
puberty; alterations in the reproductive cycle; oocyte toxicity;
premature reproductive senescence; weight and histopathology of the
ovary, the uterus, and the pituitary gland; and the pregnancy outcomes
described for males above. In human females, the feasible measures of
reproductive toxicity are the measures of fertility and pregnancy
outcomes (Ex. 5- 122)

While studies of human populations provide the strongest evidence of the
reproductive toxicity of a substance, such studies are usually limited
in their ability to detect risk. Like epidemiological studies of cancer
mortality and other discrete outcomes, studies of reproductive toxicity
in human populations often suffer from lack of statistical power
(usually due to small sample size), inexact exposure measurements, and
an inability to control for all potential confounding factors. Studies
of reproductive toxicity in human populations, however, have additional
limitations. Assessment of reproductive endpoints is often dependent
upon voluntary participation and self-reporting of outcomes which, in
turn, may be influenced by privacy considerations and religious
considerations. In addition, there are fewer endpoints which may be
feasibly measured in humans than may be measured in laboratory animals.
Thus, because of these limitations, reproductive risks are usually
assessed from animal studies

2\. 2-ME

A number of studies showing reproductive effects in male animals exposed
to 2-ME are described in the

**\[page 15566\]**

Health Effects section of this preamble. Results from studies of animals
exposed to 2-ME through inhalation are supported by the results from
studies of animals exposed to 2-ME through ingestion

The lowest NOEL observed in laboratory animals was observed in a study
of New Zealand white rabbits by Miller et al of the Dow Chemical Company
(Exs. 4-045 and 5-023). Groups of five male rabbits were exposed to 2-ME
at concentrations of 30, 100, or 300 ppm through inhalation for 6 hours
per day, 5 days per week, for 13 weeks. A group of 5 male rabbits served
as controls. Food and water was provided to the animals ad libitum
except during periods of exposure when neither was available

Following 13 weeks of exposure, all surviving animals were sacrificed.
Two rabbits in the 300 ppm group died during the exposure phase of the
study. The cause of death for one was bronchopneumonia. The cause of
death for the second was unknown. All animals were given a complete
gross pathological exam, and a histological exam was performed on
selected tissues from each animal

Reduced testes weight was observed in rabbits in the 300 ppm and 100 ppm
exposure groups, and although this effect was statistically significant
for the 300 ppm group only, the study authors attributed the observation
in both groups to exposure. Gross pathological exam showed that all of
the rabbits in the 300 ppm group had very small and flaccid testes. A
slight to moderate decrease in testes size relative to the control
animals was observed in 4 out of 5 of the rabbits in the 100 ppm group
(p=0.024, Fisher\'s Exact Test), and 2 out of 5 of the rabbits in the 30
ppm, group (p \> 0.05). Histopathologic exam confirmed the gross
pathological observations. A dose-related increase in both the incidence
and severity of testicular degenerative changes was seen in the test
animals. In all three of the rabbits on the 300 ppm group, which
survived through the end of the study, the degeneration was diffuse and
severe with virtually every tubule affected. In the three rabbits with
testicular degeneration in the 100 ppm group, more of a spectrum of
effects was noted in that within the same testes, some tubules were
relatively normal in appearance while others contained no germinal
elements at all. In the 30 ppm group, the microscopic degenerative
changes were apparent in the testes of only one of the two rabbits
observed to have decreased testes size in the gross pathological exam.
The microscopic degenerative changes observed in this animal were an
excess of tubules in which the germinal epithelium was thinner than
normal, with a complete complement of germinal stages but very few
spermatozoa

Histopathologic exam of the epididymis found that the epididymal sperm
content generally reflected the degree of testicular damage with
noticeable decreases in those cases which were moderately to severely
affected. Degenerating spermatic elements were commonly observed, but
secondary changes in accessory sex glands were not seen

Despite the small number of animals in each exposure group, a
significant dose-related effect was observed. Based upon the outcome of
decreased testes size, one of the outcomes identified by EPA as an
adverse reproductive outcome, the NOEL for reproductive effects of 2-ME
in rabbits is 30 ppm

Given that the NOEL for reproductive effects from 2-ME has been derived
from animal studies, OSHA believes that an uncertainty factor of 100 is
appropriate for derivation of the ADI as was the case for the assessment
of developmental risks from exposure to 2-ME. Here again, an uncertainty
factor of 100 provides a factor of 10 for inter-species variability and
a factor of 10 for intra-species variability. Therefore, based upon this
study Miller et al, the ADI for 2-ME would be 30/100 or 0.3 ppm on the
basis of reproductive risks. The ADI for 2-ME based on developmental
risks is 0.1 ppm, somewhat lower than the ADI based on reproductive
risks but the two ADIs are very close. Thus an ADI, of 0.1 ppm would
cover both reproductive and developmental effects, i.e. at this level
humans are unlikey to exhibit adverse effects (both reproductive and
developmental) similar to those observed in animals

3\. 2-EE

There are fewer studies of the reproductive effects of 2-EE in the
literature than there are of 2-ME, but like 2- ME, 2-EE has been found
to induce adverse reproductive effects in laboratory animals

This was the finding of Terrill et al who conducted a study for the
Chemical Manufacturers Association exposing rabbits to 2-EE (Exs. 4-108
and 5-084). Groups of ten male New Zealand white rabbits were exposed to
2-EE at concentrations of 25, 100, and 400 ppm through inhalation for 6
hours per day, 5 days per week, for 13 weeks. A group of ten male
rabbits served as controls. Food and water was provided to the animals
ad libitum except during periods of exposure when neither was available

All animals survived the exposure phase of the study. At terminal
sacrifice, all animals were given a complete gross post mortem exam.
Animals in the control and high dose groups were given a complete
histopathological exam, but for the low and middle dose groups, only the
bone marrow, the testes with epididymis, the kidneys, the liver, the
lymph nodes, the spleen, the thymus, and any observed gross lesion or
tissue mass were examined

In the 400 ppm group, there was a statistically significant decrease in
absolute testes weight and in testes weight relative to body weight.
Gross postmortem examination revealed that in three of the ten rabbits
from this group, there was slight focal tubule degeneration. Based upon
decreased testes weight, the NOEL for reproductive effects for 2-EE in
rabbits is 100 ppm

Although there are fewer animal studies of the reproductive effects of
exposure to 2-EE than 2-ME, the results of the animal studies are
supported by observation in human populations. In a study of male
workers at Precision Castparts Corporation, NIOSH reported significantly
reduced sperm count among workers exposed to 2-EE compared to workers
with no such exposure (Ex. 5-003). Welch et al also found reduced sperm
in a group of shipyard painters exposed to 2-EE, but theses workers were
also exposed to 2-ME, so it is impossible to determine whether the
effect was due to 2-EE, 2-ME, or both glycol ethers (Ex. 5-104). These
studies are discussed in greater detail in the Health Effects Section of
this preamble

Applying an uncertainty factor of 100 to the NOEL of 100 ppm reported by
Terrill et al in their study of New Zealand white rabbits, one would
arrive at an ADI of 100/100 or 1 ppm for 2-EE basee on reproductive
risk. Here again, however, the ADI must be based on developmental risks
as well as reproductive risks. The ADI for 2-EE based on developmental
risks is 0.5 ppm, lower than the ADI based reproductive risks. As is the
case for 2-ME, for 2-EE the ADI based on reproductive risks is very
close to the ADI based on developmental risks. At an ADI of 0.5ppm 2-EE
humans are unlikely to exhibit effects (both reproductive and
developmental) similar to those observed in animals

E. Assessment of Risk from Exposure to Glycol Ether Acetates

The acetates of 2-ME and 2-EE, 2-MEA and 2-EEA, have not been studied

**\[page 15567\]**

as extensively as have the parent compounds. As noted in the Health
Effects section of this preamble, however, the acetates have been shown
to induce adverse reproductive, developmental, and hematological effects
in animals similar to those induced by 2-ME and 2- EE. Furthermore, as
discussed in the Health Effects section, it has been shown that 2-MEA
and 2-EEA are metabolized to the same acetic acids, methoxyacetic acid
(MAA) and ethoxyacetic acid (EEA) respectively, by the same mediated
pathway, an alcohol dehydrogenase (ADH) mediated pathway, as their
parent compounds

Because of the similarity in induced effects between the acetates and
their parent compounds and because of the similarity in metabolism
between the acetates and their parent compounds, OSHA proposes that the
ADIs derived for the acetates be the same as for their parent compounds.
That is, the ADI for for 2-MEA is 0.1 ppm and the ADI for 2- EEA. is 0.5
ppm

There is some experimental evidence to support OSHA\'s proposal. As
reproductive toxicants, the acetates have been shown not only to induce
similar effects as their parent compounds, but also to induce these
effects at equivalent doses. Nagano et al found that male mice exposed
orally to 2-MEA at 500 mg/kg of body weight experienced significant
decreases in testicular weight. When this dose was converted to
mmole/kg, the authors found that on an equimolar basis, exposure to 2-ME
and 2-MEA resulted in similar effects (Ex. 4-135). Likewise, these
authors found that on an equimolar basis, male mice exposed to 2-EE and
male mice exposed to 2-EEA experienced similar adverse reproductive
outcomes (Ex. 4-135)

The acetate 2-MEA has not been tested for its potential to adversely
affect reproductive outcomes. Only limited data exist on 2-MEA,
according to CMA, because of the small production volume of this acetate
(Ex. 7-17). Nonetheless, CMA argues that although detailed evaluation of
the developmental toxicity of 2-MEA has not been conducted as it has for
2-ME, \"the NOELs determined for 2-ME can be reasonably employed for
assessing this compound. The likelihood that any effect it may cause
would occur through human metabolism of 2-MEA to 2-ME and then to the
active metabolite makes it reasonable to employ the NOELs for 2-ME to
protect humans against effects of 2-MEA\" (Ex. 7-17). OSHA concurs with
CMA\'s position

Unlike 2-MEA, 2-EEA has been tested to determine its potential as a
developmental toxicant. Nelson et al reported a statistically
significant excess of developmental effects in rats exposed to 2-EEA at
levels as low as 130 ppm (Ex. 5-091). This level was the lowest exposure
level used in this bioassay therefore no NOEL was established for this
study. Doe et al exposed pregnant Dutch rabbits to 0, 25, 100, or 400
ppm of 2-EEA, and the fetuses of rabbits exposed to levels as low as 100
ppm showed a dose-related increase in skeletal defects (Ex. 5-071). Tyl
et al exposed pregnant Fischer 344 rats and pregnant New Zealand white
rabbits to 0, 50, 100, 200, or 300 ppm of 2-EEA (Ex. 5-124). Here again,
100 ppm was the LOEL for developmental effects in both species. This
level, 100 ppm, is OSHA\'s current PEL for 2-EEA. Fifty ppm was
established to be the NOEL for both the rats and the rabbits. Because
Doe et al and Tyl et al established the same LOEL in two separate
studies and in two different species, it is reasonable to use the NOEL
from the Tyl et al study, 50 ppm of 2-EEA, as the NOEL for calculating
the ADI. As with the parent compounds, an uncertainty factor of 100 is
appropriate, and this would lead to an ADI of 50 ppm/100 or 0.5 ppm.
That is, at an ADI of 0.5 ppm 2-EEA, humans are likely to exhibit
effects similar to those observed in humans

OSHA\'s proposal for deriving ADIs for the acetates at the same level as
those for the parent compound also has support from a number of
commentors who responded to OSHA\'s ANPR. For example, NIOSH wrote that
a separate PEL for each of the acetates and their parent compounds
\"should not be necessary because of the similarities in the adverse
effects, the similarity in route of exposure, and the fact that in many
situations, several of the ethers and their acetates are used
simultaneously\" (Ex. 7-22). Similarly, Du Pont noted that
\"2-methoxyethanol (2-ME) and its acetate (2- MEA) and the \[sic\]
2-ethoxyethanol (2-EE) and its acetate (2-EEA) could be regulated
together because the toxic effects of these glycol ethers and their
respective acetates are the same\" (Ex. 7-28), and Kodak proposed the
same PELs for 2-ME and 2-MEA and for 2-EE and for 2-EEA, (Ex. 7-23),
although the levels proposed are different than those proposed by OSHA.
OSHA seeks comment on this approach to deriving ADIs for the glycol
ether acetates

F. Other Approaches to the Assessment of Risk for Glycol Ethers

1\. The Crump Risk Assessment

Under contract to OSHA, K.S. Crump and Company performed a risk
assessment for developmental and reproductive effects from exposure to
2-ME, 2-EE, and their acetates (Ex. 5-136). The data used for this
analysis were from the studies of developmental effects of exposure to
2- ME by Hanley et al (Exs. 4-042a and 4-106) and to 2-EE by Tinston,
Doe et al (Exs. 4-038 and 4-039; see also Ex. 5- 071) and the studies of
reproductive effects of exposure to 2-ME by Miller et al (Ex. 5-057) and
to 2-EE by Terrill et al (Exs. 4-108 and 5-084). At the time Crump
performed its analysis, no data were available on the developmental
effects of 2-EE as measured in litters. Therefore, Crump limited its
analysis of the developmental effects of 2-EE exposure to responses
observed in fetuses. No analyses were done on data from studies of the
acetates. Crump noted that \"2-MEA and 2-EEA are believed to be quickly
hydrolized to their corresponding glycol ether. Furthermore, evidence
suggests that from that point on, their metabolism and distribution
proceed in the same manner as the ether. If that is the case, a mole of
an ether will yield the same amounts of products as a mole of the
corresponding acetate. Moreover, a given air concentration in ppm
contains the same number of moles (1 ppm is about 41 micromoles per
cubic meter at standard temperature and pressure), for all chemicals.
Consequently, in the absence of data on the acetates needed for risk
assessment, it is reasonable to assume that the acetates and their
corresponding ethers will produce the same risks at equal air
concentrations, in ppm\" (Ex. 5-136)

The goal of the Crump risk assessment was to develop dose-response
models for developmental and reproductive effects. Only brief
descriptions of the models and methods used by Crump are presented here,
and the reader is referred to the Crump report (Ex. 5-136) for
additional details. Two approaches were taken to develop these models
for the outcomes of interest. The first of these applied methods similar
to those applied to cancer data, but the dose- response models
considered were non-linear or incorporated a threshold. Four models
employed this approach: the quantal linear regression (QLR) model, the
Weibull model, the continuous linear regression (QCR) model, and the
continuous power (CP) model. The QLR and Weibull models were used for
incidence data measured in fetuses, and

**\[page 15568\]**

therefore do not take litter size or intra-litter correlation (i.e. the
litter effect) into account. The QCR and CP models were used for
incidence data measured in litters, and they account for the litter
effect but not for litter size. The QLR and QCR models assume a
threshold with a linear response above the threshold. The Weibull and CP
models are non- threshold models but can be non-linear if indicated by
the data

The second approach taken by Crump was to consider two models recently
developed specifically for assessing developmental effects, (these
models use only litter data), and to modify these for the analysis of
the glycol ethers data. The first of these was developed by Kodell et
al. This model uses the beta-binomial distribution to account for the
litter effect and takes into account the effect of litter size on the
probability of a developmental effect. The second model considered by
Crump was originally put forth by Rai and Van Ryzin. This model takes
litter size into account but does not account for the litter effect. In
its analysis, Crump used two special cases of the Kodell model, the
Kodell-QLR model which assumes a threshold but is linear above the
threshold, and the Kodell-Weibull model which assumes no threshold but
can be non-linear. Only one case of the Rai and Van Ryzin model was
considered. This model assumes no threshold and is linear. Crump felt
the shortcomings of the Rai and Van Ryzin model made it less appropriate
for assessing risk than the other models considered

Crump applied the models described here only to data on developmental
outcomes. The models developed for use with litter data could not be
used with the data Crump had on reproductive outcomes because the data
Crump had measured these outcomes in individual animals and not litters.
Likewise, the models developed for use with litter data could not be
used with the data Crump had on developmental outcomes from 2-EE
exposure because, as noted above, litter data for these effects were not
available to Crump when it did its analysis. The models developed for
use with fetal data could have been used with the data on reproductive
outcomes, but Crump did not use these models to analyze the data on
reproductive effects because of the small number of animals used in
these bioassays

Although the goal of the Crump risk assessment was to develop
dose-response models for the outcomes of interest, two additional
approaches for determining a \"safe\" level of exposure were considered.
The first of these was to calculate a NOEL using a
no-statistical-significance-of- trend or NOSTASOT approach. In this
approach, tests of statistical hypothesis were conducted to determine
whether the bioassay data provided sufficient statistical evidence to
conclude that a dose-related trend existed, (i.e. whether response
increased with dose), and if so, to determine the highest dose used in
the bioassay such that there was no statistical evidence of a
dose-related trend in response at that dose or at lower doses. The
highest dose which showed no statistical evidence of a dose-related
trend is called the NOSTASOT dose and is considered to be a
statistically determined NOEL. This approach was used for both
developmental and reproductive outcomes for both 2-ME and 2- EE

The final approach considered by Crump was calculation of a benchmark
dose as an alternative to the NOEL. A benchmark dose is defined as the
statistical 95% lower confidence limit on the dose corresponding to a 1%
increase in the extra risk. The dose corresponding to a 1% increase in
extra risk was estimated using both the QLR model and Weibull model, but
only the lower of the two benchmark doses was reported. Crump chose to
use only these two models to estimate the benchmark doses because these
two models were the only two used to analyze all of the data on adverse
reproductive outcomes for both 2-ME and 2-EE

The NOSTASOT dose and the benchmark dose calculated by Crump are much
like the NOELs calculated by OSHA in that neither of these doses alone
represents a \"safe\" level of exposure. Rather, Crump intended an
uncertainty factor to be applied to either of these doses, although
Crump did not recommend a particular uncertainty factor in his report.
Crump argues that either is preferable to a NOEL established using
traditional methods because they make use of all of the dose-response
data. Crump notes that NOELs \"determined by comparing treatment groups
individually to the control group . have low power because they involve
only the animals in two of the treatment groups, when in fact the data
from any intermediate doses are also relevant. Thus a common result is
that the trend test is significant, but none of the treated groups
differ significantly from the control group.\"

Results of the Crump analysis are presented in Tables VI- K through
VI-N. Although the sources of the data used by Crump were the same as
those used by OSHA, the adverse outcomes considered and the specific
estimates of incidence were different. These data are presented in the
Crump report

Table VI-K shows that for 2-ME, NOELs established using the NOSTASOT
approach are identical to those established by OSHA using more
traditional methods. For 2-EE, Table VI-L shows that for all but one
outcome in rats, total abnormal ribs, Crump\'s NOSTAOTs are the same as
OSHA\'s NOELs, but for rabbits, Crump\'s NOELs are lower. This
difference is due to the fact that Crump used fetus data for its
analysis of 2-EE whereas OSHA used litter data in its analysis to
establish the NOEL

  ----------------- ----------------- ----------------- -----------------
  Table VI-K                                            

  NOSTASOT and                                          
  Benchmark Doses                                       

  Calculated for                                        
  2-ME Data Sets                                        
  (a)                                                   

                                                        

  DEVELOPMENTAL                                         
  EFFECTS                                               

                                                        

                                      NOSTASOT (b)      Benchmark (c)

  Species           Adverse Effect    Exposure (ppm)    Dose(ppm)

                                                        

  Rats (d)          Delayed           10                12
                    ossification of                     
                    Centra                              

                    Rib spurs         10                8.5

                    Major             10                53
                    malformations                       

  Rabbits(d)        Resorptions       10                2

                    Major             10                10
                    malformations                       

  Mice (e)          Resorptions       10                9.3

                    Extra lumbar ribs 10                2.5

  REPRODUCTIVE                                          
  EFFECTS                                               

                                                        

                                      NOSTASOT          Benchmark

  Species           Adverse Effect    Exposure (ppm)    Dose (ppm)

  Rats (f)          Testicular        100               N/C (g)
                    degeneration                        

  Rabbits(f)        Testicular        30                N/C
                    degeneration                        

                                                        

  **\[page                                              
  15569\]**                                             

                    Reduced testes    30                N/C
                    size                                

                                                        
  ----------------- ----------------- ----------------- -----------------

a - From the Crump Report, Ex. 5-136\
b - NOSTASOT = No statistical significance of trend (i.e. the NOSTASOT
exposure is the highest dose for which dta did not show a statistically
significant dose-related trend). See text for details\
c - Benchmark exposure is the 95% lower limit on doses corresponding to
an extra risk of 1%. See text for details\
d - Data from Hanley et al, Ex. 4-042a\
e - Data from Hanley et al, Ex. 4-106\
f - Data from Miller et al, Ex. 4-045\
g - N/C = not calculated

  ----------------- ------------------- ----------------- -----------------
  Table VI-L                                              

  NOSTASOT and                                            
  Benchmark Doses                                         

  Calculated for                                          
  2-EE Data Sets                                          
  (a)                                                     

                                                          

  DEVELOPMENTAL                                           
  EFFECTS                                                 

                                                          

                                        NOSTASOT(b)       Benchmark(c)

  Species           Adverse Effect      Exposure (ppm)    Dose (ppm)

                                                          

  Rats (d)          Minor skeletal      50                15
                    defects                               

                    Minor visceral      50                46
                    defects                               

                    Total abnormal ribs 10                1.8

                    Late intra-uterine  50                18
                    deaths                                

  Rabbits(e)        Minor skeletal      N/D (f)           3.5
                    defects                               

                    Skeletal variants   10                2.2

                                                          

  REPRODUCTIVE                                            
  EFFECTS                                                 

                                                          

                                        NOSTASOT          Benchmark

  Species           Adverse Effect      Exposure (ppm)    Dose (ppm)

                                                          

  Rabbits(g)        Focal tubule        100               N/C (h)
                    degeneration                          

                    Weights of          100               N/C
                    testes/epididymis                     

                                                          
  ----------------- ------------------- ----------------- -----------------

a - From the Crump Report, Ex. 5-136\
b - NOSTASOT = No statistical significance of trend (i.e. the NOSTASOT
exposure is the highest dose for which dta did not show a statistically
significant dose-related trend). See text for details\
c - Benchmark exposure is the 95% lower limit on doses corresponding to
an extra risk of 1%. See text for details\
d - Data from Tinston et al, Ex. 4-038\
e - Data from Tinston et al, Ex. 4-039\
f - Not defined. A significant effect was seen at the lowest dose\
g - Data from Terrill et al, Ex. 4-108\
h - N/C = not calculated

For almost every adverse outcome considered, Tables VI- K and VI-L show
that the benchmark dose is lower than the NOEL estimated using the
NOSTASOT approach. Here again, this could be due to the fact that
benchmark doses were estimates from models which use fetal data rather
than litter data. Were benchmark doses to be used to calculate the ADIs,
the result would be a more conservative estimate of the exposure below
which an adverse outcome is unlikely than the estimates derived by OSHA

Tables VI-M and VI-N show that despite the differences among the models
used by Crump, for the majority of data sets the models predict
surprisingly consistent risks. The largest difference in predicted risks
are found at low doses between the threshold and non-threshold models.
Much less difference can be attributed to whether the models use fetal
or litter data. Crump suggests one reason that the shape of the
dose-response curve is more important in determining a risk estimate
than the type of data used may be the low intra-litter correlation
estimated for the 2-ME data sets. Crump explains that \"\[f\]or the rat
data, intra-litter correlations, as estimated by the Kodell-QLR or
Kodell- Weibull models, did not exceed 0.05 . Somewhat larger
correlations were observed in some of the rabbit and mouse data sets
(ranging up to about 0.27). Apparently, intra- litter correlations of
this magnitude are not sufficient to cause maximum-likelihood estimates
derived ignoring the litter effect to be seriously in error.\"

  --------------- --------- ----------- --------- ----------- --------- ----------- --------
  Table VI-M                                                                        

  Estimates of                                                                      
  Number of Extra                                                                   
  Cases                                                                             

  of Various                                                                        
  Developmental                                                                     
  Effects                                                                           

  per 1000 Fetus                                                                    

  from Exposure                                                                     
  to 2-ME a                                                                         

                                                                                    

  Rats: Delayed                                                                     
  Ossification of                                                                   
  the Centra b                                                                      

                                                                                    

                                                              Kodell-   Kodell-     Rin and

  Dose(c)         QLR       Weibull     QCR       CP          QLR       Weibull     Van
                                                                                    Ryzin

                                                                                    

  25              33        31          30        27          33        31          25

                  \(50\)    \(51\)      \(47\)    \(47\)      \(46\)    \(270\)     \--

  5               4         4.1         3.6       3.1         4.1       4.1         3.1

                  \(10\)    \(10\)      (9.3)     (9.4)       (8.2)     \(62\)      \--

  1               0         0.54        0         0.36        0         0.54        0.57

                  \(2\)     (2.1)       (1.9)     (1.9)       (0.48)    \(13\)      \--

  0.5             0         0.23        0         0.14        0         0.23        0.28

                  \(1\)     \(1\)       (0.93)    (0.94)      \(0\)     (6.4)       \--

  0.1             0         0.03        0         0.016       0         0.03        0.056

                  (0.2)     (0.21)      (0.19)    (0.19)      \(0\)     (1.3)       \--

  0.03            0         0.0066      0         0.0033      0         0.0065      0.017

                  (0.061)   (0.062)     (0.056)   (0.057)     \(0\)     (0.38)      \--

                                                                                    

  Rats: Rib Spurs                                                                   
  b                                                                                 

                                                                                    

                                                              Kodell-   Kodell-     Rin and

  Dose(c)         QLR       Weibull     QCR       CP          QLR       Weibull     Van
                                                                                    Ryzin

                                                                                    

  25              89        75          89        86          97        82.4        89

  **\[page                                                                          
  15570\]**                                                                         

                  \(120\)   \(120\)     \(150\)   \(150\)     \(130\)   \(132\)     \--

  5               3.8       5.8         0         7.3         6.7       7.2         16

                  \(24\)    \(24\)      \(30\)    \(30\)      \(27\)    \(28\)      \--

  1               0         0.43        0         0.62        0         0.61        3

                  (4.8)     (4.9)       (6.1)     \(6\)       (5.6)     (5.6)       \--

  0.5             0         0.14        0         0.22        0         0.21        1.5

                  (2.4)     (2.5)       \(3\)     \(3\)       (2.8)     (2.8)       \--

  0.1             0         0.011       0         0.018       0         0.018       0.3

                  (0.48)    (0.49)      (0.61)    (0.6)       (0.56)    (0.57)      \--

  0.03            0         0.0015      0         0.0029      0         0.0028      0.091

                  (0.15)    (0.15)      (0.18)    (0.18)      (0.17)    (0.17)      \--

                                                                                    

  Rats: Total                                                                       
  Major                                                                             
  Malformations b                                                                   

                                                                                    

                                                              Kodell-   Kodell-     Rin and

  Dose(c)         QLR       Weibull     QCR       CP          QLR       Weibull     Van
                                                                                    Ryzin

                                                                                    

  25              6.2       6.2         6.5       6.5         5.3       5.4         6.2

                  \(15\)    \(15\)      \(10\)    \(12\)      \(13\)    (N/P)       \--

  5               1.3       1.3         1.3       1.3         0.64      0.97        1.3

                  (3.1)     (3.1)       \(2\)     (2.4)       (2.6)     (N/P)       \--

  1               0.25      0.25        0.26      0.26        0         0.18        0.25

                  (0.62)    (0.62)      (0.41)    (0.47)      (0.53)    (N/P)       \--

  0.5             0.13      0.13        0.13      0.13        0         0.084       0.13

                  (0.31)    (0.31)      (0.2)     (0.24)      (0.27)    (N/P)       \--

  0.1             0.025     0.025       0.026     0.026       0         0.015       0.025

                  (0.062)   (0.062)     (0.041)   (0.047)     (0.053)   (N/P)       \--

  0.03            0.0075    0.0075      0.0078    0.0078      0         0.0042      0.0075

                  (0.019)   (0.019)     (0.012)   (0.014)     (0.016)   (N/P)       \--

                                                                                    

  Rabbits:                                                                          
  Resorptions b                                                                     

                                                                                    

                                                              Kodell-   Kodell-     Rin and

  Dose(c)         QLR       Weibull     QCR       CP          QLR       Weibull     Van
                                                                                    Ryzin

                                                                                    

  25              140       140         150       150         150       150         180

                  \(190\)   \(190\)     \(210\)   \(210\)     \(240\)   \(240\)     \--

  5               31        31          29        29          33        33          49

                  \(41\)    \(41\)      \(43\)    \(43\)      \(53\)    \(53\)      \--

  1               6.2       6.2         5.8       5.8         6.7       6.7         10

                  (8.3)     (8.3)       (8.6)     (8.6)       \(11\)    \(11\)      \--

  0.5             3.1       3.1         2.9       2.9         3.3       3.3         5.2

                  (4.2)     (4.2)       (4.3)     (4.3)       (5.5)     (5.5)       \--

  0.1             0.62      0.62        0.58      0.58        0.67      0.67        1.1

                  (0.84)    (0.84)      (0.86)    (0.86)      (1.1)     (1.1)       \--

  0.03            0.19      0.19        0.18      0.18        0.2       0.2         0.32

                  (0.25)    (0.25)      (0.26)    (0.26)      (0.33)    (0.33)      \--

  25              430       2.2         360       1.4         420       36          230

                  \(490\)   \(290\)     \(430\)   \(220\)     \(520\)   \(280\)     \--

  5               0         0           0         0           0         0.0001      19

                  \(0\)     (5.4)       \(0\)     (3.5)       \(0\)     (6.3)       \--

  1               0         0           0         0           0         0           3.3

                  \(0\)     (0.088)     \(0\)     (0.056)     \(0\)     (0.12)      \--

  0.5             0         0           0         0           0         0           1.6

                  \(0\)     (0.015)     \(0\)     (0.0094)    \(0\)     (0.022)     \--

  0.1             0         0           0         0           0         0           0.31

                  \(0\)     (0.00024)   \(0\)     (0.00015)   \(0\)     (0.00042)   \--

  0.03            0         0           0         0           0         0           0.094

                  \(0\)     (0.00001)   \(0\)     \(0\)       \(0\)     (0.00002)   \--

                                                                                    

  Mice:                                                                             
  Resorptions d                                                                     

                                                                                    

                                                              Kodell-   Kodell-     Rin and

  Dose(c)         QLR       Weibull     QCR       CP          QLR       Weibull     Van
                                                                                    Ryzin

                                                                                    

  25              35        35          45        45          44        44          51

                  \(65\)    \(65\)      \(80\)    \(80\)      \(78\)    \(78\)      \--

  5               7.1       7.1         8.9       8.9         8.9       8.9         19

                  \(13\)    \(13\)      \(16\)    \(16\)      \(16\)    \(16\)      \--

  1               1.4       1.4         1.8       1.8         1.8       1.8         4.2

                  (2.7)     (2.7)       (3.2)     (3.2)       (3.3)     (3.3)       \--

  0.5             0.72      0.72        0.89      0.89        0.89      0.89        2.1

                  (1.3)     (1.3)       (1.6)     (1.6)       (1.6)     (1.6)       \--

  0.1             0.14      0.14        0.18      0.18        0.18      0.18        0.43

                  (0.27)    (0.27)      (0.32)    (0.32)      (0.033)   (0.033)     \--

  0.03            0.043     0.043       0.054     0.054       0.053     0.053       0.13

                  (0.08)    (0.08)      (0.096)   (0.096)     (0.098)   (0.098)     \--

                                                                                    

  Mice: Extra                                                                       
  Lumbar Ribs d                                                                     

                                                                                    

                                                              Kodell-   Kodell-     Rin and

  Dose(c)         QLR       Weibull     QCR       CP          QLR       Weibull     Van
                                                                                    Ryzin

                                                                                    

  25              140       140         160       160         140       140         140

                  \(190\)   \(190\)     \(240\)   \(240\)     \(240\)   \(240\)     \--

  5               29        29          31        31          30        30          34

                  \(41\)    \(41\)      \(48\)    \(48\)      \(52\)    \(52\)      \--

  **\[page                                                                          
  15571\]**                                                                         

  1               4.2       5.7         6.2       6.2         6.2       6.2         7.2

                  (8.4)     (8.4)       (9.6)     (9.5)       \(11\)    \(11\)      \--

  0.5             1.1       2.8         3.1       3.1         3.1       3.1         3.6

                  (4.2)     (4.2)       (4.8)     (4.8)       (5.4)     (5.4)       \--

  0.1             0         0.54        0.62      0.62        0.62      0.62        0.73

                  (0.84)    (0.84)      (0.96)    (0.95)      (1.1)     (1.1)       \--

  0.03            0         0.16        0.19      0.19        0.19      0.19        0.22

                  (0.25)    (0.25)      (0.29)    (0.29)      (0.32)    (0.32)      \--

                                                                                    
  --------------- --------- ----------- --------- ----------- --------- ----------- --------

a - From the Crump Report, Ex. 5-136. The models considered are the
quantal linear regression (QLR) model, the Weibull model, the continuous
linear regression (QCR) model, the continuous power (CP) model, two
cases of the Kodell model - the Kodel-QLR model and the Kodel-Weibull
model, and the Rai and Van Ryzin model. The number in parentheses are
the 95% upper confidence limit on risk. No 95% upper confidence limit
was calculated for the Rai and Van Ryzin model. See text for details\
b - Dose is adjusted by a factor of 8/6. See the Crump report for
details\
c - Data from Hanley et al, Ex. 4-042a\
d - Data from Hanley et al, Ex. 4-106

  ----------------------- ----------------------- -----------------------
  Table VI-N                                      

  Estimates of Number of                          
  Extra Cases                                     

  of Various                                      
  Developmental Effects                           

  per 1000 Fetus                                  

  from Exposure to 2-EE a                         

                                                  

  Rats: Minor Skeletal                            
  Defects b                                       

                                                  

  Dose c                  QLR                     Weibull

  5                       0                       1.8

                          \(0\)                   \(15\)

  1                       0                       0.065

                          \(0\)                   (1.4)

  0.5                     0                       0.015

                          \(0\)                   (0.51)

  0.25                    0                       0.0037

                          \(0\)                   (0.19)

  0.1                     0                       0.00056

                          \(0\)                   (0.049)

                                                  

  Rats: Minor Visceral                            
  Defects b                                       

                                                  

  Dose c                  QLR                     Weibull

  5                       1.4                     1.4

                          (2.8)                   (2.8)

  1                       0.29                    0.29

                          (0.56)                  (0.56)

  0.5                     0.14                    0.14

                          (0.28)                  (0.28)

  0.25                    0.072                   0.072

                          (0.14)                  (0.14)

  0.1                     0.029                   0.029

                          (0.056)                 (0.056)

                                                  

  Rats: Total Abnormal                            
  Ribs b                                          

                                                  

  Dose c                  QLR                     Weibull

  5                       37                      23

                          \(45\)                  \(44\)

  1                       7.5                     3.7

                          (9.1)                   (8.9)

  0.5                     3.8                     1.7

                          (4.6)                   (4.5)

  0.25                    1.9                     0.76

                          (2.3)                   (2.2)

  0.1                     0.75                    0.27

                          (0.91)                  (0.9)

                                                  

  Rabbits: Minor Skeletal                         
  Defects d                                       

                                                  

  Dose c                  QLR                     Weibull

  5                       19                      0

                          \(27\)                  \(21\)

  1                       3.9                     0

                          (5.5)                   (4.3)

  0.5                     1.9                     0

                          (2.7)                   (2.2)

  0.25                    0.97                    0

                          (1.4)                   (1.1)

  0.1                     0.39                    0

                          (0.55)                  (0.43)

                                                  

  Rabbits: Skeletal                               
  Variants d                                      

                                                  

  Dose c                  QLR                     Weibull

  5                       29                      29

                          \(41\)                  \(41\)

  1                       6                       6

                          (8.4)                   (8.4)

  0.5                     3                       3

                          (4.2)                   (4.2)

  0.25                    1.5                     1.5

                          (2.1)                   (2.1)

  0.1                     0.6                     0.6

                          (0.84)                  (0.84)

                                                  

  Rabbits: Late                                   
  Intra-uterine Death d                           

                                                  

  Dose c                  QLR                     Weibull

  5                       0                       0.0035

                          \(15\)                  \(15\)

  1                       0                       0.000022

                          \(3\)                   \(3\)

  0.5                     0                       0.000002

                          (1.5)                   (1.5)

  0.25                    0                       0

                          (0.74)                  (0.74)

  0.1                     0                       0

                          (0.3)                   (0.3)

                                                  
  ----------------------- ----------------------- -----------------------

a - From the Crump Report, Ex. 5-136. The models considered are the
quantal linear regression (QLR) model, the Weibull model, the continuous
linear regression (QCR) model, the continuous power (CP) model, two
cases of the Kodell model - the Kodel-QLR model and the Kodel-Weibull
model, and the Rai and Van Ryzin model. The number in parentheses are
the 95% upper confidence limit on risk. No 95% upper confidence limit
was calculated for the Rai and Van Ryzin model. See text for details\
b - Dose is adjusted by a factor of 8/6. See the Crump report for
details\
c - Data from Tinston et al, Ex. 4-038\
d - Data from Tinston et al, Ex. 4-039

Crump notes that although the maximum likelihood estimates (MLEs) of
risk are similar regardless of whether one accounts for the litter
effect, the 95% upper confidence level (UCL) can be noticeably affected.
Crump states that for \"several data sets for which the maximum
likelihood estimates are similar when estimated by the QLR (or Weibull)
model and the Kodell-QLR (or Kodell-Weibull) model (e.g. extra lumbar
ribs in mice, for which the intra-litter correlation estimates are
highest), the upper limits are smaller when the litter effect is
ignored.\"

For 2-ME, the models and data sets predict a range of risks of
developmental effects from 2.2 to 430 per 1000 fetuses at the current
OSHA PEL of 25 ppm. The lowest risk comes from the Weibull model applied
to data on total major malformations in rabbits. The highest risk comes
from the QLR model applied to these same data. Crump attributes this
large spread within the same data set to the non-linearity of the
dose-response relationship and \"the lack of experimental evidence
regarding the dose-response curve between 10 and 50 ppm.\" Crump
concludes that if \"there had been an additional experimental exposure
between 10 ppm and 50 ppm, the difference among the models would likely
have been sharply reduced.\"

For 2-EE, Crump did not estimate risks at the current OSHA PEL of 200
ppm. The highest dose level which Crump considered for its analysis of
2-EE was 5 ppm. At this exposure level, the models and data sets predict
a range of risk of developmental effects from 0 to 37 per 1000 fetuses.
The lowest risk comes from the QLR model applied to data on minor
skeletal defects in rats. The highest risk comes from the same

**\[page 15572\]**

model applied to data on total abnormal ribs in rats.

At 0.1 ppm, Table VI-M shows that the predicted risks of developmental
effects range from 0 to .67 per 1000 fetuses when derived from models
which incorporate thresholds and from approximately zero to 1.1 per 1000
fetuses when derived from models which do not incorporate thresholds. At
0.5 ppm, Table VI-N shows that the predicted risks of developmental
effects range from 0 to 3 per 1000 fetuses when derived from the model
which incorporates a threshold and from approximately zero to 3 per 1000
fetuses when derived from the model which does not incorporate a
threshold

Although Crump\'s approach provides methods for quantifying reproductive
and developmental risks, none of the methods proposed in the report has
been generally accepted within the risk assessment community. The
NOEL/uncertainty factor approach, on the other hand, has broad
acceptance for the assessment of reproductive and developmental risks.
Furthermore, Crump\'s risk assessment provides no criteria for selecting
one model or method over another. Since none of the models has a
biological basis, it is impossible to determine which is the most
appropriate model to use. Given the broad range of risks predicted from
each of the models, some criteria must be developed for choosing one or
another before Crump\'s approach can be used for quantitative risk
assessment. For these reasons, OSHA has not relied upon the Crump report
as the basis of its quantitative risk assessment for glycol ethers

Crump\`s risk assessment raises a number of issues including whether
developmental and reproductive risks can be quantified and these issues
deserve serious discussion. In addition to proposing dose-response
models for quantifying the risk of developmental effects, Crump has
proposed two alternatives, the NOSTASOT dose and the benchmark dose, to
the traditional NOEL used by OSHA in its risk assessment. OSHA seeks
comment on the issues raised in this report as well as on the specific
methodology employed by Crump to quantify the risk of adverse
reproductive and developmental effects

2\. The Hattis Risk Assessment

In an attempt to quantify the reproductive and developmental risks
associated with glycol ethers exposure, Dale Hattis et al developed
three quantitative approaches: one for estimating the risks of adverse
effects on male fertility (Ex. 5-109); one for estimating the risks of
adverse developmental outcomes (Ex. 5-121); and one for estimating the
risks of infant mortality (Ex. 5-121). To estimate risks on male
fertility, sperm counts and pharmacokinetically-derived exposures from
workers exposed to 2-ME and 2-EE were used as a basis for estimating
percentage reductions in fertility. Animal studies in which 2-ME and
2-EE induced fetal death and fetal malformations were used as a basis
for estimating the risk of adverse developmental outcomes in human
fetuses. Animal studies in which 2-ME and 2-EE induced fetal weight
reduction were used as a basis for estimating the risk of infant
mortality in humans. The following discussion briefly summarizes these
approaches. For a more complete description of these analyses and the
underlying assumptions, the original studies should be consulted

a\. Risk Analysis on Male Fertility Effects (Ex. 5-109)

The goal of this analysis was to quantify the effects on male fertility
that could be expected from reductions of sperm counts induced by 2-EE
and 2-ME. Thus sperm count was the basic measure used to calculate a
risk of infertility. The authors acknowledged that sperm counts are not
ideal for this purpose because sperm counts are only one of several
parameters (e.g. % normal sperm, % motile sperm, and age of patient)
that are known to have an effect on male reproductive potential. In
addition the authors stated that a direct relationship between sperm
count and male fertility performance may be an over simplification.
However the authors chose sperm counts because no other type of sperm
quality parameters were available in the underlying data used for this
quantitative analysis

The sources of experimental data used in this analysis included (1) a
pharmacokinetic model developed by Hattis et al for 2-EE (Ex. 5-095),
(2) worker exposure studies on shipyard painters (Exs.5-101, 5-102 and
5-103) and foundry workers (Ex. 5-003) and (3) a quantitative model
developed by Meistrich (Ex. 4-161) for estimating sperm reduction
factors and increases in excess infertility

In their pharmacokinetic analysis (Ex. 5-095), Hattis et al developed
four different pharmacokinetic models using clinical data from studies
in which human volunteers were exposed to 2-EE. These models described
the uptake and metabolism of 2-EE to its primary metabolite ethoxyacetic
acid (EAA). The models also described the urinary excretion of EAA.
Mathematical formulas derived from these models were presented as a
means for calculating 2-EE equivalent air exposure levels from urinary
EAA excretion data

As a first step in the risk analysis, urinary EAA excretion data from
the foundry workers and the shipyard painters were converted to 2-EE
equivalent air exposures (ppm) using the formulas derived from the
Hattis et al pharmacokinetic model. The authors noted that the shipyard
painters also had \"appreciable\" exposures to 2-ME. Thus 2- EE
equivalents for these workers were adjusted to account for 2-ME. This
was accomplished by assuming that 2-ME was 4.3 times more potent than
2-EE (based on animal studies ) and that workers were exposed to 0.8 ppm
2-ME for every 2.6 ppm 2-EE

In the second step of this analysis, sperm counts were analyzed and
found to decline among both sets of workers although neither of the
observations from these groups was statistically significant. The
percent reduction in sperm count for these groups of workers was then
compared to the calculated 2-EE equivalents air levels:

  ----------------- ----------------- ----------------- -----------------
                                                        

                                      2-EE equivalent   Overall %

                                      (ppm-8 Hr/day)    Sperm

                                                        Count

                                                        Reduction

                                                        

  Shipyard Painters                                     

                    Arithmetic Mean   6.1               27.5

                    Geometric Mean    4.9               

  Foundry workers                                       

                    Arithmetic Mean   13.9              14

                    Geometric Mean    12.8              

                                                        
  ----------------- ----------------- ----------------- -----------------

The authors noted that results from both of these studies reinforced one
another showing suggestive declines in sperm counts with 2-EE exposure.
However these results indicate that there is a stronger sperm reduction
effect with lower dose among the shipyard painters. Possible
explanations offered by the authors included (1) chance statistical
fluctuations in the data and (2) potential peak exposures prior to
sampling the population. Nevertheless, the shipyard painter data was
selected for the authors \"best estimate\" risk projections as this
study had more complete exposure data and a larger number of workers,
making this study \"more likely representative of reality\"

In the final step in this analysis, work by Meistrich (Ex. 4-161) was
applied to sperm count reductions calculated in

**\[page 15573\]**

the previous steps to estimate an \"excess infertility risk\". Meistrich
developed a method, using testicular toxicity data in rats and analyses
of sperm count distributions in \"fertile\" and \"infertile\" couples,
to calculate the \"risk of infertility\" as a function of sperm count.
In his model Meistrich defined infertility as the degree of subfertility
required to bring about a need to consult a physician. Meistrich assumed
that a 1% increase in infertility (i.e. 1 in 100 couples) was an
\"acceptable risk\". He also assumed that the background risk of
infertility in the general population was 15%. Using these assumptions
and definitions, Meistrich estimated that a 1% increase in excess
infertility corresponds to a sperm reduction factor of 1.24. Using this
basic relationship, Hattis et al. calculated sperm reduction factors and
corresponding increases in excess infertility for the sperm count
reductions observed among the shipyard painters at various 2-EE
equivalent air exposures:

  ----------------- ----------------- ----------------- -----------------
                                                        

  Geometric Mean    \% sperm count    reduction         excess

  dose (ppm)        reduction         factor            infer-

  8 Hr-TWA                                              tility

                                                        

  0.89              5.70              1.06              0.25%

  1.72              10.80             1.12              0.50%

  3.28              19.40             1.24              1.00%

  4.9               27.5              1.38              1.58%

  5.97              32.40             1.48              2.00%

                                                        
  ----------------- ----------------- ----------------- -----------------

Based on the results of this analysis Hattis concluded that in order to
achieve a goal of having no more than 1 in 100 couples (i.e. 1%)
suffering \"infertility\", exposures to 2-EE must be kept below a
geometric mean of 3.3 ppm. Achieving a goal of no more than 1 in 400
couples suffering infertility would require exposures 1/4 of that level
(i.e. 0.82 ppm). Furthermore assuming that 2-ME is 4.3 times more potent
than 2-EE, Hattis estimates that a corresponding dose for 2-ME of 0.46
ppm would be required to assure that no more than 1 in 100 couples will
suffer from infertility

These quantitative estimates must be viewed in light of the
uncertainties and assumptions used to calculate them. First, both the
shipyard painter and foundry worker studies had a small number of
exposed workers with sperm count reductions bordering on statistical
significance. Furthermore, as noted by Hattis et al, as well as the
original authors of the shipyard painter studies, the EAA excretion
levels calculated from these may be a poor proxy for exposures
associated with sperm count reduction. The EAA excretion levels
represented exposure to 2-EE in the last few days whereas the sperm
counts which were measured at approximately the same time. would have
been effected by exposures weeks earlier. Because the shipyard painters
changed tasks at the shipyard frequently, EAA excretion levels
representing these workers\' exposure within the last few days may not
adequately represent exposure levels weeks earlier which would have been
responsible for the sperm counts collected

Second, the Meistrich approach for calculating sperm reduction factors
assumes a \"one-hit\" killing function for sperm which may or may not be
biologically correct. Furthermore Meistrich uses a very subjective
definition of infertility (i.e. degree of subfertility required to bring
about the need to consult a physician)

These sources of uncertainty are compounded by the uncertainty of the
2-EE air equivalents which were calculated using the Hattis
pharmacokinetic model. This pharmacokinetic model carries with it its
own set of assumptions and uncertainties. Thus considerable uncertainty
is associated with the quantitative estimates derived from this risk
analysis on male fertility

b\. Risk Analysis on Developmental Effects (Ex. 5-121)

The goal of this analysis was to quantify the risk of adverse
developmental effects associated with in utero exposure to glycol
ethers. Two separate approaches were employed. In the first approach,
quantal effects data from animal studies (e.g. fetal death and
malformations) were used to estimate the risk of similar adverse effects
in humans. In the second approach, continuous effects data from animal
studies (e.g. changes in fetal weight) were used to project changes in
birth weight and potential changes in infant mortality in humans.
Quantal Effects Analysis

Hattis et al selected six different animal studies examining the
developmental toxicity of various glycol ethers. \[Andrew and Hardin
(Ex. 5-069), Doe (Ex. 5-0710, Hardin and Eisenmann (Ex. 5-097), Weir
(Ex. 5-120), Greene (Ex. 5-096), and Hanley et al (Ex. 4-120)\]. These
studies reported statistically significant increases in the incidence of
adverse developmental effects including fetal death, skeletal defects,
external malformations and digit or limb malformations. Dose response
data from the animal studies were used to calculate an ED50 for those
effects which were statistically significantly different from the
controls. An ED50 is the dose at which 50% of an otherwise unaffected
proportion of the population suffers an effect. The ED50 was derived
using a log-probit analysis. This probit analysis assumes that effects
occur in individual animals when specific thresholds of dose are
exceeded and that there is a lognormal distribution of thresholds in the
exposed group of animals or humans. ED50s from the animal studies were
then converted to 8 hour human ED50s (ppm). This ED50 represents a dose
at which 50% of an population will be affected by the chemical after an
8 hour exposure. Overall ED50 estimates were derived by taking geometric
means of ED50s calculated for 2-ME and 2-EE for individual effects. Six
\"best estimates\" were derived in this manner. These \"best estimates\"
were then used to calculate the doses of 2-ME or 2-EE corresponding to
risks of one in a hundred (10-2), one in ten thousand (10-4) and one in
a million (10-6) for a particular developmental effect (Table VI-O)

  --------------- -------------- -------------- -------------- --------------
  TABLE VI-O                                                   

  Doses (ppm) at                                               
  \"Best                                                       
  Estimate\"                                                   
  Risks of One in                                              
  a Hundred,                                                   

  One in Ten                                                   
  Thousand, and                                                
  One in a                                                     
  Million                                                      

                                                               

                  ED50           Dose           Dose           Dose

  Response        humans         (ppm)          (ppm)          (ppm)

                  8 hr(ppm)      at 10-2        at 10-4        at 10-6

                                 risk           risk           risk

                                                               

  post                                                         
  implantation                                                 
  loss                                                         

  2-EE            127            8.7            1.8            0.53

  2-ME            16             1.1            0.22           0.067

  minor skeletal                                               
  defects                                                      

  2-EE            5.3            0.36           0.073          0.022

  malformations                                                

  2-EE                                                         

  \"external\"    255            17             3.5            1.1

  2-ME                                                         

  \"total\"       9.9            0.68           0.14           0.042

  **\[page                                                     
  15574\]**                                                    

  \"forepaw\"     35             2.4            0.48           0.147

                                                               

  Extracted from                                               
  Table 3-7,                                                   
  Hattis et al,                                                
  (Ex. 5-121)                                                  
  --------------- -------------- -------------- -------------- --------------

Assuming that a ppm exposure in humans would present the same risk as
those observed in animals, Hattis et al concluded that these projections
suggest that doses as low as 0.36 ppm 2-EE would produce a risk of one
in a hundred for skeletal defects and doses as low as 0.68 ppm 2-ME
would produce a risk of one in a hundred for total malformations. It is
interesting to note that from these two estimates 2-ME appears to be
less potent than 2-EE which is contrary to most of the experimental data

Continuous Effects Analysis

In this analysis animal data showing fetal weight reduction after
exposure to 2-ME and 2-EE were used to calculate percentage reductions
in fetal weight as a function of dose of 2-ME or 2-EE. For purposes of
this analysis it was assumed that animals and humans would exhibit equal
growth retardation for a given rate of glycol ether exposures expressed
in ppm-hours per day. It was further assumed that percentage changes in
fetal weight prior to birth would reflect similar percentage changes in
birth weight. Percentage reductions in birth weight could then be used
to project likely effects on infant mortality

As a first step, Hattis et al analyzed birth weight distributions and
infant mortality rates from both black and white infants in the United
States . These distributions were used to derive a relationship between
infant mortality and birth weight changes

As a second step, the relationship between fetal weight reduction (i.e.
birth weight reduction) and the dose of 2-ME or 2-EE from the animal
studies were combined with the relationship between birth weight changes
and infant mortality from human infants. These two sets of relationships
were used together to estimate expected changes in infant mortality for
a given 8 hour exposure to 2-EE or 2-ME. Table VI-P presents the
projected changes in infant mortality due to possible changes in infant
birth weight associated with 2-EE and 2-ME exposures

  ----------------------- ----------------------- -----------------------
  TABLE VI-P                                      

  Projected Changes in                            
  Infant Mortality Due to                         
  possible Changes                                

  in Infant Birth Weights                         
  Associated with 2-ME                            
  and 2-EE Exposures                              

  PPM Exposure            Projected %             Total Excess

  Level                   Birthwt Reduction       Infant Mortality

                                                  

  2-EE:                                           

  0.01                    .0003                   1.45 x 10-7

  0.1                     .003                    1.45 x 10-6

  1                       .03                     1.45 x 10-5

  5                       .15                     7.3 x 10-5

  25                      .75                     3.7 x 10-4

  2-ME:                                           

  0.01                    .00243                  1.18 x 10-6

  0.1                     .0243                   1.18 x 10-5

  1                       .243                    1.18 x 10-4

  5                       1.215                   6.1 x 10-4

  25                      6.075                   3.6 x 10-3

                                                  
  ----------------------- ----------------------- -----------------------

Extracted from Table 4-6, Hattis et al (Ex. 5-121)

As was the case for the male fertility analysis, the quantitative
estimates derived from both the quantal and continuous effects data
incorporate a number of large assumptions. The largest of these may be
the assumption that a particular defect observed in an animal will
translate into a similar defect in humans. As discussed earlier in the
Health Effects section of this preamble, although adverse developmental
effects in animals provide clear evidence of a chemical\'s potential
ability to perturb development in humans, the effects observed in
animals may not necessarily be identical to those which could
potentially occur in humans. Even the authors themselves acknowledge
that the risk calculations are based on a series of assumptions which
carry considerable uncertainty. OSHA acknowledges that assumptions are
often necessary for quantitative risk analyses. However given the lack
of knowledge about the biological processes involved in reproductive and
developmental toxicity, OSHA believes that the assumptions of these
quantitative analyses may carry much more uncertainty than for other
types of health outcomes such as cancer where the biological mechanisms
are better understood

In summary, the quantitative approaches of Hattis et al are very
innovative. These approaches however, require that a number of large
assumptions be made. These assumptions create considerable uncertainty
in the quantitative risk estimates which are derived. In addition, the
underlying data upon which these approaches are constructed have
weaknesses of their own which further compound the uncertainties in the
risk estimates. Nevertheless, these approaches do provide a starting
point for a discussion of the quantitative risk assessment for
reproductive and developmental toxins. Therefore OSHA welcomes all
comments and analyses on these approaches for deriving quantitative risk
estimates for adverse reproductive and developmental effects

3\. The Environ Risk Assessment

Under contract to the Chemical Manufacturer\'s Association (CMA),
Environ Corporation prepared a report entitled \"Scientific Basis for
Safety Factors Needed to Protect Workers from Reproductive Toxicities of
Glycol Ethers\" (Ex. 4-016f). This report contains a brief review of the
data available for a qualitative analysis of the health effects
associated with glycol ethers and their acetates, but the primary focus
of the report is the choice of uncertainty factor for determining an
acceptable daily intake (ADI) for each of the substances

Environ\'s approach for choosing an uncertainty factor, (which Environ
refers to as a safety factor), was to compare the lowest effective dose
(i.e. the LOEL) in humans measured in milligrams per kilogram per day
for ten substances known to cause developmental effects with the lowest
effective dose measured in milligrams per kilogram per day in the most
sensitive species of animal in which the substance has been tested and
in which the observed effects were similar to those in humans. These
data come from two sources: a 1981 report from the Council on
Environmental Quality (CEQ) entitled \"Chemical Hazards to Human
Reproduction\" and a 1984 report from the National Center for
Toxicological Research (NCTR) entitled \"Reliability of Experimental
Studies for Prediction of Hazards to Human Development.\" By examining
these data on other developmental toxicants,

**\[page 15575\]**

Environ sought to obtain information which could be \"useful for judging
the magnitude of the uncertainty factor needed to protect humans from
the developmental effects of \[glycol ethers\].\"

> Environ drew two conclusions from its analysis:
>
> 1\. Application of a safety factor of 10 to NOELs from the most
> sensitive animal species would have been adequate to protect humans
> from the effects of most developmental toxicants for which
> quantitative dose-response data are available; and
>
> 2\. A safety factor of 50, similarly applied, would have been adequate
> to protect humans from the effects of all developmental toxicants for
> which quantitative human dose-response data are available, although
> this factor may not have been adequate for one substance, thalidomide,
> assuming the rabbit (rather than the most sensitive species) had been
> chosen as the basis for establishing acceptable human exposures. If
> the most sensitive species had been chosen for thalidomide, a safety
> factor of 10-20 would have been adequate

Environ supplemented this approach with an examination of historical
precedents for the selection of uncertainty factors used to protect
worker populations from the types of toxicity associated with glycol
ethers or from other serious forms of toxicity. Environ stated that such
information, \"while not strictly scientific in nature, can further
assist decision-making because it reveals the range of safety margins
which other responsible decision-makers have accepted, and presumably
reveals the safety margins that have proved adequate to protect worker
populations. Information on the expected relative susceptibilities of
the worker and the general populations and on how this has influenced
the selection of safety factors will also be useful.\"

Environ looked at the guidelines or standards for protecting workers
from reproductive hazards developed by OSHA, NIOSH, ACGIH, and the
American Industrial Hygiene Association (AIHA) \"in order to provide an
estimation of the margin of safety associated with \[their\] standards
and guidelines.\" Environ noted that \"\[u\]nlike the case of standards
developed for general population exposure to chemicals, \[for worker
populations\] there has been no generic approach we can identify for the
application of safety factors to the NOEL identified in experimental
animals. This is true for both reproductive and other non- carcinogenic
effects.\"

Environ found that as of 1985, the date of the Environ report, OSHA had
regulated five substance principally on the basis of reproductive
toxicity. These substances and their respective margins of safety were
carbaryl, 5 times lower than the NOEL identified in animals; carbon
disulfide, 1.3 times higher than the LOEL identified in animals; DBCP,
38 times lower than the NOEL identified in animals; chloroprene, 5 to 25
times higher than the LOEL identified in humans; and PCBs, 6 times lower
than the LOEL identified in humans. (OSHA notes that the Environ report
was written prior to promulgation of OSHA\'s Final Rule for Air
Contaminants, 29 CFR Part 1910, published January 19, 1989. In that
rulemaking, OSHA reduced the permissible exposure limits for both carbon
disulfide and chloroprene.) In comparison, Environ found that NIOSH used
uncertainty factors in its recommended standards for the same five
substances ranging from 1 for a 15 minute exposure ceiling for
chloroprene to 6000 for PCBs. The ACGIH had issued TLVs for all these
substances except DBCP, and these TLVs ranged from 2 to 10 times higher
than the LOEL identified in humans for chloroprene to 6 times lower than
the LOEL identified in animals for PCBs. According to Environ, the AIHA
had established a workplace environmental exposure level only for the
reproductive toxicant piperidine, and in making its recommendation, the
AIHA provided no margin of safety below the NOEL for embryotoxicity in
the rat

On the basis of its analysis of the CEQ data, the NCTR data, and
historical precedent, Environ concludes that \"the 100-fold \[safety\]
factor has not been used for worker protection\" and \"there is support
for a safety factor of 10 as adequate to protect workers against the
developmental toxicities of the \[glycol ethers and their acetates\].\"
Environ goes on to note that a safety factor of 10 \"appears to be
adequate to cover most cases and it also accords with most past
occupational risk management practices. If one seeks a margin that has
limited historical precedent but which appears more certain to cover all
likely cases, then a factor of 50 is recommended.\"

Noting that the factors 10 and 50 are not alternatives and that \"it may
be reasonable to settle on a factor between these two values\", Environ
applied these two uncertainty factors to the NOELs identified for the
glycol ethers and their acetates. In its review of the literature,
Environ, like OSHA, found the NOELs to be 10 ppm for 2-ME, 10 ppm for
2-MEA, 50 ppm for 2-EE, and 50 ppm for 2-EEA. (Environ found no data on
the reproductive effects of 2-MEA, and like OSHA, used the NOEL
identified for 2-ME to estimate the ADI for 2-MEA.) In its estimation of
the ADI\'s, however, Environ took a different approach. First, that
species most sensitive to the effects of the glycol ethers or their
acetates was identified. In each case, this was found to be the rabbit.
Next, the NOEL was converted from units of ppm to units of milligrams
per kilogram per day. Then, the safety factors of 10 or 50 were applied
to the converted NOEL to arrive at two estimates of the ADI. These
estimates, in turn, were converted back to units of ppm assuming human
parameters. Results of these calculations are presented in Table VI-Q

  ------------ ---------- ---------- ---------- ---------- ---------- ------
  Table VI-Q                                                          

  Estimates of                                                        
  Acceptable                                                          
  Human Daily                                                         
  Intakes                                                             
  (ADIs)                                                              

  Of Four                                                             
  Glycol                                                              
  Ethers                                                              

  Based on                                                            
  Animal Data                                                         
  and Safety                                                          
  Factors of                                                          
  10 and 50 a                                                         

                                                                      

  Glycol       NOEL b     ADI/10 c   ADI/50 d   ADI/10 e              

  ADI/50 f                                                            

  Ether        mg/kg/d    Species    mg/kg/d    mg/kg/d    ppm        

  ppm                                                                 

  2-ME         4.3        Rabbit     0.43       0.086      0.9        

  0.18                                                                

  2-EE         25.5       Rabbit     2.6        0.52       4.6        

  0.92                                                                

  2-MEA        6.7 g      0.67       0.13       0.9                   

  0.18                                                                

  2-EEA        18.8       Rabbit     2.6        0.52       4.6        

  0.92                                                                

                                                                      
  ------------ ---------- ---------- ---------- ---------- ---------- ------

a - From the Environ Report (Ex. 4-016f)\
b - The NOEL identified in the most sensitive species converted from
units of ppm to units of milligram per kilogram per day\
c - ADI based on a safety factor of 10 and measured in units of
milligrams per kilograms per day\
d - ADI based on a safety factor of 50 and measured in units of
milligrams per kilograms per day\
e - ADI based on a safety factor of 10 and measured in units of ppm as
an 8 hour time weighted average\
f - ADI based on a safety factor of 50 and measured in units of ppm as
an 8 hour time weighted average\
g - No data available. Assumes 2-MEA is equipotent with 2-ME on a mole
basis.

**\[page 15576\]**

The interesting result in Table VI-Q is that the ADIs estimated by
Environ using a uncertainty factor of 50 are not very different than the
ADIs estimated by OSHA using an uncertainty factor of 100 without
conversion of the NOEL to milligrams per kilogram per day. For 2-ME and
2-MEA, Environ found the ADI to be 0.18 ppm whereas OSHA found the ADI
to be 0.1 ppm. For 2-EE and 2-EEA, Environ found the ADI to be 0.92 ppm
whereas OSHA found the ADI to be 0.5 ppm. Obviously, the results are not
so similar when an uncertainty factor of 10 is used

Despite the similarity in results, OSHA has a number of concerns about
the approach used by Environ to estimate the ADI for the glycol ethers
and their acetates. First of all, OSHA questions the appropriateness of
using the CEQ data and the NCTR data to establish the magnitude of
safety factors needed to protect humans from the developmental effects
of glycol ethers. Environ acknowledges a number of the data\'s
limitations including the varying quality and extensiveness of the data
bases from which these data were drawn, the subjective determination
regarding the meaning of the term \"lowest effective dose\", the
relatively small number of compounds examined, and the difficulty of
obtaining accurate estimates of the human doses responsible for
producing developmental toxicity

OSHA believes that these limitations alone make these data unsuitable
for the use to which Environ has put them. OSHA, however, sees
additional limitations. Environ is comparing experimental LOELs in the
most sensitive species to LOELs observed in humans to determine adequate
safety factors. Implicit in this approach is the assumption that
experimental LOELs are the \"true\" LOELs and that any exposure below
that LOEL for either humans or animals will not result in adverse
effects. As noted in a previous section of this risk assessment, there
is in fact little reason to believe that the LOEL (or NOEL) identified
in any study is indeed the \"true\" LOEL. Environ\'s approach makes no
allowance for such a possibility

Another limitation which Environ acknowledges is that it is not known
whether the empirical relationships observed in the data reflect only
interspecies differences or whether they reflect both interspecies
differences and intraspecies differences. Environ concludes that it
\"seems likely although it is not certain, that the empirical relations
discussed above would be protective of the most sensitive members of the
human population\", but OSHA notes that the opposite conclusion could
just as easily be drawn. If the human data represent responses for the
mid-range of the distribution of human responses, then, as Environ
states, \"the empirical relations reflect only interspecies differences,
and an additional safety factor would seem necessary to compensate for
intraspecies variability.\"

OSHA is also concerned about Environ\'s use of historical precedent to
determine the margin of safety acceptable for protecting worker
populations. Of the five substances reported by Environ to have been
regulated by OSHA on the basis of reproductive toxicity, all but one,
DBCP, were adopted as consensus standards by the Agency in 1971 under
Section 6(a) of the Occupational Safety and Health Act of 1970. Under
that Section of the Act, Congress directed the Agency to \"promulgate as
an occupational safety and health standard any national consensus
standard, and any established Federal standard, unless \[the Secretary
of Labor\] determines that the promulgation of such a standard would not
result in improved safety or health for specifically designated
employees\" (29 U.S.C. 651 et seq). In the case of DBCP, the only one of
the five substances to be considered individually in a 6(b) rulemaking,
the standard set by OSHA, as Environ acknowledges, was constrained by
technological feasibility and not by acceptable margin of safety. In as
much as standards for four of these substances were adopted without
consideration of the individual substance and the standard for the fifth
was constrained by technological feasibility, it is disingenuous of
Environ to conclude that OSHA finds any particular margin of safety as
acceptable for working populations

Finally, OSHA questions the appropriateness of Environ\'s conversion of
NOELs from units of ppm to units of milligrams per kilograms per day to
estimate an ADI. On the one hand, Environ states that with regard to
interspecies differences, \"the available data on the ethers show a
remarkably consistent pattern among the species tested. This suggests
that the 10-fold factor conventionally used for interspecies
extrapolation is not indicated.\" On the other hand, when the NOEL is
converted into units of milligrams per kilogram per day, this
\"remarkable\" consistency vanishes. For example, for 2-ME, Environ
found that a NOEL of 10 ppm in rabbits corresponds to 4.3 mg/kg/day. For
mice, however, the NOEL of 10 ppm found by Hanley et al (Ex. 4-106)
corresponds to approximately 9.2 mg/kg/day, (using the mean weight for
the 10 ppm exposure group on day 12, half-way through exposure, and
assuming, like Environ, 100% absorption), more than two times greater
than the NOEL for rabbits measured in the same units. For rats, the NOEL
of 10 ppm found by Hanley et al (Ex. 4-042a) corresponds to
approximately 5.93 mg/kg/day (also using the mean weight for the 10 ppm
group on day 12, half-way through exposure, and assuming 100%
absorption.) Thus, if Environ is going to convert the NOEL into units of
milligrams per kilogram per day, an adjustment for interspecies
variation must be considered

OSHA seeks comment on whether the NOEL should be expressed in units of
ppm or units of milligrams per kilogram per day. A number of commentors
support the latter measure including CMA (Ex. 7-17) and NIOSH (Ex.
7-22), but the Agency notes that those commentors who calculated their
own ADIs did no such conversion of units (see, for example, Ex. 7-23).
Furthermore, the Agency is uncertain as to how one would convert a NOEL
from units of ppm to units of milligram per kilogram per day from a
study of developmental effects. Animals exposed during gestation are
gaining weight rapidly. Thus, as a study progresses, the dose an animal
receives decreases in terms of milligrams per kilogram per day. Clearly
weight gain will be a function not only of the genetics of an individual
animal but also of the number of fetuses a pregnant female is carrying.
OSHA seeks comment on whether these factors should be accounted for in
measuring dose, and if so, how this should be done

VII\. Significance Of Risk

OSHA believes that the type of significant risk analysis the Agency has
undertaken in this rulemaking is consistent with the studies generally
available and, for the reasons set forth below and in the section on
risk assessment, is a valid, accepted and customary scientific approach

Section 6(b)(5) of the OSH Act vests authority in the Secretary of Labor
to issue health standards. This section provides, in part, that :

The Secretary, in promulgating standards dealing with toxic materials or
harmful physical agents under this subsection, shall set the standard
which most adequately assures, to the extent feasible,on the basis of
the best available evidence, that no employee will suffer material
impairment of health or functional capacity even if such employee has
regular exposure to the hazard dealt

**\[page 15577\]**

with by such standard for the period of his working life.

OSHA is required to make two threshold findings before it can issue a
health standard under section 6 (b)(5) of the Act. In accordance with
the Supreme Court\'s decision in the benzene case, Industrial Union
Department, AFL\\CIO v. American Petroleum Institute, 448 U.S. 601, 642
(1980), OSHA may promulgate a standard only if it finds that it is at
least more likely than not that the risk OSHA seeks to regulate is
\"significant\" and that the change in practices contemplated in the
issuance of a standard would reduce or eliminate that risk

OSHA\'s analytical approach to making a determination that a significant
risk of material impairment exists from exposure to hazardous materials
or harmful physical agents in the workplace takes into consideration a
number of factors that are consistent with recent court interpretations
of the Act and with rational, objective policy formulation. As
prescribed by section 6(b)(5) of the Act, OSHA examines the body of the
\"best available evidence\" on the adverse effects of the toxic
materials or harmful physical agents to determine the nature and extent
of possible health consequences resulting from exposure to the hazard in
question. Where possible, quantitative assessments are conducted and the
results are considered along with other relevant information, such as
the nature and severity of the health consequences, as well as other
qualitative evidence and expert opinion, to determine whether a hazard
poses a significant risk to workers

The Court gave some general guidance to the Agency for determining
significant risk:

Some risks are plainly acceptable and others are plainly unacceptable.
If, for example, the odds are one in a billion that a person will die
from cancer by taking a drink of chlorinated water, the risk clearly
could not be considered significant. On the other hand, if the odds are
one in a thousand that regular inhalation of gasoline vapors that are 2
percent benzene will be fatal, a reasonable person might well consider
the risk significant and take the appropriate steps to decrease or
eliminate it. (I.U.D. v. A.P.I., 448 U.S., 607, 655)

The Court indicated, that where possible, the determination of
significant risk should be based upon quantitative risk assessment.
However, recognizing the uncertainties involved, the Court qualified its
predilection for quantitative assessment, saying:

\[T\]he requirement that a \"significant\" risk be identified is \"not a
mathematical straitjacket. It is OSHA\'s responsibility to determine, in
the first instance, what it considers to be a \"significant\" risk. Id.
The Court also pointed out that: OSHA is not required to support its
findings that a significant risk exists with anything approaching
scientific certainty. . . .\[Section\] 6 (b)(5) \[of the Act\]
specifically allows the Secretary to regulate on the basis of the \"best
available evidence.\" . . . Thus, so long as they are supported by a
body of reputable scientific thought, the Agency is free to use
conservative assumptions . . .risking error on the side of
overprotection rather than under protection. Id., at 656.

The Court noted that the ultimate determination that a particular level
of risk is significant \"will be based largely on policy
considerations.\" Id., at 655-56, n. 62

Quantification of risk, the Court understood, cannot be achieved for
every hazard. The four-judge plurality, speaking for the Court in the
benzene decision, did not intend to require OSHA to do what cannot be
done. The concurring opinion of Mr. Justice Powell and the dissenting
opinion of Mr. Justice Marshall, speaking for four other members of the
Court, confirm this. Mr. Justice Powell stated:

The statutory preferences for the \"best available evidence\" . .
.implies that OSHA must use the best known techniques for the accurate
estimation of risks and benefits when such techniques are available. But
neither the statute nor the legislative history suggests that OSHA\'s
hands are tied when reasonable quantification cannot be accomplished by
any known methods. . . .In this litigation, OSHA found that \"it is
impossible to precisely quantify the anticipated benefits. . . \" If
this finding is supported by substantial evidence, the statute does not
prevent the Secretary from finding a significant health hazard on the
basis of the weight of expert testimony and opinion. I do not understand
the plurality to hold otherwise. Id., at 666-7.

Similarly, Mr. Justice Marshall, in dissent, stated \"\[i\]t is
fortunate indeed that at least a majority of the Justices reject the
view that the Secretary is prevented from taking regulatory action when
the magnitude of a health risk cannot be quantified on the basis of
current techniques\" and concluded that \"the Court appears willing not
to require quantification when it is not fairly possible.\" Id., 690,
716-17

As a part of the overall significant risk determination, OSHA considers
a number of factors. These include the type of risk presented, the
quality of the underlying data, the reasonableness of the risk
assessments, the statistical significance of the findings and the
significance of risk (48 FR 1864; January 14, 1983)

The types of risk posed by exposure to glycol ethers are of the most
serious kind. Developing fetuses exposed to glycol ethers may suffer the
effects of such exposure for a lifetime, leading to a life of dependency
instead of a life as a productive member of society. As noted by the
Office of Technology Assessment in its report on Reproductive Hazards in
the Workplace, \"risk to a fetus may also be a risk to the woman
herself. It may be direct, as in the risk of her own reproductive
health; less direct, as in the risk to her health posed by spontaneous
abortion; or indirect, in that she may suffer psychological damage and
diminished life prospects with the occurrence of a miscarriage or on the
birth of a dead or damaged baby.\" (Ex. 5-135, p. 330). It is also
important to note that the father may also share the harm caused by the
birth of a dead or damaged child

The reproductive effects from exposure to glycol ethers are not solely
loss of fertility, a serious effect in and of itself, but also include
major dysfunction of the reproductive organs. Obviously material
impairment of health includes not only death, but also impairments in
basic biological processes, such as normal reproductive function, which
can be of extraordinary personal importance. In its report on
Reproductive Hazards in the Workplace, OTA states, and OSHA agrees, that
\"\[c\]oncern about reproductive processes is not limited to the brief
periods in an individual\'s life during which reproduction may actually
occur. Reproductive function is an integral part of everyday human
health and well being. Before, during, and after the child bearing
years, reproductive hormones may act, for example, on such variables as
resistance to heart disease and cancer, immune function, complexion,
bone mineral content, and feeling and mood. Threats to reproductive
function can take place at nearly any point during an individual\'s life
span.\" (Ex. 5-135, p.43)

The hematological effects associated with exposure to glycol ethers may
be reversible but are nonetheless debilitating and may reduce a
worker\'s normal functional capacity. In addition, reduction in the
white blood cell count may compromise an individual\'s capacity to fend
off diseases, and for these reasons the hematological effects from
exposure to glycol ethers must be considered to represent additional
material impairment of health

The data which support the finding of adverse health effects from
exposure to glycol ethers are of the highest quality. As described in
the Health Effects Section of this preamble, studies in

**\[page 15578\]**

several animal species, by various routes of exposure, have consistently
shown that exposure to 2-ME, 2-EE and their acetates cause adverse
reproductive, developmental and hematological effects. For example, male
test animals exposed to 2-ME, 2-EE and their acetates have exhibited
interferences in spermatogenesis resulting in reduced sperm count and
decreased fertility. Exposed males have also exhibited degeneration of
the seminiferous tubules resulting in testicular atrophy. Pregnant
females exposed to these glycol ethers exhibited signs of maternal
toxicity such as decreases in maternal weight, decreased organ weights
and increases in the lengths of gestation. Developmental effects among
litters from exposed females include increased rates of resorptions
(early embryonic death), decreased litter sizes, decreased fetal
weights, visceral malformations, skeletal malformations, heart defects,
neurochemical alterations and behavioral abnormalities. Experimental
studies have also demonstrated exposure related decreases in several
blood parameters including white blood cell counts, red blood cell
counts and hemoglobin concentrations. Studies of humans exposed to these
agents have reported findings of testicular atrophy, reduced sperm count
and blood abnormalities

In this preamble, OSHA has assessed the risk of adverse health effects
from exposure to 2-ME, 2-EE, and their acetates and has determined that
exposure to these glycol ethers poses developmental, reproductive, and
hematological risks. While the Agency has assessed these risks, the
present risk assessment differs from most previous OSHA risk assessments
in that the Agency has not quantified the risks in the manner as it
usually does. Instead, OSHA has performed a risk assessment using an
uncertainty factor approach to determine its proposed permissible
exposure limits (PELs)

The uncertainty factor approach entails identifying the most appropriate
studies for each glycol ether (i.e., high quality studies using the most
sensitive species) and determining the no observed effect level (NOEL)
for each study. The NOELs are then divided by an uncertainty factor to
arrive at estimates of the acceptable daily intakes (ADIs). These ADIs
have been put forth as OSHA\'s proposed PELs

For 2-ME, the same NOEL was identified for reproductive effects in three
species: rats, rabbits, and mice. The replication of the NOEL in each of
these bioassays lends confidence that the finding of any individual
bioassay is not a statistical artifact. Likewise the replication of the
NOELs for reproductive effects in two species exposed to 2- EE, rats and
rabbits, also lends confidence in these studies\' results. A NOEL for
reproductive effects was identified in only one species for 2-EEA and in
no species for 2-MEA, (this last substance has not been tested), but
knowledge of the metabolism and pharmacokinetics of 2-ME and 2-EE
supports using the results of studies of these substances to assess the
risk from exposure to their acetates

OSHA\'s approach to the assessment of reproductive and developmental
risks is consistent with the approach to non- carcinogenic risk
assessment adopted by a number of governmental agencies and
international organizations including the U.S. Environmental Protection
Agency (EPA), the U.S. Food and Drug Administration (FDA), the Joint
Food and Agricultural Organization of the World Health Organization
(FAO/WHO), and the National Academy of Sciences (NAS). This approach is
favored because it requires no assumptions akin to those underlying
carcinogenic risk assessment (i.e., that cancer is a multi-stage
process). Little is known about the processes that lead to developmental
and reproductive effects from exposure to toxic substances, and there
are no generally accepted, biologically-based models for assessing these
risks

In addition, uncertainty factors and qualitative risk assessment have
been utilized in other health standards when there have not been
quantitative models available like those used to assess carcinogenic
risk. (e.g., Hazard Communication, 48 FR 53280; Ethylene Oxide, 49 FR
25734; Field Sanitation, 52 FR 16050; Formaldehyde, 52 FR 46196)1. In an
analogous context, the Court of Appeals for the District of Columbia
Circuit has upheld EPA\'s use of \"margins of safety\" in setting
ambient air standards to address uncertainties associated with
inconclusive scientific and technical information. American Petroleum
Institute v. Costle, 665 F.2d 1176, 1186-87 (1981), cert. denied, 449
U.S. 1042 (1980)

1 In the update of the air contaminants standard, 54 FR 2332,
uncertainty factors were also used in the significant risk analysis for
non-carcinogens. On July 7, 1992, the Court of Appeals for the Eleventh
Circuit determined that OSHA\'s use of uncertainty factors was
unsupported. OSHA has addressed the concerns raised by the Eleventh
Circuit in this preamble. In this and the preceding section, OSHA has
provided a detailed analysis of the data and evidence that supports use
of the NOEL-Uncertainty Factor approach as well as the appropriateness
of an uncertainty factor of 100. In addition, OSHA has requested public
comment on the appropriateness of the NOEL-Uncertainty Factor approach
for making risk assessment regarding reproductive/developmental health
effects and the use of an uncertainty factor of 100. Moreover, OSHA has
requested interested parties to discuss alternative safety factors and
methodologies for assessing risk of reproductive/developmental health
effects

OSHA\'s choice of an uncertainty factor for estimating a human ADI from
animal studies is also consistent with the recommendations of many of
these organizations. For example, the FDA recommends using an
uncertainty factor of 100 when NOELs are identified in chronic studies
(such as those used by OSHA) in animals. Likewise, the NAS recommends an
uncertainty factor of 100 when calculating an ADI from a NOEL found in
animals. Although the choice of uncertainty factor may appear to be
arbitrary, Dourson and Stara have provided a review of experimental
evidence supporting this choice (Ex. 4-113)

The 100-fold uncertainty factor used by OSHA in this risk assessment is
comprised of two factors: a ten-fold factor to account for inter-species
variability (i.e., varying sensitivity across species) and a ten-fold
factor to account for intra-species variability (i.e., varying
sensitivity among members of a population). By making these adjustments,
we increase the certainty that the ADI represents an exposure level
below which adverse effects are unlikely

By choosing a 100-fold uncertainty factor, however, OSHA is not
regulating below the level of significant risk. A ten-fold factor for
inter-species variability and a ten- fold factor for intra-species
variability are necessary to assure that exposure at or below the OSHA
proposed PELs will be unlikely to cause adverse health effects

The ten-fold factor for inter-species variability is necessary to
account for the potential differences between species\' sensitivity to
toxic agents. Differences in sensitivity may result from differences in
metabolism or differences in reproductive function. For example, as
noted by EPA in their guidelines for assessing male reproductive
toxicity (Ex. 5-123), males of most test species produce sperm in
numbers that greatly exceed the minimum requirements for fertility.
However, human males, in general, produce fewer sperm relative to the
number required for fertility. Thus, human males may be more sensitive
to a reduction in sperm, as they may function nearer to the threshold
for the number of sperm needed to ensure reproductive competence. Also
differences in sensitivity may result from differences in metabolism. In
the case of glycol ethers, both animals and humans appear to utilize the
same metabolic pathway to produce the same

**\[page 15579\]**

primary metabolite. This primary metabolite is generally considered to
be the active agent in the induction of adverse reproductive and
developmental effects. However, the evidence also indicates that the
biological half life of the metabolites in humans is greater than in
animals. Thus the accumulation rates between animals and humans are not
directly comparable. The above reasons reinforce the general support for
the use of a ten fold uncertainty factor for inter species variability

Furthermore, while it may appear that there is no inter-species
variation in the NOELs for 2-ME and 2-EE, as discussed in the Risk
Assessment Section of this preamble, this is a function of the study
designs used by Hanley et al and Tinston et al and does not prove there
is no inter- species variation in developmental risk from these glycol
ethers. Lastly, although the bounds of normal reproductive function can
be very broad, the complexity in the reproductive processes and the
difficulty in conducting studies on the broad range of possible outcomes
have resulted in experimental studies concentrating for the most part on
only a few distinct periods in normal reproductive functioning. OSHA has
relied upon these studies to determine the reproductive and
developmental risks associated with glycol ethers, but the limitations
of these studies provide additional support for a ten-fold factor for
inter-species variability

The ten-fold factor for intra-species variability is also necessary, and
use of this factor does not result in reducing insignificant risk.
Worker populations exposed to glycol ethers are not as homogeneous as
the animal populations used in experimental studies. Furthermore, even
if workers are healthier than the general population, it does not
necessarily follow that this \"healthy worker effect\" will be conferred
upon a developing fetus. In addition, both parents of the fetus need not
necessarily be \"healthy workers\", and the fetus may inherit the
genetic traits of either parent

In utilizing the uncertainty factors in setting the proper PELs for the
glycol ethers under consideration in this rulemaking, it has not been
the Agency\'s objective to apply an uncertainty factor to eliminate all
risk. If that had been the Agency\'s objective or mandate under the Act,
a much higher uncertainty factor would have to have been applied to
ensure elimination of all risks. Rather, the Agency has used uncertainty
factors to take into account only the highest uncertainties, such as
inter-species and intra-species variability. The Agency believes that it
has used the uncertainty factors in a reasonable manner and in utilizing
the uncertainty factors the Agency has had as its goal reducing risks
that are significant

After considering the severity of the types of risk as shown by the
qualitative analysis of the data, OSHA preliminarily concludes that
exposure to 2-ME, 2-EE and their acetates presents a significant risk to
employees exposed to these substances at the current PELs. The current
PELs for 2-ME and 2-MEA are 25 ppm, two and one-half times larger than
the NOEL for 2-ME in three species (i.e., 10 ppm). The current PELs for
2-EE and 2-EEA are 200 ppm and 100 ppm respectively. For 2-EE, this PEL
is four times greater than the NOEL identified in two species (i.e., 50
ppm), and for 2-EEA, this PEL is two times greater than the NOEL
identified in one species (i.e., 50 ppm). If the NOEL is an estimate of
the threshold of exposure resulting in adverse effects in animals, and
if humans have the same degree of sensitivity as animals, exposure at
the current PELs poses risk of material impairment of health. If humans
are more sensitive than animals and respond to exposure in a less
homogeneous manner, then the risk is greater still that workers exposed
at the current PELs will suffer adverse effects from such exposure

OSHA also preliminarily concludes that the new glycol ethers standard
will result in a reduction of significant risk. However as discussed
earlier in the section on Risk Assessment there are uncertainties to the
NOEL/Uncertainty Factor approach. It is assumed that at exposure levels
derived by dividing an experimental NOEL by an uncertainty factor of
100, humans are unlikely to exhibit effects observed in experimental
animals. However the ADI does not represent a level of exposure above
which there is significant risk and below which there is no significant
risk. For some individuals there may be some remaining risk below the
ADI. For these reasons OSHA believes that the ancillary provisions of
the standard such as exposure monitoring and medical surveillance will
provide greater assurance that workers will not be at significant risk.
Thus OSHA believes that these provisions are reasonably necessary

VIII\. Summary Of The Regulatory Impact And Regulatory Flexibility
Analysis

Introduction

Executive Order 12291 (46 FR 13197, Feb. 19, 1981) requires that a
regulatory analysis be conducted for any rule having major economic
consequences on the national economy, individual industries,
geographical regions, or levels of government. The Regulatory
Flexibility Act (5 U.S.C. 601 et. seq.) similarly requires the
Occupational Safety and Health Administration (OSHA) to consider the
impact of the proposed regulation on small entities

Consistent with these requirements, OSHA has prepared a Preliminary
Regulatory Impact and Regulatory Flexibility Analysis (PRIA) for the
proposed glycol ethers standard with 8-hour time-weighted average (TWA)
permissible exposure limits (PELs) of 0.1 parts per million (ppm) for 2-
methoxyethanol (2-ME) and 2- methoxyethanol acetate (2-MEA), and 0.5 ppm
for 2-ethoxyethanol (2-EE) and 2-ethoxyethanol acetate (2-EEA) (Ex.
5-165). This analysis describes the industries affected by the standard,
the regulatory alternatives considered, some of the potential benefits
that will accrue to employees exposed to glycol ethers at their places
of work, the costs of the proposed standard, and the technological and
economic feasibility of the proposed provisions. The following is a
summary of this analysis

Background

The chemicals 2-ME, 2-EE, 2-MEA, and 2-EEA are members of the family of
ethylene glycol ethers. Referred to collectively in this analysis as
\"glycol ethers\", these four chemicals have versatile solvent
properties that make them useful in a wide variety of industries. The
principal uses of glycol ethers are in chemical intermediates, paints
and coatings, inks, and electronics

The current OSHA PELs for 8-hour TWAs are 25 ppm for 2- ME and 2-MEA,
200 ppm for 2-EE, and 100 ppm for 2-EEA. They were established in 1971
based on the 1968 Threshold Limit Values (TLVs) recommended by the
American Conference of Governmental Industrial Hygienists (ACGIH). These
TLVs were based on hematotoxic and neurotoxic effects and on exposure
concentrations reported in the early case reports on human health
effects. More recent information from animal studies, however, indicates
that adverse reproductive effects may occur at much lower
concentrations. The ACGIH now recommends for all four glycol ethers an
8-hour TLV of 5 ppm, plus a \"skin\" notation to draw attention to the
need to prevent cutaneous absorption

In 1984, the U.S. Environmental Protection Agency (EPA) published an
Advance Notice of Proposed Rulemaking (ANPR) regarding 2-ME, 2-

**\[page 15580\]**

EE, 2-MEA, and 2-EEA. In 1986, the EPA referred the issue of rulemaking
for these chemicals to OSHA. Subsequently, OSHA made a preliminary
determination that the occupational risks identified by EPA could be
eliminated or reduced by a revised OSHA standard. In 1987, OSHA
published an ANPR announcing its intention to initiate rulemaking action
for four glycol ethers (OSHA Docket, Ex. 6.)

The objective of this analysis is to measure the regulatory impact of
the proposed TWAs and associated requirements, including Excursion
Limits (ELs) equivalent to five times each TWA and action levels (ALs)
equivalent to one-half of each TWA

The principal source of information for this analysis is a study
conducted for OSHA by PEI Associates, Inc., Technological Feasibility
and Economic Impact Assessment of a Proposed Revision to the Glycol
Ethers Standards, 1990, OSHA Docket, Ex. 5-164. A major source for
PEI\'s report was an earlier study conducted for OSHA by Meridian
Research, Inc., Industry Profile and Analysis of Processes, Occupational
Exposures, and Substitutes for Glycol Ethers, 1987, OSHA Docket, Ex.
5-108

PEI conducted three major data collection activities:

1\) All available monitoring data from work establishments were
collected, categorized, and tabulated. These historical data were
obtained primarily from OSHA, the National Institute for Occupational
Safety and Health (NIOSH), and a study that PEI had conducted previously
for EPA. Only post-1984 data were used because of a change in the limit
of detection in the glycol ether sampling and analytical method in 1984

2\) A joint PEI/NIOSH team visited nine facilities selected to be
representative of the industries currently manufacturing, processing,
and/or using at least one of the glycol ethers under consideration.
Information was obtained at each site regarding processes, use of
engineering and work practice controls and personal protective equipment
(PPE), characteristics of the exposed work force, medical and industrial
hygiene programs, and experience with substitute chemicals. To
characterize full-shift and peak exposures in each job category with
potential for exposure to glycol ethers, NIOSH also sampled at least one
shift at each site

3 )PEI mailed a survey questionnaire to approximately 2500 randomly
selected potential users of glycol ethers in order to characterize the
following:

-Extent of usage of glycol ethers in different industry segments

-Process operations

-Demographics of potentially exposed workers

-Engineering and work practice controls currently in place and those
necessary to achieve specified exposure levels

-PPE currently in place and PPE necessary to achieve specified exposure
levels

-Financial characteristics of the industries

-Experience with potential substitutes for glycol ethers

Usable responses were obtained from 1,424 facilities through the mail
questionnaire and subsequent telephone followup. Of the establishments
submitting usable responses, 70 percent had never handled any of the
four glycol ethers which are the subjects of this rulemaking, 13 percent
had discontinued handling them, and 17 percent currently handled at
least one of them

Based primarily on data from the survey questionnaire and site visits,
PEI developed model plants to represent average establishments in each
industry category. The model plants were used to develop an exposure
profile and estimate compliance costs. The number of model plants
developed for each industry category depended on market structure and
work force characteristics, including exposures. PEI also developed
model plants for small businesses

Industry Profile

The estimated 1987 domestic net sales (i.e., production less inventory
changes) of the four glycol ethers amounted to 286 million pounds. The
most widely distributed chemical was 2-EE (149 million pounds in 1987),
followed by 2-EEA (85 million pounds), 2-ME (51 million pounds), and
2-MEA (1 million pounds). The largest consumption category for these
chemicals was export (45 percent of sales), followed by use as chemical
intermediates (24 percent of sales). The remaining 31 percent of sales
of the glycol ethers was primarily for solvent use

Table VIII-1 presents estimates of the number of glycol ether-using
establishments covered by the proposed regulation, percent of small
establishments, total employment, and number of exposed workers.
Although jet fuel additives consume much 2-ME, they are excluded from
this analysis because they are used almost exclusively in military
applications. All other miscellaneous uses not addressed in this
analysis are estimated to account for less than 1 percent of total usage
of the glycol ethers

Sales of the four glycol ethers have declined steadily over the past
decade, probably as a result of increased concern over environmental and
health issues

Manufacture of Glycol Ethers

Four establishments operated by three companies (Union Carbide, Eastman
Chemical, and Oxy Petrochemical) currently produce at least one of the
four glycol ethers. (In 1990, Union Carbide, the sole producer of 2-MEA,
discontinued its manufacture and sale. A submission by the Chemical
Manufacturers Association (CMA) to OSHA reported that \"only a very few
users\" were working off inventories of 2-MEA, OSHA Docket, Ex. 3-002.)
Because of similarities in the production processes, plant capacity can
be shifted from one of the four

  ----------------- --------- --------- ----------- ------------------------------------------------------ --------- ----------
  TABLE VIII-1                                                                                                       

  GLYCOL ETHERS                                                                                                      
  INDUSTRY PROFILE                                                                                                   

                                                                                                                     

                    Estima-                                                                                          

                    ted                                                                                              

                    number                          Estimated Exopsed Workers                                        

                    of        Percent   Estimated   \_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_             

                    Estab-    small     total                                                                        

                    lish-     estab-    employ-                                                                      Females

                    ments     lish-     ment        Total                                                  Males     under

                    using     ments                                                                                  age

  Industry          glyco     (\*)                                                                                   45

  Category          ethers                                                                                           

                                                                                                                     

  Manufacture                                                                                                        

     of Glycol      4         0         5,120       344                                                    320       24

     Ethers                                                                                                          

  Manufacture                                                                                                        

     Of             5         0         44,500      80                                                     60        20

     Chemical                                                                                                        

     inter-                                                                                                          

     Mediates                                                                                                        

  Formulation                                                                                                        

     Of             183       57        13,176      2,745                                                  2,562     183

     paints and                                                                                                      

     Coatings                                                                                                        

  Aircraft          54        NA        244,782     1,998                                                  1,998     0

     manufacturing/                                                                                                  

     Repainting                                                                                                      

  Motor vehicle                                                                                                      

     Body           16        57        69,920      736                                                    736       0

     manufacturing                                                                                                   

  Other metal       366       55        37,698      1,464                                                  1,464     0

     applications                                                                                                    

  Automobile        8,777     75        43,885      26,331                                                 26,331    0

     refinishing                                                                                                     

  Wood                                                                                                               

     Furniture      370       67        27,750      8,140                                                  3,330     2,590

     manufacturing                                                                                                   

  Formulation                                                                                                        

     of inks        86        67        5,848       946                                                    860       86

  Inks                                                                                                               

  Application                                                                                                        

     of inks        86        89        11,180      946                                                    516       430

  Inks                                                                                                               

  Semiconductor     142       54        47,428      1,704                                                  710       852

     manufacturing                                                                                                   

  **\[page                                                                                                           
  15581\]**                                                                                                          

  Printed                                                                                                            

     Circuit        44        61        7,392       352                                                    220       132

     Board                                                                                                           

     manufacturing                                                                                                   

  Total             10,133    .         558,679     45,786                                                 39,107    4,317

                                                                                                                     
  ----------------- --------- --------- ----------- ------------------------------------------------------ --------- ----------

(\*) Establishments with fewer than 20 employees\
NA = Not Available\
Source: PEI chemicals to another, as well as to other ethylene oxide
derivatives

Manufacture of Chemical Intermediates

In addition to the plants that produce 2-EEA and 2-MEA, four major
producers of chemicals use 2-EE or 2-MEA as an intermediate in five
other plants: Eastman Chemical, Reichold Chemical, CPS Chemical, and
Sartomer Company. The major use of 2-EE (86 percent of domestic
consumption) is as a chemical intermediate. Its principal product is 2-
EEA; 2-EE is also used as a chemical intermediate in the manufacture of
ethoxyethyl methacrylate, ethoxyethyl ricinoleate, ethoxyethyl acrylate,
and di(ethoxyethyl) phthalate

The use of 2-ME as an intermediate to produce other chemicals, including
2-MEA, accounts for 24 percent of its domestic consumption. These
chemicals also include di(2- methoxyethyl) phthalate (DEMP), which is
used as a plasticizer in the manufacture of 35-mm film, vinyl-tris-B-
methoxyethoxysilane, methoxyethylacrylate, 2-methoxyethyl silicate,
methoxyethyl oleate, methoxyethyl acetyl ricinoleate, methoxyethyl
ricinoleate, and methoxyethyl stearate

Formulation of Paints and Coatings

Glycol ethers are used in polymerization, as a medium for pigment
dispersion, and as a \"let down\" solvent to achieve desired coating
application properties. They are used primarily in the formulation of
Original Equipment Manufacture (OEM) paints for automobiles, metal
furniture, and appliances and also as special-purpose coatings. The
formulation of paints and coatings involves mixing glycol ethers and
other solvents with resins, pigments, or base materials

Aircraft Manufacturing/Repainting

Glycol ethers are contained in aircraft top coat paint and sometimes in
paint additives. Aircraft are generally repainted every 4 to 5 years.
Painting takes place in open bays in aircraft hangars, where the paints
are applied by brush, roller, airless spray, or electrostatic spray.
Smaller parts and support equipment are usually spray painted in a
separate paint shop

Motor Vehicle Body Manufacturing

Glycol ethers can be contained in electrocoat primers that are initially
applied for corrosion protection, as well as in other primer and
exterior color coatings. Electrocoats are applied to vehicle bodies by
using conveyors to dip them into tanks containing the primer. Other
primers and paints are generally applied by electrostatic guns in spray
booths equipped with downdraft flow-through ventilation. Automatic spray
guns are used to apply the primer coats on passenger car bodies

Other Metal Applications

This industry category includes miscellaneous other establishments at
which paints and coatings are spray painted onto metal:

> SIC 2514 (Metal Household Furniture)\
> SIC 2522 (Metal Office Furniture)\
> SIC 3411 (Metal Cans)\
> SIC 3412 (Metal Shipping Barrels, Drums, Kegs, and Pails)\
> SIC 34421 (Metal Doors, Sash and Frames Except Storm Doors)\
> SIC 34699 (Other Stamped and Pressed Metal Products)\
> SIC 3523 (Farm Machinery and Equipment)\
> SIC 3563 (Air and Gas Compressors)\
> SIC 3631 (Household Cooking Equipment)\
> SIC 3632 (Household Refrigerators and Home and Farm Freezers)\
> SIC 3714 (Motor Vehicle Parts and Accessories)

Automobile Refinishing

Some paints and coatings used in automobile refinishing contain small
quantities of glycol ethers. Some spray painting operations take place
in a spray booth, while other painting operations occur in the general
shop environment. Wood Furniture Manufacturing

Glycol ethers are used in some wood stains or lacquers because of their
solvent properties. In general, the stains or lacquers are applied by
spraying in booths, followed by additional hand-padding operations. The
stains or lacquers may also be blended prior to the finishing
operations. Formulation of Inks

Glycol ethers are used as a solvent in inks, primarily in gravure,
flexographic, and screen inks. They serve as co- solvents for ink resins
and dyes in water-based inks. They are also used as solvents for textile
printing and as active solvents to dissolve organic dyes. Glycol ethers
are used in inks that are typically manufactured in small batches, to
achieve the desired viscosity

Application of Inks

Glycol ethers are used as ink solvents and thinners in silk screen,
flexographic, and gravure printing. In silk screening, solvent-based
inks are spread over and squeezed through the pores of a screen to print
an image. After printing, the screen is washed by hand with a lacquer
thinner. In flexographic printing, the plate with the image area is
fastened to a cylinder, which is then immersed into the ink-filled
reservoir of a letterpress. The image is transferred from the raised
surface of the plate to a

**\[page 15582\]**

flexible substrate. In gravure printing, an image is etched into the
surface of a cylinder, which is then immersed in the reservoir of a web
rotogravure or sheet-fed press. In a high-speed process, ink is
transferred from the cylinder to the substrate by a capil-lary action.
Printing operators may be exposed to glycol ethers during blending of
inks and cleaning of printing press rollers

Semiconductor Manufacturing

Glycol ethers are used primarily as photoresists in the
photolithographic portion of the wafer manufacturing process. The
photoresist may be applied to the silicon wafer either manually by
syringe or in an automated system that pumps the solution directly from
storage to a spin coater. Glycol ethers may also be used as components
of the inks used for marking the completed devices with a part number.
The cleaning compounds used to dissolve the epoxy resin that mounts
wafers to polishing fixtures also may contain glycol ethers

Printed Circuit Board Manufacturing

Glycol ethers are used as a solvent in epoxy resin that is laminated
onto fiberglass reinforcement. It is normally applied in enclosed spray
chambers. Glycol ethers also may be present in formulations used for
marking, bonding, and labeling the printed circuit boards

Worker Exposures

Workers may be exposed to glycol ethers in many of the activities in the
12 industry categories evaluated in this study. Table VIII-2 lists the
principal job categories in each industry category and the current
weighted plant geometric mean (GM) exposures and weighted plant
arithmetic mean (AM) exposures for each glycol ether

Geometric means are usually the preferred measure of expressing central
tendency for observations which are log- normally distributed. By
design, the formula for geometric means suppresses the value of outlying
data observations. When used in combination with prescriptions for
engineering controls to reduce employee exposure levels, for example, it
makes the case for technological feasibility clearer by using geometric
means (compared with a single arithmetic mean calculation, in which the
values of outlyers are not suppressed)

  -------------------------------------------------------------------------------------- ---- -------------- ---- ---------------------------------------------------- ---- -------------- ---- ------------ ---- -------------- ---- ------------------------------------------------------ ---- ---------------- ---- -------------- ---- ------------
  TABLE VIII-2                                                                                                                                                                                                                                                                                                                              

  EXPOSURE CHARACTERIZATION BY INDUSTRY AND JOB CATEGORY                                                                                                                                                                                                                                                                                    

                                                                                                                                                                                                                                                                                                                                            

                                                                                         \|                  \|                                                                                                                  \|                                                                                                         

  Industry                                                                               \|   Esti-          \|   Weighted plant                                                                                                 \|   Weighted plant                                                                                        

  catagory                                                                               \|   mated          \|   geometric mean                                                                                                 \|   arithmetic mean                                                                                       

     and                                                                                 \|   number         \|   baseline                                                                                                       \|   baseline                                                                                              

     job                                                                                 \|   of             \|   exposure, PPM                                                                                                  \|   exposure, PPM                                                                                         

  category                                                                               \|   expos-         \|                                                                                                                  \|                                                                                                         

                                                                                         \|   ed             \|   \_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_                                                             \|   \_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_                                                  

                                                                                         \|   work-          \|                                                        \|                  \|                \|                  \|                                                          \|                    \|                  \|   

                                                                                         \|   ers            \|   2-ME\*                                               \|   2-MEA\*        \|   2-EE\*       \|   2-EEA          \|   2-ME\*                                                 \|   2-MEA\*          \|   2-EE\*         \|   2-EEA

  \_\_\_\_\_\_\_\_\_                                                                     \|   \_\_\_\_\_\_   \|   \_\_\_\_\_                                           \|   \_\_\_\_\_\_   \|   \_\_\_\_\_   \|   \_\_\_\_\_\_   \|   \_\_\_\_\_                                             \|   \_\_\_\_\_\_\_   \|   \_\_\_\_\_\_   \|   \_\_\_\_\_

                                                                                                                                                                                                                                 \|                                                                                                         

  Manufacture of Glycol Ethers:                                                                                                                                                                                                  \|                                                                                                         

    All                                                                                                                                                                                                                          \|                                                                                                         

     workers                                                                                  344                                                                                                                                \|                                                                                                         

    Loading                                                                                                                                                                                                                      \|                                                                                                         

     Tech                                                                                     96                  0.046                                                     N/A                 0.022             0.027          \|   0.151                                                       \(a\)                 0.047               0.043

    Process                                                                                                                                                                                                                      \|                                                                                                         

     Tech                                                                                     72                  0.032                                                     N/A                 0.092             0.049          \|   0.044                                                       \(a\)                 0.177               0.077

    Lab Tech                                                                                  68                  0.023                                                     N/A                 0.015             0.023          \|   0.027                                                       \(a\)                 0.017               0.031

    Maint.                                                                                                                                                                                                                       \|                                                                                                         

     Tech                                                                                     92                  \(b\)                                                     N/A                 0.057             0.058          \|   \(b\)                                                       \(c\)                 0.079               0.116

    Super-                                                                                                                                                                                                                       \|                                                                                                         

     visor                                                                                    16                  0.017                                                     N/A                 0.026             0.017          \|   0.017                                                       \(a\)                 0.047               0.017

                                                                                                                                                                                                                                 \|                                                                                                         

  Manufacture of Chemical Intermediates\*\*:                                                                                                                                                                                     \|                                                                                                         

    All                                                                                                                                                                                                                          \|                                                                                                         

     workers                                                                                  80                                                                                                                                 \|                                                                                                         

     Tech                                                                                     50                  0.046                                                     N/A                 0.022             N/A            \|   0.151                                                       N/A                   0.047               N/A

    Process                                                                                                                                                                                                                      \|                                                                                                         

     Tech                                                                                     10                  0.032                                                     N/A                 0.092             N/A            \|   0.044                                                       N/A                   0.177               N/A

    Lab Tech                                                                                  10                  0.023                                                     N/A                 0.015             N/A            \|   0.027                                                       N/A                   0.017               N/A

    Maint.                                                                                                                                                                                                                       \|                                                                                                         

     Tech                                                                                     10                  \(b\)                                                     N/A                 0.057             N/A            \|   \(b\)                                                       N/A                   0.079               N/A

                                                                                                                                                                                                                                 \|                                                                                                         

  Formulation of Paints and Coatings:                                                                                                                                                                                            \|                                                                                                         

    All                                                                                                                                                                                                                          \|                                                                                                         

     workers                                                                                  2,745                                                                                                                              \|                                                                                                         

    Packer                                                                                    732                 \(b\)                                                     \(c\)               1.249             1.370          \|   \(b\)                                                       \(c\)                 1.980               3.643

    Batch-                                                                                                                                                                                                                       \|                                                                                                         

     maker                                                                                    1,464               0.354                                                     \(a\)               0.673             0.870          \|   0.906                                                       \(a\)                 0.714               1.072

    Lab Tech                                                                                  549                 0.215                                                     \(a\)               \(d\)             0.107          \|   0.215                                                       \(a\)                 \(d\)               0.118

                                                                                                                                                                                                                                 \|                                                                                                         

  Aircraft Manufacturing/Repainting:                                                                                                                                                                                             \|                                                                                                         

    Spray                                                                                                                                                                                                                        \|                                                                                                         

     paint                                                                                    1,998               N/A                                                       N/A                 \(d\)             3.781          \|   N/A                                                         N/A                   \(d\)               7.916

                                                                                                                                                                                                                                 \|                                                                                                         

  Motor Vehicle Body Manufacturing:                                                                                                                                                                                              \|                                                                                                         

    All                                                                                                                                                                                                                          \|                                                                                                         

     workers                                                                                  736                                                                                                                                \|                                                                                                         

    Spray                                                                                                                                                                                                                        \|                                                                                                         

     painter                                                                                  576                 N/A                                                       N/A                 \(d\)             0.005          \|   N/A                                                         N/A                   \(d\)               0.035

    Dip                                                                                                                                                                                                                          \|                                                                                                         

     painter                                                                                  64                  N/A                                                       N/A                 \(d\)             0.012          \|   N/A                                                         N/A                   \(d\)               0.013

    Paint                                                                                                                                                                                                                        \|                                                                                                         

     mixer                                                                                    96                  N/A                                                       N/A                 \(d\)             0.010          \|   N/A                                                         N/A                   \(d\)               0.227

                                                                                                                                                                                                                                 \|                                                                                                         

  Other Metal Applications:                                                                                                                                                                                                      \|                                                                                                         

    Painter                                                                                   1,464               0.218                                                     0.104               0.052             0.072          \|   0.275                                                       0.364                 0.111               0.397

                                                                                                                                                                                                                                 \|                                                                                                         

  Automobile Refinishing\*\*\*:                                                                                                                                                                                                  \|                                                                                                         

    Spray                                                                                                                                                                                                                        \|                                                                                                         

     paint-                                                                                                                                                                                                                      \|                                                                                                         

     er                                                                                       26,331              0.218                                                     0.104               0.052             0.071          \|   0.275                                                       0.364                 0.111               0.395

                                                                                                                                                                                                                                 \|                                                                                                         

  Wood Furniture Manufacturing:                                                                                                                                                                                                  \|                                                                                                         

    Finisher                                                                                  8,140               \(e\)                                                     N/A                 \(d\)             0.656          \|   \(e\)                                                       N/A                   \(d\)               0.830

                                                                                                                                                                                                                                 \|                                                                                                         

  Formulation of Inks\*\*\*\*:                                                                                                                                                                                                   \|                                                                                                         

    All                                                                                                                                                                                                                          \|                                                                                                         

     workers                                                                                  946                                                                                                                                \|                                                                                                         

    Packer                                                                                    86                  \(b\)                                                     \(c\)               1.249             1.370          \|   \(b\)                                                       \(c\)                 1.980               3.643

  Batchmaker                                                                                  602                 0.354                                                     \(a\)               0.673             0.870          \|   0.906                                                       \(a\)                 0.714               1.072

    Lab Tech                                                                                  258                 0.215                                                     \(a\)               \(d\)             0.107          \|   0.215                                                       \(a\)                 \(d\)               0.118

                                                                                                                                                                                                                                 \|                                                                                                         

  Application of Inks:                                                                                                                                                                                                           \|                                                                                                         

    Printing                                                                                  946                 0.035                                                     \(a\)               0.056             0.038          \|   0.043                                                       \(a\)                 2.441               2.071

    operator                                                                                                                                                                                                                     \|                                                                                                         

  Semiconductor Manufacturing:                                                                                                                                                                                                   \|                                                                                                         

    Techni-                                                                                                                                                                                                                      \|                                                                                                         

     cian                                                                                     ,704                0.020                                                     \(a\)               \(d\)             0.011          \|   0.022                                                       \(a\)                 \(d\)               0.048

                                                                                                                                                                                                                                 \|                                                                                                         

  Printed Circuit Board Manufacturing:                                                                                                                                                                                           \|                                                                                                         

    All                                                                                                                                                                                                                          \|                                                                                                         

     workers                                                                                  352                                                                                                                                \|                                                                                                         

    Coater                                                                                    176                 0.078                                                     \(a\)               0.017             0.012          \|   0.378                                                       \(a\)                 0.031               0.030

    Lab Tech                                                                                  132                 \(e\)                                                     \(c\)               \(d\)             0.134          \|   \(e\)                                                       \(c\)                 \(d\)               0.217

    Mfg Spec.                                                                                 44                  N/A                                                       N/A                 N/A               N/A            \|   N/A                                                         N/A                   N/A                 N/A

  **\[page 15583**\]                                                                                                                                                                                                                                                                                                                        

       Total                                                                                  45,786                                                                                                                             \|                                                                                                         

                                                                                                                                                                                                                                 \|                                                                                                         

  \_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_                                                                                                                                           \|   \_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_                                                  
  -------------------------------------------------------------------------------------- ---- -------------- ---- ---------------------------------------------------- ---- -------------- ---- ------------ ---- -------------- ---- ------------------------------------------------------ ---- ---------------- ---- -------------- ---- ------------

\* If no monitoring data were available for a substance, PEI assumed
that exposures were equal to those for similar glycol ether in the same
industry and job category:

> \(a\) indicates 2-MEA exposures were assumed to equal 2-ME exposures\
> (b) indicates 2-ME exposures were assumed to equal 2-EE exposures\
> (c) indicates 2-MEA exposures were assumed to equal 2-EEA exposures\
> (d) indicates 2-EE exposures were assumed to equal 2-EEA exposures\
> (e) indicates 2-ME exposures were assumed to equal 2-EEA exposures

\*\* Baseline exposures were assumed to equal those for Manufacture of
Glycol Ethers

\*\*\* Baseline exposures were assumed to equal those for Other Metal
Applications

\*\*\*\* Baseline exposures were assumed to equal those for Formulation
of Paints and Coatings

N/A = Not Applicable

Source: PEI

But there is a problem for health analysis when the traditional
geometric mean representation is used to categorize employee exposures
to hazardous substances. Epidemiological and animal studies often
document or suggest the greater vulnerability of the human organism to
short term high dose exposures to hazardous substances, as opposed to
continual, routine exposure at lower doses. In statistical terms, the
intermittent, infrequent, high dose exposures represent outlyers in the
data. The values which are potentially most threatening or harmful to
humans are deliberately suppressed when a geometric mean is used to
categorize the data

In policy terms, because the underlying distribution is normally
distributed (lognormal) and susceptible to a geometric mean
representation, does not require that this measure of central tendency
be used for health benefits calculations. In fact, to the extent that it
camouflages or distracts attention from potentially dangerous short term
exposure conditions, it probably should not be used for such
calculations or used only in combination with information on the
distribution of the outlying data. In this analysis, geometric mean
analysis is supplemented with arithmetic mean data which better reflect
the influence of the outlying observations. In most industry/job
categories, average exposures are already below the proposed TWAs
(although it is possible that individual exposures may exceed the
proposed levels). The lowest average exposures occur during the
manufacture of glycol ethers and in the manufacture of semiconductors
and printed circuit boards

There are a total of 45,786 exposed workers in 10,133 establishments in
the 12 industry categories. The largest number of exposed workers occurs
in the automobile refinishing category, which also has the lowest number
of exposed workers per establishment

Benefits Analysis

The benefits of reducing employee exposure to glycol ethers are
estimated using incidence data from animal studies and worker exposure
data. The levels above which adverse health effects are likely to occur
in humans are developed from the animal studies using an uncertainty
factor of 100; that is, each \"no observed effect level\" (NOEL)
observed in the animal studies is reduced by a factor of 100 to yield
the corresponding human exposure level

OSHA\'s analysis of the benefits that are likely to occur as a result of
limiting exposures to glycol ethers does not consider decreases in
adverse hematological effects and in behavioral abnormalities in the
offspring of exposed adults. Also, OSHA\'s analysis relies on animal
studies that use inhalation as the route of exposure; the dosages of
glycol ethers administered in inhalation studies are more readily
quantifiable than those in absorption or ingestion studies and the
majority of job categories considered at risk involve the inhalation of
glycol ether vapors. However, dermal workplace exposures do occur, but
these were not quantified. Thus, the benefits in this analysis are
underestimated. The health effects estimated in this analysis and shown
in Table VIII-3 are the estimated incidence of developmental effects of
glycol ether exposure on the pregnancies of females under age 45 and the
estimated incidence of adverse reproductive effects in male employees.
The benefits were calculated assuming a 45 year working lifetime for
both sexes. No effort is directed at delineating the types of fetal
defects avoided. Since both 2-ME and 2-MEA are metabolized in humans to
methoxyacetic acid, the benefits of limiting exposure to these compounds
are displayed together. Similarly, the benefits associated with
reductions in 2-EE and 2-EEA exposures are displayed together

  ----------------- ----------------- ----------------- -----------------
  TABLE VIII-3                                          

  PROJECTED                                             
  BENEFITS OF                                           
  PROPOSED STANDARD                                     

                                                        

                                      Number             

                                      of                Annual

                                      Workers           Number of

                                      Exposed           Adverse

                                      above             Effects

                                      Proposed          or Cases

  Effects                             PEL               Avoided

                                                        

  Developmental                                         
  Effects/                                              

    Female Workers                                      
  Aged 18 to 45                                         

      From Exposure                   157               0.4 to 4.5
  to 2-ME/2-MEA                                         

      From Exposure                   573               1.7 to 8.0
  to 2-EE/2-EEA                                         

      Total                           730               2.0 to 12.4
  Developmental                                         
  Effects                                               

  Reproductive                                          
  Cases/                                                

    Male Workers                                        

      From Exposure                   2,604             200 to 490
  to 2-ME/2-MEA                                         

  **\[page                                              
  15584\]**                                             

      From Exposure                   4,294             63 to 611
  to 2-EE/2-EEA                                         

      Total                           6,898             262 to 1,101
  Reproductive                                          
  Cases                                                 

                                                        

  Note:             Other benefits                      
                    have not been                       
                    quantified:                         
                    reductions                          

                    in hematological                    
                    effects,                            
                    behavioral                          
                    abnormalities                       

                    in offspring, and                   
                    effects of dermal                   
                    exposure                            

  Sources:          PEI, Office of                      
                    Regulatory                          
                    Analysis                            
  ----------------- ----------------- ----------------- -----------------

An estimated total of 2.0 to 12.4 adverse effects on fetal development
per year would be avoided under the proposed standard (TWAs of 0.1 ppm
for 2-ME and 2-MEA; 0.5 ppm for 2-EE and 2-EEA). These adverse
developmental effects would be avoided principally in ink application,
electronics, formulation of paints and coatings, and wood furniture
manufacturing

For male workers, an estimated 262 to 1,101 adverse reproductive
conditions (reduced testes size, reduced sperm count and/or other
impairment of reproductive functioning) would be avoided per year under
the proposed standard. The impairments will persist in exposed workers
for as long as they are exposed. New cases will develop among new
workers as, over time, work forces turn over and new individuals become
exposed. These benefits would occur principally in automobile
refinishing, aircraft manufacturing and repainting, and formulation of
paints and coatings

Technological Feasibility

OSHA has preliminarily determined that the proposed standard is
technologically feasible. OSHA determines that the proposed TWAs are
capable of being achieved in most of the operations most of the time by
means of engineering and work practice controls. In certain situations
for a very limited number of employees (i.e., under 2% of all full-time
equivalent (FTE) workers exposed to glycol ethers in the industries
involved) supplementary respiratory protection may be necessary. In most
instances, when the 8-hour TWA has been met through engineering
controls, no use of respirators would be necessary to meet the 15-minute
EL

For example, in auto refinishing, which employs an estimated 26,331
exposed workers, who constitute 58% of all workers exposed to glycol
ethers, OSHA estimates that the exposure levels for 98% of these workers
can be reduced to or below the proposed TWAs and ELs by means of
substitution, engineering, and work practice controls. OSHA estimates
that, on an FTE basis, fewer than 1% of all currently exposed auto
refinishing workers would require respiratory protection. In addition,
OSHA preliminarily determines that exposure levels, as measured by
geometric means, can be controlled to or below the proposed 8-hour TWAs
solely by means of engineering and work practice controls in a vast
majority of operations across the affected industries. Specifically,
geometric mean exposure levels can be controlled to or below the TWAs in
16 of 22 2-ME operations, in 8 of 12 2-MEA operations, in 25 of 26 2-EE
operations, and in 17 of 18 2-EEA operations

The best evidence of technological feasibility is that the proposed
levels are already being achieved in the affected industries with
current controls. Across industries using glycol ethers, geometric mean
exposures are already at or below the proposed TWAs in a majority of
operations. These exposure data suggest that relatively few additional
controls would be necessary to consistently reduce 8-hour exposures and
peak exposures to or below the proposed standard

In order to assess technological feasibility, PEI considered
substitution of other solvents for glycol ethers, other engineering
controls, personal protective equipment (PPE), and administrative
measures, such as inspections to detect leaks in areas where glycol
ethers are handled. PEI applied specific engineering or other controls
until the predicted exposure level for each industry/job category was
reduced to no more than one-half of each of the proposed alternative
TWAs for each glycol ether. The exposure level for determining when
additional controls would be necessary was based on weighted plant
geometric mean exposures or weighted plant arithmetic mean exposures.
The purpose of conducting the technological feasibility analysis using
each of the two types of means was to determine if the costs and
exposure levels differ significantly with the varying degrees of
engineering controls and respirators necessitated by the two different
approaches. In most cases, there is little difference

The technological feasibility of meeting ELs that were equivalent to
five times each TWA was assessed separately. During its site visits, PEI
was able to collect both short- term and full-shift monitoring data on
some individuals whose jobs involved the potential for peak exposures.
PEI assumed that job categories with TWA levels that are currently below
one-half the proposed TWA would not experience excursions above the EL
during normal operations. In establishments that required only
engineering controls to meet a proposed TWA, the use of ASRs would be
required for about one quarter of the workers in job categories that had
a potential for peak exposures. With both respirators and engineering
controls, no additional requirements were assumed to be necessary to
meet the EL

Engineering Controls

The systems which PEI specified were based on American Conference of
Governmental Industrial Hygienists (ACGIH) recommendations for good
engineering practice. They are conventional, readily available, and in
use today. The primary engineering control recommended for most
categories was local exhaust ventilation (LEV). Process enclosures,
which provide greater exposure control than hoods, were recommended for
some operations

The following incremental engineering controls are considered
technically feasible for the industry categories in this study:

Manufacture of Glycol Ethers:\
- Closed-loop transfer for loading operations\
- Enclosed sampling systems with sample coolers\
- Laboratory hood in quality control (QC) laboratory

Manufacture of Chemical Intermediates:\
- Automated drum filling station with LEV\
- Enclosed sampling systems with sample coolers\
- Laboratory hood in QC laboratory

Formulation of Paints and Coatings:

**\[page 15585\]**\
- Closed-loop transfer system\
- LEV on packaging line\
- LEV on mixing tank\
- Drum hoist/scale (small formulator plants)\
- Laboratory hood in QC and R&D laboratories

Aircraft Manufacturing/Repainting:\
- Paint spray booth for small parts\
- Airless spray guns with \"cup collars\"

Motor Vehicle Body Manufacturing:\
- LEV on paint mixing tank\
- Paint spray booth

Other Metal Applications:\
- Paint spray booth

Automobile Refinishing:\
- Paint spray booth

Wood Furniture Manufacturing:\
- Paint spray booth

Formulation of Inks:\
- Closed-loop transfer system\
- LEV on packaging line\
- LEV on mixing tank\
- Drum hoist/scale (small formulator plants)\
- Laboratory hood in QC and R&D laboratories

Application of Inks:\
- LEV at press rollers and inkwell\
- Process enclosure of press

Semiconductor Manufacturing:\
- LEV at the application of photoresist\
- Process enclosure at the application of photoresist

Printed Circuit Board Manufacturing:\
- LEV on blending/mixing operations\
- LEV on masking operation\
- LEV on coating operation\
- Process enclosure of coating operation

Personal Protective Equipment

When the implementation of engineering controls did not reduce the
predicted exposures for a job category to below the target level, ASRs
were prescribed. Cartridge respirators are considered inadequate because
the odor thresholds of the four glycol ethers do not allow workers to
adequately detect breakthrough at concentrations as low as the proposed
regulatory alternatives

Dermal exposure can be reduced through gloves, protective clothing, and
eye protection. Evidence indicates that butyl rubber gloves may be
appropriate for operations that involve heavy handling and high
potential for direct contact. Neoprene gloves may be appropriate for
some production-related activities, such as loading rail cars and taking
quality control samples. Latex gloves may be appropriate for operations
that involve light handling and only occasional contact

Substitution

Substitution of other chemicals is an option for eliminating exposure to
2-ME, 2-MEA, 2-EE, and 2-EEA, although no single \"drop in\" substitute
exists for all applications. The most common substitutes, according to
PEI\'s survey, are propylene glycol monomethyl ether (PGME), ethylene
glycol monobutyl ether (2-BE), ethylene glycol monopropyl ether (2-PE),
and their acetates. Together, these six chemicals account for almost 90
percent of reported substitutions. Evidence suggests that they would
pose a lower hazard in the workplace than the four glycol ethers being
considered in this standard

A substitution rate was assumed for each industry category based on the
availability, suitability, and cost of substitutes; the capital and
operating and maintenance (O&M) costs of compliance techniques; and the
industry category\'s position in the chain of distribution (i.e., its
flexibility in forcing or responding to substitution). The rate of
substitution is assumed to be the same for the geometric mean and
arithmetic mean exposure approaches. The following substitution rates
were developed:

Manufacture of Glycol Ethers and Intermediates: No substitution; export
and chemical intermediate uses represent large proportions of total
production of all four glycol ethers

Formulation of Paints and Coatings: 90%; most formulators already have
or are developing substitutes

Aircraft Manufacturing/Repainting: 70%

Motor Vehicle Body Manufacturing: 70%

Other Metal Applications: 70%

Automobile Refinishing: 90%

Wood Furniture Manufacturing: 90%; use of glycol ethers is already
dropping rapidly

Formulation and Application of Inks: 90%; much substitution has already
taken place

Semiconductors: 10%; acceptable substitutes are not generally available

Printed Circuit Boards: 50%; acceptable substitutes are generally
available

Exposure Reduction

Tables VIII-4 through VIII-7 show exposure reductions for each glycol
ether after applying engineering controls. In many industry/job
categories, no engineering controls would be needed to meet the proposed
TWAs, although respirators might be needed to meet the proposed ELs.

Of the workers who are currently exposed to glycol ethers, only five
percent (under either the geometric mean approach or the arithmetic mean
approach) would require air- supplied respirators. The highest
percentages of workers who would require ASRs are found in aircraft
manufacturing/repainting and \"other\" metal applications. On a
full-time equivalent basis, only two percent (under either approach)
would require ASRs. (See Tables VIII-8 and VIII- 9.)

  ---------------------- ------------- ---------------------- ---- ------------------------------------------------ ---- ---------------------- ---- ------------------------------------------------ ---- ----------------------
  TABLE VIII-4                                                                                                                                                                                             

  EXPOSURE REDUCTIONS                                                                                                                                                                                      
  FOR 2-ME AFTER                                                                                                                                                                                           
  APPLYING ENGINEERING                                                                                                                                                                                     
  CONTROLS                                                                                                                                                                                                 

                                                                                                                                                                                                           

                         \|                                   \|                                                                                \|                                                         

                         \|                                   \|   Geometric mean                                                               \|   Arithmetic mean                                       

  Industry               \|            Current                \|   approach                                                                     \|   approach                                              

  category               \|            utili-                 \|   \_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_                               \|   \_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_        

  and job                \|            zation                 \|                                                    \|                          \|                                                    \|    

  category               \|            of eng-                \|   Baseline                                         \|   Average                \|   Baseline                                         \|   Average

                         \|            ineering               \|   weighted                                         \|   exposures              \|   weighted                                         \|   exposures

                         \|            controls               \|   plant                                            \|   after                  \|   plant                                            \|   after

                         \|            (percent)              \|   geometric                                        \|   applying               \|   arthmatic                                        \|   applying 

                         \|                                   \|   mean                                             \|   engineering            \|   mean                                             \|   engineering

                         \|                                   \|   exposure                                         \|   controls               \|   exposure                                         \|   controls

                         \|                                   \|   (ppm)                                            \|   (ppm)                  \|   (ppm)                                            \|   (ppm)

  \_\_\_\_\_\_\_\_\_\_   \|            \_\_\_\_\_\_\_\_\_\_   \|   \_\_\_\_\_\_\_\_\_\_                             \|   \_\_\_\_\_\_\_\_\_\_   \|   \_\_\_\_\_\_\_\_\_\_                             \|   \_\_\_\_\_\_\_\_\_\_

  Manufacture of Glycol                                                                                                                                                                                    
  Ethers:                                                                                                                                                                                                  

    Loading                                                                                                                                                                                                

      Tech                             50                          0.046                                                 NC                          0.151                                                 0.008

    Process                                                                                                                                                                                                

      Tech                             90                          0.032                                                 NC                          0.044                                                 NC

    Laboratory                                                                                                                                                                                             

      Tech                             90                          0.023                                                 NC                          0.027                                                 NC

    Maintenance                                                                                                                                                                                            

      Tech                             0                           0.057\*                                               NC                          0.079\*                                               NC

      Supervisor                       0                           0.017                                                 NC                          0.017                                                 NC

  Manufacture of                                                                                                                                                                                           
  Chemical                                                                                                                                                                                                 
  Intermediates:                                                                                                                                                                                           

    Loading                                                                                                                                                                                                

      Tech                             90                          0.046                                                 NC                          0.151                                                 0.027

    Process                                                                                                                                                                                                

      Tech                             90                          0.032                                                 NC                          0.044                                                 NC

  **\[page 15586\]**                                                                                                                                                                                       

    Laboratory                                                                                                                                                                                             

      Tech                             90                          0.023                                                 NC                          0.027                                                 NC

    Maintenance                                                                                                                                                                                            

      Tech                             0                           0.057\*                                               NC                          0.079\*                                               NC

   Formulation of Paints                                                                                                                                                                                   
  and Coatings:                                                                                                                                                                                            

   Packer                              10                          1.249\*                                               0.250                       1.980\*                                               0.396

    Batchmaker                         70                          0.354                                                 0.223                       0.906                                                 0.289

    Laboratory                                                                                                                                                                                             

      Tech                             70                          0.215                                                 0.019                       0.215                                                 0.025

   Other Metal                                                                                                                                                                                             
  Applications:                                                                                                                                                                                            

   Painter                             90                          0.218                                                 0.212                       0.275                                                 0.242

   Auto Refinishing:                                                                                                                                                                                       

    Spray                                                                                                                                                                                                  

      Painter                          67                          0.218                                                 0.060                       0.275                                                 0.110

  Wood Furniture Mfg:                                                                                                                                                                                      

    Finisher                           90                          0.656\*\*                                             0.485                       0.830\*\*                                             0.490

   Formulation of Inks:                                                                                                                                                                                    

    Packer                             20                          1.249\*                                               0.431                       1.980\*                                               0.532

    Batchmaker                         80                          0.354                                                 0.223                       0.906                                                 0.289

    Laboratory                                                                                                                                                                                             

      Tech                             70                          0.215                                                 0.019                       0.215                                                 0.025

  Application of Inks:                                                                                                                                                                                     

    Printing                                                                                                                                                                                               

      Operator                         63                          0.035                                                 NC                          0.043                                                 NC

  Semiconductor Mfg:                                                                                                                                                                                       

    Technician                         82                          0.020                                                 NC                          0.022                                                 NC

  Printed Circuit Board                                                                                                                                                                                    
  Manufacturing:                                                                                                                                                                                           

  Manufacturing                                                                                                                                                                                            

      Specialist                       63                          0.078                                                 0.021                       0.378                                                 0.054

   Coater                              63                          0.134\*\*                                             0.027                       0.217\*\*                                             0.043

                                                                                                                                                                                                           

  NC =                   No change                                                                                                                                                                         
                         from                                                                                                                                                                              
                         baseline; no                                                                                                                                                                      
                         use of                                                                                                                                                                            
                         engineering                                                                                                                                                                       
                         controls                                                                                                                                                                          

                         (although                                                                                                                                                                         
                         respirators                                                                                                                                                                       
                         may be                                                                                                                                                                            
                         required to                                                                                                                                                                       
                         meet EL)                                                                                                                                                                          

  \*                     No data on                                                                                                                                                                        
                         baseline                                                                                                                                                                          
                         8-hour TWA                                                                                                                                                                        
                         exposure to                                                                                                                                                                       
                         2-ME                                                                                                                                                                              
                         available for                                                                                                                                                                     

                         this job                                                                                                                                                                          
                         category.                                                                                                                                                                         
                         Data for 2-EE                                                                                                                                                                     
                         were used                                                                                                                                                                         

  \*\*                   No data on                                                                                                                                                                        
                         baseline                                                                                                                                                                          
                         8-hour TWA                                                                                                                                                                        
                         exposure to                                                                                                                                                                       
                         2-ME                                                                                                                                                                              
                         available for                                                                                                                                                                     

                         this job                                                                                                                                                                          
                         category.                                                                                                                                                                         
                         Data for                                                                                                                                                                          
                         2-EEA were                                                                                                                                                                        
                         used                                                                                                                                                                              

  Source: PEI                                                                                                                                                                                              
  ---------------------- ------------- ---------------------- ---- ------------------------------------------------ ---- ---------------------- ---- ------------------------------------------------ ---- ----------------------

  ---------------------- ------------- ---------------------- ---- ------------------------------------------------ ---- ---------------------- ---- ------------------------------------------------ ---- ----------------------
  TABLE VIII-5                                                                                                                                                                                             

  EXPOSURE REDUCTIONS                                                                                                                                                                                      
  FOR 2-MEA AFTER                                                                                                                                                                                          
  APPLYING ENGINEERING                                                                                                                                                                                     
  CONTROLS                                                                                                                                                                                                 

                                                                                                                                                                                                           

                         \|                                   \|                                                                                \|                                                         

                         \|                                   \|   Geometric mean                                                               \|   Arithmatic mean                                       

  Industry               \|            Current                \|   approach                                                                     \|   approach                                              

  category               \|            utili-                 \|   \_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_                               \|   \_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_        

  and job                \|            zation                 \|                                                    \|                          \|                                                    \|    

  category               \|            of eng-                \|   Baseline                                         \|   Average                \|   Baseline                                         \|   Average

                         \|            ineering               \|   weighted                                         \|   exposures              \|   weighted                                         \|   exposures

                         \|            controls               \|   plant                                            \|   after                  \|   plant                                            \|   after

                         \|            (percent)              \|   geometric                                        \|   applying               \|   arthmatic                                        \|   applying 

                         \|                                   \|   mean                                             \|   engineering            \|   mean                                             \|   engineering

                         \|                                   \|   exposure                                         \|   controls               \|   exposure                                         \|   controls

                         \|                                   \|   (ppm)                                            \|   (ppm)                  \|   (ppm)                                            \|   (ppm)

  \_\_\_\_\_\_\_\_\_\_   \|            \_\_\_\_\_\_\_\_\_\_   \|   \_\_\_\_\_\_\_\_\_\_                             \|   \_\_\_\_\_\_\_\_\_\_   \|   \_\_\_\_\_\_\_\_\_\_                             \|   \_\_\_\_\_\_\_\_\_\_

  Formulation of paints                                                                                                                                                                                    
  and coatings:                                                                                                                                                                                            

    Packer                             10                          1.370\*\*                                             0.274                       3.643\*\*                                             0.729

    Batchmaker                         70                          0.354\*                                               0.223                       0.906\*                                               0.289

    Laboratory                                                                                                                                                                                             

     Technicion                        70                          0.215\*                                               0.019                       0.215\*                                               0.025

  Other metal                                                                                                                                                                                              
  applications:                                                                                                                                                                                            

    Painter                            90                          0.104                                                 0.043                       0.364                                                 0.233

  Auto refinishing:                                                                                                                                                                                        

   Spray                                                                                                                                                                                                   

     painter                           67                          0.104                                                 0.043                       0.364                                                 0.233

  Formulation of inks:                                                                                                                                                                                     

    Packer                             20                          1.370\*\*                                             0.330                       3.643\*\*                                             0.757

    Batchmaker                         80                          0.354\*                                               0.223                       0.906\*                                               0.532

    Laboratory                                                                                                                                                                                             

     technician                        70                          0.215\*                                               0.019                       0.215\*                                               0.025

  Application of inks:                                                                                                                                                                                     

   Printing                                                                                                                                                                                                

     operator                          63                          0.035\*                                               NC                          0.043\*                                               NC

  Semiconductor                                                                                                                                                                                            
  manufacturing:                                                                                                                                                                                           

    Technician                         82                          0.020\*                                               NC                          0.022\*                                               NC

  Printed circuit board                                                                                                                                                                                    
  manufacturing:                                                                                                                                                                                           

   Manufacturing                                                                                                                                                                                           

     specialist                        63                          0.078\*                                               0.021                       0.378\*                                               0.054

    Coater                             63                          0.134\*\*                                             0.027                       0.217\*\*                                             0.043

                                                                                                                                                                                                           

  NC =                   No change                                                                                                                                                                         
                         from                                                                                                                                                                              
                         baseline; no                                                                                                                                                                      
                         use of                                                                                                                                                                            
                         engineering                                                                                                                                                                       
                         controls                                                                                                                                                                          

                         (although                                                                                                                                                                         
                         respirators                                                                                                                                                                       
                         may be                                                                                                                                                                            
                         required to                                                                                                                                                                       
                         meet EL)                                                                                                                                                                          

  \*                     No monitoring                                                                                                                                                                     
                         data on                                                                                                                                                                           
                         baseline                                                                                                                                                                          
                         8-hour TWA                                                                                                                                                                        
                         exposure to                                                                                                                                                                       
                         2-MEA                                                                                                                                                                             

                         were                                                                                                                                                                              
                         available.                                                                                                                                                                        
                         Data for 2-ME                                                                                                                                                                     
                         were used                                                                                                                                                                         

  \*\*                   No monitoring                                                                                                                                                                     
                         data on                                                                                                                                                                           
                         baseline                                                                                                                                                                          
                         8-hour TWA                                                                                                                                                                        
                         exposure to                                                                                                                                                                       
                         2-MEA                                                                                                                                                                             

                         were                                                                                                                                                                              
                         available.                                                                                                                                                                        
                         Data for                                                                                                                                                                          
                         2-EEA were                                                                                                                                                                        
                         used                                                                                                                                                                              

  Source: PEI                                                                                                                                                                                              

  **\[page 15587**\]                                                                                                                                                                                       
  ---------------------- ------------- ---------------------- ---- ------------------------------------------------ ---- ---------------------- ---- ------------------------------------------------ ---- ----------------------

  ---------------------- ------------- ---------------------- ---- ------------------------------------------------ ---- ---------------------- ---- ------------------------------------------------ ---- ----------------------
  TABLE VIII-6                                                                                                                                                                                             

  EXPOSURE REDUCTIONS                                                                                                                                                                                      
  FOR 2-EE AFTER                                                                                                                                                                                           
  APPLYING ENGINEERING                                                                                                                                                                                     
  CONTROLS                                                                                                                                                                                                 

                                                                                                                                                                                                           

                         \|                                   \|                                                                                \|                                                         

                         \|                                   \|   Geometric mean                                                               \|   Arithmatic mean                                       

  Industry               \|            Current                \|   approach                                                                     \|   approach                                              

  category               \|            utili-                 \|   \_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_                               \|   \_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_        

  And job                \|            zation                 \|                                                    \|                          \|                                                    \|    

  category               \|            of eng-                \|   Baseline                                         \|   Average                \|   Baseline                                         \|   Average

                         \|            ineering               \|   weighted                                         \|   exposures              \|   weighted                                         \|   exposures

                         \|            controls               \|   plant                                            \|   after                  \|   plant                                            \|   after

                         \|            (percent)              \|   geometric                                        \|   applying               \|   arthmatic                                        \|   applying 

                         \|                                   \|   mean                                             \|   engineering            \|   mean                                             \|   engineering

                         \|                                   \|   exposure                                         \|   controls               \|   exposure                                         \|   controls

                         \|                                   \|   (ppm)                                            \|   (ppm)                  \|   (ppm)                                            \|   (ppm)

  \_\_\_\_\_\_\_\_\_\_   \|            \_\_\_\_\_\_\_\_\_\_   \|   \_\_\_\_\_\_\_\_\_\_                             \|   \_\_\_\_\_\_\_\_\_\_   \|   \_\_\_\_\_\_\_\_\_\_                             \|   \_\_\_\_\_\_\_\_\_\_

  Manufacture of Glycol                                                                                                                                                                                    
  Ethers:                                                                                                                                                                                                  

   Loading                                                                                                                                                                                                 

      Technician                       50                          0.022                                                 NC                          0.047                                                 NC

   Process                                                                                                                                                                                                 

      Technician                       90                          0.092                                                 0.049                       0.177                                                 0.119

   Laboratory                                                                                                                                                                                              

      Technician                       90                          0.015                                                 NC                          0.017                                                 NC

   Maintenance                                                                                                                                                                                             

      Technician                       0                           0.057                                                 NC                          0.079                                                 NC

    Supervisor                         0                           0.026                                                 NC                          0.047                                                 NC

  Manufacture of                                                                                                                                                                                           
  Chemical                                                                                                                                                                                                 
  Intermediates:                                                                                                                                                                                           

   Loading                                                                                                                                                                                                 

      Technician                       90                          0.022                                                 NC                          0.047                                                 NC

   Process                                                                                                                                                                                                 

      Technician                       90                          0.092                                                 0.049                       0.177                                                 0.119

   Laboratory                                                                                                                                                                                              

      Technician                       90                          0.015                                                 NC                          0.017                                                 NC

   Maintenance                                                                                                                                                                                             

      Technician                       0                           0.057                                                 NC                          0.079                                                 NC

  Formulation of Paints                                                                                                                                                                                    
  and Coatings:                                                                                                                                                                                            

    Packer                             10                          1.249                                                 0.250                       1.980                                                 0.396

    Batchmaker                         70                          0.673                                                 0.324                       0.714                                                 0.361

   Laboratory                                                                                                                                                                                              

      Technician                       70                          0.107\*                                               0.041                       0.118\*                                               0.056

  Aircraft                                                                                                                                                                                                 
  Mfg/Repainting:                                                                                                                                                                                          

   Spray                                                                                                                                                                                                   

      painter                          67                          3.781\*                                               1.569                       7.916\*                                               2.160

  Motor Vehicle Body                                                                                                                                                                                       
  Manufacturing:                                                                                                                                                                                           

   Spray                                                                                                                                                                                                   

      painter                          90                          0.005\*                                               NC                          0.035\*                                               NC

   Dip                                                                                                                                                                                                     

      painter                          90                          0.012\*                                               NC                          0.013\*                                               NC

   Paint                                                                                                                                                                                                   

      mixer                            50                          0.010\*                                               NC                          0.227\*                                               0.050

  Other Metal                                                                                                                                                                                              
  Applications:                                                                                                                                                                                            

    Painter                            90                          0.052                                                 0.051                       0.111                                                 0.098

  Auto Refinishing:                                                                                                                                                                                        

   Spray                                                                                                                                                                                                   

      Painter                          67                          0.052                                                 0.048                       0.111                                                 0.080

  Wood Furniture Mfg:                                                                                                                                                                                      

    Finisher                           90                          0.656\*                                               0.485                       0.830\*                                               0.490

  Formulation of Inks:                                                                                                                                                                                     

    Packer                             20                          1.249                                                 0.431                       1.980                                                 0.532

    Batchmaker                         80                          0.673                                                 0.324                       0.714                                                 0.361

   Laboratory                                                                                                                                                                                              

      Technician                       70                          0.107\*                                               0.041                       0.118\*                                               0.056

  Application of Inks:                                                                                                                                                                                     

   Printing                                                                                                                                                                                                

      Operator                         63                          0.056                                                 0.046                       2.441                                                 NC

  Semiconductor Mfg:                                                                                                                                                                                       

    Technician                         82                          0.011\*                                               NC                          0.048\*                                               NC

  Printed Circuit Board                                                                                                                                                                                    
  Manufacturing:                                                                                                                                                                                           

   Manufact-                                                                                                                                                                                               

      uring Spec                       63                          0.017                                                 NC                          0.031                                                 NC

    Coater                             63                          0.134\*                                               0.027                       0.217\*                                               0.043

                                                                                                                                                                                                           

  NC =                   No change                                                                                                                                                                         
                         from                                                                                                                                                                              
                         baseline; no                                                                                                                                                                      
                         use of                                                                                                                                                                            
                         engineering                                                                                                                                                                       
                         controls                                                                                                                                                                          

                         (although                                                                                                                                                                         
                         respirators                                                                                                                                                                       
                         may be                                                                                                                                                                            
                         required to                                                                                                                                                                       
                         meet EL)                                                                                                                                                                          

  \*                     No data on                                                                                                                                                                        
                         baseline                                                                                                                                                                          
                         8-hour TWA                                                                                                                                                                        
                         exposure to                                                                                                                                                                       
                         2-EE                                                                                                                                                                              
                         available for                                                                                                                                                                     

                         this job                                                                                                                                                                          
                         category.                                                                                                                                                                         
                         Data for                                                                                                                                                                          
                         2-EEA were                                                                                                                                                                        
                         used                                                                                                                                                                              

  Source: PEI                                                                                                                                                                                              
  ---------------------- ------------- ---------------------- ---- ------------------------------------------------ ---- ---------------------- ---- ------------------------------------------------ ---- ----------------------

<table>
<colgroup>
<col style="width: 15%" />
<col style="width: 1%" />
<col style="width: 14%" />
<col style="width: 1%" />
<col style="width: 15%" />
<col style="width: 1%" />
<col style="width: 15%" />
<col style="width: 1%" />
<col style="width: 15%" />
<col style="width: 1%" />
<col style="width: 15%" />
</colgroup>
<tbody>
<tr class="odd">
<td colspan="11">TABLE VIII-7</td>
</tr>
<tr class="even">
<td colspan="11">EXPOSURE REDUCTIONS FOR 2-EEA AFTER APPLYING
ENGINEERING CONTROLS</td>
</tr>
<tr class="odd">
<td colspan="11"></td>
</tr>
<tr class="even">
<td> </td>
<td>|</td>
<td> </td>
<td>|</td>
<td colspan="3"> </td>
<td>|</td>
<td colspan="3"> </td>
</tr>
<tr class="odd">
<td> </td>
<td>|</td>
<td> </td>
<td>|</td>
<td colspan="3">Geometric mean</td>
<td>|</td>
<td colspan="3">Arithmatic mean</td>
</tr>
<tr class="even">
<td>Industry</td>
<td>|</td>
<td>Current</td>
<td>|</td>
<td colspan="3">approach</td>
<td>|</td>
<td colspan="3">approach</td>
</tr>
<tr class="odd">
<td>category</td>
<td>|</td>
<td>utili-</td>
<td>|</td>
<td colspan="3">_______________________</td>
<td>|</td>
<td colspan="3">_______________________</td>
</tr>
<tr class="even">
<td>And job</td>
<td>|</td>
<td>zation</td>
<td>|</td>
<td> </td>
<td>|</td>
<td> </td>
<td>|</td>
<td> </td>
<td>|</td>
<td> </td>
</tr>
<tr class="odd">
<td>category</td>
<td>|</td>
<td>of eng-</td>
<td>|</td>
<td>Baseline</td>
<td>|</td>
<td>Average</td>
<td>|</td>
<td>Baseline</td>
<td>|</td>
<td>Average</td>
</tr>
<tr class="even">
<td> </td>
<td>|</td>
<td>ineering</td>
<td>|</td>
<td>weighted</td>
<td>|</td>
<td>exposures</td>
<td>|</td>
<td>weighted</td>
<td>|</td>
<td>exposures</td>
</tr>
<tr class="odd">
<td> </td>
<td>|</td>
<td>controls</td>
<td>|</td>
<td>plant</td>
<td>|</td>
<td>after</td>
<td>|</td>
<td>plant</td>
<td>|</td>
<td>after</td>
</tr>
<tr class="even">
<td> </td>
<td>|</td>
<td>(percent)</td>
<td>|</td>
<td>geometric</td>
<td>|</td>
<td>applying</td>
<td>|</td>
<td>arthmatic</td>
<td>|</td>
<td>applying </td>
</tr>
<tr class="odd">
<td> </td>
<td>|</td>
<td> </td>
<td>|</td>
<td>mean</td>
<td>|</td>
<td>engineering</td>
<td>|</td>
<td>mean</td>
<td>|</td>
<td>engineering</td>
</tr>
<tr class="even">
<td> </td>
<td>|</td>
<td> </td>
<td>|</td>
<td>exposure</td>
<td>|</td>
<td>controls</td>
<td>|</td>
<td>exposure</td>
<td>|</td>
<td>controls</td>
</tr>
<tr class="odd">
<td> </td>
<td>|</td>
<td> </td>
<td>|</td>
<td>(ppm)</td>
<td>|</td>
<td>(ppm)</td>
<td>|</td>
<td>(ppm)</td>
<td>|</td>
<td>(ppm)</td>
</tr>
<tr class="even">
<td>__________</td>
<td>|</td>
<td>__________</td>
<td>|</td>
<td>__________</td>
<td>|</td>
<td>__________</td>
<td>|</td>
<td>__________</td>
<td>|</td>
<td>__________</td>
</tr>
<tr class="odd">
<td colspan="11">Manufacture of Glycol Ethers:</td>
</tr>
<tr class="even">
<td colspan="11"> Loading</td>
</tr>
<tr class="odd">
<td>   Technician</td>
<td> </td>
<td>50</td>
<td> </td>
<td>0.027</td>
<td> </td>
<td>NC</td>
<td> </td>
<td>0.043</td>
<td> </td>
<td>NC</td>
</tr>
<tr class="even">
<td colspan="11"> Process</td>
</tr>
<tr class="odd">
<td>   Technician</td>
<td> </td>
<td>90</td>
<td> </td>
<td>0.049</td>
<td> </td>
<td>NC</td>
<td> </td>
<td>0.077</td>
<td> </td>
<td>0.062</td>
</tr>
<tr class="even">
<td colspan="11"> Laboratory</td>
</tr>
<tr class="odd">
<td>   Technician</td>
<td> </td>
<td>90</td>
<td> </td>
<td>0.023</td>
<td> </td>
<td>NC</td>
<td> </td>
<td>0.031</td>
<td> </td>
<td>NC</td>
</tr>
<tr class="even">
<td colspan="11"> Maintenance</td>
</tr>
<tr class="odd">
<td>   Technician</td>
<td> </td>
<td>0</td>
<td> </td>
<td>0.058</td>
<td> </td>
<td>NC</td>
<td> </td>
<td>0.116</td>
<td> </td>
<td>NC</td>
</tr>
<tr class="even">
<td> Supervisor</td>
<td> </td>
<td>0</td>
<td> </td>
<td>0.017</td>
<td> </td>
<td>NC</td>
<td> </td>
<td>0.017</td>
<td> </td>
<td>NC</td>
</tr>
<tr class="odd">
<td colspan="11">Formulation of Paints and Coatings:</td>
</tr>
<tr class="even">
<td> Packer</td>
<td> </td>
<td>10</td>
<td> </td>
<td>1.370</td>
<td> </td>
<td>0.274</td>
<td> </td>
<td>3.643</td>
<td> </td>
<td>0.729</td>
</tr>
<tr class="odd">
<td> Batchmaker</td>
<td> </td>
<td>70</td>
<td> </td>
<td>0.870</td>
<td> </td>
<td>0.450</td>
<td> </td>
<td>1.072</td>
<td> </td>
<td>0.581</td>
</tr>
<tr class="even">
<td colspan="11"> Laboratory</td>
</tr>
<tr class="odd">
<td>   Technician</td>
<td> </td>
<td>70</td>
<td> </td>
<td>0.107</td>
<td> </td>
<td>0.041</td>
<td> </td>
<td>0.118</td>
<td> </td>
<td>0.056</td>
</tr>
<tr class="even">
<td colspan="11">Aircraft Mfg/Repainting:</td>
</tr>
<tr class="odd">
<td colspan="11"> Spray</td>
</tr>
<tr class="even">
<td>   painter</td>
<td> </td>
<td>67</td>
<td> </td>
<td>3.781</td>
<td> </td>
<td>1.569</td>
<td> </td>
<td>7.916</td>
<td> </td>
<td>2.160</td>
</tr>
<tr class="odd">
<td colspan="11">Other Metal Applications:</td>
</tr>
<tr class="even">
<td> Painter</td>
<td> </td>
<td>90</td>
<td> </td>
<td>0.072</td>
<td> </td>
<td>0.063</td>
<td> </td>
<td>0.397</td>
<td> </td>
<td>0.210</td>
</tr>
<tr class="odd">
<td colspan="11"><p><strong>[page 15588]</strong></p>
<p>Wood Furniture Mfg:</p></td>
</tr>
<tr class="even">
<td> Finisher</td>
<td> </td>
<td>90</td>
<td> </td>
<td>0.656</td>
<td> </td>
<td>0.485</td>
<td> </td>
<td>0.830</td>
<td> </td>
<td>0.490</td>
</tr>
<tr class="odd">
<td colspan="11">Formulation of Inks:</td>
</tr>
<tr class="even">
<td> Packer</td>
<td> </td>
<td>20</td>
<td> </td>
<td>1.370</td>
<td> </td>
<td>0.330</td>
<td> </td>
<td>3.643</td>
<td> </td>
<td>0.757</td>
</tr>
<tr class="odd">
<td> Batchmaker</td>
<td> </td>
<td>80</td>
<td> </td>
<td>0.870</td>
<td> </td>
<td>0.450</td>
<td> </td>
<td>1.072</td>
<td> </td>
<td>0.581</td>
</tr>
<tr class="even">
<td colspan="11"> Laboratory</td>
</tr>
<tr class="odd">
<td>   Technician</td>
<td> </td>
<td>70</td>
<td> </td>
<td>0.107</td>
<td> </td>
<td>0.041</td>
<td> </td>
<td>0.118</td>
<td> </td>
<td>0.056</td>
</tr>
<tr class="even">
<td colspan="11">Application of Inks:</td>
</tr>
<tr class="odd">
<td colspan="11"> Printing</td>
</tr>
<tr class="even">
<td>   Operator</td>
<td> </td>
<td>63</td>
<td> </td>
<td>0.038</td>
<td> </td>
<td>NC</td>
<td> </td>
<td>2.071</td>
<td> </td>
<td>0.111</td>
</tr>
<tr class="odd">
<td colspan="11">Semiconductor Manufacturing:</td>
</tr>
<tr class="even">
<td> Technician</td>
<td> </td>
<td>82</td>
<td> </td>
<td>0.011</td>
<td> </td>
<td>NC</td>
<td> </td>
<td>0.048</td>
<td> </td>
<td>NC</td>
</tr>
<tr class="odd">
<td colspan="11">Printed Circuit Board Manufacturing:</td>
</tr>
<tr class="even">
<td colspan="11"> Manufacturing</td>
</tr>
<tr class="odd">
<td>   Specialist</td>
<td> </td>
<td>63</td>
<td> </td>
<td>0.012</td>
<td> </td>
<td>NC</td>
<td> </td>
<td>0.030</td>
<td> </td>
<td>NC</td>
</tr>
<tr class="even">
<td> Coater</td>
<td> </td>
<td>63</td>
<td> </td>
<td>0.134</td>
<td> </td>
<td>0.027</td>
<td> </td>
<td>0.217</td>
<td> </td>
<td>0.043</td>
</tr>
<tr class="odd">
<td colspan="11"></td>
</tr>
<tr class="even">
<td>NC =</td>
<td colspan="10">No change from baseline; no use of engineering
controls</td>
</tr>
<tr class="odd">
<td></td>
<td colspan="10">(although respirators may be required to meet EL)</td>
</tr>
<tr class="even">
<td colspan="11">Source: PEI</td>
</tr>
</tbody>
</table>

  ------------------------ ---- -------------------- ---- -------------------- ---- -------------------- ---- ---------------- ---- -------------------- ---- ----------------------
  TABLE VIII-8                                                                                                                                                

  METHODS OF CONTROLLING                                                                                                                                      
  EMPLOYEE EXPOSURES                                                                                                                                          

  (GEOMETRIC MEAN                                                                                                                                             
  APPROACH)                                                                                                                                                   

                                                                                                                                                              

                           \|                        \|                        \|                        \|                    \|                        \|   

                           \|                        \|   Estimated            \|                        \|                    \|                        \|   

                           \|                        \|   number of            \|                        \|                    \|                        \|   FTE

                           \|   Estimated            \|   workers              \|   Estimated            \|   Percent          \|   Estimated            \|   workers

                           \|   total                \|   with                 \|   number of            \|   of               \|   number of            \|   in

  Industry                 \|   exposed              \|   exposures            \|   workers              \|   total            \|   full-time            \|   ASRs

  category                 \|   workers              \|   reduced              \|   in air-              \|   exposed          \|   equiva-              \|   due

                           \|                        \|   to TWA by            \|   supplied             \|   workers          \|   lent                 \|   to

                           \|                        \|   substi-              \|   respir-              \|   in ASRs          \|   workers              \|   standard

                           \|                        \|   tution or            \|   ators                \|   due              \|   in ASRs              \|   as

                           \|                        \|   engineer-            \|   due to               \|   to               \|   due to               \|   percent

                           \|                        \|   ing                  \|   standard             \|   stand-           \|   standard             \|   of total

                           \|                        \|   controls             \|                        \|   ard              \|                        \|   workers

  \_\_\_\_\_\_\_\_\_\_\_   \|   \_\_\_\_\_\_\_\_\_   \|   \_\_\_\_\_\_\_\_\_   \|   \_\_\_\_\_\_\_\_\_   \|   \_\_\_\_\_\_\_   \|   \_\_\_\_\_\_\_\_\_   \|   \_\_\_\_\_\_\_\_\_\_

  Manufacture                                                                                                                                                 

   of Glycol                                                                                                                                                  

   Ethers                       344                       330                       14                        4%                    7                         2%

  Manufacture                                                                                                                                                 

   of                                                                                                                                                         

   Chemical                                                                                                                                                   

   Intermedi-                                                                                                                                                 

   ates                         80                        80                        0                         0%                    0                         0%

  Formulation                                                                                                                                                 

   of                                                                                                                                                         

   Paints and                                                                                                                                                 

   Coatings                     2,745                     2,637                     108                       4%                    26                        1%

  Aircraft                                                                                                                                                    

   Manufact-                                                                                                                                                  

   uring/Re-                                                                                                                                                  

   painting                     1,998                     1,488                     510                       26%                   255                       13%

  Motor                                                                                                                                                       

   Vehicle                                                                                                                                                    

   Body                                                                                                                                                       

   Manufact-                                                                                                                                                  

   uring                        736                       736                       0                         0%                    0                         0%

  Other                                                                                                                                                       

   Metal                                                                                                                                                      

   Applica-                                                                                                                                                   

   tions                        1,464                     1,243                     221                       15%                   221                       15%

  Automobile                                                                                                                                                  

   Refinish-                                                                                                                                                  

   ing                          26,331                    25,893                    438                       2%                    54                        0%\*

  Wood                                                                                                                                                        

   Furniture                                                                                                                                                  

   Manufact-                                                                                                                                                  

   uring                        8,140                     7,384                     756                       9%                    152                       2%

  Formulation                                                                                                                                                 

   of Inks                      946                       894                       52                        5%                    20                        2%

  Application                                                                                                                                                 

   of Inks                      946                       946                       0                         0%                    0                         0%

  Semi-                                                                                                                                                       

   conductor                                                                                                                                                  

   Manufact-                                                                                                                                                  

   uring                        1,704                     1,704                     0                         0%                    0                         0%

  Printed                                                                                                                                                     

   Circuit                                                                                                                                                    

   Board                                                                                                                                                      

   Manufact-                                                                                                                                                  

   uring                        352                       306                       46                        13%                   12                        4%

  Total                         45,786                    43,641                    2,145                     5%                    795                       2%

                                                                                                                                                              

  \* More than zero, but                                                                                                                                      
  less than 0.5%                                                                                                                                              

  Source: PEI                                                                                                                                                 

  **\[page 15589\]**                                                                                                                                          
  ------------------------ ---- -------------------- ---- -------------------- ---- -------------------- ---- ---------------- ---- -------------------- ---- ----------------------

  ------------------------ ---- -------------------- ---- -------------------- ---- -------------------- ---- ---------------- ---- -------------------- ---- ----------------------
  TABLE VIII-9                                                                                                                                                

  METHODS OF CONTROLLING                                                                                                                                      
  EMPLOYEE EXPOSURES                                                                                                                                          

  (ARITHMETIC MEAN                                                                                                                                            
  APPROACH)                                                                                                                                                   

                                                                                                                                                              

                           \|                        \|                        \|                        \|                    \|                        \|   

                           \|                        \|   Estimated            \|                        \|                    \|                        \|   

                           \|                        \|   number of            \|                        \|                    \|                        \|   FTE

                           \|   Estimated            \|   workers              \|   Estimated            \|   Percent          \|   Estimated            \|   workers

                           \|   total                \|   with                 \|   number of            \|   of               \|   number of            \|   in

  Industry                 \|   exposed              \|   exposures            \|   workers              \|   total            \|   full-time            \|   ASRs

  category                 \|   workers              \|   reduced              \|   in air-              \|   exposed          \|   equiva-              \|   due

                           \|                        \|   to TWA by            \|   supplied             \|   workers          \|   lent                 \|   to

                           \|                        \|   substi-              \|   respir-              \|   in ASRs          \|   workers              \|   standard

                           \|                        \|   tution or            \|   ators                \|   due              \|   in ASRs              \|   as

                           \|                        \|   engineer-            \|   due to               \|   to               \|   due to               \|   percent

                           \|                        \|   ing                  \|   standard             \|   stand-           \|   standard             \|   of total

                           \|                        \|   controls             \|                        \|   ard              \|                        \|   workers

  \_\_\_\_\_\_\_\_\_\_\_   \|   \_\_\_\_\_\_\_\_\_   \|   \_\_\_\_\_\_\_\_\_   \|   \_\_\_\_\_\_\_\_\_   \|   \_\_\_\_\_\_\_   \|   \_\_\_\_\_\_\_\_\_   \|   \_\_\_\_\_\_\_\_\_\_

  Manufacture                                                                                                                                                 

   of Glycol                                                                                                                                                  

   Ethers                       344                       315                       29                        8%                    10                        3%

  Manufacture                                                                                                                                                 

   Of                                                                                                                                                         

   Chemical                                                                                                                                                   

   Interme-                                                                                                                                                   

   Diates                       80                        68                        12                        15%                   3                         4%

  Formulation                                                                                                                                                 

   of Paints                                                                                                                                                  

   And                                                                                                                                                        

   Coatings                     2,745                     2,637                     108                       4%                    26                        1%

  Aircraft                                                                                                                                                    

   Manufact-                                                                                                                                                  

   uring/Re-                                                                                                                                                  

   Painting                     1,998                     1,488                     510                       26%                   255                       13%

  Motor                                                                                                                                                       

   Vehicle                                                                                                                                                    

   Body                                                                                                                                                       

   Manufact-                                                                                                                                                  

   Uring                        736                       736                       0                         0%                    0                         0%

  Other                                                                                                                                                       

   Metal                                                                                                                                                      

   Applica-                                                                                                                                                   

   Tions                        1,464                     1,216                     248                       17%                   248                       17%

  Automobile                                                                                                                                                  

   Refinishing                  26,331                    25,600                    731                       3%                    91                        0%\*

  Wood                                                                                                                                                        

   Furniture                                                                                                                                                  

   Manufact-                                                                                                                                                  

   Uring                        8,140                     7,384                     756                       9%                    152                       2%

  Formulation                                                                                                                                                 

   of Inks                      946                       894                       52                        5%                    20                        2%

  Application                                                                                                                                                 

   of Inks                      946                       930                       16                        2%                    5                         1%

  Semiconductor                                                                                                                                               

   Manufact-                                                                                                                                                  

   Uring                        1,704                     1,704                     0                         0%                    0                         0%

  Printed                                                                                                                                                     

   Circuit                                                                                                                                                    

   Board                                                                                                                                                      

   Manufact-                                                                                                                                                  

   Uring                        352                       306                       46                        13%                   12                        4%

  Total                         45,786                    43,278                    2,508                     5%                    822                       2%

                                                                                                                                                              

  \* More than zero, but                                                                                                                                      
  less than 0.5%                                                                                                                                              

  Source: PEI                                                                                                                                                 
  ------------------------ ---- -------------------- ---- -------------------- ---- -------------------- ---- ---------------- ---- -------------------- ---- ----------------------

Costs Of The Proposed Regulation

OSHA has preliminarily determined that the proposed standard is
economically feasible. It is performance- oriented. Employers may choose
any combination of engineering and work practice controls, or
substitution of other chemicals for glycol ethers, to reduce exposures
to or below the proposed TWAs and ELs

Table VIII-10 shows estimated first year costs by industry category. All
substitution costs are expected to be incurred in the first year only.
By substituting, establishments would avoid all other costs in the first
year, as well as all costs in future years

Total first-year regulatory costs (substitution and compliance) would be
\$30.7 million under the geometric mean approach or \$30.9 million under
the arithmetic mean approach

Total substitution costs exceed total compliance costs, primarily
because of the large amount of substitution that would occur in
formulation of paints and coatings. The highest first-year cost is
estimated for the paints and coatings formulation category. Substitution
occurs in all industry categories except the manufacturing of glycol
ethers and chemical intermediates; however, substitution costs occur in
only four categories: formulation of paints and coatings, formulation of
inks, semiconductor manufacturing, and printed circuit board
manufacturing

  ------------------------ --------------- ------------------------------------------------------ ---- ------------------ ---- ------------------ ---- ---------------------------------------------------------- ---- ------------------ ---- ----------------------
  TABLE VIII-10                                                                                                                                                                                                                                

  FIRST YEAR COSTS OF                                                                                                                                                                                                                          
  PROPOSED STANDARD, BY                                                                                                                                                                                                                        
  INDUSTRY CATEGORY                                                                                                                                                                                                                            

                                                                                                                                                                                                                                               

                           \|                                                                                                                     \|                                                                                           

                           \|              Geometric mean approach                                                                                \|   Arthmatic mean approach                                                                 

                           \|              \_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_                                                   \|   \_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_                                

   Industry                \|                                                                     \|                      \|                      \|                                                              \|                      \|   

   Category                \|              Cost of                                                \|   Cost of            \|   Cost of            \|   Cost of                                                    \|   Cost of            \|   Cost of

                           \|              comp-                                                  \|   substi-            \|   regula-            \|   comp-                                                      \|   substi-            \|   regulation

                           \|              liance\*                                               \|   tution\*\*         \|   tion               \|   liance\*                                                   \|   tution\*\*         \|   (\$000)

                           \|              (\$000)                                                \|   (\$000)            \|   (\$000)            \|   (\$000)                                                    \|   (\$000)            \|   

  \_\_\_\_\_\_\_\_\_\_\_   \|              \_\_\_\_\_\_\_\_                                       \|   \_\_\_\_\_\_\_\_   \|   \_\_\_\_\_\_\_\_   \|   \_\_\_\_\_\_\_\_                                           \|   \_\_\_\_\_\_\_\_   \|   \_\_\_\_\_\_\_\_\_\_

  Manufacture                                                                                                                                                                                                                                  

   of Glycol                                                                                                                                                                                                                                   

   Ethers                                  67                                                          0                       67                      85                                                              0                       85

  Manufacture                                                                                                                                                                                                                                  

   Of                                                                                                                                                                                                                                          

   Chemical                                                                                                                                                                                                                                    

   Inter-                                                                                                                                                                                                                                      

   mediates                                40                                                          0                       40                      47                                                              0                       47

  Formulation                                                                                                                                                                                                                                  

   Of                                                                                                                                                                                                                                          

   Paints and                                                                                                                                                                                                                                  

   Coatings                                556                                                         15,400                  15,956                  559                                                             15,400                  15,959

  Aircraft                                                                                                                                                                                                                                     

   Manufact-                                                                                                                                                                                                                                   

   uring/Re-                                                                                                                                                                                                                                   

   painting                                695                                                         0                       695                     695                                                             0                       695

  Motor Vehicle                                                                                                                                                                                                                                

   Body                                                                                                                                                                                                                                        

   Manufact-                                                                                                                                                                                                                                   

   uring                                   57                                                          0                       57                      66                                                              0                       66

  Other Metal                                                                                                                                                                                                                                  

   Applica-                                                                                                                                                                                                                                    

   tions                                   903                                                         0                       903                     997                                                             0                       997

  Automobile                                                                                                                                                                                                                                   

   Refinish-                                                                                                                                                                                                                                   

   ing                                     5,866                                                       0                       5,866                   5,866                                                           0                       5,866

  Wood                                                                                                                                                                                                                                         

   Furniture                                                                                                                                                                                                                                   

   Manufact-                                                                                                                                                                                                                                   

   uring                                   997                                                         0                       997                     997                                                             0                       997

  Formulation                                                                                                                                                                                                                                  

   of Inks                                 136                                                         3,900                   4,036                   139                                                             3,900                   4,039

  Application                                                                                                                                                                                                                                  

   of Inks                                 67                                                          0                       67                      103                                                             0                       103

  Semiconductor                                                                                                                                                                                                                                

   Manufact-                                                                                                                                                                                                                                   

   uring                                   525                                                         650                     1,175                   525                                                             650                     1,175

  Printed                                                                                                                                                                                                                                      

   Circuit                                                                                                                                                                                                                                     

   Board                                                                                                                                                                                                                                       

   Manufact-                                                                                                                                                                                                                                   

   uring                                   217                                                         600                     817                     249                                                             600                     849

  Total                                    10,124                                                      20,550                  30,674                  10,328                                                          20,550                  30,878

                                                                                                                                                                                                                                               

  \*                       The first year                                                                                                                                                                                                      
                           costs of                                                                                                                                                                                                            
                           engineering                                                                                                                                                                                                         
                           controls are                                                                                                                                                                                                        
                           annualized;                                                                                                                                                                                                         

                           costs of                                                                                                                                                                                                            
                           workplace                                                                                                                                                                                                           
                           monitoring,                                                                                                                                                                                                         
                           medical                                                                                                                                                                                                             
                           surveillance                                                                                                                                                                                                        
                           and                                                                                                                                                                                                                 

                           recordkeeping                                                                                                                                                                                                       
                           are estimated                                                                                                                                                                                                       
                           to be higher                                                                                                                                                                                                        
                           during the                                                                                                                                                                                                          
                           first                                                                                                                                                                                                               

                           year than they                                                                                                                                                                                                      
                           will be in                                                                                                                                                                                                          
                           subsequent                                                                                                                                                                                                          
                           years                                                                                                                                                                                                               

  \*\*                     Although                                                                                                                                                                                                            
                           substitution                                                                                                                                                                                                        
                           costs are                                                                                                                                                                                                           
                           incurred in                                                                                                                                                                                                         
                           only four                                                                                                                                                                                                           
                           industry                                                                                                                                                                                                            

                           categories,                                                                                                                                                                                                         
                           substitution                                                                                                                                                                                                        
                           takes place in                                                                                                                                                                                                      
                           all industry                                                                                                                                                                                                        
                           categories                                                                                                                                                                                                          

                           except                                                                                                                                                                                                              
                           manufacture of                                                                                                                                                                                                      
                           glycol ethers                                                                                                                                                                                                       
                           and manufacture                                                                                                                                                                                                     
                           of chemical                                                                                                                                                                                                         

                           Intermediates                                                                                                                                                                                                       
  ------------------------ --------------- ------------------------------------------------------ ---- ------------------ ---- ------------------ ---- ---------------------------------------------------------- ---- ------------------ ---- ----------------------

Source: PEI

Table VIII-11 shows estimated annual costs by industry category. These
total \$7.2 million (geometric mean approach) or \$7.4 million
(arithmetic mean approach). The highest annual cost is estimated to be
for the automobile refinishing category. This is due to the large number
of establishments; other industry categories have higher per-
establishment recurring costs

Tables VIII-12 shows estimated first year and annual costs by
requirement. Substitution is the most significant component of the first
year costs. Engineering controls (annualized) and exposure monitoring
are the most significant components of annual costs.

  ------------------------------------------------------ ---- ------------------------------------ ---- ------------------------------------
  TABLE VIII-11                                                                                         

  ANNUAL COSTS OF PROPOSED STANDARD, BY INDUSTRY                                                        
  CATEGORY                                                                                              

                                                                                                        

                                                         \|                                        \|    

                                                         \|   Geometric                            \|   Arithmetic

                                                         \|   Mean Approach                        \|   Mean Approach

  Industry Category                                      \|   \_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_   \|   \_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_

                                                         \|                                        \|    

                                                         \|   Total Cost                           \|   Total Cost

                                                         \|   (\$000)                              \|   (\$000)

  \_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_   \|   \_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_   \|   \_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_

  Manufacture of Glycol                                                                                 

    Ethers                                                    15                                        20

  Manufacture of Chemical                                                                               

    Intermediates                                             18                                        23

  Formulation of Paints and                                                                             

     Coatings                                                 418                                       421

  Aircraft                                                                                              

  Manufacturing/Repainting                                    525                                       525

  Motor Vehicle Body                                                                                    

  Manufacturing                                               21                                        21

  Other Metal Applications                                    683                                       757

  Automobile Refinishing                                      4,254                                     4,254

  Wood Furniture Manufacturing                                762                                       762

  Formulation of Inks                                         106                                       109

  Application of Inks                                         34                                        59

  Semiconductor Manufacturing                                 244                                       244

  Printed Circuit Board                                                                                 

  Manufacturing                                               125                                       157

  Total                                                       7,205                                     7,353

                                                                                                        

  Source: PEI                                                                                           
  ------------------------------------------------------ ---- ------------------------------------ ---- ------------------------------------

  ---------------------------- ---- ------------------------------------------------------ ---- ---------------------------- ---- ------------------------------------------------------ ---- ----------------------------
  TABLE VIII-12                                                                                                                                                                               

  FIRST YEAR AND ANNUAL COSTS                                                                                                                                                                 
  OF PROPOSED STANDARD, BY                                                                                                                                                                    
  REQUIREMENT                                                                                                                                                                                 

                                                                                                                                                                                              

                               \|                                                                                            \|                                                               

                               \|   Geometric mean approach                                                                  \|   Arithmetic mean approach                                    

                               \|   \_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_                                     \|   \_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_        

  Regulatory                   \|                                                          \|                                \|                                                          \|   

  requirement                  \|   First year                                             \|   Annual                       \|   First year                                             \|   Annual

                               \|   (\$000)                                                \|   (\$000)                      \|   (\$000)                                                \|   (\$000)

  \_\_\_\_\_\_\_\_\_\_\_\_\_   \|   \_\_\_\_\_\_\_\_\_\_\_\_                               \|   \_\_\_\_\_\_\_\_\_\_\_\_\_   \|   \_\_\_\_\_\_\_\_\_\_\_\_                               \|   \_\_\_\_\_\_\_\_\_\_\_\_\_

  Engineering                                                                                                                                                                                 

   Controls                         2,611                                                       2,611                             2,642                                                       2,642

  Protective                                                                                                                                                                                  

   Clothing                         707                                                         707                               707                                                         707

  Exposure                                                                                                                                                                                    

   Monitoring                       3,309                                                       1,815                             3,377                                                       1,882

  Medical                                                                                                                                                                                     

   Surveillance                     1,445                                                       618                               1,524                                                       641

  Respirator                                                                                                                                                                                  

   Protection                       763                                                         763                               784                                                         784

  Respirator                                                                                                                                                                                  

   Fit Testing                      20                                                          20                                20                                                          20

  Regulated                                                                                                                                                                                   

   Areas, Signs,                                                                                                                                                                              

   Labels                           22                                                          22                                23                                                          23

  Hygiene                                                                                                                                                                                     

   Facilities                       160                                                         160                               160                                                         160

  Information                                                                                                                                                                                 

   and Training                     194                                                         194                               194                                                         194

   Housekeeping                     37                                                          37                                37                                                          37

   Recordkeeping                    857                                                         259                               860                                                         262

  Total                                                                                                                                                                                       

   Compliance                                                                                                                                                                                 

   Costs                            10,124                                                      7,205                             10,328                                                      7,353

  Substitution                                                                                                                                                                                

   Costs                            20,550                                                      0                                 20,550                                                      0

   GRAND TOTAL                      30,674                                                      7,205                             30,878                                                      7,353

                                                                                                                                                                                              

  Source: PEI                                                                                                                                                                                 
  ---------------------------- ---- ------------------------------------------------------ ---- ---------------------------- ---- ------------------------------------------------------ ---- ----------------------------

Economic Feasibility Analysis

OSHA preliminarily determines that companies in the industries involved
in this rulemaking should be able to absorb the costs of compliance with
the proposed standard without experiencing undue burden. In addition,
OSHA also preliminarily determines that the compliance costs of this
rulemaking will not threaten massive dislocation in any of the affected
industries, will not threaten the competitive stability of any of the
affected industries, and will not lead to undue concentration in any of
the industries. see American Iron and Steel Institute v. OSHA, 939 F.2d
975, 980 (D.C. Cir. 1991; United Steelworkers of America v. Marshall,
647 F.2d 1189, 1265-66 (D.C. Cir. 1980), cert. denied, 453 U.S. 913
(1981). Therefore, OSHA preliminarily concludes that it is economically
feasible to achieve the proposed standard by means of engineering and
work practice controls and substitution

PEI compared regulatory costs to financial and economic parameters to
determine the impacts of a revised standard for glycol ethers on
affected industries. They examined the extent to which establishments
can pass costs of regulation on to their customers, absorb costs that
cannot be passed on, and finance capital and up-front regulatory costs.
They also analyzed the impacts of regulatory requirements on competition
and the differential impacts on small businesses. Information for these
analyses was obtained from Dun & Bradstreet industry financial profiles
and various reports issued by the Commerce Department. Industry-wide
impacts of first year and recurring costs of the proposed standard are
shown in Tables VIII-13 and VIII-14.

\[page 15591\]

  -------------------------- --------------- ---------------------------------------------------------- ---- -------------------- ---- ------------------ ---- -------------------------------------------------------- ---- ------------------ ---- ------------------
  TABLE VIII-13                                                                                                                                                                                                                                      

  INDUSTRY-WIDE IMPACTS OF                                                                                                                                                                                                                           
  FIRST YEAR\* COSTS OF                                                                                                                                                                                                                              
  PROPOSED STANDARD                                                                                                                                                                                                                                  

                                                                                                                                                                                                                                                     

                             \|                                                                                                                           \|                                                                                         

                             \|              Geometric mean approach                                                                                      \|   Arthmatic mean approach                                                               

                             \|              \_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_                                                     \|   \_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_                                

  Industry                   \|                                                                                                                           \|                                                                                         

  Category                   \|              First year regulatory costs                                                                                  \|   First year regulatory costs                                                           

                             \|              \_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_                                                     \|   \_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_                                

                             \|                                                                         \|                        \|                      \|                                                            \|                      \|   

                             \|                                                                         \|   As                   \|   As                 \|                                                            \|   As                 \|   As

                             \|              Thousands                                                  \|   percent              \|   percent            \|   Thousands                                                \|   percent            \|   percent

                             \|                                                                         \|   Of                   \|   of                 \|                                                            \|   of                 \|   of

                             \|                                                                         \|   revenue              \|   profit             \|                                                            \|   revenue            \|   profit

  \_\_\_\_\_\_\_\_\_\_\_\_   \|              \_\_\_\_\_\_\_\_\_                                         \|   \_\_\_\_\_\_\_\_\_   \|   \_\_\_\_\_\_\_\_   \|   \_\_\_\_\_\_\_\_\_                                       \|   \_\_\_\_\_\_\_\_   \|   \_\_\_\_\_\_\_\_

  Manufacture                                                                                                                                                                                                                                        

   of Glycol                                                                                                                                                                                                                                         

   Ethers                                    67                                                              0.04%                     1.71%                   85                                                            0.05%                   2.17%

  Manufacture                                                                                                                                                                                                                                        

   of Chemical                                                                                                                                                                                                                                       

   Interme-                                                                                                                                                                                                                                          

   diates                                    40                                                              0.21%                     8.25%                   47                                                            0.24%                   9.76%

  Formulation                                                                                                                                                                                                                                        

   of Paints                                                                                                                                                                                                                                         

   And                                                                                                                                                                                                                                               

   Coatings                                  15,956                                                          1.05%                     16.41%                  15,959                                                        1.05%                   16.42%

  Aircraft                                                                                                                                                                                                                                           

   Manufact-                                                                                                                                                                                                                                         

   uring/Re                                                                                                                                                                                                                                          

   painting                                  695                                                             0.01%                     0.43%                   695                                                           0.01%                   0.43%

  Motor                                                                                                                                                                                                                                              

   Vehicle                                                                                                                                                                                                                                           

   Body                                                                                                                                                                                                                                              

   Manufact-                                                                                                                                                                                                                                         

   uring                                     57                                                              0.001%                    0.02%                   66                                                            0.001%                  0.02%

  Other                                                                                                                                                                                                                                              

   Metal                                                                                                                                                                                                                                             

   Applica-                                                                                                                                                                                                                                          

   tions                                     903                                                             0.06%                     1.07%                   997                                                           0.07%                   1.18%

  Automobile                                                                                                                                                                                                                                         

   Refinish-                                                                                                                                                                                                                                         

   ing                                       5,866                                                           0.02%                     0.25%                   5,866                                                         0.02%                   0.25%

  Wood                                                                                                                                                                                                                                               

   Furniture                                                                                                                                                                                                                                         

   Manufact-                                                                                                                                                                                                                                         

   uring                                     997                                                             0.09%                     0.96%                   997                                                           0.09%                   0.96%

  Formulation                                                                                                                                                                                                                                        

   of Inks                                   4,036                                                           1.15%                     27.25%                  4,039                                                         1.15%                   27.28%

  Application                                                                                                                                                                                                                                        

   of Inks                                   67                                                              0.02%                     0.25%                   103                                                           0.03%                   0.38%

  Semiconductor                                                                                                                                                                                                                                      

   Manufact-                                                                                                                                                                                                                                         

   uring                                     1,175                                                           0.04%                     0.55%                   1,175                                                         0.04%                   0.55%

  Printed                                                                                                                                                                                                                                            

   Circuit                                                                                                                                                                                                                                           

   Board                                                                                                                                                                                                                                             

   Manufact-                                                                                                                                                                                                                                         

   uring                                     817                                                             0.27%                     2.77%                   849                                                           0.28%                   2.88%

     Total                                   30,674                                                          0.05%                     0.90%                   30,878                                                        0.05%                   0.91%

                                                                                                                                                                                                                                                     

  \*                         First year                                                                                                                                                                                                              
                             costs of                                                                                                                                                                                                                
                             engineering                                                                                                                                                                                                             
                             controls are                                                                                                                                                                                                            
                             annualized;                                                                                                                                                                                                             
                             costs                                                                                                                                                                                                                   

                             of workplace                                                                                                                                                                                                            
                             monitoring,                                                                                                                                                                                                             
                             medical                                                                                                                                                                                                                 
                             surveillance,                                                                                                                                                                                                           
                             and                                                                                                                                                                                                                     
                             recordkeeping                                                                                                                                                                                                           

                             are estimated                                                                                                                                                                                                           
                             to be higher                                                                                                                                                                                                            
                             during the                                                                                                                                                                                                              
                             first year than                                                                                                                                                                                                         
                             they will                                                                                                                                                                                                               

                             be in                                                                                                                                                                                                                   
                             subsequent                                                                                                                                                                                                              
                             years                                                                                                                                                                                                                   

  Source: PEI                                                                                                                                                                                                                                        
  -------------------------- --------------- ---------------------------------------------------------- ---- -------------------- ---- ------------------ ---- -------------------------------------------------------- ---- ------------------ ---- ------------------

  -------------------------- ---- ---------------------------------------------------------- ---- -------------------- ---- ------------------ ---- -------------------------------------------------------- ---- ------------------ ---- ------------------
  TABLE VIII-14                                                                                                                                                                                                                           

  INDUSTRY-WIDE IMPACTS OF                                                                                                                                                                                                                
  ANNUAL COSTS OF PROPOSED                                                                                                                                                                                                                
  STANDARD                                                                                                                                                                                                                                

                                                                                                                                                                                                                                          

                             \|                                                                                                                \|                                                                                         

                             \|   Geometric mean approach                                                                                      \|   Arithmetic mean approach                                                              

                             \|   \_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_                                                     \|   \_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_                                

   Industry                  \|                                                                                                                \|                                                                                         

   category                  \|   Annual regulatory costs                                                                                      \|   Annual regulatory costs                                                               

                             \|   \_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_                                                     \|   \_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_                                

                             \|                                                              \|                        \|                      \|                                                            \|                      \|   

                             \|                                                              \|   As                   \|   As                 \|                                                            \|   As                 \|   As

                             \|   (Thous-                                                    \|   percent              \|   percent            \|   (Thous-                                                  \|   percent            \|   percent

                             \|   ands)                                                      \|   of                   \|   of                 \|   ands)                                                    \|   of                 \|   of

                             \|                                                              \|   revenue              \|   profit             \|                                                            \|   revenue            \|   profit

  \_\_\_\_\_\_\_\_\_\_\_\_   \|   \_\_\_\_\_\_\_\_\_                                         \|   \_\_\_\_\_\_\_\_\_   \|   \_\_\_\_\_\_\_\_   \|   \_\_\_\_\_\_\_\_\_                                       \|   \_\_\_\_\_\_\_\_   \|   \_\_\_\_\_\_\_\_

  Manufacture                                                                                                                                                                                                                             

   of Glycol                                                                                                                                                                                                                              

   Ethers                         15                                                              0.01%                     0.38%                   20                                                            0.01%                   0.51%

  Manufacture                                                                                                                                                                                                                             

   of Chemical                                                                                                                                                                                                                            

   Interme-                                                                                                                                                                                                                               

   diates                         18                                                              0.09%                     3.68%                   23                                                            0.12%                   4.79%

  Formulation                                                                                                                                                                                                                             

   of Paints                                                                                                                                                                                                                              

   And                                                                                                                                                                                                                                    

   Coatings                       418                                                             0.03%                     0.43%                   421                                                           0.03%                   0.43%

  Aircraft                                                                                                                                                                                                                                

   Manufact-                                                                                                                                                                                                                              

   uring/Re                                                                                                                                                                                                                               

   painting                       525                                                             0.01%                     0.32%                   525                                                           0.01%                   0.32%

  Motor                                                                                                                                                                                                                                   

   Vehicle                                                                                                                                                                                                                                

   Body                                                                                                                                                                                                                                   

   Manufact-                                                                                                                                                                                                                              

   uring                          21                                                              0.0004%                   0.01%                   21                                                            0.0004%                 0.01%

  Other Metal                                                                                                                                                                                                                             

   Applications                   683                                                             0.04%                     0.81%                   757                                                           0.05%                   0.90%

  Automobile                                                                                                                                                                                                                              

   Refinishing                    4,254                                                           0.01%                     0.18%                   4,254                                                         0.01%                   0.18%

  Wood                                                                                                                                                                                                                                    

   Furniture                                                                                                                                                                                                                              

   Manufact-                                                                                                                                                                                                                              

   uring                          762                                                             0.07%                     0.73%                   762                                                           0.07%                   0.73%

  Formulation                                                                                                                                                                                                                             

   of Inks                        106                                                             0.03%                     0.72%                   109                                                           0.03%                   0.74%

  Application                                                                                                                                                                                                                             

   of Inks                        34                                                              0.01%                     0.13%                   59                                                            0.02%                   0.22%

  Semiconductor                                                                                                                                                                                                                           

   Manufact-                                                                                                                                                                                                                              

   uring                          244                                                             0.01%                     0.11%                   244                                                           0.01%                   0.11%

  Printed                                                                                                                                                                                                                                 

   Circuit                                                                                                                                                                                                                                

   Board                                                                                                                                                                                                                                  

   Manufact-                                                                                                                                                                                                                              

   uring                          125                                                             0.04%                     0.42%                   157                                                           0.05%                   0.53%

    Total                         7,205                                                           0.01%                     0.21%                   7,353                                                         0.01%                   0.22%

                                                                                                                                                                                                                                          
  -------------------------- ---- ---------------------------------------------------------- ---- -------------------- ---- ------------------ ---- -------------------------------------------------------- ---- ------------------ ---- ------------------

Source: PEI

Substitution is not believed to place a significant burden on those
firms which would be able to use that method of responding to the
proposed regulation. Substituting firms would fund substitution costs in
the first year of the proposed regulation; there would be no recurring
substitution costs

For those firms which do not choose to substitute, compliance costs
should not pose a significant problem. In most cases, costs can be
recovered through a price increase. Possible exceptions are automobile
refinishing and wood furniture manufacturing. If complying wood office
furniture makers cannot increase prices, their compliance costs would
cause their net income to decline by as much as 11 percent under the
proposed standard. If complying automobile repair shops and paint shops
cannot increase prices, their net income could decline by as much as 13
percent under the proposed standard. In general, automobile refinishers
should be able to accommodate these impacts. However, they would likely
present a financial hardship for some operations with marginal profits

Regulatory Flexibility Analysis

The revised standards would have a greater impact on small than
average-sized businesses because compliance costs would not necessarily
be proportional to establishment size. Thus, small establishments would
have a greater incentive to substitute than would larger establishments.
Because of their comparatively small size (revenue of \$400,000 or
less), small printed circuit board manufacturers within the electronics
industry could encounter difficulty financing the up-front costs of
substitution. However, small semiconductor operations (also within the
electronics sector) should have no trouble complying; at most, a price
increase of only 0.2 percent would be needed to recover compliance
costs. In the absence of a price increase, net income would decline by
2.4 percent for this industry category

If small printed circuit board manufacturers cannot achieve price
increases of from 0.5 to 0.8 percent to recover costs of the proposed
standard, their earnings would decline by 5 to 8 percent.

**\[page 15592\]**

IX\. Environmental Impact

Introduction

OSHA has preliminarily determined that no significant environmental
impact will result from the lower PELs and ancillary provisions being
considered for the four glycol ethers \-- 2-methoxyethanol (2-ME),
2-methoxyethanol acetate (2-MEA), 2-ethoxyethanol (2-EE), and
2-ethoxyethanol acetate (2-EEA). The principal source for this analysis
is a study conducted for OSHA by PEI Associates, Inc., Technological
Feasibility and Economic Impact Assessment of A Proposed Revision to the
Glycol Ethers Standards, 110, OSHA Docket, Ex. 5-164

PEI determined on the basis of survey results and site visits that the
following six substances (all of them also glycol ethers) are the most
frequently used substitutes for 2-ME, 2-MEA, 2-EE and 2-EEA: ethylene
glycol monopropyl ether and its acetate, ethylene glycol monobutyl ether
and its acetate, and propylene glycol monomethyl ether and its acetate.
The potential for environmental impact resulting from these six
substitutes is examined

Air Emissions

The major Federal air pollution regulation that affects glycol ether
users or manufacturers is 40 CFR 60, New Source Performance Standards
(NSPS), which covers volatile organic compounds (VOCs). Users or
manufacturers of glycol ethers regulated under this standard are
Automobile and Light Truck Surface Coating, Graphic Arts and Rotogravure
Printing, Synthetic Organic Chemicals Manufacturing and Surface Coating
of Large Appliances

Mono-, di- and tri-ethers of ethylene glycol and their acetates are
listed as toxic chemicals under Section 313 of the Emergency Planning
and Community Right-to-Know Act (Title III of the Superfund Amendments
and Reauthorization Act of 1986), which requires recordkeeping and
reporting of emissions for all chemicals listed for facilities meeting
the threshold requirements of the Act. Thus, the major substitutes for
the glycol ethers would be covered by Section 313 in the same manner as
are the glycol ethers

For industries that use or manufacture glycol ethers and their
substitutes, Federal regulations will prevent increases in emissions
beyond those now permitted. Also, the glycol ethers and their major
substitutes have low vapor pressures, which results in low
concentrations in air exhaust streams. Thus, no incremental air
environmental impact is likely to occur as a result of reductions in the
workplace exposure limit

Glycol ether-using industries that are not subject to NSPS Federal
regulations (such as the electronics industry) use some engineering
controls to control workplace air concentrations, but do not appear to
use emission controls. That portion of the glycol ethers used that does
nor remain with the product eventually evaporates and may enter the
environment

OSHA action to reduce workplace levels is projected to increase the
trend to substitute other substances for glycol ethers. This
substitution should reduce the quantity of glycol ethers entering the
environment. The substitutes are generally less toxic than the four
glycol ethers under study and are expected to have little environmental
impact. Water Emissions

Because of the way glycol ethers are sued, a water pollution problem
does not appear likely. Neither the glycol ethers nor their substitutes
are subject to pretreatment standards that regulate discharges of
industrial waste or municipal sewage to publicly owned treatment works.
State and local standards regarding biological oxygen demand and
chemical oxygen demand should be sufficient to prevent nay increase in
releases to water that might occur as a result of more stringent
occupational exposure limits. Thus, no negative impact on the
environment is projected

X. Summary And Explanation Of The Proposed Standard

OSHA believes that the proposed requirements set forth in this notice
are necessary and appropriate to provide adequate protection to
employees exposed to ethylene glycol ethers based on currently available
information. Numerous reference works, journal articles, and other data
obtained by OSHA have been taken into consideration in the development
of this proposed standard

Scope and Application: Paragraph (a)

The proposed standard would apply to all occupational exposures to the
ethylene glycol ethers 2-Methoxyethanol (2-ME), 2-Ethoxyethanol (2-EE),
and their respective acetates 2-Methoxyethanol Acetate (2-MEA), and
2-Ethoxyethanol Acetate (2-EEA) except where the exposure occurs from 1)
liquid mixtures which contain less than 1%, by volume, of the above
compounds unless the employer has reason to believe that such mixtures
could release vapors in quantities sufficient to result in an airborne
concentration which meets or exceeds the ALs or ELs of the compounds or
could present a hazard through dermal contact; and 2) solids made from
or containing 2-ME, 2-MEA, 2-EE, or 2-EEA that are incapable of
releasing these compounds into the workplace air at or above the ALs or
above the ELs

The exemption for liquids with less than 1% glycol ethers is consistent
with the Hazard Communication Standard (HCS), 29 CFR 1910.1200,
paragraph (g)(2)(C)(1), which does not require inclusion of a
non-carcinogenic chemical on a Material Safety Data Sheet (MSDS) if it
comprises less than 1% of the composition of the mixture. However while
OSHA believes, in general, that liquid mixtures containing less than 1%
glycol ethers may present little hazard, there may be situations where
the mixture, despite its low concentration of glycol ethers, might
release vapors at or above the action levels or above the excursion
levels or present a hazard through dermal contact. For example a large
volume of a mixture containing less than 1% of glycol ethers may be
released (e.g. spill or tank rupture) and give rise to high airborne
levels of the glycol ethers by virtue of the large volume of mixture
that is released. Also a work practice involving a prolonged or repeated
dermal contact to a mixture containing less than 1% glycol ethers could
provide enough exposure to the glycol ethers in the mixture to result in
a significant dermal exposure. Thus it is proposed that if an employer
has reason to believe that liquid mixtures with less than 1% glycol
ethers could release glycol ethers vapors in concentrations at or above
the action levels or above the excursion levels or could present a
hazard through dermal contact, then that employer must comply with all
provisions of the standard for glycol ethers. An employer\'s belief of
the potential for such occurrences may be based on such things as
information from a manufacturer or trade association or the employer\'s
knowledge about chemical processes or work practices in his workplace

OSHA also proposes that solids made from or containing glycol ethers
that are capable of releasing those glycol ethers into the workplace air
at or above the action levels or above the excursion levels are also
exempt from the scope of this standard. In general glycol ethers are
used as solvents in compounds which are used in the workplace. During
the use of these compounds, the glycol ethers evaporate. Thus upon
drying there is no glycol ether left in the

**\[page 15593\]**

dried compound which could off gas vapors to the workplace air. Since
these solids would present little hazard, it is proposed that they be
exempted from the scope of the standard. However if there are situations
where solids containing glycol ethers could release vapors at or above
the action levels or above the excursion levels, then these solids would
be covered under the scope of the standard. OSHA is unaware of any such
situations and requests information on the existence of such occurrences
in the workplace

This proposed standard covers only the four ethylene glycol ethers
(2-ME, 2-MEA, 2-EE, and 2-EEA) referred to OSHA by EPA under section
9(a) of the TSCA. In the ANPR for these substances OSHA discussed the
possibility of expanding the scope of the rulemaking to cover other
glycol ethers. In that notice, OSHA stated that, based on their
similarities in structure and routes of metabolism, the adverse effects
of at least some of the other glycol ethers may be similar to 2-ME, 2-EE
and their acetates. For these reasons OSHA stated that it might be
appropriate to include other glycol ethers within the scope of a
proposed standard for glycol ethers

Several commentors to the ANPR (Exs. 7-11, 7-12, 7-13, 7- 14, 7-16,
7-17, 7-18, 7-20, 7-21, 7-23, 7-24 and 7-28) did not support expanding
the scope of the rulemaking. In general these commentors stated that
because of the differences in the toxicities between the four subject
glycol ethers and longer chain glycol ethers, they did not believe that
it was appropriate to promulgate a generic standard for all glycol
ethers. In particular, ARCO (Ex. 7- 19) stressed the differences between
ethylene glycol ethers and propylene glycol ethers. ARCO presented
statements and evidence that propylene glycol ethers are metabolized by
different pathways than the ethylene glycol ethers resulting in
different primary metabolites of lesser toxicity. Furthermore ARCO added
that the propylene glycol ethers have not been shown to induce adverse
reproductive and/or developmental effects similar to 2-ME, 2-EE and
their acetates. NIOSH (Ex. 7-22) stated that in general they would
support a generic approach to rulemaking. However, in the case of other
glycol ethers they stated that the data were limited and therefore they
recommended one standard with two PELs, one for 2-ME/2-MEA and one for
2-EE/2-EEA. Two commentors to the ANPR, TVA and Public Citizen (Exs. 7-
15 and 7-25), did support a generic glycol ethers standard, stating that
the effects may potentially be similar for other glycol ethers

As discussed in Section V - Health Effects, OSHA believes that the data
are limited on the toxicity for glycol ethers other than 2-ME, 2-EE and
their acetates. The data which are available, indicate that toxicities,
as well as the uses of other glycol ethers, may vary to such an extent
that a generic standard for all glycol ethers may be inappropriate. For
this reason the scope of this proposal is limited to occupational
exposure to 2-ME, 2-EE and their acetates. OSHA requests comments on
this approach. In particular, the Agency is interested in health effects
data on other glycol ethers

OSHA is also proposing that construction be included under the scope of
the standard, by amending section 1910.19 to add a new paragraph (n) for
glycol ethers. OSHA\'s reasoning is as follows. Firstly, based on
current evidence, OSHA believes that the proposed standard would have
little impact on construction. However a significant source of exposure
may occur in maintenance operations at facilities that manufacture,
formulate or use glycol ethers or liquids containing glycol ethers.
Exposure during these operations may be relatively high and it is
necessary, therefore, that employees wear respirators, receive medical
examinations and be protected by the other provisions of the proposed
glycol ethers standard. Sometimes such facilities hire outside
contractors to perform maintenance operations. The contention is
sometimes made that the maintenance operations should be considered to
be construction activities and not subject to general industry
standards. Employees of such contractors are subject to the same levels
of glycol ethers and need the same protection as other exposed
employees. OSHA proposes to cover these employees under the glycol
ethers standard

Thus, although the impact of the standard will be limited, OSHA believes
that construction should not be exempted from the standard. OSHA
believes that a loophole would be opened in the enforcement of the
standard if construction were exempted. The distinction between
maintenance and construction activities is often an ambiguous one. The
independent contractors who perform maintenance clearly need to be
covered. If construction were excluded, these maintenance contractors
might argue that their work is \"construction\" and that they are not
covered by the standard. By covering construction, this ambiguity does
not arise. This approach is consistent with other standards (e.g.,
Ethylene Oxide, 29 CFR 1910.1047 and Benzene, 29 CFR 1910.1028). OSHA
requests comments on this approach for glycol ethers. OSHA also welcomes
data on the exposure and use of glycol ethers in the construction
industry which may be different from those in general industry

Definitions: Paragraph (b)

Action level is defined as an airborne concentration of 0.05 ppm for
2-ME and 2-MEA and an airborne concentration of 0.25 ppm for 2-EE and
2-EEA, calculated as an 8-hour time weighted average (TWA). For workers
exposed at or above the action level, without regard to the use of
respiratory protection, medical surveillance and air monitoring are
required. Generally, where exposures are determined to be below the
action levels of 0.05 ppm (2-ME, 2-MEA) and 0.25 ppm (2-EE, 2-EEA), no
further action is required of the employer except provision of training
as required by paragraph (m) of this section and provision of
appropriate personal protective equipment as required by paragraph (h)
of this section

Measurements of employee exposure can vary considerably for a number of
reasons including process variations, sampling and analytical methods
limitations, and seasonal changes. Therefore, even if all the
measurements taken on a given day fall below the 8-hour time weighted
average (TWA) permissible exposure limit, the possibility exists that on
unmeasured days an employee\'s actual exposure may exceed the TWA. More
explicitly, when measured exposure levels are over one-half of the TWA,
the employer cannot have a high degree of confidence that employees are
not overexposed to glycol ethers during unmeasured periods of the work
week. Conversely, when the measured concentrations are below the action
level, the employer can have a reasonable degree of confidence that the
TWA is not being exceeded on days when exposure measurements are not
being performed

Based on the above concept, the action level provides a means of
triggering various provisions of the proposed regulation relative to the
exposure levels of employees. This approach increases cost-effectiveness
and performance orientation of the standard while enhancing employee
protection. For example, it is proposed that employers who maintain
employee exposure below the action level be relieved of the obligations
of further monitoring and medical surveillance of those employees.
Employers are thereby encouraged to develop cost-effective,

**\[page 15594\]**

innovative approaches for reducing employee exposures below the action
level in order to eliminate the expense of implementing certain
provisions of the standard Employees will benefit by improved protection
since their exposures will be less than one-half of the TWA permissible
exposure limit. In addition, employers can focus their attention on
employees whose exposure levels may be significant. Those employees
exposed at or above the action level will have the added protection of
medical surveillance, monitoring, and other provisions of the proposed
standard

The use of action levels to trigger provisions of the proposed standard
and the setting of the action level at one-half of the TWA is consistent
with other OSHA health standards, such as Asbestos (51 FR 22612, June
20, 1986; 29 CFR 1910.1001), Benzene (52 FR 34460, September 11, 1987;
29 CFR 1910.1028), and Formaldehyde (52 FR 46168, December 4, 1987; 29
CFR 1910.1048). This uniformity provides administrative consistency and
continuity in developing and implementing compliance strategies for this
and other applicable OSHA health standards at individual worksites

Authorized Person means any person specifically authorized by the
employer, whose duties require the person to enter a regulated area, or
any person entering such an area as a designated representative of
employees for the purpose of exercising the right to observe monitoring
and measuring procedures under paragraph (d) of this section, or any
other person authorized by the Act or regulations issued under the Act.
Examples of such people would include, but are not limited to, employees
who normally work in the regulated area, union representatives, and OSHA
compliance officers

Emergency is defined to mean any occurrence such as, but not limited to,
equipment failure, rupture of containers, or failure of control
equipment which may or does result in an unexpected release of a
significant amount of glycol ethers. Every spill or leak does not
automatically constitute an emergency situation. The exposure to
employees must be high as well as unexpected. This is a
performance-oriented definition relying upon judgment

Employee exposure is defined as that exposure to airborne or liquid
glycol ethers which would occur if the employee were not using
respiratory protective equipment or other personal protective equipment.
This definition is consistent with OSHA\'s previous use of the term in
other standards

Ethylene Glycol Ethers for the purposes of this section, means
2-Methoxyethanol (2-ME) (CAS No. 109-86-4), 2-Methoxyethanol acetate
(2-MEA) (CAS No. 110-49-6), 2-Ethoxyethanol (2-EE) (CAS No. 110-80-5),
and 2-Ethoxyethanol acetate (2-EEA) (CAS No. 111-15-9). The family of
ethylene glycol ethers is comprised of a large number of compounds. At
the present time, however, this proposed standard will deal with only
those four compounds noted above. These four chemicals are also known by
a variety of chemical and trade names. Therefore, to eliminate confusion
as to which compounds are being considered for regulation, they have
also been identified by their CAS number. This number is assigned by the
Chemical Abstract Service and, without regard to system of chemical
nomenclature or trade name, is unique to a specific chemical. A detailed
discussion of the chemical properties of these compounds can be found in
Section IV, \"Chemical Identification, Production and Use of Ethylene
Glycol Ethers\" of this document. Glycol Ethers is defined the same as
\"Ethylene glycol ethers\"

above and for the purpose of the document is used interchangeably with
the above term

Objective Data means information demonstrating that a particular product
or material containing glycol ethers or a specific process, operation,
or activity involving glycol ethers cannot release glycol ethers in
airborne concentrations at or above the action level or above the
excursion limit or result in dermal exposure, even under worst-case
release conditions of foreseeable use. A more detailed discussion of
\"objective data\" can be found in paragraph (d), Exposure Monitoring,
of this section

Regulated Area means any area where airborne concentrations of glycol
ethers exceed or can reasonably be expected to exceed the permissible
exposure limits, either the 8-hour time-weighted average (TWA)
permissible exposure limits of 0.1 ppm (2-ME, 2-MEA) and 0.5 ppm (2-EE,
2-EEA) or the 15-minute excursion limits (EL) of 0.5 ppm (2-ME, 2-MEA)
and 2.5 ppm (2-EE, 2-EEA). Regulated areas must be established anytime
the airborne concentration of glycol ethers exceeds or can be expected
to exceed the TWAs and/or ELs. Their existence may be of extended
duration, such as when currently feasible engineering and work practice
controls are inadequate to lower airborne glycol ether concentrations
below the PELs, or they may exist for only a short period of time as
could be expected during a maintenance operation. Requirements
specifically pertaining to regulated areas are found in paragraph (e) of
this section

Permissible Exposure Limits: Paragraph (c)

OSHA proposes, in paragraph (c)(1), to establish new permissible
exposure limits for ethylene glycol ethers by amending the current
standards found in 29 CFR 1910.1000, Table Z-1-A, which are 8-hour time
weighted averages (TWAs) of 200 ppm for 2-EE, 100 ppm for 2-EEA, and 25
ppm for both 2-ME and 2-MEA. OSHA is proposing new permissible exposure
limits of 0.1 ppm for 2-ME and 2-MEA and 0.5 ppm for 2-EE and 2-EEA
calculated as an 8-hour TWA. In addition, the Agency is proposing, in
paragraph (c)(2), 15-minute excursion limits (ELs) of 0.5 ppm (2-ME,
2-MEA) and 2.5 ppm (2-EE, 2-EEA). These limits are the airborne
concentration, averaged over a 15-minute sampling period, resulting from
monitoring conducted during an employee\'s anticipated highest level of
exposure

OSHA has proposed to amend the current TWAs based upon evidence that
occupational exposure to ethylene glycol ethers at the current standards
presents a significant risk of adverse hematologic, reproductive and
developmental effects while the proposed TWAs would achieve a
significant reduction in that risk. The basis for this action is
discussed in the significance of risk, health effects, and feasibility
sections preceding this section. Overall, however, OSHA has made the
preliminary determination that the proposed TWAs reduce significant risk
and are feasible

In conjunction with the 8-hour TWAs, OSHA is proposing 15-minute
excursion limits for these ethylene glycol ethers in paragraph (c)(2).
The Agency feels that establishing ELs will further reduce significant
risk. As discussed in the preliminary risk assessment section, the
proposed TWAs of 0.1 ppm for 2-ME and 2-MEA and 0.5 ppm for 2-EE and
2-EEA were derived by dividing the NOELs from experimental studies by
uncertainty factors of 100. OSHA believes that using an uncertainty
factor of 100 results in a level at which workers will be less likely to
experience adverse reproductive or developmental effects such as those
observed in animal studies. However, it should be kept in mind that
these levels (0.1 and 0.5 ppm) represent eight-hour time weighted
averages. Thus, it is possible that the levels for 2-ME/2-MEA and
2-EE/2-EEA could reach as high as 3.2 ppm or 16.0 ppm, respectively, for
any 15-minute period and still meet the 8-hour

**\[page 15595\]**

TWAs of 0.1 and 0.5 ppm, provided that there are no other exposures in
the 8-hour period. Under this exposure scenario, the uncertainty factor
is lowered from 100 to approximately 3. This reduction in the margin of
safety may be important in the case of reproductive and developmental
effects where peak doses rather than cumulative doses may play an
important role in the biological effects. For example, peak doses
occurring at critical periods of fetal or spermatogenic development may
induce adverse effects due to the sensitivity of that particular period
of development. Thus, OSHA believes that it is important to reduce peak
exposures to the extent possible. Implementing excursion limits five
times the TWAs (i.e., 0.5 for 2-ME/2-MEA and 2.5 ppm for 2-EE/2-EEA)
will decrease the reduction in the uncertainty factors and thus provide
a greater likelihood that workers will not suffer an adverse
reproductive or developmental effect from exposure

While OSHA is proposing 15-minute excursion limits of 5 times the
respective TWAs, it should be noted that paragraph (c)(2)(A) prohibits
an employee\'s exposure from exceeding the TWAs through such 15-minute
exposures. Therefore, even though an employee receives his/her exposure
in short bursts, the overall exposure level cannot exceed the TWAs when
the excursion limit exposures are calculated as an 8- hour time weighted
average. In addition, when an employee\'s 15-minute excursion exposures,
calculated as an 8-hour time weighted average, are at or above the
action level, then all provisions of this section which are triggered at
the action level must be implemented for that employee

In addition to exposure by inhalation, glycol ethers are readily
absorbed through the skin. As a result, both the OSHA PELs and the
American Conference of Governmental Industrial Hygienists (ACGIH) TLVs
carry a \"skin\" notation for the four glycol ethers under
consideration. Studies have shown that dermal absorption of these
compounds, either alone or in conjunction with inhalation exposure, is
capable of inducing adverse effects in animals and/or humans (Exs.
4-121, 4-139, 5-049, 5-073). The Agency, therefore, has proposed in
paragraph (c)(3) that the employer assure that no employee is exposed to
glycol ethers through dermal contact

Exposure Monitoring: Paragraph (d)

Paragraphs (d)(1) through (d)(7) of the proposed standard would impose
monitoring requirements pursuant to Section 6(b)(7) of the OSH Act (29
U.S.C. §655) which mandates that any standard promulgated under section
6(b) shall, where appropriate, \"provide for monitoring or measuring of
employee exposure at such locations and intervals, and in such manner as
may be necessary for the protection of employees.\"

The Agency believes that the employer\'s knowledge of exposures existing
among employees is fundamental to the provision of a healthful
workplace. The purposes served by requiring initial and periodic air
sampling for employee exposures to glycol ethers include: prevention of
employee overexposure; determination of the extent of exposure at the
worksite; identification of the sources of exposure to glycol ethers;
collection of exposure data so that the employer can select the proper
control methods to be used; and evaluation of the effectiveness of the
selected methods. Monitoring enables employers to meet the legal
obligation of the standard to ensure that their employees are not
exposed to ethylene glycol ethers in excess of the prescribed levels and
to notify employees of their exposure levels, as required by section
8(c)(3) of the Act. In addition, collection of exposure monitoring data
enables the examining physician to be informed of the existence and
extent of potential sources of occupational diseases

Exposure monitoring is critical to determining the specific levels of
glycol ethers to which employees are exposed. A number of obligations
are delineated by specific exposure levels above which certain
provisions have to be implemented to protect the employees and achieve
compliance with the standard. Medical surveillance and exposure
monitoring provisions of the standard are triggered, for example, for
employees exposed at or above the AL or above the EL. The remaining
provisions of the standard are triggered by employee exposure above the
TWA

The exposure monitoring provision of paragraph (d)(1)(i) would require
each employer who has a workplace or work operation covered by this
section to accurately determine employee exposure to ethylene glycol
ethers. While initial evaluation of employee exposure would require
either actual monitoring of each employee or the use of objective data,
subsequent determinations may be carried out through representative
sampling and would not necessarily entail sampling of all exposed
employees

Paragraph (d)(1)(ii) would require that these determinations be made
from samples that are taken within the employee\'s breathing zone
(personal samples) and which accurately reflect the employee\'s
exposure, without regard to the use of respirators, to airborne
concentrations of glycol ethers over an eight-hour period. This permits
the employer to ascertain compliance with the ALs and the TWAs. In
addition, the employer must monitor employees over a fifteen minute
period to determine whether they are in compliance with the excursion
limits (ELs) at operations where there is reason to believe that
exposures may be above the ELs. Examples of situations which may present
the potential for elevated short term exposures include, but are not
limited to, where tanks are opened, filled, unloaded, or gauged; where
containers or process equipment are opened; where glycol ethers are
transferred between containers or added to mixtures in open systems; and
where glycol ethers are used for cleaning or as a solvent in an
uncontrollable situation as may be found, for example, in the cleaning
of machinery where neither permanent nor temporary engineering or work
practice controls are adequate to reduce the levels of glycol ethers to
or below the ELs

Paragraph (d)(1)(iii) would require the employer to determine TWA and EL
employee exposures for each employee in each job classification, in each
work area, and for each shift whenever exposure to glycol ethers exists.
Except for the initial monitoring that would be required by this
section, paragraph (d)(1)(iv) states that a representative sampling
strategy may be developed which will measure sufficient exposure levels
within each job classification or for each job task (if there is task
variation within a job classification which could result in different
exposure levels within that job classification) for each workshift, in
each work area to correctly characterize and not underestimate the
exposure of any employee within each exposure group. However, exposure
levels shall be determined for each employee in each job classification
in each work area for each shift unless the employer can document that
exposure levels for a given job classification are equivalent for
different work shifts

Representative exposure sampling is permitted when there are a number of
employees performing the same job function in the same job
classification under the same conditions. For such employees, it may be
sufficient to monitor some fraction of such employees in order to obtain
data that are \"representative\" of the remaining employees.
Representative personal sampling of these employees must include that
member(s) of the exposed group reasonably expected to have the

**\[page 15596\]**

highest exposure. This result can then be applied to the remaining
employees of the group. In developing a representative sampling
strategy, the employer must systematically examine process and workplace
variables to identify which employees are to be monitored. Strategy
development should include: 1) investigation of worksites where the
nature of the operation or process indicates possible release of glycol
ethers into the work environment to identify the sources of these
emissions; 2) investigation of worksites where there have been employee
complaints or symptoms indicative of possible exposure to glycol ethers;
3) analysis of exposure patterns within the worksite, including each
employee\'s distance from the source of glycol ethers, variations in
tasks among employees in the same job classification, employee mobility,
air movement patterns, and differences in work habits

As stated in paragraph (d)(1)(v), objective data \[as defined in
paragraph (b)\] may also be used by the employer to document that the
presence of glycol ethers in the workplace or products containing glycol
ethers cannot result in the release of airborne concentrations of glycol
ethers that would cause any employee to be exposed at or above the
action level or above the EL under worst-case release conditions of
foreseeable use. If the employer can adequately demonstrate with
objective data that the preceding conditions exist, then the employer is
relieved of measuring employee exposure to glycol ethers

A detailed discussion of \"objective data\" can be found in the final
standard for Formaldehyde (52 FR 46255). Pertinent portions of that
discussion are reproduced here for the sake of convenience and
clarification

.Employers can use data on physical properties, combined with
information as to room dimensions, air exchange rates, and other
pertinent data, including, for example, information on work practices,
to estimate the maximum exposures that could be anticipated in the
workplace. Relying on such an approach to estimate worker exposures from
objective data requires the use of safety factors to account for uneven
distribution of formaldehyde vapor in the air and the proximity of
workers to emissions sources (Ex. 73-176). Objective data could also
include historical data on employee exposures, area monitoring conducted
to determine ambient formaldehyde levels and emissions from sources of
formaldehyde releases, or carefully evaluated monitoring conducted for
other than a full shift or 15-minute period. .OSHA recognizes that many
workplace factors must be taken into account by employers relying on
objective data (see 50 FR 50473).

In retaining the objective data requirement, OSHA does not intend that
employers engage in complex modeling exercises as a substitute for
employee exposure monitoring, and the Agency recognizes that, in
workplaces where many complex factors must be considered to use
objective data, a high degree of uncertainty will be associated with
trying to assess employee exposures from objective data. In these
instances, employers should conduct exposure monitoring instead of
relying on objective data so that they can have confidence that they are
in compliance with the standard\'s provisions

Moreover, in workplaces where many complex factors combine to influence
employee exposures to formaldehyde, employers may find it easier, more
useful, and less costly to monitor rather than to try to evaluate
employee exposures through generation and evaluation of objective data

Briefly summarizing the above discussion, a number of workplace factors
must be taken into account when relying on objective data (e.g.
temperature, humidity, ventilation rate, employee proximity to
contaminant source), however, it is not the Agency\'s intent that
employers engage in complex modeling exercises in place of employee
exposure monitoring. In workplaces where a number of complex factors
must be considered, the employer should conduct exposure monitoring,
rather than relying upon objective data, to increase confidence that
they are in compliance with the standard\'s provisions. Initial
monitoring of workplace exposures would be required of all employers who
have a place of employment covered under the scope of this standard.
Paragraph (d)(2)(i) would require the employer to identify all employees
who, without regard to respirator use, are exposed or may reasonably be
anticipated to be exposed, at or above the action level or above the EL
and to perform initial monitoring to accurately determine the exposure
of employees so identified. The initial monitoring must be conducted
within 60 days of the effective date of the final standard as set forth
in paragraph (o)(2)(i). However, to relieve some of the monitoring
burden and associated cost, paragraph (d)(2)(ii) of the proposal would
permit an employer who has comparable and adequate workplace monitoring
data gathered within 180 days prior to the effective date of the
standard to rely on those data to satisfy the requirements of the
initial monitoring. To meet the \"comparable and adequate\" intent of
this provision, such monitoring data must have been gathered under
conditions closely resembling those currently prevailing in the
workplace, each employee must have been monitored, and the monitoring
must satisfy all other requirements of this section including accuracy
of the analytical method at the proposed action levels

It should be noted that this provision would require initial monitoring
to be performed for all employees who are potentially exposed to glycol
ethers at or above the ALs or above the ELs. For the purpose of this
section, representative sampling will not be an accepted method of
initial monitoring. The reasoning behind this is that the permissible
exposure limits for the 8-hour TWAs are being reduced to such an extent
(e.g., from 25 ppm to 0.1 ppm for 2-ME) that the Agency does not believe
that the initial assessment of employee exposure can be accurately
determined through representative sampling. This approach is further
supported when one considers that the action levels of these compounds
are even lower, 0.05 ppm (2-ME, 2-MEA) and 0.25 ppm (2-EE, 2-EEA). At
these levels, minor variations in employee work practices or job tasks,
workplace ventilation, compound concentration, and so forth can affect
the level of employee exposure and thereby implementation of various
provisions of this proposal. It is OSHA\'s belief, therefore, that
employee exposure levels relative to the TWAs, ELs, and ALs can be
accurately determined only by conducting initial monitoring for each
employee. The only exception to performing initial monitoring is the use
of objective data as discussed in paragraph (d)(1)(v). In assembling
objective data, however, it should be noted that the Agency would
question historical data used to substantiate claims of exposure levels
below the proposed action levels, since the proposed action levels are
near the level of reliable quantitation of the 1985 OSHA analytical
method for these substances (the proposed action level for 2-ME is
actually below the level of quantitation or LOQ of the 1985
methodology). The level of quantitation (LOQ)/level of detection (LOD)
discussion in the 1985 analytical method states: (Ex. 5-005)

The reliable quantitation limits and detection limits reported in the
method are based upon optimization of the instrument for the smallest
possible amounts of analytes. When target concentration of an analyte is
exceptionally higher than these limits, they may not be attainable at
the routine operating parameters.

Since the previous permissible exposure limits range from 25 ppm
(2-ME/2-MEA) to 200 ppm (2-EE), it is doubtful that normal analytical
procedures and apparatus would be optimized to achieve a target
concentration at the

**\[page 15597\]**

method\'s LOD/LOQ. Therefore, the Agency would seriously question the
accuracy and reliability of historical monitoring results at such levels

The outcome of the monitoring determines what subsequent action must be
taken by the employer. If initial or periodic monitoring results show
employee exposure to be below the action level, the employer may
discontinue monitoring for that employee unless there is a change in
production, equipment, process, personnel, control measures, or any
other such factor which may result in new or additional exposure to
glycol ethers. However, paragraph (d)(3)(i) stipulates that if initial
monitoring reveals employee exposure to be at or above the AL or above
the EL, then periodic monitoring must be initiated as discussed below
and in paragraphs (d)(3)(ii) through (d)(3)(iv) of the proposed standard

Periodic measurements are one of the most informative ways of detecting
hazardous shifts in exposure concentrations, an indicator that
engineering controls are not working properly or that good work
practices are not being followed. The results of monitoring determine
the monitoring frequency which must be adopted by the employer.
Paragraph (d)(3)(ii) states that if the initial or periodic monitoring
results show employee exposures at or above the AL, but at or below the
TWA then the employer must repeat monitoring for these individuals at
least every six months. As discussed previously, when monitoring results
are above the action level, the employer can no longer be confident that
employees are not being exposed over the TWA. Therefore, OSHA feels that
periodic monitoring of employees exposed at or above the action level is
necessary to assure employers that their employees are not overexposed

If initial or periodic exposures are above the TWA then the employer
must monitor every three months as would be required by paragraph
(d)(3)(iii) of this section. Once employee exposures exceeding the TWA
have been identified, the employer is obligated to implement measures
directed at eliminating or minimizing those exposures. More frequent
monitoring is warranted to determine the effectiveness of the measures
in protecting workers

Monitoring for the EL is generally to be carried out simultaneously
with, and according to, the required monitoring frequencies discussed
above. However, as stated in paragraph (d)(3)(iv), if an employee is
exposed in excess of the EL, that employee shall be monitored at least
every three months under conditions of highest exposure. As related
previously in the discussion on excursion limits, exposure to short
bursts of elevated levels of glycol ethers may play an important role in
biological effects of these compounds. Therefore, protection against
this type of exposure could be of equal concern compared to exposures
exceeding the TWA. As a result, the same periodic monitoring frequency
has been proposed for exposures in excess of either the TWAs or ELs

OSHA believes these frequencies, which are similar to those required by
other OSHA standards, such as Arsenic (43 FR 19854 May 5, 1978; 29 CFR
1910.1018) and Ethylene Oxide (49 FR 25734 June 22, 1984 and 53 FR 11414
April 6, 1988; 29 CFR 1910.1047), are necessary and sufficient for
providing useful information to evaluate employees\' exposures. Periodic
re-monitoring provides the employer with assurance that employees are
not experiencing higher exposures that may require the use of additional
controls. In addition, these measurements remind employees and employers
of the continued need to protect against the hazards which could result
from exposure to glycol ethers

Employees are further protected because additional monitoring would be
required by paragraph (d)(4) when there has been a change in production,
equipment, raw materials, process, personnel, or work practices which
may result in new or additional exposures to glycol ethers at or above
the ALs or above the ELs, or whenever the employer has any other reason
to suspect that a change may result in new or additional exposures at or
above the ALs or above the ELs

OSHA recognizes that monitoring can be a time-consuming, expensive
endeavor. Therefore, this proposal offers employers the incentive to
minimize employees\' exposures by allowing employers to discontinue
monitoring for employees under certain conditions. It is hoped that such
a provision will encourage employers to maintain their employees\'
exposures to glycol ethers below the Al and the EL, thus maximizing the
protection of employees\' health

Paragraph (d)(5)(i) through (d)(5)(iii) would permit the employer to
discontinue monitoring for an employee, except as noted otherwise in
paragraph (d)(4) of this section, if the initial monitoring results show
the employee\'s exposure to be below the AL and at or below the ELs. If
periodic monitoring results indicate, by at least two consecutive
measurements taken at least seven days apart, that employee exposures
have fallen below the ALs, and are at or below the ELs, the employer may
discontinue monitoring for those employees whose exposures are
represented by such monitoring. However, the results must be
statistically representative and consistent with the employer\'s
knowledge of the job and work operation. Also, paragraph (d)(5)(iii)
states that if the initial or periodic monitoring reveals the employee
to be at or above the AL but, on two consecutive measurements taken at
least seven days apart, the employee is not exposed above the EL, no
further monitoring for the EL is necessary except as required by
paragraph (d)(4) of this section

When considering termination of monitoring an employee\'s exposure
level, the employer should have reasonable confidence that the
employee\'s exposure has truly been reduced below the AL and/or EL.
Variations in job task, daily production, ventilation patterns, and so
forth could result in a non-characteristically low exposure measurement
and, if only one sample is considered, lead the employer to incorrectly
deduce that the employee is no longer overexposed. To minimize the
possibility of the occurrence of such an incorrect supposition, increase
the employer\'s confidence in terminating monitoring, and to further
protect employees against overexposure, the Agency would require that,
at a minimum, the employer monitor the employee\'s exposure level a
second time, at least seven days later, to confirm the reduced exposure
level before termination of monitoring. This requirement is consistent
with other recent OSHA standards

Paragraph (d)(6) would require the employer to use monitoring and
analytical methods which have an accuracy (at a confidence level of 95%)
within plus or minus 25% for airborne concentrations of glycol ethers at
or above the level being investigated. This is necessary to assure that
95 percent of the measurements are accurate to within plus or minus 25
percent of the \"true\" exposure level. OSHA has included this accuracy
requirement in other toxic substance standards (Formaldehyde, 29 CFR
1910.1048). A method of measurement is presently available to detect
ethylene glycol ethers to this degree of accuracy and is described in
Appendix (E). The proposed standard, in paragraph (d)(7), would require
that employers notify each of their employees individually of the
results of personal monitoring samples. This notification is to be given
within 15 days of receipt of exposure monitoring results and is to be
given in writing and

**\[page 15598\]**

by posting a notice in an appropriate location accessible to affected
employees. A written notice ensures that each employee is notified while
posting the results ensures that employers and supervisors are aware of
the results. Posting results also permits employees to compare their
monitoring results with those of co-workers and results obtained from
other shifts

If the results of the monitoring show employee exposure to be in excess
of the TWA and/or EL permissible exposure limits, the written notice to
the employees shall include a statement that the TWA and/or EL has been
exceeded and a description of the corrective action which is being taken
by the employer to decrease the exposure to within the permissible
exposure limits. This requirement to inform employees is in accordance
with section 8(c)(3) of the OSH Act and is necessary to assure employees
that the employer is making efforts to furnish them with a safe and
healthful work environment

As required by Section 8(c)(3) of the Act \[29 U.S.C. 657(c)(3)\], this
proposal contains provisions for employee observation of exposure
monitoring. Paragraph (d)(8)(i) would require employers to provide
affected employees or their designated representative with the
opportunity to observe any monitoring of employee exposures to glycol
ethers as required by this section. In paragraph (d)(8)(ii), observation
procedures are set forth which would require the employer to provide the
observer with the personal protective clothing and equipment (e.g.
coveralls, gloves, respiratory protection, protective eyewear) that is
required to be worn by the employees who are working in the area. In
addition, the employer must ensure that the observer uses such clothing
and equipment and complies with all other applicable safety and health
procedures. This requirement ensures that the observer receives adequate
protection from exposure to glycol ethers

Regulated Areas: Paragraph (e):

In paragraph (e)(1), the proposed standard would require the employer to
establish regulated areas wherever exposures to glycol ethers exceed or
can be expected to exceed the TWA and/or EL permissible exposure limits.
Such areas must be established even though no employee is routinely
assigned to the area; the potential for overexposure is the determining
factor

The Agency feels that it is the existence of a hazard which is the basis
for determining the need for protective measures rather than the type of
operation being performed. Therefore, establishment of a regulated area
is to be carried out not only for situations where the concentration of
airborne glycol ethers must unavoidably exceed the permissible exposure
limits for extended periods but also for areas where exposures are
temporarily over either the TWA or EL for short periods, such as might
be expected while maintenance is being performed. The establishment of
regulated areas is consistent with good industrial hygiene practice as
it provides an effective means of limiting excess exposure to as few
employees as possible. In addition, the regulated area provision of this
standard conforms with similar provisions in other OSHA health
standards. It should also be noted that this requirement has additional
benefits to employers in that by limiting access to these areas to only
authorized persons, the employer\'s obligation to implement the
provisions of this standard triggered by exposure above the TWAs or ELs
is limited to a minimum number of employees

The purpose of designating regulated areas is to ensure that employers
make employees aware of the presence of glycol ethers in the workplace
at levels above the permissible exposure limits, thereby helping to
minimize the number of employees exposed and ensuring that employees who
must enter the area are provided with training and appropriate personal
protective equipment. Paragraph (e)(1)(i) would require that regulated
areas be demarcated from the rest of the workplace in any manner that
adequately establishes and alerts employees to the boundary of the
regulated area while paragraph (e)(1)(ii) stipulates that these areas be
posted at all entrances and accessways with signs meeting the
requirements specified in paragraph (m)(1)(i) of this standard. To
increase the performance orientation of the standard, no detailed
requirements are specified on how regulated areas should be demarcated.
However, it must be assured that the manner of demarcation chosen
adequately alerts employees to the boundaries of the area. In addition,
readily observable signs at all entrances and accessways serve to alert
the employee not only to the existence of the regulated area but reminds
them to use proper personal protective equipment and respiratory
protection and to observe good personal hygiene practices, such as
refraining from smoking or eating in regulated areas and washing hands
and face after leaving the area

The proposed standard also states, in paragraph (e)(2), that the
employer shall limit access to regulated areas to only authorized
persons. By limiting access to authorized persons only, the employer
minimizes the number of persons exposed to glycol ethers. In addition,
this requirement assures that only those persons who have been properly
trained and utilize proper protective equipment are permitted into the
area

In paragraph (e)(3) of the proposal, it is stipulated that whenever an
employer at a multi-employer worksite establishes a regulated area, that
employer shall communicate the location and restrictions of access to
the regulated area to other employers with work operations at that
worksite. This requirement would lessen the possibility that
unauthorized, unprotected people would enter the area and be
inadvertently exposed. OSHA is concerned that employees at nearby sites
be aware of the existence of the hazard and remain outside of the
regulated area. Even though the signs posted by the first employer serve
to warn employees of a second employer to stay out of the area, there is
no assigned accountability for these employees. Therefore, if the second
employer is aware of the hazards, then it is the responsibility of the
second employer to assure that his employees do not enter the regulated
area of the first employer without permission and proper protective
equipment

It would be required, under paragraph (e)(4) of the proposal, that each
person entering a regulated area be provided with and required to use
appropriate personal protective equipment, including respiratory
protection selected in accordance with paragraph (g)(3). This provision
is also consistent with other OSHA standards (e.g., Asbestos, 29 CFR
1910.1001). This provision applies not only to employees working \"full
time\" in the regulated area but to any person entering the area. This
approach provides a number of benefits: 1) \"walk through\" by employees
will be discouraged since use of appropriate personal protective
equipment will be required of all persons entering the area; 2)
employees whose duties require them to be in the area for a longer
period of time than originally anticipated will be adequately protected
since it eliminates the need for employees to estimate length of time in
the regulated area and make individual decisions regarding personal
protective equipment; and 3) enforcement will be simplified for the
employer since the use of personal protective equipment will be
uniformly required of all persons in the regulated area, regardless of
the length of time they will be present in the area.

**\[page 15599\]**

Methods of Compliance: Paragraph (f)

Paragraph (f)(1) of the proposed standard would require employers to
institute engineering and work practice controls, to the extent
feasible, as the primary means to reduce and maintain employee exposures
to glycol ethers to levels at or below the TWAs or the ELs and to
eliminate dermal exposure . Paragraph (f)(2) also requires employers,
whenever they establish that feasible engineering and work practice
controls are not sufficient to lower exposures to or below the TWAs or
the ELs or to eliminate foreseeable dermal exposure, to nonetheless
implement such controls to reduce employee exposures to the lowest
levels achievable and then to provide supplemental personal protective
equipment to eliminate dermal exposure and/or achieve the TWAs or ELs
through the use of respirators that comply with the requirements of
paragraph (g) of this proposed standard

Engineering controls serve to reduce employee exposure in the workplace
by either removing or containing the hazard or isolating the worker from
exposure. These controls include, but are not limited to, process or
equipment redesign (including substitution of glycol ethers with a less
toxic chemical), installation of ventilation equipment (localized and/or
general), process or equipment enclosure, and employee isolation. In
general, engineering controls act on the source of the hazard and
eliminate or reduce employee exposure without reliance on the employee
taking self-protective action or intervention. Once implemented,
engineering controls protect the employee, subject only, to periodic
replacement or preventative maintenance. Engineering controls are:
reliable; provide consistent levels of protection to a large number of
workers; are not dependent upon individual human performance; can be
monitored continually/inexpensively; allow for predictable performance
levels; remove hazards from the workplace. Once removed, the health
hazard no longer poses a threat to the employee. Engineering controls
are preferred by OSHA since they remove hazards from the workplace

Engineering controls can be grouped into 3 categories: (1) substitution,
(2) isolation, and (3) ventilation, both general and localized. Quite
often a combination of these controls can be applied to an industrial
hygiene control problem to achieve satisfactory air quality. It may not
be, and usually is not, necessary or appropriate to apply all these
measures to any specific potential hazard

Substitution should not be overlooked as an appropriate solution to an
industrial hygiene problem. One of the best ways to keep people from
being exposed to a toxic substance is to stop using it entirely. This is
not always possible, but at least the following question should be
asked: \"Can a less toxic material be substituted in the process?\"
Other examples of substitution which may provide effective control of an
air contaminant are changing from one type of process equipment to
another, or even in some cases changing the process itself

In general, a change in any process from a batch to a continuous type of
operation carries with it an inherent reduction in potential hazard.
This is true primarily because the frequency and duration of worker\'s
potential contact with the process materials is reduced when the overall
process approach becomes one of continuous operation. The substitution
of processes can be applied on a fundamental basis. For example,
substitution of airless spray for conventional spray equipment can
reduce the exposure of a painter to toxic substances. Substitution of a
paint dipping operation for the paint spray operation can reduce the
potential hazard even further. In any of these cases the automation of
the process can further reduce the potential hazard

In addition to substitution, the principle of isolation should be
considered. Although \"isolation\" is frequently envisioned as
consisting of installation of a physical barrier between a hazardous
operation and the workers, isolation can be provided without a physical
barrier by appropriately placing the employee at greater distance from
the source of the glycol ethers exposure and by controlling employees\'
exposures by scheduling work assignments when the fewest employees are
present. Examples of this latter method would be operating a
contaminant-producing operation at night in the absence of most of the
employees. Clean-up operations in which toxic substances are involved
sometimes can be performed at night in the absence of the usual
production staff. Such methods of controlling worker exposures to
contaminants by work assignment away from the contaminant are known as
administrative controls

Frequently the application of the principle of isolation maximizes the
benefits of additional engineering concepts such as local exhaust
ventilation. For example, the charging of mixers is the most significant
operation in many processes that use formulated ingredients. When one of
the ingredients in the formulation is of relatively high toxicity, it is
worthwhile to isolate the mixing operation, that is, install a mixing
room, thereby confining the airborne contaminants potentially generated
by the operation to a small area rather than having them influence a
larger area of the plant. By ensuring containment, the application of
ventilation principles to control the contaminant at the source (i.e.,
the mixer) is much more effective

Ventilation, applied as either a general or local control, is by far the
most important engineering control principle available to the industrial
hygienist. Its principal application is to maintain airborne
concentrations of contaminants at acceptable levels in the workplace

A local exhaust system is used to carry off an air contaminant by
capturing it at or near its source, before it spreads throughout the
workplace. Some examples of local ventilation systems include a canopy
hood over a hot process, slot ventilation around the periphery of a vat,
and a laboratory hood enclosure. General ventilation, on the other hand,
lets the contaminant spread throughout the workroom but dilutes it by
circulating large quantities of air into and out of the workroom. A
local exhaust system is generally preferred to ventilation-by-dilution
(general ventilation only) because it provides a cleaner and healthier
work environment

By comparison, work practice controls reduce the likelihood of exposure
through alteration of the manner in which a task is performed such as
how an employee positions himself/herself relative to the source and/or
engineering control. While work practice controls also act on the source
of the hazard, the protection they provide is based upon employer and
employee behavior rather than installation of a physical device such as
a ventilation system. Examples of some basic work practices include, but
are not limited to, (1) limiting access to regulated work areas to
authorized and specially-trained personnel with proper personal
protective equipment, (2) drawing tank car samples from an upwind
position, and (3) performing glycol ether analyses, such as quality
checks, within a chemical fume hood

In many instances, the two control methodologies discussed above work in
tandem as it is often necessary to employ work practices to insure
effective operation of engineering controls. For example, if an employee
inappropriately performs an operation

**\[page 15600\]**

outside of an exhaust hood then the protection afforded by the
engineering control (i.e., the exhaust hood) will be of little or no
use. As can be seen, therefore, in many situations it is important not
only that an engineering control be functioning properly but also that
employees are aware of the work practices that are necessary to assure
effectiveness of the control

Primary reliance on engineering controls and work practices is
consistent with good industrial hygiene practice and with the Agency\'s
traditional adherence to a particular hierarchy of preferred controls.
This hierarchy specifies that engineering controls and work practices
are to be used in preference to respirators. OSHA has traditionally
relied less on respirators in the hierarchy of controls because there
are so many problems associated with their use. Often work is strenuous
and the increased breathing resistance of the respirator reduces its
acceptability to employees. Safety problems are presented by respirators
since they limit vision. In some difficult and dangerous jobs, effective
communication facilitates a safe, efficient operation. Voice
transmission through a respirator can be difficult, annoying, and
fatiguing. Movement of the jaw in speaking causes leakage thereby
reducing the efficiency of the respirator and decreasing the employee\'s
protection against glycol ethers exposures. Also, skin irritation can
result from wearing a respirator in hot, humid conditions. Such
irritation can cause considerable distress and disrupt work schedules.
To be used effectively, respirators must be individually selected and
fitted, conscientiously and properly worn, regularly maintained, and
replaced as necessary. In many workplaces, these conditions are
difficult, if not impossible, to satisfy. For these reasons and others,
OSHA has concluded that reliance on respirators should be minimized

Paragraph (f)(3) of the proposal would require that engineering controls
be inspected and maintained or replaced on a regular schedule to ensure
their effectiveness. Regularly-scheduled inspections are required to
confirm that engineering controls such as protective shields have not
been broken or removed; that ventilation systems are operating properly;
that filters are being replaced on a sufficiently frequent interval; and
that any other physical, mechanical, or replacement-dependent controls
are functioning as intended

In consideration of glycol ethers\' ability to be absorbed through the
skin and thereby contribute to overall exposure, paragraph (f)(4) would
require the employer to permit employees to leave the work area
immediately or as soon as feasible to wash skin areas which have had
contact with glycol ethers

Whenever the TWAs and/or ELs are exceeded or dermal exposure exists,
paragraph (f)(5)(i) would require employers to establish and implement a
written compliance program to reduce employee exposure to or below the
TWAs and/or ELs and eliminate dermal exposure. The plan should provide
for this reduction to be accomplished, where feasible, through the use
of engineering and work practice controls. If engineering and work
practice controls cannot reduce exposures to or below the TWA and EL
permissible exposure limits and eliminate dermal exposures then the plan
shall include the use of whatever respiratory protection equipment is
necessary to achieve compliance and all appropriate personal protective
equipment necessary to eliminate contact with glycol ethers. In
addition, the Agency believes that the emergency plan prescribed in
paragraph (k) is inherently a part of the overall compliance program
since it addresses prevention of employee exposure in emergency
situations. Therefore, paragraph (f) (5) (i) (B) would require that the
the written emergency plan be included in the compliance plan

The written program requirement commits the employer to evaluating
employee exposure and setting down an organized and complete plan of
reducing employee exposures to permissible limits. Inclusion of personal
protective equipment, including respiratory protection, in the plan
assures that the appropriate protective equipment is selected, based on
level and mode of exposure, and written into the plan for reference

Paragraph (f)(5)(ii) would require that the written compliance program
be reviewed and updated at least annually, or more often if necessary,
to reflect significant changes in the employer\'s compliance status. By
requiring, at a minimum, annual review of the compliance program, the
Agency assures that the employer will update the program to reflect the
current compliance status of the workplace. This review would require
the employer to evaluate all new or altered tasks, procedures,
processes, and so forth to determine whether they would result in
occupational exposure and, if so, what exposure reduction methods must
be implemented

Paragraph (f)(5)(iii) states that the employer\'s written compliance
program shall be submitted upon request for examination and copying to
the Assistant Secretary, the Director, affected employees, and
authorized employee representatives. Employee and employee
representative access allows workers to gain an awareness of where the
permissible exposure limits are exceeded, what steps the employer is
taking to reduce or eliminate exposure, and the appropriate respiratory
protection and personal protective equipment to use in these areas.
Access to the plan by the Assistant Secretary is important for
compliance enforcement. Access by the Director is required for that
agency to carry out the various investigations and research it deems
necessary. For example, performing health hazard evaluations of a plant,
determining the current exposure patterns and control methodologies in
industry use, and conducting epidemiological studies

Respiratory Protection: Paragraph (g)

Respirators serve as supplemental protection to reduce employee
exposures when engineering and work practice controls are not sufficient
to achieve the necessary reduction to or below the TWAs and ELs. The
proposed standard, in paragraph (g)(1), states that where respiratory
protection is required the employer shall provide, at no cost to the
employee, and shall assure the proper use of respirators which comply
with the requirements of this section to reduce employee exposures to or
below the TWA and EL permissible exposure limits

In paragraph (g)(1)(i) through (g)(1)(iv), the proposed standard would
require that respiratory protection be worn (1) during the interval
necessary to install or implement feasible engineering and work practice
controls; (2) in work operations, such as maintenance and repair
activities and during brief or intermittent operations, for which the
employer has established that engineering and work practice controls are
not yet feasible; (3) in work situations where the employer has
implemented all feasible engineering and work practice controls and such
controls are not sufficient to reduce exposure to or below the TWA
and/or EL permissible exposure limits; and (4) in emergencies.

In some circumstances (e.g., certain maintenance and repair operations,
emergencies, or during periods when engineering and work practice
controls are being installed and implemented) OSHA recognizes that
respirators may be essential to guarantee worker health and safety.
Therefore, provision is made in paragraph (g)(1) for their use as

**\[page 15601\]**

primary controls in these instances where engineering and work practice
controls cannot be used to achieve the TWAs or ELs. In other
circumstances where engineering and work practice controls alone cannot
reduce exposure levels to the TWAs or ELs, respirators may also be used
for supplemental protection However, it must be kept in mind that the
burden of proof of infeasibility rests with the employer in those
circumstances where respiratory protection is used in lieu of
engineering and work practice controls

It would be required that all employees who wear respiratory protection
be medically screened to determine whether any health conditions exist
which could affect the employee\'s ability to wear a respirator.
Considering the health problems which may be exacerbated with respirator
use and their associated detrimental effects on an employee, the
proposal states in paragraph (g)(2) that no employee shall be assigned
tasks requiring the use of respiratory protection if, based upon his or
her most recent medical examination, an examining physician determines
that the employee will be unable to function normally while wearing a
respirator. Common health problems which could present difficulty with
respirator use include claustrophobia (an intolerance of feeling
enclosed and a subjective feeling of breathing difficulty), chronic
rhinitis, nasal allergies (necessitating frequent removal of the
respirator to deal with nasal discharges), and chronic sinusitis. In
addition, difficulties with use of respirators may arise in employees
with respiratory or cardiac diseases. Respiratory diseases include
chronic obstructive pulmonary disease, emphysema, asthma, and moderate
to severe pneumoconiosis. Cardiac or cardiorespiratory diseases that may
affect respirator wear include coronary thrombosis, any type of
congestive heart disease, other ischemic heart diseases, and
hypertension

This paragraph would also require that such employees be given the
opportunity to transfer to a position where no respirator use is
required. That position shall be with the same employer, in the same
geographical area, and with the same seniority and rate of pay the
employee had just prior to such a transfer, if such a position is
available. The Agency believes that this provision will minimize the
reluctance of all employees, including those experiencing difficulty
with respirator use, to participate in the Medical Surveillance Program
for fear of losing his or her job due to the possible inability to wear
a respirator

Paragraph (g)(3) specifies the type of respirators that may be used to
provide protection from exposure to glycol ethers. This proposal would
permit only supplied-air respirators and would prohibit the use of
air-purifying respirators equipped with organic vapor cartridges or
canisters. The rationale behind this decision relates, in part, to the
odor threshold of the glycol ethers. Generally, an employee using an air
purifying respirator can detect a poor facepiece seal or sorbent
cartridge breakthrough by the odor of a chemical as it finds its way
into the respirator, provided the chemical possesses good warning
properties. If the odor threshold of a compound exceeds the permissible
exposure limit, however, the employee is deprived of such an inherent
odor warning and is not aware of a respirator inadequacy until he/she is
overexposed to the compound. Consequently, an important factor in the
selection of appropriate respiratory protection is the odor threshold of
the chemical of concern

When considering the odor threshold of a substance, one finds that
reported values are widely divergent. Two major factors which influence
odor detection are differences between individuals in the ability to
perceive a particular odor and the methodology employed in conducting
the odor threshold determination. In their \"Guide to Industrial
Respiratory Protection - Appendix C\" (Ex. 5-142), NIOSH states:

**Amoore and Hautala (33) found that on average, 95% of a population
will have a personal odor threshold that lies within the range from
about one-sixteenth to sixteen times the reported mean \"odor
threshold\" for a substance.**

In further explanation, Amoore and Hautala state: (Ex. 5-141)

The ability of members of the population to detect a given odor is
strongly influenced by the innate variability of different persons\'
olfactory powers, their prior experience with that odor, and by the
degree of attention they accord the matter.

This statement addresses not only personal factors which influence odor
detection but also raises the issue of differences in testing
methodology. Examples of methodology differences include: awareness or
lack of awareness of the test subject to the purpose of the test (i.e.,
to detect an odor) thereby increasing his/her attentiveness to odor
detection; presentation mode of the odor samples to the test subject;
purity of the test compound; vapor modality (liquid or gaseous); and
number of trials. As can be seen, lack of standard testing methodology
in conjunction with individual differences in odor perception can lead
to the wide variation of odor thresholds found in the literature

OSHA is aware of two documents that have attempted to account for the
variabilities of reported odor thresholds - Amoore and Hautala\'s \"Odor
as an Aid to Chemical Safety: Odor Thresholds Compared with Threshold
Limit Values and Volatilities for 214 Industrial Chemicals in Air and
Water Dilution\" (Ex. 5-141) and the American Industrial Hygiene
Association\'s (AIHA) \"Odor Thresholds for Chemicals with Established
Occupational Health Standards\" (Ex. 5-143)

Both documents calculated and utilized the geometric means of the odor
thresholds reported in their respective data collections to deal with
the broad range of values. In the absence of conducting new,
standardized testing,the Agency believes that this is a sound approach
to obtaining a single odor threshold value which can be used in
evaluating warning properties of compounds

Amoore and Hautala also present a method for comparing the exposure
limit of a substance and its odor threshold through calculation of an
\"odor safety factor\" (i.e., exposure limit divided by odor threshold).
The odor safety factor can then be used to classify a compound, using
the scale shown in Table A, and thereby determine what percentage of
attentive persons can detect the compound at the exposure limit and what
percentage of distracted persons will detect a warning of the compound
at the exposure limit

  ----------------- ----------------------- -----------------------------
  Table A                                   

  Class             Odor Safety Factor      Interpretation

                                            

  A                 \> 550                  \> 90% of distracted persons

                                            perceive warning of TLV

                                            concentration in air

                                            

  B                 26 - 550                50 -- 90% of distracted

                                            persons perceive warning of

                                            TLV concentration in air

                                            

  C                 1 - 26                  \<50% of distracted persons

                                            perceive warning of TLV

                                            concentration in air

                                            

  D                 0.18 - 1                10 -- 50% of attentive
                                            persons

                                            can detect TLV concentration

                                            in air

                                            

  E                 \<0.18                  \<10% of attentive persons
                                            can

                                            detect TLV concentration in

                                            air
  ----------------- ----------------------- -----------------------------

Utilizing this methodology and the odor thresholds calculated by Amoore
and Hautala, the four glycol ethers

**\[page 15602\]**

under consideration, at the proposed TWA permissible exposure limits,
yield the following classifications:

  -------------- -------------- -------------- -------------- --------------
                                                              

  Table B                                                     

                 Proposed       Odor           Odor           

  Compound       TWA (ppm)      Threshold      Class          
                                (ppm) Safety                  
                                Factor                        

                                                              

    2-ME         0.1            2.3            0.04           E

    2-MEA        0.1            N/A            N/A            N/A

    2-EE         0.5            2.7            0.2            D

    2-EEA        0.5            0.056          8.9            C

                                                              
  -------------- -------------- -------------- -------------- --------------

Both 2-ME and 2-EE have very low odor safety factors with resultant
classifications of Class E and Class D, respectively, which means that
most employees would not be able to detect breakthrough of these
compounds at the proposed TWA permissible exposure limits. The highest
classification, Class C, is achieved in the case of 2-EEA, in which less
than 50% of distracted persons perceive a warning of 2-EEA at the
proposed TWA concentration. The Agency does not find this to be adequate
warning capability to permit use of air-purifying respirators

Table C presents the results obtained when the odor thresholds given in
the AIHA document are utilized in the above methodology. One should note
that the AIHA lists two odor thresholds for the four glycol ethers: 1)
the detection threshold (d) which is the lowest concentration at which a
specific percentage of the test subjects, usually 50%, can detect the
stimulus as different from odor-free blanks and 2) the recognition
threshold (r) which is the lowest concentration at which a specific
percentage of the test subjects, usually 50%, can ascribe a definite
character to the odor (Ex. 5-143). The AIHA detection threshold values
are very similar to the odor threshold values presented in Amoore and
Hautala\'s paper and give the same classification results, therefore,
only odor safety factors and classifications associated with recognition
threshold values appear in Table C

  -------------- -------------- -------------- -------------- -------------
                                                              

                                                              

  Table C                                                     

    Proposed     Odor           Odor                          

   Compound TWA  Threshold      Safety Factor  Class          
  (ppm)          (ppm)                                        

    2-ME         0.1            2.4 (d)                       

                 4.4 (r)        0.011          E              

    2-MEA        0.1            0.33 (d)                      

                 0.64 (r)       0.17           E              

    2-EE         0.5            2.7 (d)                       

                 6.5 (r)        0.08           E              

    2-EEA        0.5            0.06 (d)                      

                 0.13 (r)       3.8            C              

                                                              

                                                              
  -------------- -------------- -------------- -------------- -------------

Performing the calculations using the recognition thresholds again
results in 2-EE and 2-MEA having very low odor safety factors. The AIHA
data also yields a low odor safety factor for 2-MEA (Amoore and Hautala
present no odor threshold for this substance). 2-EEA once more achieves
the highest odor safety factor and classification, Class C, which, as
stated previously, can be interpreted to mean that less than 50% of
distracted persons will perceive a warning of the compound at the
proposed TWA concentration

Amoore and Hautala state that their thresholds represent the most
favorable conditions for odor testing, that is, the subjects were aware
of the test, were attentive, and were trying to detect an odor

The studies utilized by the AIHA for determining the odor thresholds of
the four glycol ethers also appear to have utilized test subjects who
were aware of their objective and therefore would be concentrating on
detecting and/or recognizing an odor. OSHA does not believe that such
idealized circumstances for odor detection normally occur in the
workplace. An employee would be distracted by performing other tasks
(e.g., operating machinery, reviewing charts, observing production
processes) and would not normally be focusing his/her attention on
detecting a minimal odor level. Even the higher recognition threshold
values are likely not to be indicative of odor perception of a
distracted employee in the workplace with actual odor recognition
occurring at even higher concentrations

Considering the preceding information, the Agency does not feel that any
of the four glycol ethers display adequate warning properties at the
proposed TWA permissible exposure limits to permit use of air-purifying
respirators. Therefore, only supplied-air respiratory protection is
deemed appropriate for use with these compounds

The use of supplied-air respiratory protection is supported by the
following NIOSH comments to the ANPR: (Ex. 7-22)

In NIOSH CIB #39: The Glycol Ethers, with particular reference to
2-methoxyethanol and 2- ethoxyethanol, NIOSH recommended that exposure
to the glycol ethers be reduced to the lowest extent feasible. Only the
most protective respirators are consistent with that recommendation:
self-contained breathing apparatus with full facepiece operated in the
pressure demand mode, or a combination respirator which includes a Type
C supplied-air respirator with a full facepiece operated in the
pressure-demand mode and an auxiliary self- contained breathing
apparatus operated in the pressure-demand mode.

NIOSH goes on to state that if the proposed permissible exposure limits
are below the odor threshold and OSHA decides not to follow their
recommendation to permit only supplied-air respiratory protection, then

**\[page 15603\]**

only cartridge or canister respirators with effective
end-of-service-life indicators should be allowed. The Agency is not
aware of any NIOSH/MSHA approved cartridges or canisters with
end-of-service-life indicators for glycol ethers

Following a conservative approach and allowing only supplied-air
respirators eliminates the question of whether employees could be
unknowingly exposed as a result of the compound\'s actual odor threshold
being above the permissible exposure limits since the employee is no
longer inhaling ambient air through a sorbent cartridge. While the
employer must select the appropriate respirator from the table based
upon the airborne concentration of glycol ethers, the employer may
always select a respirator providing greater protection (i.e., one
prescribed for higher concentrations of glycol ethers than are present
in the workplace)

The respirator selection table in the proposed standard lists the type
of respiratory protection which, at a minimum, must be provided and used
at each airborne concentration of glycol ethers in the workplace. In no
circumstance shall a respirator be used in atmospheric concentrations
which exceed that respirator\'s assigned protection factor. The
respirators selected by the employer must be approved by the Mine Safety
and Health Administration (MSHA) and by the National Institute for
Occupational Safety and Health (NIOSH) under the provisions of 30 CFR
Part 11 or any future revisions. It should be noted that NIOSH is
currently in the process of revising the 30 CFR Part 11 respirator
testing and certification standards. When published, this revision will
be listed as 42 CFR Part 84. OSHA will expect employers to base
respirator selection on the most recent published standards of the
aforementioned agencies

In those situations in which respirator use is required, the employer
shall institute a respiratory protection program in accordance with 29
CFR 1910.134 (b), (d), (e), and (f) as would be required by paragraph
(g)(4) of this proposed standard. This general industry standard (29 CFR
1910.134) includes provisions for the selection, fit, use, cleaning, and
maintenance of respirators. In addition, it contains requirements for a
written respiratory protection program and minimum air quality standards
for supplied-air respiratory protection systems

A drawback to respirator use is the skin irritation that can develop
with some employees, particularly in hot, humid, and/or dirty
environments. The Agency recognizes that this irritation adds to the
discomfort and inconvenience already experienced by employees wearing
respirators and has included paragraph (g)(5) with the intent of
minimizing skin irritation and assuring adequate employee protection

This provision states that employers must permit employees to leave the
work area to wash their faces and respirator facepieces as needed to
prevent skin irritation from respirator use

Paragraph (g)(6) deals with the fit testing of respirators. The employer
would be required, by paragraph (g)(6)(i), to assure that the respirator
issued to the employee exhibits the least possible facepiece leakage and
that the respirator is fitted properly and will not permit the employee
to inhale glycol ethers in excess of either the TWAs or ELs. Good face
fit is critical in assuring proper performance of respiratory
protection. When an employee inhales through a respirator which fits
poorly, contaminated workplace air can enter the respirator through gaps
and leaks in the seal between the face and the facepiece. Obtaining a
proper respirator fit may require the fit testing of a variety of
different mask sizes from several manufacturers to select the facepiece
with the best fit (least leakage around the faceseal) for each employee.
This methodology will reduce inhalation leakage to a minimum

Quantitative fit testing is a procedure whereby the level of penetration
of a test agent of a known concentration is measured inside the
facepiece of the respirator. It provides a quantitative assessment of
the fit (the fit factor). It allows the employer to continue testing
different facepieces until the optimum or best fitting respirator is
identified and selected for the employee. Quantitative fit testing
requires the use of moderately sophisticated testing equipment and is
more expensive to perform than qualitative fit testing, which may reduce
its availability in some worksites. Also testing services may not be
available in all parts of the country to provide quantitative fit
testing services for small employers

Qualitative fit testing does not provide a numerical measure of the
quality of the fit but simply determines whether a respirator fits or
not. Qualitative fit testing is a technique whereby a person wearing a
respirator is tested to see whether a test agent with a detectable odor
or taste threshold can be detected inside the respirator. If the test
agent is not detected by the employee wearing the respirator, the
respirator is said to fit. Qualitative fit testing is more subjective
than quantitative testing because it depends on the individual\'s
ability to detect the test agent

OSHA believes that while quantitative fit testing may have some
advantages, qualitative testing conducted in accordance with the
protocols described in Appendix F can adequately accomplish the intent
of the standard of ensuring that each employee is assigned and wears the
respirator that provides a proper fit with the least possible leakage.
Comments are requested on all aspects of fit testing

Paragraph (g)(6)(ii) states that for each employee wearing a
tight-fitting supplied-air respirator, the employer shall perform either
a qualitative or quantitative fit test. Fit testing may be accomplished
by testing the particular facepiece to be used (make, model, and size),
without any air supplying equipment or attachments

Testing is conducted by equipping the facepiece with appropriate air
purifying elements. Upon obtaining adequate fit with a particular
facepiece, then that facepiece is to be used with the supplied-air
system (i.e., air-supplying equipment or attachments). When quantitative
fit testing is performed, half mask facepieces must exhibit a fit factor
of 100 and full facepieces a fit factor of 500, at a minimum. Regardless
of the fit testing protocol utilized, qualitative or quantitative,
respirator protection factors are to be assigned according to the
respirator selection table in the proposed standard

Paragraph (g)(6)(iii) would require the employer to perform and certify
the results of the appropriate fit tests at the time of an employee\'s
initial fitting, at least annually thereafter, when a different size or
make of respirator is used, and when a change in facial structure
occurs. This frequency of fit testing is necessary to assure that
factors which may affect the proper fit of a respirator are detected and
necessary adjustments are performed to assure the integrity of the
faceseal. For example, the fit of respirators is not standardized
between manufacturers. Fit testing would be required, therefore,
whenever a different size or make of respirator is used. In addition, a
change in an employee\'s facial structure can compromise a respirator\'s
faceseal. Examples of such changes include loss of weight, cosmetic
surgery, facial scarring, and the installation of dentures. Therefore,
fit testing is required at least annually and when any facial changes,
such as those mentioned above, occur.

**\[page 15604\]**

In order to assure that employees willingly participate in fit testing
and that such procedures are standardized, paragraph (g)(6)(iv) would
require that all tests be performed at a reasonable time and place and
at no cost to the employee and must be conducted in accordance with
Appendix F of this proposal

Personal Protective Equipment: Paragraph (h)

The underlying premise of personal protective equipment is that its use
will protect against exposure during performance of a task. Paragraph
(h) of the proposal contains a number of provisions concerned with the
use of personal protective equipment. In this paragraph, employers would
be required to select and provide appropriate personal protective
equipment in accordance with 29 CFR 1910.132 (General Requirements) and
29 CFR 1910.133 (Eye and Face Protection) of the General Industry
Standards as often as necessary throughout the work shift to prevent
employee exposure to glycol ethers. Based on good industrial hygiene
practice, paragraph (h)(1)(i) of the proposed standard would require
that selection of personal protective equipment must be based upon the
type of exposure anticipated (e.g., hand contact, splashing, spraying,
inhalation), conditions of use (i.e. suitability of the equipment to
maintain its protective capabilities under the conditions in which it
will be used), and the hazard to be prevented (e.g., splashes to the
face, eye irritation, dermal exposure, aerosol inhalation). This
approach is performance oriented as it requires that the employer
evaluate each process or task which could present a possibility of
exposure and then implement the most efficient means for protecting
against the exposure

The employer would also be required by paragraph (h)(1)(ii) of the
proposal to provide the appropriate personal protective equipment at no
cost to the employee and assure that employees use this equipment

Provision of personal protective equipment at no cost to the employee
helps assure employees\' acceptance of its use in exposure situations.
Since it is the employer\'s obligation to prevent employee exposure to
glycol ethers in the workplace, the responsibility to provide personal
protective equipment and assure its use rightfully rests with the
employer

In order to prevent employees from being unwittingly exposed and to
achieve adequate protection, paragraph (h)(1)(iii) states that personal
protective equipment such as, but not limited to, coveralls, gloves,
faceshields, and rubber boots, must be made of materials sufficiently
impervious to glycol ethers to prevent employee exposure to these
compounds. For example, information submitted in response to the ANPR
included breakthrough and permeation studies of various glove materials
relative to glycol ethers (Exs. 4-017c, 7-22 attachment 17). Both the
study by Union Carbide and that of Dow Chemical indicate that butyl
rubber gloves provide good protection against exposure to these
compounds. The proposed regulation is performance oriented, however, and
does not stipulate that protective gloves or other protective equipment
be made of a specific material but simply that any equipment selected be
adequate to prevent employee contact with glycol ethers. In this way,
the proposed standard will not interfere with any developing technology
or innovative techniques that may efficiently protect employees from
contact with glycol ethers

Paragraph (h)(1)(iv) is closely related to the preceding provision in
that it would require employers to provide uncontaminated personal
protective equipment as often as necessary throughout the work shift to
prevent employee exposure to glycol ethers

Removal and storage of personal protective equipment is covered under
paragraph (h)(2) of the proposal. Employers would be required to assure
that employees remove all personal protective equipment contaminated
with glycol ethers prior to leaving the work area or as soon as feasible
if the potential for soak-through/breakthrough exists. This paragraph
would also require that removal of contaminated personal protective
equipment be done in an area which would minimize exposure of other
employees to glycol ethers

Paragraph (h)(2)(ii) states that the employer must assure that no
employee takes home glycol ethers contaminated personal protective
equipment. In addition, paragraph (h)(2)(iii) would require the employer
to assure that no employee takes glycol ether contaminated equipment out
of the workplace unless authorized to do so for the purposes of
laundering, cleaning, maintenance, or disposal

As stated previously, the intent of personal protective equipment is to
protect the employee against exposure. Therefore, if a situation arises
in which glycol ethers may soak through the equipment provided then the
employer must assure that the employee removes the equipment as soon as
possible to prevent dermal absorption. In addition, contaminated
equipment is to be removed prior to leaving the work area and in an area
which would minimize exposure of other employees in order to minimize
migration of the contaminant away from the worksite and prevent possible
exposure of additional individuals such as fellow employees and family
members through airborne or dermal routes. Only authorized employees are
to be permitted to take contaminated protective equipment out of the
workplace and only for the purposes of laundering, cleaning,
maintenance, or disposal. It should be noted that the Agency does not
intend for employees to be authorized to launder and clean contaminated
items at home or at a public laundromat. Therefore, these activities
have been specifically prohibited. Instead, only those employees who are
trained and informed as required in paragraphs (h)(3)(ii) and
(h)(3)(iii) are to be authorized to remove contaminated personal
protective equipment from the workplace

Contaminated personal protective equipment must be stored in such a
manner so as to minimize employee exposure and shall not be worn again
until cleaned or laundered. Thus, the area where protective equipment
dampened with glycol ethers or glycol ether-containing compounds are
stored must be sufficiently apart from areas where employees work or
congregate to prevent additional exposure to employees. Re-wearing of
contaminated equipment is prohibited to prevent additional employee
exposure and an enhanced potential for dermal absorption. Storage areas
or containers with glycol ethers contaminated personal protective
equipment must have either a sign or a label, respectively, as specified
in paragraph (m)(1)(ii)

Paragraph (h)(3)(i) would require that each employer must clean,
launder, repair, or replace, at no cost to the employee, all required
personal protective equipment for each affected employee as necessary to
assure its effectiveness and stipulates that the employer is responsible
for disposal of these items. The requirement to repair or replace the
protective equipment is necessary to insure the proper functioning of
these items and, thereby, proper employee protection. Requiring that the
employer be responsible for cleaning, laundering, repair, and disposal
insures that contaminated equipment will be handled only by personnel
who have been trained in the proper work practices for handling this
equipment as specified in paragraph (h)(3)(ii) and (h)(3)(iii). Overall,
this

**\[page 15605\]**

paragraph assures that contaminated equipment remains under the control
of the employer. This approach permits standardized, consistent
cleaning, laundering, repair, and replacement of these items thereby
maximizing their effectiveness and helping to assure that they are
properly disposed of at the end of their service life

The employer would also be required by paragraph (h)(3)(ii) to assure
that only trained persons remove contaminated personal protective
equipment from storage for the purpose of laundering, cleaning, repair
or disposal. In this way, only those employees who are aware of the
hazards of glycol ethers and use proper handling work practices will
contact the equipment. Whether the employer has an on-site
laundry/cleaning/repair facility or sends the equipment off- site for
laundering, cleaning, or repair, the employer shall inform any person
who may have contact with such equipment of glycol ethers\' potentially
harmful effects and of procedures to safely handle the personal
protective equipment as would be required by paragraph (h)(3)(iii)

Paragraph (h)(3)(iv) states that the employer shall assure that
laundering, cleaning, maintenance, and disposal are performed only at
facilities which are appropriate to handle glycol ethers contaminated
personal protective equipment. Therefore, as stated previously,
activities such as laundering contaminated personal protective equipment
at a public laundromat or in an employee\'s home would be prohibited.
This is to assure that these operations are properly performed and to
prevent inadvertent exposure of unknowing individuals

Paragraph (h)(3)(v) stipulates that when contaminated personal
protective equipment is destined for disposal, it shall be placed in a
sealed container which is labeled in accordance with paragraph
(m)(1)(ii) of this section. This provision will assure that those
individuals who may come in contact with the container will be protected
against exposure and will be warned of the container\'s contents

Hygiene Protection: Paragraph (i)

A characteristic of a number of solvents, including glycol ethers, is
that they can be readily absorbed through the skin. Therefore, if
employees may become splashed with liquids containing glycol ethers,
paragraph (i)(1) would require the employer to provide conveniently
located quick drench showers and assure that affected employees use
these facilities immediately. Quick drench showers must be able to
rapidly drench the employee with a forceful flow of water in order to
effectively remove the glycol ether, thereby minimizing dermal
absorption. These showers must also be located in the immediate work
area of an employee who could be splashed so that they may be reached
quickly should an accidental splash occur, once again reducing the
length of time glycol ethers remain in contact with the skin and
consequently the absorption of these compounds into the body. It is
particularly important to locate showers in areas where employees do not
normally wear full body protective clothing yet could potentially be
accidently splashed or in areas where large volume splashes could occur.
Criteria for assessing quick-drench showers and eyewashes can be found
in consensus standards such as ANSI Z358.1-1981 and NSA Data Sheet
1-686-80. References such as these can be used to evaluate
characteristics such as flowrate, accessibility, construction, testing
schedules, and so forth

Paragraph (i)(2) would require the employer to provide eye- wash
fountains within the immediate work area of employees whose eyes could
possibly be splashed with liquids containing glycol ethers since these
compounds are eye irritants. For the same reasons as above, an employee
must be able to reach the fountains quickly so that the flushing can be
initiated as soon as possible after an accidental eye splash. In
addition, eye- wash fountains should be capable of maintaining an
appropriate water pressure for an appropriate length of time to remove
glycol ethers from the eyes

OSHA has not proposed that separate change rooms and shower facilities
be provided. In addition, showering at the end of the work shift would
not be required. Based upon its understanding of glycol ethers usage
patterns, the Agency envisions the use of personal protective equipment
as a temporary measure utilized intermittently during performance of an
employee\'s duties and worn over the employee\'s regular work clothes.
It is felt that prohibiting removal of this equipment in common areas
will provide adequate protection from exposure for other employees. Due
to the dermal absorption properties of glycol ethers, the Agency feels
that requiring showering at the end of the work shift would not provide
added protection since absorption would have already occurred. Minor
splashes can be washed off in normal lavatory facilities while quick-
drench showers are available for major exposures. In both cases, other
provisions of this standard require employers to assure removal of
glycol ethers from the skin immediately or as soon as feasible and
replacement of contaminated equipment

Paragraph (i)(3) would prohibit eating, drinking, smoking, and
application of cosmetics in areas of glycol ethers exposure. The purpose
of this provision is to prevent inadvertent ingestion, inhalation, or
dermal application of glycol ethers. In addition, paragraph (i)(4) would
prohibit wearing of personal protective equipment in lunch areas to
prevent migration of glycol ethers to an area where other employees may
be unknowingly exposed

Housekeeping: Paragraph (j)

Paragraph (j)(1) would require that all surfaces (e.g. floors, working
surfaces, exterior surfaces of equipment) be kept free of glycol ethers
to the extent feasible. Not only is this consistent with the intent of
General Industry Standards 29 CFR 1910.141 (a)(3), Housekeeping, but
this provision minimizes both the unnecessary spread of glycol ethers in
the workplace and an increased potential for employee exposure

Paragraph (j)(2) would require employers to conduct a program to detect
leaks and spills, including visual inspections of operations involving
liquids containing glycol ethers. The intent of this provision is to
minimize the number of employees who could be inadvertently exposed
through either dermal contact with liquid glycol ethers or elevated
airborne concentrations evolving from evaporation of such liquids

In addition to the above program, paragraph (j)(3) would require
preventative maintenance of equipment that handle glycol ethers,
including surveys for leaks at intervals appropriate to assure proper
functioning of equipment. This provision should assist in reducing
exposure resulting from leakage caused by items such as cracked joints,
corroded tanks, broken gaskets, worn valve packings, malfunctioning
equipment, and so forth

Periodic inspection and maintenance of process equipment and control
equipment such as ventilation systems is an important work practice
control. In plants where total containment is used as an engineering
control, the failure of process equipment or the ventilation system can
seriously increase the probable occurrence of exposures. Frequently,
equipment which is near failure or in disrepair will not perform
normally. Regular inspections can detect abnormal conditions so that
maintenance can then be performed. If equipment is routinely inspected,
replaced, or repaired before failure is

**\[page 15606\]**

likely, the risk of exposure occurring will be reduced.

The Agency has intentionally kept inspection and maintenance
requirements in performance-oriented terms rather than dictating
specific time intervals for these activities. OSHA is aware that
different industry sectors and even different manufacturing processes
within the same facility may vary in the frequency of occurrence of
leaks/spills or the need for preventative maintenance of equipment. The
employer, therefore, is afforded the flexibility to determine the
frequency of inspection/maintenance and, as a result, gain any cost
savings accrued through elimination of an arbitrarily assigned frequency
schedule

In areas where spillage may occur, paragraph (j)(4) stipulates that the
employer must make provisions to contain the spill, to decontaminate the
work area, and to dispose of the waste generated by the clean-up. Should
a spill occur, having such provisions in place will assist in quickly
limiting the area affected by the spill, facilitate its clean-up, and
will permit more rapid and efficient decontamination of the spill area
and proper disposal of clean-up waste. The intent of this proposed
requirement is to increase preparedness for the eventuality of a spill,
thereby minimizing employee exposure by reducing the time necessary to
control and clean up a spill and properly dispose of waste. Since glycol
ethers exist in a variety of work environments, it is left to employers
to assess what methods are appropriate to their workplace and conditions
of use and are protective of their employees

Paragraph (j)(5) would require that upon discovery of a leak or spill
the employer assure that repair of the leak and/or clean up of the spill
is initiated promptly in order to limit the area affected and eliminate
the source of leakage. The employees performing this repair and clean up
must be adequately protected by suitable personal protective equipment,
which may include respiratory protection, to prevent exposure during
these operations. These employees must also be trained in proper methods
for clean-up and decontamination so that such operations can be
accomplished safely, efficiently, and without exacerbating the hazard

The final provision of the housekeeping section, paragraph (j)(6), would
require that waste and debris contaminated with glycol ethers be placed
in sealed containers bearing a warning label as specified in paragraph
(m)(1)(ii). The containers will minimize airborne concentrations
resulting from evaporation of glycol ethers from the wastes and prevent
possible accidental employee contact or re-spillage of the material. The
warning label is necessary to warn employees who may handle the
containers of the hazard they contain. The Agency recognizes that wastes
destined for disposal may need to meet packaging and labeling
requirements of other local, State or Federal regulatory bodies. It is
not OSHA\'s intent to issue duplicative or conflicting regulations. This
provision is directed at protecting and warning employees at the
worksite. However, OSHA notes that the containers should leave the
worksite for final disposal in a form that meets the requirements of the
appropriate regulatory bodies

Emergencies: Paragraph (k)

This paragraph addresses the handling of emergency situations involving
glycol ethers. The proposal requires that for each workplace or work
operation where there is a possibility of an emergency involving glycol
ethers, the employer must develop a written emergency plan including, at
a minimum, those elements prescribed in 29 CFR 1910.38 (a). For example,
29 CFR 1910.38 (a) includes provisions concerning emergency escape
procedures and escape route assignments; procedures to be followed by
employees remaining to operate critical plant operations before they
evacuate; alarm systems; evacuation plans; employee training; fire
protection; and so forth. It should be noted that development of this
plan is not dependent upon the existence of employee exposure but is
based on the possibility of an emergency situation arising. That is, an
employee may be exposed to glycol ethers and yet the potential for an
emergency may not exist in the employee\'s work area. Conversely, there
may be no employees in an area where there is a large quantity of glycol
ethers, such as a storage tank, but the potential for an emergency
exists (e.g., rupture of the tank). An emergency could be a massive
release affecting a large area or may be a spill or leak which creates
an emergency situation only in the immediate area. Emergency situations,
therefore, may not be likely to occur in every workplace. Consequently,
the Agency has adopted a performance oriented approach which allows the
employer to evaluate and tailor the emergency plan to fit the workplace
so long as it meets the requirements of 29 CFR 1910.38 (a) and the
specific provisions of this section

In addition to requiring that the emergency plan comply with the
requirements of 29 CFR 1910.38 (a), paragraph (k)(1) also states the
provisions of paragraph (q) of the Hazardous Waste Operations and
Emergency Response standard, 29 CFR 1910.120, remain in effect as
applicable. Also, an emergency response plan meeting requirements of 29
CFR 1910.120 (q) would be deemed to meet the requirements for an
emergency response plan under paragraph (k)

Paragraph (q) of the Hazardous Waste Operations and Emergency Response
standard, 29 CFR 1910.120, deals with emergency responses by employees
outside the immediate worksite to releases of hazardous substances that
occur at locations other than uncontrolled hazardous waste sites and
hazardous treatment, storage and disposal operations conducted under the
Resource, Conservation and Recovery Act of 1976 as amended \[42 U.S.C.
6901 et. seq.\]. The typical site covered by paragraph (q) would include
hazardous substance releases at chemical manufacturing facilities.
Paragraph (k)(1) makes clear that this paragraph does not override the
provisions of 29 CFR 1910.120 (q) and that paragraph (q) remains
applicable pursuant to its terms. In addition, paragraph (k)(1)
specifies that an emergency response plan meeting the requirements of
paragraph (q) shall also be deemed to meet the requirements of paragraph
(k) for all employees responding to an emergency

Paragraph (k)(2) would require that all employees be trained in their
responsibilities in the event of an emergency to minimize employee
exposure, injury, and loss of life while increasing efficiency in
dealing with the situation

Generally, emergencies entail large quantities of free glycol ethers
resulting in elevated airborne concentrations, increased chance of
dermal contact, and, in some circumstances, the possibility of fire. In
view of this, paragraph (k)(3) would require the employer to assure that
only designated personnel furnished with appropriate personal protective
equipment, including respiratory protection, and trained in re- entry
procedures are permitted to correct the emergency conditions. The
employer would also be responsible for assuring that the appropriate
personal protective equipment, housekeeping, and other emergency
equipment and supplies for handling the emergency are located in each
area where an emergency could occur so that the situation can be dealt
with quickly and safely. As stipulated in paragraph (k)(5), all
employees, except those designated to correct the situation, must be
evacuated from and normal

**\[page 15607\]**

operations halted in the area where the emergency has occurred until the
emergency conditions have been abated. This will minimize the number of
employees exposed and eliminate the presence of untrained personnel in
the area. In addition, this provision minimizes the potential for
exacerbation of the hazard as a result of attempting to maintain
operations during an emergency situation

Paragraph (k)(6) of this section would require the employer to make
provisions for immediate evacuation, transportation, and medical
assistance at a designated medical facility for affected employees. This
provision will help assure that acutely exposed employees will receive
appropriate medical attention as quickly as possible after exposure. By
having such arrangements made beforehand, confusion or delay in
obtaining prompt medical attention for the employee will be minimized

Medical Surveillance: Paragraph (l)

Paragraph (l)(1)(i) of the proposal requires each employer to institute
a medical surveillance program for all employees who are or will be
exposed at or above the action level or above the EL. Providing medical
surveillance for employees exposed at or above the action level or above
the EL is consistent with other health standards that incorporate an
action level or an EL and is considered by OSHA to be necessary and
appropriate for monitoring the adequacy of the exposure limit to protect
individual employees

The proposal requires that the medical surveillance program provide each
covered employee with an opportunity for a medical examination.
Paragraph (l)(1)(ii) provides that all examinations and procedures be
performed by or under the supervision of a qualified physician and be
provided without cost to the employee. Clearly, a qualified physician is
the appropriate person to be supervising and evaluating a medical
examination. However, certain parts of the required examination do not
necessarily require the physician\'s expertise and may be conducted by
another person under the supervision of the physician

OSHA is proposing to require that persons who administer the pulmonary
function tests required by this proposal, must complete a training
course in spirometry sponsored by an appropriate governmental, academic,
or professional institution. This provision is consistent with other
OSHA standards, Benzene (29 CFR 1910.28) and Cotton Dust (29 CFR
1910.1043), and it will assure that employees who must wear respiratory
protection will receive adequate assessment of their lung capacity, a
vital test in determining if they are capable of wearing a respirator

This standard provides that all examinations and procedures shall be
performed at a reasonable time and place. It is necessary that exams be
convenient and be provided during the workday without loss of pay to the
employee to assure that they are taken. The employer is required to
establish and maintain an accurate record for each employee subject to
medical surveillance

Paragraph (l)(2) would require that the employer provide an initial
medical examination to each employee. The purpose of the initial medical
examination is to: (1) establish the current health status of the
employee and to determine whether employment in areas with glycol ethers
exposure is appropriate; (2) establish essential baseline data against
which to measure any change which might be attributable to glycol ethers
exposure; and (3) determine whether the individual can safely wear a
respirator. OSHA believes that the preplacement examination assessing
each worker\'s state of health prior to the beginning of exposure to
glycol ethers is essential to determine whether an employee\'s health
changes over the period of employment and to determine pre-existing
conditions that could influence initial job placement

The medical examination proposed is to include: (1) medical and work
histories with emphasis on the pulmonary and mucous membranes and
hematologic system, (2) a reproductive history, (3) a physical
examination, (4) a blood analysis including at least a red blood cell
count, white cell count, hemoglobin and hematocrit, (5) a pulmonary
function test for respirator wearers and (6) any additional tests deemed
appropriate by the examining physician

This information, in conjunction with a complete physical examination,
will assist the physician in the determination of the employee\'s health
status, possible past exposures to glycol ethers or other substances
that may have damaged organs or systems susceptible to glycol ethers
toxicity, and suitability for employment in an area where exposure to
glycol ethers will occur. Special emphasis is placed on the portions of
the history and physical examination which evaluate organ systems known
to be particularly susceptible to glycol ethers toxicity. Emphasis is
placed on examination of the skin as evidence indicates that glycol
ethers are rapidly absorbed through the skin. Therefore, the skin should
be examined for conditions such as dermatitis which might facilitate
absorption. Emphasis is also placed on the hematologic system because of
the human and animal evidence which has shown adverse effects on various
constituents of the blood as a result of glycol ethers exposure. The
physical examination should also include attention to the mucous
membranes and respiratory systems as these two systems can be
nonspecifically irritated by glycol ethers. The pulmonary system takes
on added importance with respirator use

Also included in the initial or preplacement examination are any
additional tests deemed appropriate by the examining physician. This
provision authorizes the physician to include further tests which could
assist the physician in determining the employee\'s suitability for work
in an area in which glycol ethers exposure will occur or in determining
whether a worker can safely wear a respirator

In the proposed medical examination, OSHA has not prescribed any
specific tests for the surveillance of adverse reproductive or
developmental effects. Information presently available to OSHA is
insufficient for the Agency to justify specification of the precise
tests to be administered. Few tests are available which can reliably be
used to detect the early onset of reproductive/developmental effects.
For example, serum hormones such as follicle stimulating hormone(FSH),
luteinizing hormone (LH), prolactin, and testosterone, may provide
information on alterations in endocrine function which might be early
indicators of adverse reproductive functioning. However, due to the
cyclical nature of these hormones, multiple and sequential blood samples
rather than single time point samples would be required to detect
exposure related fluctuations in hormone levels. Furthermore, OSHA is
not aware of any data specifically correlating alterations in endocrine
function and glycol ethers exposure. Other tests such as sperm count or
measurement of testes size are very invasive and the results of these
types of tests are highly variable and thus difficult to standardize.
For these reasons, employees may be unwilling to submit to testing. Due
to the variability, results from individual workers may be difficult to
interpret and may not provide meaningful diagnostic information. Because
these types of tests are invasive and unlikely to give meaningful
information on an individual basis, they have not been included in
provisions for a medical

**\[page 15608\]**

examination. OSHA is seeking comment on the availability of tests which
can be used to detect the early onset of adverse
reproductive/developmental effects

OSHA has proposed that the employer provide his/her employees with the
opportunity for medical advice or counseling with respect to their
ability to produce a healthy child. Glycol Ethers have been shown to
produce adverse reproductive and developmental effects in several animal
species and thus may potentially effect exposed workers ability to
produce healthy children. Therefore, workers who have past or current
exposure to glycol ethers and are experiencing difficulties in
conceiving a child should be afforded the opportunity for medical
advice, counseling, and reproductive testing where it is deemed
appropriate by the examining physician. This approach is consistent with
other health standards for substances shown to induce adverse
reproductive and developmental effects (e.g., Lead, 29 CFR 1910.1025 and
Ethylene Oxide, 29 CFR 1910.1047)

OSHA proposes periodic medical examinations to be administered annually.
The purposes of the annual examination are: (1) the early detection of
biological effects of glycol ethers; (2) the detection of
non-occupationally-related diseases that might require reduction of
glycol ethers exposure; (3) the assessment of fitness for respirator
usage; and (4) the monitoring of general health status and recent
illnesses. The requirement that medical examinations be provided
annually, as a minimum, is consistent with other OSHA health standards
(e.g., Formaldehyde, 1910.1048 and Benzene, 1910.1028). In addition, the
adverse effects of overexposure to glycol ethers are subchronic in
nature (i.e., the effects may occur within a year). Periodic
examinations performed at one year intervals will allow for the
detection of these effects. More frequent reviews of specific biological
tests may be performed, if evidence indicates such tests are necessary

OSHA also proposes a periodic medical re-evaluation of workers required
to wear respirators. The re-evaluation is necessary because an illness,
a new medication or a change in facial structure may affect and impact
on an employee\'s continuing ability to wear a respirator. The
re-evaluation will enable the physician to determine whether the
individual can safely continue to wear the same type of respirator,
should be re-fitted with another type, or should be removed from any
area where respirator use is required

In addition to routine medical surveillance, the proposal also requires
that employers make medical examinations available as soon as possible
to all employees who may have been acutely exposed to glycol ethers in
an emergency. The emergency surveillance provisions reflect OSHA\'s
concern for those employees who, because of equipment breakdown,
container rupture or other causes, may be exposed to higher doses of
glycol ethers. Medical evaluations should be made available in the event
that such emergencies occur. No specific examination elements have been
stipulated in this provision in order to provide the physician with
sufficient flexibility to deal with the nature and degree of exposure
sustained

OSHA has not included a medical examination at the termination of
employment. Because of the relatively short biological half life of
glycol ethers (i.e., 24-48 hours) and the subchronic nature of the
reproductive/developmental effects associated with glycol ethers, a
examination at the termination of employment may not be necessary.
However, medical records at termination of employment may be useful to
physicians to determine the status of an employee\'s health and to
identify any potential future health effects. Thus, OSHA requests
comments on whether provisions for medical examinations at termination
of employment should be included in a final standard for glycol ethers

The employer is required, in paragraph (l)(5), to provide the physician
with the following information: A copy of this standard and its
appendices; a description of the affected employee\'s former and current
duties as they relate to the employee\'s glycol ethers exposure level;
the employee\'s former and current exposure level or anticipated
exposure level; a description of any personal protective and respiratory
equipment used or to be used; and information or medical records from
the employee\'s previous medical examinations that were provided or made
available by the employer to the affected employee. Making this
information available to the physician will aid in the evaluation of the
employee\'s health in relation to assigned duties and fitness to wear
personal protective equipment, when required

In paragraph (l)(6), the employer is required to obtain a written
opinion from the examining physician containing the results of the
medical examination as they relate to occupational exposures; the
physician\'s opinion as to whether the employee has any detected medical
conditions which would place the employee at increased risk of material
health impairment from exposure to glycol ethers; the physician\'s
opinion as to whether the employee is exhibiting any symptoms/signs from
overexposure to glycol ethers; any recommended restrictions upon the
employee\'s exposure to glycol ethers or upon the use of protective
clothing or equipment such as respirators; and a statement that the
employee has been informed by the physician of the results of the
medical examination and of any medical conditions which require further
evaluation or treatment. This written opinion must not reveal specific
findings or diagnoses unrelated to occupational exposures. The employer
must provide a copy of the opinion to the affected employee

The purpose in requiring the employer to obtain a written opinion from
the examining physician is to provide the employer with a medical basis
to aid in the determination of initial placement of employees and to
assess the employee\'s ability to use protective clothing and equipment.
The physician\'s opinion will also provide information to the employer
as to whether the employee may be suffering from overexposure to glycol
ethers. The employer can then reassess the employee\'s exposure and work
practices and take steps to reduce that employee\'s exposure. The
requirement that a physician\'s opinion be in written form will ensure
that employers have had the benefit of this information. The employer
shall provide a copy of the physician\'s written opinion to the affected
employee within 15 days of its receipt. The requirement that an employee
be provided with a copy of the physicians\'s written opinion will ensure
that the employee is informed of the results of the medical examination.
The requirement that the physician sign the opinion is to ensure that
the information that is given to the employer has been seen and read by
the physician

The purpose in requiring that specific findings or diagnoses unrelated
to occupational exposures not be included in the written opinion is to
encourage employees to participate in the medical surveillance program
by removing any concern that the employer will obtain adverse
information about the employee\'s physical condition that is unrelated
to occupational exposures

In the proposed standard, in Appendix D, OSHA has included a
non-mandatory, reproductive history questionnaire. The questionnaire
which was excerpted and modified comes from

**\[page 15609\]**

the Office of Technology Assessment\'s (OTA) report, Reproductive Health
Hazards in the Workplace (Ex. 5-135, pp.382-388) and is included in the
standard to give guidance on conducting reproductive histories for
workers exposed to glycol ethers. As stated in the OTA report, this
questionnaire is a composite derived from several research facilities,
it is not a validated questionnaire. Nevertheless it has value in
providing guidance and information on pertinent factors which may be
important in understanding a worker\'s medical background

Communication of Glycol Ethers Hazards to Employees:

Paragraph (m)

Paragraph (m) of this proposal entitled: \"Communication of Glycol
Ethers Hazards to Employees\" addresses the issue of transmitting
information to employees about the hazards of ethylene glycol ethers
through the use of: (1) signs and labels, (2) material safety data
sheets, and (3) information and training. While previous OSHA health
standards generally included separate paragraphs on employee information
and training and signs and labels, both of these areas have been
incorporated into this single paragraph, along with material safety data
sheet provisions, to provide consistency with the Hazard Communication
Standard (HCS) which addresses these areas

The Hazard Communication Standard (HCS), 29 CFR 1910.1200, requires all
chemical manufacturers and importers to assess the hazards of the
chemicals they produce or import, and all employers to provide
information concerning the hazards of such chemicals to their employees.
The transmittal of hazard information to employees is to be accomplished
by means of comprehensive hazard communication programs, which are to
include container labeling and other forms of warning, material safety
data sheets and employee training. The HCS also addresses the
responsibility of producers of chemicals to provide information to
downstream employers

In paragraph (m) of this proposal, it is the intent of the Agency to
avoid repetition of those requirements comprehensively laid out in
§1910.1200, while specifying additional requirements that are directed
at protecting employees against the particular hazards associated with
exposure to glycol ethers

The proposed standard, paragraph (m)(1)(i), would require that all entry
and accessways to regulated areas be posted with appropriate warning
signs which bear, at a minimum, the legend: \"Danger, Glycol Ethers
\[specific chemical name(s)\], Blood and Reproductive Hazard, Eye and
Respiratory System Irritant, Avoid Inhalation and Skin/Eye Contact,
Authorized Personnel Only, Respiratory Protection Required\"

In addition, these signs should include any other appropriate warnings
such as \"Flammable - No Smoking, Sparks, or Open Flames\" whenever such
hazards may exist. It is intended that these signs will serve to warn
employees, who may otherwise not know, that they are entering a
regulated area. These warning signs are required to be posted whenever a
regulated area exists, that is, whenever airborne concentrations exceed
or can reasonably be expected to exceed the permissible exposure limits

It could be possible that at some work sites or operations the airborne
concentrations of glycol ethers cannot be reduced below the permissible
exposure limits through the use of engineering controls. In such
instances, a regulated area may exist for an extended period of time.
Signs would be needed in these circumstances to warn employees that
entry is permitted only if the employee is authorized, is wearing
respiratory protection, and there is a specific need to enter the area

Regulated areas may also exist on a temporary basis, as would occur
during maintenance and/or emergency situations. In these types of
situations, the use of warning signs is also important since a
maintenance or emergency situation is by nature a new or unexpected
source of exposure to employees who are regularly scheduled to work at
these sites. It is expected and required by other provisions of this
standard that employees will also be provided with any other personal
protective equipment and training that is necessary to assure their
health and safety while in these areas

These signs will also supplement the training which employees are to
receive under the other provisions of this paragraph, since even trained
employees need to be reminded of the locations of regulated areas (or
made aware of new ones) and of the precautions necessary to be taken
before entering these areas

The wording of the warning signs for regulated areas has been specified
in the proposal in order to ensure that an adequate warning is given to
employees. OSHA believes that the use of the word \"Danger\" is
appropriate, based on the evidence of the toxicity of glycol ethers.
\"Danger\" is used to attract the attention of workers, to alert them to
the fact that they are in an area where the permissible exposure limits
are exceeded, and to emphasize the importance of the message that
follows. The use of the word \"Danger\" is consistent with other recent
OSHA health standards such as Formaldehyde (29 CFR 1910.1048). Inclusion
of the statements \"Blood and Reproductive Hazard\" and \"Eye and
Respiratory System Irritant\" is consistent with the effects that have
been demonstrated to be associated with these substances (see Section V,
Health Effects, of this document). The signs are also required to bear
the legend, \"Respiratory Protection Required\". While OSHA recognizes
that some employees entering the regulated areas may not be exposed
above either the 8-hour TWAs of 0.5 ppm (2-EE, 2-EEA) and 0.1 ppm (2-ME,
2-MEA) or the Els of 2.5 ppm (2-EE, 2-EEA) and 0.5 ppm (2-ME, 2-MEA) as
averaged over a 15-minute period, it is still possible that some
employees who are assigned to work in these areas without the use of
respiratory protection may remain in these locations for long enough
periods of time so that they would be needlessly overexposed to glycol
ethers. To ensure that these employees are adequately protected, it is
necessary to post the sign in order to alert them to the need to wear
respirators. The employer should note that in addition to respiratory
protection, paragraph (e)(4) requires that all persons entering a
regulated area be provided with and required to use appropriate personal
protective equipment while paragraph (m)(4) would require training of
these persons

Inclusion of the phrase \"Authorized Personnel Only\" on these signs
serves to notify employees that only those persons specifically
authorized by the employer are permitted in the regulated area

Paragraph (m)(2) would require that warning labels or other appropriate
forms of warning complying with the requirements of 29 CFR 1910.1200 (f)
of the General Industry Standards be affixed to all shipping and storage
containers containing glycol ethers or glycol ethers-contaminated
materials. These labels must state: \"Caution, Contains Glycol Ethers
\[specific chemical name(s)\], Blood and Reproductive Hazard, Eye and
Respiratory System Irritant, Avoid Inhalation and Skin/Eye Contact\". In
addition, the label shall include any other hazard warnings (e.g.,
\"Flammable - Keep away from heat, sparks, and flame\") which are
appropriate to the contents of the container along with any other
information required by the Hazard Communication Standard, 29 CFR
1910.1200. It is proposed that required labels would remain affixed not
only to

**\[page 15610\]**

containers being used at the work site/operation but also those leaving
the workplace

The purpose of this requirement is to assure that downstream employers
and employees are informed of the presence of glycol ethers, their
associated hazards, and that special practices may need to be
implemented to insure against exposure. An employer\'s obligation, under
section 6(b)(7) of the Act, to inform employees of hazardous conditions
is not limited to the employer\'s own employees. When an employer
manufactures, formulates, or sells a product, it may unavoidably expose
the employees of downstream employers to the hazards of glycol ethers.
This is especially important when the manufacturer, formulator, or
seller is the only employer able, through his knowledge of the product,
to provide the information necessary to protect employees. Furthermore,
hazard labels alert other employers who, in the absence of such labels ,
might not know that glycol ethers are present in their workplace and
that they have incurred the obligation of complying with the standard

In addition to being consistent with the requirements of the HCS, these
requirements are consistent with the mandate of section 6(b)(7) of the
Act, which requires OSHA health standards to prescribe the use of labels
or other appropriate forms of warning to apprise employees of the
hazards to which they are exposed

OSHA also proposes in paragraph (m)(3) of this standard to require the
employer to obtain or develop and to distribute and provide access to
material safety data sheets for ethylene glycol ethers in accordance
with the requirements of 29 CFR 1910.1200 (g). OSHA feels that a
properly completed material safety data sheet (MSDS), if readily
available to employees, can serve as an excellent, concise source of
information regarding the hazards associated with glycol ethers. OSHA\'s
primary intent in this section of the proposed standard, as stated in
the Hazard Communication Standard (HCS), is to ensure that employees
will receive as much information as is needed concerning the hazards
posed by chemicals in their workplaces

The material safety data sheet ensures that this information will be
available to them in a usable, readily accessible and concise form. The
material safety data sheet also serves as the central source of
information to employees and downstream employers who must be provided
with an MSDS if glycol ethers or a product containing glycol ethers is
produced and shipped out of the plant. In addition, the MSDS serves as
the basic source of information on the hazards of ethylene glycol ethers
essential to the training provisions of this and other applicable health
standards

Producers and importers have the primary responsibility, under the HCS
to develop, update, and distribute the material safety data sheet. The
manufacturer or importer is most likely to have the best access to
information about the product, and is therefore responsible for
disseminating this information to downstream users of the material. The
requirements for the information that is to be contained on the material
safety data sheet are explained in detail at 29 CFR 1910.1200 (g)

All employers with employees potentially exposed to glycol ethers must
maintain material safety data sheets and provide their employees with
access to them in accordance with 29 CFR 1910.1200 (g). For employers
whose employees\' exposure to glycol ethers is from products received
from outside sources, the information necessary for a complete MSDS or
the MSDS itself is to be obtained from the manufacturer and made
available to affected employees

Paragraphs (m)(4)(i) through (m)(4)(iii) of this proposed standard would
require employers who have a workplace or work operation covered by this
section to provide information and training to all employees who are
potentially exposed to these chemicals. The training program is to be in
accordance with the requirements of the HCS paragraph (h), including
specific information required to be provided by that section and those
items stipulated in paragraph (m)(4)(iv) of this standard. In addition,
paragraph (m)(4)(ii) would require the employer to institute a training
program for all employees who are potentially exposed to glycol ethers,
to assure each employee\'s participation in the program and maintain a
record of this participation, and to maintain a record of the contents
of such programs. This will assist the employer in determining which
employees have received training, the information provided to the
employees, and those employees who are still in need of such training.
Training is to be provided, at no cost to the employee, prior to or at
the time of initial assignment to a job involving potential exposure to
glycol ethers, at least annually thereafter, and whenever a new hazard
from glycol ethers is introduced into their work area. Examples of a new
glycol ethers hazard would include, but are not limited to, use of
glycol ethers or glycol ethers-containing mixtures where none were
previously utilized and installation of a process which could result in
employee exposure to glycol ethers or increase existing exposure levels.
These types of situations would warrant additional training to ensure
that employees remain apprised of any new or increased glycol ethers
exposure hazards and the precautions necessary to protect themselves
from exposure

Paragraph (m)(4)(iv) would require that the training program be
conducted in a manner that the employee is able to understand and shall
include at least the following: A) the health hazards associated with
glycol ether exposure with special attention to the information in
Appendix A of this section; B) the quantity, location, manner of use,
release, and storage of glycol ethers at the worksite and the specific
nature of operations that could result in exposure to glycol ethers,
especially above the TWAs or ELs; C) an explanation of the importance of
engineering and work practice controls for employee protection and
necessary instruction in the use of these controls; D) the measures
employees can take to protect themselves from exposure to glycol ethers,
such as diligent personal hygiene, proper use of protective equipment,
and specific procedures the employer has implemented to protect
employees against exposure, including appropriate work practices,
emergency procedures, and personal protective equipment; E) the details
of the hazard communication program developed by the employer, including
an explanation of the signs, labeling system, and material safety data
sheets and how employees can obtain and use the appropriate hazard
information; F) the purpose, proper selection, fitting, proper use, and
limitations of respiratory protection and personal protective clothing
and eye protection; G) the purpose and a description of the medical
surveillance program required under paragraph (l) of this proposed
section including the right of any employee exposed to glycol ethers at
or above the AL or above the EL to obtain 1) medical examinations as
required by paragraph (l) of this section at no cost to the employee, 2)
the employee\'s medical records required to be maintained by paragraph
(n)(2) of this section, and 3) all air monitoring results representing
the employee\'s exposure to glycol ethers and required to be kept by
paragraph (n)(1) of this section; H) a copy of the final glycol ethers
standard and its appendices and a discussion of its contents with an
explanation of the contents of the MSDSs for glycol ethers; I)
instructions for the handling of spills and clean-up

**\[page 15611\]**

procedures; and J) a review of emergency procedures including specific
duties or assignments of each employee in the event of an emergency

Paragraph (m)(4)(iv)(A) is of primary importance in communicating
hazards and training employees. Until employees understand the health
hazards of a compound to which they are potentially exposed, the work
practices, engineering controls, use of personal protective equipment,
and any other precautions which should be taken have little meaning. The
Agency feels, therefore, that effectively communicating a compound\'s
health hazards to employees is the initial step in their understanding
of other steps necessary to protect them against exposure. OSHA feels
strongly that it is important for each worker to be able to recognize
how and where he or she might be occupationally exposed to glycol ethers
and what steps should be taken to limit exposure. Therefore, the Agency
has required, in paragraphs (m)(4)(iv)(B), (C), (D), (E), (F), and (I),
that workers be provided information and trained in practices pertinent
to location, use, and so forth of glycol ethers in the workplace; work
practices and engineering controls; spills and clean-up; self protective
measures; the employer\'s hazard communication program; and personal
protective equipment as they apply to glycol ethers and reduction of
exposure. Providing a description of the medical surveillance program
and its purpose, as stipulated in paragraph (m)(4)(iv)(G), will allow
employees to understand what medical follow-up has been initiated and is
available to evaluate occupational exposure. This section would also
require that employees be informed that the medical examinations
required under paragraph (l) are to be provided at no cost to the
employee. The Agency anticipates that this fact, along with an
understanding of the medical surveillance program, will encourage
employees to participate. In addition, employees must be informed of
their right to access of their personal medical records and all air
monitoring results representing their exposure to glycol ethers since
these records are concerned directly with the employee\'s health as it
relates to exposure to glycol ethers. The purpose of paragraph
(m)(4)(iv)(H) is to assure that employees are aware of the existence of
the standard and material safety data sheet(s) and are familiarized with
the information contained in these documents. In order to assist in
successfully achieving the goals outlined in the emergency plan,
paragraph (m)(4)(iv)(J) states that employees must be trained in
emergency procedures including their specific responsibilities should an
emergency occur

Finally, this section would require that employees be informed that the
medical examinations required under paragraph (l) are to be provided at
no cost to the employee. The Agency anticipates that this fact, along
with an understanding of the medical surveillance program, will
encourage employees to participate. In addition, employees must be
informed of their right to access of their personal medical records and
all air monitoring results representing their exposure to glycol ethers
since these records are concerned directly with the employee\'s health
as it relates to exposure to glycol ethers

OSHA has determined during other rulemakings that an information and
training program, as incorporated in this proposed standard in an
overall \"Communication of Hazards to Employees\" paragraph, is
essential to inform employees of the hazards to which they are exposed
and to provide employees with the necessary understanding of the degree
to which they themselves can minimize the health hazard potential.
Training is essential to an effective overall hazard communication
program and serves to explain and reinforce the information presented to
employees on signs, labels, and material safety data sheets. These
written forms of information and warning will be relevant and meaningful
only when employees understand the information presented and are aware
of the actions to be taken to avoid or minimize exposures. Active
employee participation in training sessions can result in the effective
communication of hazard information to employees which can further
result in workers taking conscientious protective actions at their job
duties, thereby decreasing the possibility of occupationally-induced
illnesses and injuries

OSHA proposes the training provisions of this standard to be in
performance-oriented, rather than specified and detailed language. The
proposed standard, in requiring training to be in accordance with the
requirements of 29 CFR 1910.1200, lists the categories of information to
be transmitted to employees and not the specific ways that this is to be
accomplished. The Agency believes that the employer is in the best
position to determine how the training he or she is providing is being
received and absorbed by the employees. OSHA has therefore laid out the
objectives to be met and the intent of its training to ensure employees
are made aware of the hazards in their workplace and how they can help
to protect themselves. The specifics of how this is to be accomplished
are left up to the employer. The Agency anticipates that the use of such
performance-oriented requirements will encourage employers to tailor
their training needs to their specific workplaces, consequently
resulting in the most effective training program suitable for each
specific workplace

Recordkeeping: Paragraph (n)

Section 8(c) of the Occupational Safety and Health Act obligates
employers to keep and make available such records as the Secretary may
prescribe as necessary or appropriate for the enforcement of the Act, or
for developing information regarding occupational injuries and
illnesses. Accordingly, paragraph (n) of this proposal requires
employers to keep several types of records to achieve the intent of this
section of the Act. These include records of 1) exposure measurements
and all objective data relied on as a basis for exemption from the
monitoring requirements, 2) medical surveillance, and 3) training

Paragraph (n)(1) of the proposal mandates that the employer establish
and maintain exposure records consistent with 29 CFR 1910.20, to
accurately reflect the extent and duration of employee exposure to
glycol ethers. Specifically, records must include the following
information: (a) the name, social security number, and job
classification of the employee(s) monitored and of all other employees
whose exposure the monitoring is intended to represent; (b) the dates of
monitoring, sample identification number, sampling duration, time of
day, and exposure monitoring results of each of the samples taken
including a description of the procedure used to determine
representative employee exposures; (c) the operation(s) covered by the
monitoring; (d) the sampling and analytical methods used and evidence of
their accuracy; (e) the type of respiratory protective devices, if any,
worn by the employee; and (f) any other conditions that might have
affected the employee monitoring results. Unusual conditions which may
affect monitoring results generally stem from, but are not limited to,
situations which could cause an abnormal increase/decrease in the
airborne concentration of glycol ethers. Examples of such situations are
a temporary increase/decrease in production; failure of an engineering
control to operate properly; release of glycol ethers in the employee\'s
vicinity

**\[page 15612\]**

as may occur during an emergency or maintenance operation; seasonal
variations caused by increased/decreased air movement resulting from
opening or closing of doors and windows or use of fans; or a change in
an employee\'s mobility or proximity to a source of glycol ethers. The
proposal would require that employee exposure measurement records be
maintained for each measurement taken. The record may represent several
employee exposure measurements if representative sampling, as described
in paragraph (d), is conducted. The exposure monitoring results that
would be required under paragraph (n)(1)(ii)(B) above must be expressed,
at a minimum, as either an 8-hour time weighted average (TWA) or a
15-minute excursion limit (EL), whichever is applicable. OSHA believes
that this is necessary to allow employees, their designated
representatives, and others accessing these records to be able to
determine employee exposure levels without performing numerous and
sometimes unfamiliar calculations

This proposal has included a provision for the use of objective data in
place of initial monitoring to minimize the costs of initial monitoring
in circumstances where the employer can demonstrate that insignificant
amounts of glycol ethers are present in the workplace and the potential
for exposure to glycol ethers above the ALs or ELs does not exist. OSHA
feels that requiring an employer to document objective data
determinations and retain them, as stipulated in paragraph (n)(1)(iii),
should discourage abuse of this provision since employees and their
representatives are permitted access to this information. Access would
enable employees and their representatives to ensure that the exemption
determination is a reasonable one, thereby encouraging use of objective
determinations only in cases where the data warrant such use.
Maintaining a record of the data employed for objective determinations
will also permit OSHA to ascertain whether compliance with the standard
has been achieved

For the purpose of acquiring the capability of correlating employee
exposure level data with an individual\'s medical surveillance results,
OSHA is proposing in paragraph (n)(1)(iv) that exposure monitoring
records be maintained for at least duration of employment plus 30 years

In addition to records on employee exposure measurements, paragraph
(n)(2)(i) would require the employer to establish and maintain an
accurate individual record for each employee subject to medical
surveillance as stipulated by paragraph (l) of the proposed standard, in
accordance with 29 CFR 1910.20. OSHA believes that medical records, like
exposure monitoring records, are necessary and appropriate both to the
enforcement of the standard, and to the development of information
regarding the causes and prevention of occupational illnesses.
Furthermore, medical records are necessary for the proper evaluation of
the employee\'s health

Paragraph (n)(2)(ii) would require that this record include at least the
following: 1) the name and social security number of the employee; 2)
the physician\'s written opinion on the initial, periodic, and
additional examinations; 3) any employee medical complaints related to
exposure to ethylene glycol ethers; 4) a copy of the information
provided by the employer to the physician as required by paragraph
(l)(6) of this section; and 5) a copy of the medical and reproductive
histories, medical questionnaire responses, and results of any medical
tests required by the standard or mandated by the examining physician

Paragraph (n)(2)(iii) would require the employer to retain these medical
records for at least the duration of employment plus 30 years. The
extended record retention period is needed because diagnosis of disease
in employees is assisted by, and in some cases can only be made by,
having present and past exposure data as well as the results of present
and past medical examinations. In revising 29 CFR 1910.20 \"Access to
Employee Exposure and Medical Records\" OSHA initially proposed to
reduce the retention period for medical records. However, in the final
rule the Agency states:

\"Based on the evidence submitted, OSHA has determined that the proposed
reduction in the retention period for medical records is not justified.
The long-term retention of records is necessary to provide a data base
for the detection of occupational diseases that may not manifest
themselves for many years after onset of exposure.\" (53 FR 38154
September 29, 1988)

The Agency therefore believes that maintenance of records for duration
of employment plus thirty years is prudent and warranted for developing
information regarding the causes and prevention of
occupationally-induced illness

With regard to training records, paragraph (n)(3) would require the
employer to retain all employee training records for 1 year beyond the
last date of employment for that employee

Paragraph (n)(4)(i) mandates that the employer assure that all records
required to be maintained by this section are made available upon
request to the Assistant Secretary and the Director for examination and
copying. In addition to being given records access specifically by this
section, the Assistant Secretary and the Director are empowered to
examine and copy records by Section 8(c)(1) of the OSH Act. This portion
of the Act states:

Each employer shall make, keep and preserve, and make available to the
Secretary or the Secretary of Health, Education, and Welfare \[now
Health and Human Services (HHS)\], such records regarding his activities
relating to this Act as the Secretary, in cooperation with the Secretary
of Health, Education and Welfare \[HHS\], may prescribe by regulation as
necessary or appropriate for the enforcement of this Act or for
developing information regarding the causes and prevention of
occupational accidents and illness.

While the Assistant Secretary is empowered to examine and copy records,
access to personally identifiable records is subject to Agency rules of
practice and procedure which have been published at 29 CFR 1913.10 (45
FR 35384)

Paragraph (n)(4)(ii) would require the employer to provide upon request
for examination and copying, all employee exposure monitoring records
required to be maintained by paragraph (n)(1) of this section to
affected employees, former employees, and designated representatives in
accordance with 29 CFR 1910.20 (a) through (e) and (g) through (i). In
addition, paragraph (n)(4)(iii) would require employers to provide upon
request for examination and copying, all employee medical records
required to be maintained by paragraph (n)(2) of this section to the
subject employee and to anyone having the specific written consent of
the subject employee in accordance with 29 CFR 1910.20

Section 8(c) of the Act explicitly provides employees and their
representatives with the right to have access to monitoring records.
Several other provisions of the Act contemplate that employees and their
representatives are entitled to have an active role in the enforcement
of the Act . Employees and their representatives need the pertinent
information concerning exposures to toxic substances and the
consequences to the health and safety of the employees if they are to
benefit properly from these statutorily-created rights

In 29 CFR 1910.20, are spelled out the procedures for access to records
by

**\[page 15613\]**

OSHA, employees, and employees\' designated representatives. This
General Industry Standard was promulgated as the generic rule for access
to employee exposure and medical records

It is discussed here to make the employer aware that it applies not only
to records created pursuant to specific standards but also to records
which are voluntarily created by employers. A more detailed discussion
of the rationale and provisions for 29 CFR 1910.20 can be found at 45 FR
35312 (May 23, 1980)

The transfer of employee exposure monitoring and medical records is to
be in accordance with the provisions of paragraph (h) of 29 CFR 1910.20.
If an employer ceases to do business and there is no successor employer
to receive and retain the records for the prescribed period, the
employer is to notify the Director at least 90 days prior to disposal
and transmit the records to the Director for retention, if requested by
the Director within that period

Requirements for recordkeeping under the Paperwork Reduction Act are
discussed under Section XI - Clearance of Information Collection
Requirements

Dates: Paragraph (o)

It is proposed that the final standard become effective 60 days after
its publication in the Federal Register (the Effective Date). This will
permit time for public distribution of the standard and provides a
sufficient period for employers to familiarize themselves with the
regulatory provisions. All obligations under the final standard will
commence on the Effective Date except those discussed in the following
paragraphs, which will be phased-in during the indicated periods of time

The initial exposure monitoring required by paragraph (d) and the
training required by paragraph (m)(4) of this section are proposed to be
completed as soon as possible but not later than 90 days after the
effective date of the final standard. The Agency believes that this is
adequate time to conduct monitoring and train employees, even in those
workplaces which operate on a multi-shift work schedule

Upon receipt and evaluation of the monitoring results, regulated areas
can be established; respiratory protection can be selected and provided;
and medical surveillance can be implemented. Therefore, those
requirements found in paragraphs (e),(g), and (l) respectively, are to
be complied with as soon as possible but not later than 120 days after
the effective date of the final standard

Since development of the emergency plan necessitates, among other
things, purchase of and distribution/placement of appropriate equipment
and supplies, evaluation of potential emergency sites in the facility
and appropriate evacuation routes, and additional training of employees,
it is proposed that the emergency plan required by paragraph (k) be
completed as soon as possible but not later than 180 days after the
effective date

Development of the written compliance plan stipulated in paragraph
(f)(6) of this section requires that the employer determine effective
and appropriate engineering controls and work practices to reduce
employee exposure levels. Since the provisions in this paragraph may
require an in-depth analysis of the workplace and could necessitate
obtaining outside expertise, a longer period of time has been allotted
for compliance. However, the written compliance plan is to be completed
no later than 1 year after the effective date

In addition, the installation of emergency showers and eyewashes
required in paragraph (i) may also demand extra time for the completion
of necessary plumbing and construction. Therefore, the Agency is
proposing that eyewashes and showers be installed and usable as soon as
possible but in any event not later than 1 year after the effective date

The Agency believes that the implementation of engineering controls will
be the most time-consuming aspect of the final standard. While the
initial evaluation and planning of these controls will have been
completed as a result of the development of the compliance plan, OSHA
realizes that additional time could be required for ordering and
installing the necessary equipment. Therefore, engineering controls are
to be implemented as soon as possible but no later than 2 years after
the effective date

Overall, work practices are to be implemented as soon as possible. Those
work practices directly related to engineering controls being installed
in accordance with the compliance plan are to be implemented as soon as
possible after these engineering controls are functional. OSHA solicits
comments on the appropriateness of these proposed start-up dates

Appendices: Paragraph (p)

The proposed standard contains 5 appendices which are designed to assist
employers and employees in implementing the provisions of this standard.
Appendices A, B, C, D and E are nonmandatory and are included primarily
to provide information and guidance. In addition these appendices are
not intended to detract from any obligation that the proposed standard
imposes

In particular Appendix D, is a sample Reproductive History
Questionnaire. This questionnaire was derived from Appendix B of the
Office of Technology and Assessment\'s (OTA) report Reproductive Hazards
in the Workplace (Ex. 5-135). As noted by the OTA, elements of the
questionnaire were derived from various research facilities to develop a
composite questionnaire. They also note that it is not a validated
questionnaire. Nevertheless, OSHA believes that this sample
questionnaire provides useful information which may provide guidance and
information on pertinent factors in conducting a reproductive history.
OSHA seeks comment on the usefulness of this questionnaire. OSHA also
welcomes other information on other reproductive history questionnaires
which may be more useful or appropriate

The appendices which are included in the standard are: Appendix
A-Substance Safety Data Sheet for Glycol Ethers; Appendix B-Substance
Technical Guidelines for Glycol Ethers; Appendix C-Medical Surveillance
Guidelines for Glycol Ethers; Appendix D-Reproductive History
Questionnaire; Appendix E-Sampling and Analytical Method for Glycol
Ethers; Appendix F-Qualitative and Quantitative Fit Test Procedures

XI\. Clearance Of Information Collection Requirements

On March 31, 1983, the Office of Management and Budget (OMB) published a
new 5 CFR Part 1320, implementing the information collection provisions
of the Paperwork Reduction Act of 1980, 44 U.S.C. 3501 et seq. (48 FR
13666). Part 1320, which became effective on April 30, 1983, sets forth
procedures for agencies to follow in obtaining OMB clearance for
collection of information requirements contained in proposed rules to
OMB not later than the date of publication of the proposal in the
Federal Register. It also requires agencies to include a statement in
the notice of proposed rulemaking, indicating that such information
requirements have been submitted to OMB for review under Section 3504
(h) of the Paperwork Reduction Act

In accordance with the Paperwork Reduction Act of 1980 (44 U.S.C. 3501
et. seq.), and the regulation issued pursuant thereto (5 CFR Part 1320),
OSHA certifies that is has submitted the information collection
requirements contained in this proposed standard to the Office of
Management and Budget (OMB) for review under Section 3504 (h) of the
Act. Paragraph (n) is the provision

**\[page 15614\]**

that makes the major contribution to the information collection
requirements in the proposed standard. Comments on these information
collection requirements may be submitted by interested parties to the
Office of Information and Regulatory Affairs of OMB, Attention: Desk
Officer for the Occupational Safety and Health Administration, New
Executive Office Building, Washington, D.C. 20503. OSHA requests that
copies of such comments also be submitted to the OSHA rulemaking docket,
at the following address: Docket Officer, Docket No. H-044, Room N2625,
U.S. Department of Labor, 200 Constitution Avenue., N.W., Washington,
D.C. 20210

Public Reporting Burden

Public reporting burden for this collection of information is estimated
to be approximately 24 hours initially and approximately 24 recurring
hours with and average .08 hours per response. Send comments regarding
this burden estimate or any other aspect of this collection of
information, including suggestions for reducing this burden, to the OSHA
rulemaking docket, at the address previously set forth; and to the
Office of Information and Regulatory Affairs of OMB

XII\. Public Participation - Notice Of Hearing

Interested persons are invited to submit written data, views, and
arguments with respect to this proposed standard. These comments must be
postmarked on or before June 7, 1993, and submitted in quadruplicate to
the Docket Officer, Docket No. H-044, Room N2625, U.S. Department of
Labor, 200 Constitution Avenue NW, Washington, DC 20210. Comments
limited to 10 pages or less also may be transmitted by facsimile to
(202) 219-5046, provided the original and three copies are sent to the
Docket Officer thereafter

Written submissions must clearly identify the provisions of the proposal
which are being addressed and the position taken with respect to each
issue. The data, views, and arguments that are submitted will be
available for public inspection and copying at the above address. All
timely written submissions will be made a part of the record of the
proceeding

Pursuant to section 6(b)(3) of the Act, an opportunity to submit oral
testimony concerning the issues raised by the proposed standard will be
provided at an informal public hearing scheduled to begin at 10:00 A.M.
on July 20, 1993, in Washington, DC in the auditorium of the Frances
Perkins Building, U.S. Department of Labor, 200 Constitution Avenue, NW,
Washington, DC, 20210

Notice of Intention to Appear

All persons desiring to participate at the hearings must file in
quadruplicate a Notice of Intention to Appear, postmarked on or before
June 7, 1993, addressed to Mr. Tom Hall, OSHA Division of Consumer
Affairs, Docket No. H-044, Room N-3649, U.S. Department of Labor, 200
Constitution Avenue N.W., Washington, D.C. 20210; telephone (202)
219-8615. The Notice of Intention to Appear also may be transmitted by
facsimile to (202) 219-5046, provided the original and 3 copies of the
Notice are sent to the above address thereafter

The Notices of Intention to Appear, which will be available for
inspection and copying at the OSHA Docket Office (Room N-2625),
telephone (202) 219-7894, must contain the following information:

\(1\) The name, address, and telephone number of each person to appear;
(2) The capacity in which the person will appear;

\(3\) The approximate amount of time requested for the presentation; (4)
The specific issues that will be addressed;

\(5\) A detailed statement of the position that will be taken with
respect to each issue addressed; and

\(6\) Whether the party intends to submit documentary evidence, and if
so, a brief summary of that evidence

Filing of Testimony and Evidence Before Hearings

Any party requesting more than 10 minutes for a presentation at the
hearing, or who will submit documentary evidence, must provide in
quadruplicate the complete text of the testimony, including any
documentary evidence to be presented at the hearing to the OSHA Division
of Consumer Affairs. This material must be postmarked by June 28, 1993,
and will be available for inspection and copying at the OSHA Docket
Office. Each such submission will be reviewed in light of the amount of
time requested in the Notice of Intention to Appear. In those instances
where the information contained in the submission does not justify the
amount of time requested, a more appropriate amount of time will be
allocated and the participant will be notified of that fact

Any party who has not substantially complied with this requirement may
be limited to a 10-minute presentation. Any party who has not filed a
Notice of Intention to Appear may be allowed to testify, as time
permits, at the discretion of the Administrative Law Judge

OSHA emphasizes that the hearing is open to the public, and that
interested persons are welcome to attend. However, only persons who have
filed proper notices of intention to appear will be entitled to ask
questions and otherwise participate fully in the proceeding

Conduct and Nature of Hearings

The hearings will commence at 10:00 a.m. on July 20, 1993. At that time
any procedural matters relating to the proceeding will be resolved

The nature of an informal hearing is established in the legislative
history of section 6 of the Act and is reflected by the OSHA hearing
regulations (see 29 CFR 1911.15 (a)). Although the presiding officer is
an Administrative Law Judge and questioning by interested persons is
allowed on crucial issues, the proceeding shall remain informal and
legislative in type. The essential intent is to provide an opportunity
for effective oral presentations which can proceed expeditiously, in the
absence of rigid procedures which impede or protract the rulemaking
process

Additionally, since the hearing is primarily for information gathering
and clarification, it is an informal administrative proceeding, rather
than an adjudicative one. The technical rules of evidence, for example,
do not apply. The regulations that govern hearings and the pre-hearing
guidelines to be issued for this hearing will ensure fairness and due
process and also facilitate the development of a clear, accurate and
complete record. Those rules and guidelines will be interpreted in a
manner that furthers that development. Thus, questions of relevance,
procedure and participation generally will be decided so as to favor
development of the record

The hearing will be conducted in accordance with 29 CFR Part 1911. The
hearing will be presided over by an Administrative Law Judge who makes
no recommendation on the merits of OSHA\'s proposal. The responsibility
of the Administrative Law Judge is to ensure that the hearing proceeds
at a reasonable pace and in an orderly manner. The Administrative Law
Judge, therefore, will have all the powers necessary and appropriate to
conduct a full and fair informal hearing as provided in 29 CFR Part 1911
and the prehearing guidelines, including the powers:

> 1\. To regulate the course of the proceedings;
>
> 2\. To dispose of procedural requests, objections, and comparable
> matters;
>
> **\[page 15615\]**
>
> 3\. To confine the presentation to the matters pertinent to the issues
> raised;
>
> 4\. To regulate the conduct of those present at the hearing by
> appropriate means;
>
> 5\. At the Judge\'s discretion, to question and permit the questioning
> of any witness and to limit the time for questioning; and
>
> 6\. At the Judges\'s discretion, to keep the record open for a
> reasonable, stated time to written information and additional data,
> views and arguments from any person who has participated in the oral
> proceeding

Certification of Record and Final Determination After Hearing

Following the close of the posthearing comment period, the presiding
Administrative Law Judge will certify the record to the Assistant
Secretary of Labor for Occupational Safety and Health. The
Administrative Law Judge does not make or recommend any decisions as to
the content of the final standard

The proposed standard will be reviewed in light of all testimony and
written submissions received as part of the record, and a standard will
be issued based on the entire record of the proceeding, including the
written comments and data received from the public

List of Subjects in 29 CFR Pat 1910

Chemicals, 2-Ethoxyethanol, 2-Ethoxyethanol Acetate, Glycol Ethers,
2-Methoxyethanol, 2-Methoxyethanol Acetate, Occupational Safety and
Health, Reproductive and Developmental Toxicity

XIII\. Authority and Signature

This document was prepared under the direction of David C. Zeigler,
Acting Assistant Secretary of Labor, 200 Constitution Avenue, N.W.,
Washington, D.C., 20210

It is issued under sections 4, 6, and 8 of the Occupational Safety and
Health Act of 1970 (29 U.S.C. 653, 655, 657),Secretary of Labor\'s Order
1-90 (55 FR 9033) and 29 CFR Part 1911

Signed at Washington, D.C., this 9th day of March, 1993

David C. Zeigler Acting Assistant Secretary of Labor

XIV\. The Proposed Standard

Part 1910 - \[AMENDED\]

Part 1910 of title 29 of the Code of Federal Regulation is hereby
proposed to be amended as follows: Subpart B - \[AMENDED\]

1\. The authority citation for subpart B of 29 CFR part 1910 continues
to read as follows:

Authority: Secs. 4, 6, and 8 of the Occupational Safety and Health Act,
29 U.S.C. 653, 655, 657; Walsh-Healy Act, 41 U.S.C. 35 et seq; Service
Contract Act of 1965, 41 U.S.C. 351 et seq; sec. 107, Contract Work
Hours and Safety Standards Acts (Construction Safety Act), 40 U.S.C.
333; sec 41, Longshoremen\'s and Harbor Worker\'s Compensation Act, 33
U.S.C. 941; National Foundation of Arts and Humanities Act, 20 U.S.C.
951 et seq., Secretary of Labor\'s Order No., 12-71 (36 FR 8754); 8-76
(41 FR 25059), or 9-83 (48 FR 35736), as applicable; and 29 CFR Part
1911

Sections 1910.16 and 1910.19 also issued under 29 CFR Part 1911

2\. A new paragraph (n) is proposed to be added to 1910.19 to read as
follows:

1910.19 special provisions for air contaminants. (n) Glycol ethers.
Section 1910.1031 shall apply to the exposure of every employee to
glycol ethers, as defined in section 1910.1031, in every employment and
place of employment covered by 1910.12, 1910.13, 1910.14, 1910.15,
1910.16, 1926 and 1928 in lieu of any different standard on exposures to
glycol ethers which would otherwise be applicable by virtue of those
sections

Subpart Z - \[AMENDED\]

3\. The authority citation for Subpart Z of Part 1910 continues to read
as follows:

Authority: Secs. 6, 8 Occupational Safety and Health Act, 29 U.S.C. 655,
657: Secretary of Labor\'s Order 12-71 (36 FR 8754), 9-76 (41 FR 25059),
9-83 (48 FR 35736) or 1-90 (55 FR 9033), as applicable; and 29 CFR Part
1911

All of subpart Z issued under section 6(b) of the Occupational Safety
and Health Act, listed in the Final Rule Limits columns of Table Z-1-A,
which have identical limits listed in the Transitional Limits columns of
Table Z-1-A, Z-2 or Table Z-3. The latter were issued under section 6(a)
(29 U.S.C. 655 (a))

Section 1910.1000, the Transitional Limits columns of Table Z-1-A, Table
Z-2 and TableZ-3 not issued under 5 U.S.C. 553

1910.1000, the Transitional limits columns of Table Z-1-A. Table Z-2 and
Table Z-3 not issued under 29 CFR part 1911 except for the arsenic,
benzene, cotton dust, and formaldehyde listings

Section 1910.1001 also issued under sec. 107 of Contract Work Hours and
Safety Standards Act, 40 U.S.C. 333

Section 1910.1002 not issued under 29 U.S.C. 655 or 29 CFR part 1911;
also issued under 5 U.S.C. 553

Sections 1910.1003 through 1910.1018 also issued under 29 CFR U.S.C. 653

Section 1910.1025 also issued under 29 U.S.C. 653 and 5 U.S.C. 553.
Section 1910.1028 also issued under 29 U.S.C. 653. Section 1910.1043
also issued under 5 U.S.C. 551 et seq. Sections 1910.1045 and 1910.1047
also issued under 29 U.S.C. 653. Section 1910.1048 also issued under 29
U.S.C. 653

Sections 1910.1200, 1910.1499 and 1910.1500 also issued under 5 U.S.C.
553

Section 1910.1450 is also issued under sec. 6(b), 8(c) and 8(g)(2), Pub.
L. 91-596, 84 Stat. 1593, 1599, 1600; 29 U.S.C. 655, 657. 1910.1000
\[AMENDED\]

4\. The entries \"2-Ethoxyethanol \* \* \* 110-80-5) \* \* \* 200 ppm \*
\* \* 740 mg/m3, \"2-Ethoxyethyl acetate (Cellosolve Acetate) \* \*
\*111-15-9 \* \* \* 100 ppm \* \* \* 540 mg/m3, \"2- Methoxyethanol; see
Methyl Cellosolve\", \"Methyl Cellosolve (2- Methoxyethanol) \* \* \*
109-86-4 \* \* \* 25 ppm \* \* \* 80 mg/m3\" and \"Methyl Cellosolve
Acetate (2-Methoxyethyl Aceate) \* \* \* 110- 49-6 25 ppm \* \* \* 120
mg/m3 \" are proposed to be deleted from Table Z-1-A of 1910.1000

5\. A new 1910.1031 and Appendices A, B, C, D, E and F to the section
are proposed to be added to subpart Z to read as follows:

1910.1031 - Glycol ethers

\(a\) Scope and application - (1) This section applies to all
occupational exposures to 2-Methoxyethanol (2-ME), 2-Methoxyethanol
Acetate (2-MEA), 2-Ethoxyethanol (2-EE) and 2-Ethoxyethanol Acetate
(2-EEA) Chemical Abstracts Service Registry Nos. 109-86-4, 110-49-6,
110-80-5 and 111-15-9, respectively, except as provided for in paragraph
(a)(2) of this section. (2) This section does not apply to:

\(i\) Work operations where the only exposure to 2-ME, 2-MEA, 2-EE, or
2-EEA is from liquid mixtures containing less than 1% 2-ME, 2-MEA, 2-EE
or 2-EEA, respectively, by volume, unless the employer has reason to
believe that such mixtures could release vapors in quantities sufficient
to result in an airborne concentration which meets or exceeds the action
levels or exceeds the excursion limits for these compounds or could
present a hazard through dermal contact

\(ii\) Work operations using solid materials made from or containing
2-ME, 2-MEA, 2-EE or 2-EEA that are incapable of releasing 2-ME, 2-MEA,
2-EE or 2-EEA to the workplace air in concentrations at or above the AL
or above the EL

\(b\) Definitions. For purposes of this standard, the following
definitions shall apply:

Action Level (AL) means airborne concentrations of 0.05 ppm (2-ME or
2-MEA) and 0.25 ppm (2-EE or 2-EEA) calculated as an 8-hour
time-weighted average (TWA)

Assistant Secretary means the Assistant Secretary of Labor for

**\[page 15616\]**

Occupational Safety and Health, U.S. Department of Labor, or designee

Authorized person means any person specifically authorized by the
employer whose duties require the person to enter a regulated area, or
any person entering such an area as a designated representative of
employees for the purpose of exercising the right to observe monitoring
and measuring procedures under paragraph (d) of this section, or any
other person authorized by the Act or regulations issued under the Act

Director means the Director of the National Institute for Occupational
Safety and Health, U.S. Department of Health and Human Services, or
designee

Emergency means any occurrence such as, but not limited to, equipment
failure, rupture of containers, or failure of control equipment which
may or does result in an unexpected significant release of glycol ethers

Employee exposure means the exposure to airborne or liquid glycol ethers
which would occur if the employee were not using respiratory protective
equipment or other personal protective equipment

Ethylene glycol ethers, for the purposes of this section, means
2-Methoxyethanol (2-ME)(CAS No. 109-86-4), 2-Methoxyethanol acetate
(2-MEA)(CAS No. 110-49-6), 2-Ethoxyethanol (2-EE)(CAS No. 110-80-5) and
2-Ethoxyethanol acetate (2-EEA)(CAS No. 111-15-9). Glycol ethers is
defined the same as \"Ethylene glycol ethers\"

above

Objective Data means information which can be used to reliably calculate
the anticipated airborne concentration of a compound in a work area.
Such information may include, but is not limited to, physical properties
of the compound, room dimensions, air exchange rates, information on
work practices, historical data on employee exposures, and employee
proximity to emissions sources

Regulated area means any area where airborne concentrations of glycol
ethers exceed or can reasonably be expected to exceed the permissible
exposure limits (PELs), either the 8-hour time weighted average (TWA)
limits of 0.1 ppm (2-ME, 2-MEA) and 0.5 ppm (2-EE, 2-EEA) or as the
15-minute excursion limits (ELs) of 0.5 ppm (2-ME, 2-MEA) and 2.5 ppm
(2-EE, 2-EEA)

\(c\) Permissible exposure limits (PELs) - (1) Eight-Hour Time Weighted
Average (TWA) The employer shall assure that no employee is exposed to
an airborne concentration of glycol ethers which exceeds 0.1 ppm for
2-ME and 2-MEA or 0.5 ppm for 2-EE and 2-EEA, calculated as an 8-hour
time-weighted average (TWA)

\(2\) Excursion Limit (EL) The employer shall assure that no employee is
exposed to an airborne concentration of glycol ethers in excess of 0.5
ppm for 2-ME and 2-MEA or 2.5 ppm for 2-EE and 2-EEA, averaged over a
sampling period of 15 minutes. Monitoring for EL is to be conducted
during the period in which the employee would be expected to receive
his/her highest level of exposure

\(3\) Dermal Exposure The employer shall assure that no employee is
exposed to glycol ethers through dermal contact

\(d\) Exposure monitoring - (1) General - (i) Except as provided by
paragraph (d)(1)(v) of this section, each employer who has a workplace
or work operation covered by this section shall accurately determine the
level of employee exposure to glycol ethers

\(ii\) Determinations of employee exposure shall be made from personal
breathing zone air samples that accurately reflect each employee\'s
average exposures to airborne glycol ethers over an 8-hour period (AL
and TWA) and over a 15-minute period at operations where there is reason
to believe that exposures may be above the excursion limit (EL)

\(iii\) The employer shall determine 8-hour TWA employee exposures for
each employee in each job classification in each work area during each
shift. At operations where there is reason to believe that exposures may
be above the excursion limit (EL), the employer shall determine the EL
employee exposures for each job classification in each work area during
each shift

\(iv\) Except for initial monitoring required in paragraphs (d)(2)(i)
and (d)(2)(ii) of this section, the employer may develop a
representative sampling strategy that sufficiently monitors exposure
levels within each job classification or for each job task, for each
workshift, in each work area to correctly characterize and not
underestimate the exposure of any employee within each exposure group.
In representative sampling, the employer shall sample those employees
expected to have the highest exposures. Exposure levels shall be
determined for each employee in each job classification in each work
area for each shift unless the employer can document that exposure
levels for a given job classification are equivalent for different work
shifts

\(v\) Where the employer has objective data, as defined in paragraph (b)
of this section, showing the presence of glycol ethers in the workplace
or products containing glycol ethers cannot result in the release of
airborne concentrations of glycol ethers that would cause any employee
to be exposed at or above the AL or above the EL, under worst-case
release conditions of foreseeable use, the employer may rely upon such
data and is not required to monitor employee exposure levels to glycol
ethers

\(2\) Initial Monitoring. (i) Except as provided in paragraphs (d)(1)(v)
or (d)(2)(ii) of this section, each employer shall identify all
employees who, without regard to respirator use, are exposed or may
reasonably be anticipated to be exposed, at or above the AL or above the
EL and shall perform initial monitoring to accurately determine the
exposure of all employees so identified

\(ii\) Where the employer has monitored an employee who is at or above
the AL and/or above the EL after \[180 days prior to Effective Date\]
and the monitoring occurred under conditions closely resembling those
currently prevailing and that monitoring satisfies all other
requirements of this section, the employer may rely on such monitoring
results to satisfy the requirements of paragraph (d)(2)(i) of this
section with respect to the employee monitored

\(3\) Periodic monitoring. (i) The employer shall periodically measure
and accurately determine exposure to glycol ethers for employees shown
by the initial or other monitoring to be exposed at or above the action
level (AL) or above the EL

\(ii\) If the initial or periodic monitoring results reveal employee
exposure to be at or above the AL but at or below the TWA, the employer
shall monitor these employees at least every 6 months

\(iii\) If the initial or periodic monitoring results reveal employee
exposure above the TWA, the employer shall monitor these employees at
least every 3 months

\(iv\) If the initial or periodic monitoring results reveal employee
exposure above the EL, the employer shall monitor these employees at
least every 3 months under conditions of highest exposure

\(4\) Additional monitoring. The employer shall also institute the
exposure monitoring required under paragraphs (d)(2)(i) and (d)(3) of
this section each time there is a change in production, equipment, raw
materials, process, personnel, or work practices that may result in new
or additional exposure to glycol ethers at or above the ALs or above the
ELs, or whenever the employer has any other reason to

**\[page 15617\]**

suspect that a change may result in new or additional exposures at or
above the ALs or above the ELs

\(5\) Termination of Monitoring. (i) If the initial monitoring reveals
employee exposure to be below the ALs and at or below the ELs, the
employer may discontinue monitoring for that employee, except as noted
otherwise in paragraph (d)(4) of this section

\(ii\) If the periodic monitoring indicates that employee exposures are
below the ALs and at or below the ELs and that result is confirmed by
the results of another monitoring taken at least 7 days later, the
employer may discontinue the monitoring for those employees whose
exposures are represented by such monitoring. The results must be
statistically representative and consistent with the employer\'s
knowledge of the job and work operation

\(iii\) If initial or periodic monitoring reveals employee exposure at
or above the AL, but on two consecutive measurements taken at least
seven days apart, the employee exposure is not above the EL, no further
monitoring for the EL is necessary except as required by paragraph
(d)(4) of this section

\(6\) Accuracy of measurement. The employer shall use a method of
monitoring and analysis that shall be accurate, (to a 95 percent
confidence level), to within plus or minus 25 percent for airborne
concentrations of glycol ethers at or above the level being investigated

\(7\) Employee notification of monitoring results. (i) Within 15 working
days of receiving the results of exposure monitoring conducted under
this section, the employer shall notify each affected employee,
individually, of these results in writing. In addition, within the same
period, the employer shall post the results in an appropriate location
that is accessible to affected employees

\(ii\) Whenever monitoring results indicate that employee exposure is
over the TWA and/or EL permissible exposure limits, the employer shall
include in the written notice a statement that the TWA and/or EL has
been exceeded and a description of the corrective action being taken by
the employer to decrease the exposure to within the permissible exposure
limits

\(8\) Observation of monitoring. (i) The employer shall provide affected
employees or their designated representative an opportunity to observe
any monitoring of employee exposure to glycol ethers required by this
section

\(ii\) When observation of the monitoring of employee exposure to glycol
ethers requires entry into an area where the use of protective clothing
or equipment is required, the employer shall provide and require the
observer to use such clothing and equipment and shall assure that the
observer complies with all other applicable safety and health procedures

\(e\) Regulated areas. (1) The employer shall establish regulated areas
wherever exposures to glycol ethers exceed or can be expected to exceed
either the TWA or EL permissible exposure limits prescribed in paragraph
(c) of this section

\(i\) These areas shall be demarcated from the rest of the workplace in
any manner that adequately establishes and alerts employees to the
boundary of the regulated area

\(ii\) Regulated areas shall be posted at all entrances and accessways
with signs as specified in paragraph (m)(1)(i) of this section

\(2\) The employer shall limit access to regulated areas to authorized
persons

\(3\) Whenever an employer at a multi-employer worksite establishes a
regulated area, that employer shall communicate the location and
restrictions of access to the regulated area to other employers with
work operations at that worksite

\(4\) The employer shall assure that each person entering a regulated
area is provided with and required to use appropriate personal
protective equipment, including respiratory protection selected in
accordance with paragraph (g)(3) of this section

\(f\) Methods of compliance - (1) Engineering controls and work
practices. Whenever any employee is exposed to glycol ethers above
either the TWA or EL permissible exposure limits prescribed in paragraph
(c) of this section or may forseeably experience dermal exposure to
glycol ethers, the employer shall institute engineering and work
practice controls to reduce and maintain employee exposures to glycol
ethers at or below the TWAs and the ELs and to eliminate dermal exposure
to glycol ethers, except to the extent that the employer can establish
that these controls are not feasible or where the provisions of
paragraph (g) of this section apply

\(2\) Whenever feasible engineering and work practice controls which can
be instituted are not sufficient to reduce employee exposure to or below
the TWA and/or EL permissible exposure limits or eliminate foreseeable
dermal exposure , the employer shall implement them to reduce employee
exposures to the lowest levels achievable and shall supplement such
controls with personal protective equipment and/or respiratory
protection that complies with the requirements of paragraph (g) of this
section

\(3\) Engineering controls shall be inspected and maintained or replaced
to ensure their effectiveness

\(4\) The employer shall permit employees to leave the work area
immediately or as soon as feasible to wash skin areas which have had
contact with glycol ethers

\(5\) Compliance program . (i) Where the TWAs and/or ELs are exceeded or
dermal exposure exists, the employer shall establish and implement a
written compliance program to reduce employee exposure to or below the
TWA and/or EL permissible exposure limits and eliminate dermal exposure
by means of engineering and work practice controls, as required by
paragraph (f) of this section. To the extent that engineering and work
practice controls cannot reduce exposures to or below the TWAs and/or
ELs and/or eliminate dermal exposure, the employer shall include in the
written compliance program the use of appropriate respiratory protection
and/or personal protective equipment to achieve compliance. The
compliance program shall include the written plan for emergency
situations prescribed in paragraph (k) of this section

\(ii\) The written compliance programs shall be reviewed and updated at
least annually, or more often if necessary, to reflect significant
changes in the employer\'s compliance status

\(iii\) Written compliance programs shall be submitted upon request for
examination and copying to affected employees, authorized employee
representatives, the Assistant Secretary, and the Director

\(g\) Respiratory protection - (1) General. Where respiratory protection
is required by this section, the employer shall provide it at no cost to
the employee and shall assure its proper use, in compliance with the
requirements of this paragraph, to reduce employee exposures to or below
the TWA and/or EL permissible exposure limits. Respiratory protection
shall be used in the following circumstances:

\(i\) During the interval necessary to install or implement feasible
engineering and work practice controls;

\(ii\) In work operations, such as maintenance and repair activities and
during brief or intermittent operations, for which the employer
establishes that engineering and work practice controls are not
feasible;

\(iii\) In work situations where the employer has implemented all
feasible engineering and work practice controls and such controls are
not sufficient to

**\[page 15618\]**

reduce exposure to or below the TWA and/or EL permissible exposure
limits, and;

\(iv\) In emergencies.

\(2\) Assignment of respiratory protection. No employee shall be
assigned tasks requiring the use of respiratory protection if, based
upon his or her most recent medical examination, an examining physician
determines that the employee will be unable to function normally while
wearing a respirator. Such employee shall be given the opportunity to
transfer to a position where no respirator use is required. That
position shall be with the same employer, in the same geographical area,
and with the same seniority status and rate of pay the employee had just
prior to such transfer, if such a position is available

\(3\) Respirator selection. Where respiratory protection is required
under this standard, the employer shall select and provide the
appropriate respirator as specified in Table 1. The employer shall
select respirators from among those approved by the Mine Safety and
Health Administration (MSHA) and by the National Institute for
Occupational Safety and Health (NIOSH) under the provisions of 30 CFR
Part 11 or any future revisions

Table 1-1. MINIMUM REQUIREMENTS FOR RESPIRATORY PROTECTION AGAINST 2-EE,
2-EEA, 2-ME, and 2-MEA.2

  ------------------------------- ---------------------------------------
  Condition of use                Minimum required

  or glycol ether                 

  concentration                   respirator

  (ppm 2-EE/2-EEA)                

  (ppm 2-ME/2-MEA)                

  Up to 10X the PEL               Supplied air half-mask respirator

     (1 ppm)                      in negative pressure (demand)

     (5 ppm)                      mode1

  Up to 25X the PEL               Supplied air respirator with hood

   (2.5 ppm)                      or helmet in continuous flow mode

   (12.5 ppm)                     

  Up to 50X the PEL               Supplied air half-mask in

     (2 ppm)                      continuous flow mode1

     (25 ppm)                     

                                  Supplied air full facepiece in

                                  negative pressure (demand) mode

                                  SCBA full facepiece in negative

                                  pressure (demand) mode

  Up to 250X the PEL              Supplied air full facepiece in

     (25 ppm)                     continuous flow mode

     (125 ppm)                    

  Up to 1000X the PEL             Supplied air half-mask or full

     (100 ppm)                    facepiece in pressure demand mode1

     (500 ppm)                    

  Greater then 1000X              SCBA in pressure demand mode

  the PEL                         

     (\>100 ppm)                  Supplied air full facepiece in

     (\>500 ppm)                  pressure demand mode in

                                  combination with auxiliary

                                  self-contained air supply

  Firefighting                    SCBA in pressure demand mode
  ------------------------------- ---------------------------------------

1 Full face piece is required when eye irritation is experienced

2 Respirators assigned for high environmental concentrations may be used
for lower environmental concentrations

\(4\) Respirator program. Where respirator use is required by this
standard, the employer shall institute a respiratory protection program
in accordance with 29 CFR 1910.134 (b), (d), (e), and (f)

\(5\) Respirator use. Employers shall permit employees to leave the work
area to wash their faces and respirator facepieces as needed to prevent
skin irritation from respirator use

\(6\) Respirator fit testing. (i) The employer shall assure that the
respirator issued to the employee exhibits the least possible facepiece
leakage and that the respirator is fitted properly and will not permit
the employee to inhale glycol ethers in excess of either the TWAs or ELs

\(ii\) For each employee wearing a tight-fitting supplied-air
respirator, employers shall perform either a quantitative or qualitative
face fit test of the facepiece while it is equipped with appropriate air
purifying elements. When quantitative fit testing is performed, half
mask facepieces must exhibit a fit factor of 100 and full facepieces a
fit factor of 500, at a minimum

\(iii\) The employer shall perform and certify the results of the
appropriate fit tests at the time of initial fitting, at least annually
thereafter, when a different make or size respirator is used, and when a
change in facial structure occurs

\(iv\) Fit testing shall be performed at a reasonable time and place and
at no cost to the employee and shall be conducted in accordance with
Appendix F of this section

\(h\) Personal protective equipment - (1) Provision and use. The
employer shall select and provide appropriate personal protective
equipment, including clothing and eye protection, in accordance with 29
CFR 1910.132 and 29 CFR 1910.133

\(i\) The employer shall select the appropriate personal protective
equipment based upon the type of exposure anticipated, conditions of
use, and the hazard to be prevented

\(ii\) The employer shall provide the appropriate personal protective
equipment at no cost to the employee and assure that employees use this
equipment

\(iii\) Personal protective equipment, such as, but not limited to,
coveralls, gloves, faceshields, and rubber boots, shall be made of
materials sufficiently impervious to glycol ethers to prevent employee
exposure to these compounds

\(iv\) The employer shall provide uncontaminated personal protective
equipment as often as necessary and at least weekly to prevent employee
exposure to glycol ethers

\(2\) Removal and storage. (i) The employer shall assure that employees
remove all personal protective equipment contaminated with glycol ethers
prior to leaving the work area or as soon as feasible if the potential
for soakthrough/breakthrough exists. This shall be done in an area which
minimizes exposure of other employees

\(ii\) The employer shall assure that no employee takes home personal
protective equipment contaminated with glycol ethers

\(iii\) The employer shall assure that no employee takes personal
protective equipment contaminated with glycol ethers out of the
workplace unless authorized to do so for the purposes of laundering,
cleaning, maintenance, or disposal

\(iv\) The employer shall assure that personal protective equipment
contaminated with glycol ethers shall be stored in a manner so as to
minimize employee exposure and not be worn again until cleaned or
laundered

\(v\) The employer shall assure that storage areas and containers with
glycol ethers-contaminated personal protective equipment shall have a
sign or label, respectively, as specified in paragraph (m)(1)(ii) of
this section

\(3\) Cleaning, replacement, and disposal. (i) The employer shall clean,
launder, repair, and replace, at no cost to the employee, all required
personal protective equipment for each affected employee as necessary to
assure its effectiveness and shall be responsible for the disposal of
these items

\(ii\) The employer shall assure that only trained persons remove
contaminated personal protective

**\[page 15619\]**

equipment from storage for the purpose of laundering, cleaning, repair,
or disposal

\(iii\) The employer shall inform any person who launders, cleans, or
repairs personal protective equipment contaminated by glycol ethers of
the potentially harmful effects of exposure to glycol ethers and of
procedures to safely handle the clothing and equipment

\(iv\) The employer shall assure that laundering, cleaning, maintenance,
and disposal are performed only at facilities which are appropriate to
handle glycol ethers contaminated personal protective equipment

\(v\) All contaminated personal protective equipment destined for
disposal shall be placed in a sealed container which is labeled in
accordance with paragraph (m)(1)(ii) of this standard

\(i\) Hygiene protection - (1) If employee\'s skin may become splashed
with liquids containing glycol ethers, except as provided by paragraph
(a)(2)(i) of this section, the employer shall provide conveniently
located quick drench showers and assure that affected employees use
these facilities immediately

\(2\) If there is any possibility that an employee\'s eyes may be
splashed with liquids containing glycol ethers, except as provided by
paragraph (a)(2)(i) of this section, the employer shall provide eye-wash
fountains within the immediate work area for emergency use

\(3\) Eating, drinking, smoking, and application of cosmetics is
prohibited in areas of glycol ethers exposure

\(4\) Personal protective equipment shall not be worn in lunch areas

\(j\) Housekeeping - (1) All surfaces (e.g. floors, working surfaces,
exterior surfaces of equipment) shall be kept free of glycol ethers to
the extent feasible

\(2\) The employer shall conduct a program to detect leaks and spills,
including visual inspections of operations involving liquids containing
glycol ethers

\(3\) Preventative maintenance of equipment, including surveys for
leaks, shall be undertaken at intervals appropriate to assure proper
functioning of the equipment

\(4\) In work areas where spillage may occur, the employer shall make
provisions to contain the spill, to decontaminate the work area, and to
dispose of waste

\(5\) The employer shall assure that all leaks are repaired and spills
are cleaned up as soon as possible by employees wearing suitable
protective equipment, which may include respiratory protection, and who
are trained in proper methods of cleanup and decontamination

\(6\) Waste and debris contaminated with glycol ethers shall be placed
for disposal in sealed containers bearing a label as specified in
paragraph (m)(1)(ii) of this section

\(k\) Emergencies - (1) The employer shall develop a written emergency
plan for each workplace or work operation covered by this section in
accordance with the requirements of 29 CFR 1910.38 (a). The provisions
of 29 CFR 1910.120 (q) remain in effect as applicable and an emergency
response plan meeting the requirements of 29 CFR 1910.120 (q) shall be
deemed to meet the requirements for an emergency response plan in this
paragraph

\(2\) All employees shall be thoroughly trained in their
responsibilities in the event of an emergency

\(3\) The employer shall assure that only designated personnel,
furnished with appropriate personal protective equipment which shall
include respiratory protection, and who are trained in re-entry
procedures shall correct the emergency conditions

\(4\) The employer shall assure that appropriate personal protective,
housekeeping, and other emergency equipment and supplies shall be
located in each area where an emergency could occur

\(5\) All employees, except those designated to correct the situation,
shall be evacuated from and normal operations shall be halted in the
area where the emergency occurred until the emergency has been abated

\(6\) The employer shall make provisions for immediate evacuation,
transportation, and medical assistance at a designated medical facility
for affected employees

\(l\) Medical surveillance - (1) General. (i) Employees covered. The
employer shall institute medical surveillance programs for all employees
who are or will be exposed to airborne concentrations of glycol ethers
at or above the action level or above the excursion level

\(ii\) Examination by a physician. The employer shall assure that all
medical examinations and procedures are performed by or under the
supervision of a licensed physician and are provided without cost to the
employee, without loss of pay, and at a reasonable time and place.
Persons who administer pulmonary function tests required by this
standard shall complete a training course in spirometry sponsored by an
appropriate governmental, academic or professional institution

\(2\) Initial examinations (i) Within 90 days of the effective date of
this standard or before the time of assignment, which ever comes later,
the employer shall provide each employee covered by paragraph (l)(1)(i)
of this section with a medical examination including at a minimum the
following elements:

\(A\) A medical and work history, including a reproductive history, with
emphasis on the hematologic system, skin, eyes and symptoms related to
pulmonary and mucous membrane irritation

\(B\) A physical examination with emphasis given to hematologic and
pulmonary system, mucous membranes, skin and eyes

\(C\) A complete blood count to include at a minimum a red cell count, a
white cell count, hemoglobin, and hematocrit

\(D\) Pulmonary function testing for employees who are or will be
wearing respiratory protection. As a minimum, these tests shall consist
of forced vital capacity (FVC), forced expiratory volume in one second
(FEV1), and forced expiratory flow (FEF)

\(E\) Any other test which the examining physician deems necessary

\(ii\) No initial medical examination is required to satisfy the
requirements of paragraph (l)(2)(i) of this section if adequate records
show that the employee has been examined in accordance with the
procedures of paragraph (l)(2)(i) of this section within twelve months
prior to the effective date of this standard. Results of tests meeting
such requirements shall be provided to the physician to complete the
written opinion

\(3\) Periodic examinations. (i) Periodic medical examinations shall be
made available at least annually

\(ii\) The scope of the medical examination shall be made in conformance
with the protocol established in paragraph (l)(2)(i) of this section

\(iii\) Where the results of the examination of the respiratory system
indicate abnormalities, or the employee experiences difficulty breathing
during the use of or fit testing for respirators, the physician will
further evaluate the employee\'s ability to wear a respirator

\(iv\) Anytime the employee develops signs and symptoms commonly
associated with toxic exposure to glycol ethers, or the employee desires
medical advice or tests concerning the effects of current or past
exposure to glycol ethers on the employee\'s ability to produce a
healthy child, the employer shall provide the employee with an
additional medical examination and/or a consultation which shall include
those

**\[page 15620\]**

elements considered appropriate by the examining physician

\(4\) Emergency Situations. In addition to medical surveillance required
in paragraphs (l)(1)-(l)(3) of this section, the employer shall make
medical examinations available as soon as possible to all employees who
may have been acutely exposed to glycol ethers in an emergency

\(5\) Information provided to the physician. The employer shall provide
the following information to the examining physician: (i) A copy of this
standard and appendices;

\(ii\) A description of the affected employee\'s former, current and
anticipated future duties as they relate to the employee\'s glycol
ethers exposure. (iii) The employee\'s former or current occupational
representative exposure level or anticipated exposure level;

\(iv\) A description of any personal protective equipment and
respiratory protection used or to be used by the employee; and

\(v\) Information from previous medical examinations of the affected
employee within the control of the employer

\(6\) Physician\'s written opinion. (i) The employer shall obtain a
written signed opinion from the examining physician. This written
opinion shall contain the results of the medical examination except that
it shall not reveal specific findings or diagnoses unrelated to
occupational exposure to glycol ethers. The written opinion shall
include:

\(A\) The physician\'s opinion as to whether the employee has any
medical condition that would place the employee at an increased risk of
material impairment of health from exposure to glycol ethers or from use
of a respirator

\(B\) The results of any testing or related evaluation concerning glycol
ethers exposure carried out as part of the examination

\(C\) The physician\'s opinion as to whether the employee is exhibiting
symptoms and/or signs from overexposure to glycol ethers

\(D\) The physician\'s opinion as to whether there is a need to
reevaluate the effectiveness of the respirator used by the employee

\(E\) Any recommended limitations on the employee\'s exposure to glycol
ethers or upon the use of personal protective equipment, including
respirators

\(F\) A statement that the employee has been informed by the physician
of any medical conditions which would be aggravated by exposure to
glycol ethers, whether these conditions may have resulted from past
glycol ethers exposure, and whether there is a need for further
evaluation or treatment

\(ii\) The employer shall provide a copy of the physician\'s written
opinion to the affected employee within 15 days of its receipt

\(m\) Communication of glycol ethers hazards to employees - (1) Signs.
The employer shall post signs at all entry and accessways to regulated
areas that appropriately warn of existing hazards and which bear, at a
minimum, the following legend:

DANGER

GLYCOL ETHERS\
\[Specific chemical name(s)\]

BLOOD AND REPRODUCTIVE HAZARD

EYE AND RESPIRATORY SYSTEM IRRITANT

AVOID INHALATION AND SKIN/EYE CONTACT

AUTHORIZED PERSONNEL ONLY

RESPIRATORY PROTECTION REQUIRED\
\[Any other appropriate warnings \-- e.g.,\
\"Flammable - No Smoking, Sparks, or Open Flame\"\]

\(2\) Labels. The employer shall assure that shipping and storage
containers containing glycol ethers or glycol ethers-contaminated
materials bear an appropriate warning label, which complies with the
requirements of the Hazard Communication Standard, 29 CFR 1910.1200 (f)
of the General Industry Standards. At a minimum, these labels shall
include the following legend:

DANGER

CONTAINS GLYCOL ETHERS\
\[Specific chemical name(s)\]

BLOOD AND REPRODUCTIVE HAZARD

EYE AND RESPIRATORY SYSTEM IRRITANT

AVOID INHALATION AND SKIN/EYE CONTACT

\[Any other appropriate warnings \--\
e.g. \"Flammable - Keep away from heat,\
sparks, and open flame \"\]

\(3\) Material safety data sheets. Employers who are manufacturers or
importers of glycol ethers or glycol ethers-containing compounds shall
comply with the requirements regarding development, updating, and
distribution of material safety data sheets specified in 29 CFR
1910.1200(g) of OSHA\'s Hazard Communication Standard. All employers
with employees potentially exposed to glycol ethers shall maintain
material safety data sheets and provide their employees with access to
them, in accordance with the requirements of 29 CFR 1910.1200(g)

\(4\) Employee information and training. (i) Employers who have a
workplace or work operation covered by this section shall provide
employees who are potentially exposed to glycol ethers with information
and training in accordance with the requirements of the Hazard
Communication Standard, 29 CFR 1910.1200(h) of the General Industry
Standards

\(ii\) The employer shall institute a training program for all employees
who are potentially exposed to glycol ethers, assure each employee\'s
participation in the program, maintain a record of this participation,
and maintain a record of the contents of such program

\(iii\) Training shall be provided, at no cost to the employee, prior to
or at the time of initial assignment to a job involving potential
exposure to glycol ethers, at least annually thereafter, and whenever a
new hazard from glycol ethers is introduced into their work area

\(iv\) The employer shall conduct the training program in a manner that
the employee is able to understand. The employer shall assure that each
employee is informed of at least the following:

\(A\) The health hazards associated with glycol ethers exposure with
special attention to the information in Appendix A of this section;

\(B\) The quantity, location, manner of use, release, and storage of
glycol ethers at the worksite and the specific nature of operations that
could result in exposure to glycol ethers, especially exposures above
the TWAs or ELs;

\(C\) An explanation of the importance of engineering and work practice
controls for employee protection and necessary instruction in the use of
these controls;

\(D\) The measures employees can take to protect themselves from
exposure to glycol ethers, such as diligent personal hygiene and proper
use of personal protective equipment, and specific procedures the
employer has implemented to protect employees against exposure,
including appropriate work practices, emergency procedures, and personal
protective equipment

\(E\) The details of the hazard communication program developed by the
employer, including an explanation of the signs, labeling system, and
material safety data sheets and how employees can obtain and use the
appropriate hazard information;

\(F\) The purpose, proper selection, fitting, proper use, and
limitations of respiratory protection and personal protective clothing
and eyewear;

\(G\) The purpose and description of the medical surveillance program

**\[page 15621\]**

required by paragraph (l) of this section including the right of any
employee exposed to glycol ethers at or above the AL or above the EL to
obtain:

\(1\) Medical examinations as required by paragraph (l) of this section
at no cost to the employee;

\(2\) The employee\'s medical records required to be maintained by
paragraph (n)(2) of this section;

\(3\) All air monitoring results representing the employee\'s exposure
to glycol ethers and required to be kept by paragraph (n)(1) of this
section

\(H\) A copy of this standard and its appendices with a discussion of
its contents;

\(I\) Instructions for the handling of spills and cleanup procedures;

\(J\) A review of emergency procedures including the specific duties or
assignments of each employee in the event of an emergency;

\(n\) Recordkeeping - (1) Exposure measurements. (i) The employer shall
establish and maintain an accurate record of all measurements required
by paragraph (d) of this section, in accordance with 29 CFR 1910.20.
(ii) This record shall include at least the following:

\(A\) The name, social security number, and job classification of the
employee(s) monitored and all other employees whose exposure the
measurement is intended to represent;

\(B\) The dates of monitoring, sample identification number, sampling
duration, time of day, and exposure monitoring results of each of the
samples taken, including a description of the procedure used to
determine representative employee exposures. Exposure monitoring results
shall be expressed, at a minimum, as either an 8-hour
time-weighted-average (TWA) or a 15- minute excursion limit (EL),
whichever is applicable; (C) The operation(s) covered by the monitoring;

\(D\) The sampling and analytical methods used and evidence of their
accuracy; (E) The type of respiratory protective devices worn, if any;

and

\(F\) Any other conditions that might have affected the employee
monitoring results

\(iii\) The employer shall maintain a record of the objective data
relied upon to support the determination that no employee is exposed to
glycol ethers at or above the action level or EL whenever the employer
has used objective data to determine that no monitoring is required
under this section

\(iv\) The employer shall maintain this record for at least the duration
of employment plus 30 years in accordance with 29 CFR 1910.20

\(2\) Medical surveillance. (i) The employer shall establish and
maintain an accurate record for each employee subject to medical
surveillance required by paragraph (l) of this section, in accordance
with 29 CFR 1910.20

\(ii\) This record shall include at least the following information: (A)
The name and social security number of the employee;

\(B\) The physician\'s written opinions from the initial, periodic and
additional examinations;

\(C\) Any employee medical complaints related to exposure to glycol
ethers

\(D\) A copy of the information provided by the employer to the
physician as required by paragraph (l)(5)(ii)-(l)(5)(v) of this section;

\(E\) A copy of the medical and reproductive histories, medical
questionnaire responses, and the results of any medical tests required
by the standard or mandated by the examining physician

\(iii\) The employer shall assure that this record is maintained for at
least the duration of employment plus 30 years, in accordance with 29
CFR 1910.20

\(3\) Training. The employer shall maintain all employee training
records for one(1) year beyond the last date of employment of that
employee

\(4\) Availability. (i) The employer shall assure that all records
required to be maintained by this section shall be made available upon
request to the Assistant Secretary and the Director for examination and
copying

\(ii\) The employer shall provide upon request for examination and
copying, all employee exposure monitoring records required to be
maintained by paragraph (n)(1) of this section to affected employees,
former employees, and designated representatives in accordance with 29
CFR 1910.20 (a)-(e) and (g)-(i)

\(iii\) The employer shall provide upon request for examination and
copying, all employee medical records required to be maintained by
paragraph (n)(2) of this section to the subject employee and to anyone
having the specific written consent of the subject employee in
accordance with 29 CFR 1910.20

\(5\) Transfer of records. If the employer ceases to do business, the
employer shall comply with the requirements involving transfer of
records set forth in 29 CFR 1910.20 (h)

\(o\) Dates - (1) Effective date. This section shall become effective
\[60 days after publication of the final rule\]. All obligations under
this section commence on the Effective Date (ED), except as follows:

\(2\) Start-up-dates (i) Exposure monitoring. Initial monitoring
required by paragraph (d) of this section shall be completed as soon as
possible and in any event not later than \[90 days after the Effective
Date of this section\]

\(ii\) Training. Training required by paragraph (m)(4) of this section
shall be completed as soon as possible and in any event not later than
\[90 days after the Effective Date of this section\]

\(iii\) Regulated areas. Regulated areas required to be established by
paragraph (e) of this section shall be set up as soon as possible after
the results of exposure monitoring are known and in any event not later
than \[120 days after the Effective Date of this section\]

\(iv\) Respiratory protection. Respiratory protection required by
paragraph (g) of this section shall be provided as soon as possible and
in any event not later than \[120 days after the Effective Date of this
section\]

\(v\) Medical surveillance. Medical surveillance required by paragraph
(l) of this section shall be completed as soon as possible or in any
event not later than \[120 days after the Effective Date of this
section\]

\(vi\) Emergency Plan. The emergency plan required by paragraph (k) of
this section shall be completed as soon as possible and in any event not
later than \[180 days after the Effective Date of this section\]

\(vii\) Compliance program. The written compliance program required by
paragraph (f)(5) of this section shall be completed and available for
inspection and copying as soon as possible and in any event not later
than \[1 year after the Effective Date of this section\]

\(viii\) Showers and eyewashes. Showers and eyewashes required by
paragraph (i) of this section shall be installed and usable as soon as
possible and in any event not later than \[1 year after the Effective
Date of this section\]

\(iv\) Methods of Compliance. Engineering controls required by this
standard shall be implemented as soon as possible, but no later than \[2
years after the Effective Date of this section\]. Work practices shall
be implemented as soon as possible. Work practice controls that are
directly related to engineering controls being installed in accordance
with the compliance plan shall be implemented as soon as these
engineering controls are functional

\(p\) Appendices. The information contained in Appendices A, B, C, D and

**\[page 15622\]**

E is not intended, by itself, to create any additional obligations not
otherwise imposed or to detract from existing regulations. The protocols
on respiratory fit testing in Appendix F are incorporated as part of
this section and are mandatory

APPENDIX A - Substance Safety Data Sheet for Glycol Ethers

I. Substance Identification

A. Substance: Glycol Ethers (2-Methoxyethanol,

> 2-Methoxyethanol acetate, 2-Ethoxyethanol and\
> 2-Ethoxyethanol acetate).

B. Permissible Exposure:

> 1\. Airborne:

A. 8-Hour Time Weighted Average (TWA-PEL):

> 2-ME: 0.1 ppm 2-MEA: 0.1 ppm\
> 2-EE: 0.5 ppm 2-EEA: 0.5 ppm

B. Excursion Limit (EL) 15 Minute:

> 2-ME: 0.5 ppm 2-MEA: O.5 ppm\
> 2-EE: 2.5 ppm 2-EEA: 2.5 ppm

2\. Dermal: Contact wiyh eyes or skin should be eliminated

II\. Health Hazard Data

A. Glycol ethers can affect your body if you inhale the vapor
(breathing), if it comes into contact with your eyes or skin, or if you
swallow it

B. Effects of over exposure:

1\. Short term exposure: Glycol ethers can cause eye and upper
respiratory tract irritation. In addition they can be mildly irritating
to skin. Ingestion of large doses of glycol ethers may cause vomiting or
lead to death. Systemic effects from short-term high exposures may
include lung, kidney and brain damage

2\. Long term exposure: Repeated or prolonged exposure to glycol ethers
may cause kidney, liver and lung damage as well as central nervous
system depression and anemia. Glycol ethers have also been shown to
cause testicular degeneration, reduced sperm counts, fetal with and
malformations, and adverse hematologic effects in several animal species

3\. Reporting Signs and Symptoms: You should inform your employer if you
develop any signs or symptoms and suspect they are caused by glycol
ethers

III\. Emergency First Aid Procedures

A. Eye exposure: If glycol ethers get into your eyes, wash immediately
with large amounts of water, lifting the lower and upper lids
occasionally. If irritation is present after washing, get medical
attention. Contact lenses should not be worn when working with glycol
ethers

B. Skin exposure: If glycol ethers get on the skin, promptly wash the
contaminated skin with water. If glycol ethers soak through your
clothing, remove the clothing and wash the skin with water. If
irritation persists after washing, get medical attention. Wash the
clothing thoroughly before reusing

C. Inhalation: If a person breaths in large amounts of glycol ethers,
move the exposed person to fresh air at once. If breathing has stopped
perform artificial respiration. Keep the affected person warm and at
rest. Get medical attention as soon as possible

D. Swallowing: When glycol ethers have been swallowed, get medical
attention immediately. If medical attention is not immediately
available, get the afflicted person to vomit by having him touch the
back of his throat with his finger or by giving him syrup of ipecac as
directed on the package. This non-prescription drug is available at most
drug stores and drug counters and should be kept with emergency medical
supplies in the workplace. Do not make an unconscious person vomit

E. Rescue: Move the effected person from the hazardous exposure. If the
exposed person has been overcome, notify someone else and put into
effect the established emergency rescue procedures. Do not become a
casualty. Understand the facility\'s emergency rescue procedures and
know the locations of rescue equipment before the need arises

IV\. Protective Clothing and Equipment

A. Respirators: Respirators are required for those operations in which
engineering controls or work practice controls are not feasible to
reduce exposure to the permissible level. If respirators are worn, they
must have joint Mine Safety and Health Administration and the National
Institute for Occupational Safety and Health (NIOSH) seal of approval.
For effective protection, respirators must fit the face and head snugly.
Respirators should not be loosened or removed in work situations where
their use is required. Glycol ethers do not have detectable odors except
at levels above permissible levels. Do not depend on odor to warn you
when a respirator is malfunctioning

If you experience difficulty breathing while wearing a respirator, tell
your employer. You must be thoroughly trained to use the assigned
respirator, and the training will be provided, at no cost to you, by
your employer

B. Protective Clothing: You must wear impervious clothing, gloves, face
shield, or other appropriate protective clothing to prevent skin contact
with liquid glycol ethers. Wherever protective clothing is required,
your employer is required to provide, at no cost, clean garments to you
as necessary to assure that the clothing protects you from dermal
exposure to glycol ethers

C. Eye Protection: You must wear splashproof goggles in areas where
liquid glycol ethers may contact your eyes. In addition, contact lenses
should not be worn in areas where eye contact with glycol ethers can
occur

V. Medical Requirements:

If you are will be exposed to glycol ethers at or above the action
level, \[0.05 ppm(2-ME/2-MEA) or 0.25 ppm (2-EE/2-EEA) as an 8-hour time
weighted average\], or above 0.5 ppm(2- ME/2-MEA) or 2.5 ppm(2-EE/2-EEA)
as a 15-minute excursion limit, your employer is required to provide a
medical examination and history and laboratory tests within 90 days of
the effective date of this standard or before the time of assignment to
an area at or above the action level or above the excursion limit, which
ever comes later and annually thereafter. These tests shall be provided
without cost to you. In addition, if you are accidentally exposed to
glycol ethers (either by ingestion, inhalation, or skin/eye contact)
under conditions known or suspected to constitute toxic exposure to
glycol ethers, your employer is required to make a medical examination
available to you

VI\. Observation of Monitoring

Your employer is required to make measurements that are representative
of your exposure to glycol ethers and you or your designated
representative are entitled to observe the steps taken in the
measurements procedure, and to record the results obtained. When the
monitoring procedure is in an area where respirators or personal
protective clothing must be worn you or your representative must also be
provided with, and must wear the protective clothing and equipment

VII\. Access to Records

You or your representative are entitled to see the records of
measurements of your exposure to glycol ethers upon written request to
your employer. Your medical examination records can be furnished to your
physician or designated representative upon request by you to your
employer

VIII\. Precautions for Safe Use, Handling and Storage

Glycol ether liquids are flammable. They should be stored in closed
containers in cool, well ventilated areas. Non sparking tools must be
used to open and close containers. Glycol ethers vapors may form
explosive mixtures in air. All sources of ignition must be controlled.
Fire extinguisher, where provided, must be readily available. Know where
they are located and how to operate them. Ask your supervisor where
glycol ethers are used in your work area and for additional plant safety
rules

APPENDIX B - Substance Technical Guidelines for Glycol Ethers

I. 2-Methoxyethanol

A. Physical and Chemical Data

> 1\. Substance Identification Chemical name: 2-Methoxyethanol Formula:
> CH3OCH2CH2OH Molecular Weight: 76 Chemical Abstracts Service (CAS)
> NO.: 109-86-4 Synonyms: Methyl Cellosolve; Ethylene glycol monomethyl
> ether; methyl oxitol; Ektasolve; Jeffersol EM
>
> 2\. Physical data Boiling point (760 mm Hg): 124.\*c Freezing point:
> -85.1\*c Specific Gravity (H20= 1 @ 20\*c): 0.9663 Vapor Pressure
> (20\*c): 6 mm Hg Vapor Density (air = 1 @ 20\*c): 2.6 Solubility in
> H20 (% by wt @ 20\*c): miscible in all proportions.
>
> **\[page 15623\]**
>
> Appearance and Odor: colorless liquid with a mild, pleasant odor

B. Fire, Explosion and Reactivity Data

> 1\. Fire
>
> Flammable limits in air (% by volume): Lower: 2.3 Upper: 24.5\
> Flash point: 39\*C (closed cup)\
> Extinguishing media: Dry chemical, alcohol foam, carbon dioxide\
> Fire and Explosion Hazards: Moderate fire hazard when exposed to heat
> or flame. Forms explosive peroxides in air. Vapors are heavier than
> air and may travel a considerable distance to source of ignition and
> flash back
>
> 2\. Reactivity
>
> Conditions contributing to instability: Heat Incompatibilities: Strong
> oxidizing agents, strong caustics\
> Hazardous decomposition products: Thermal decomposition products may
> include toxic oxides of carbon

C. Spill, Leak and Disposal Procedures

> 1\. Steps to be taken if the material is released or spilled. Remove
> all ignition sources and ventilate the area of spill or leak. Stop
> leak if you can do it without risk. Use water to reduce vapors. For
> small quantities, absorb on paper towels and evaporate in a safe place
> (such as a fume hood). Burn the paper in a suitable location away from
> combustible materials. Large quantities may be collected and atomized
> in a suitable combustion chamber.
>
> 2\. Disposal. 2-ME may be disposed of by atomizing in a suitable
> combustion chamber

II\. 2-Methoxyethanol acetate

A. Physical and Chemical Data

> 1\. Substance Identification\
> Chemical name: 2-Methoxyethanol acetate\
> Formula: CH3C00CH2CH2OCH3\
> Molecular Weight: 118.13\
> CAS No. 110-49-6\
> Synonyms: Methyl Cellosolve acetate, ethylene glycol monomethyl ether
> acetate,
>
> 2\. Physical data\
> Boiling point:: 144\*c\
> Freezing point: -70\*c\
> Specific Gravity (H20 = 1 @ 20\*c): 1.01\
> Vapor Pressure (20\*c): 2 mm Hg\
> Vapor Density (air = 1 @ 20\*c): 4.1\
> Solubility in H20 (% by wt @ 20\*c): completely miscible\
> Appearance and Odor: Colorless liquid with mild, ether-like odor

B. Fire, Explosion and Reactivity Data

> 1\. Fire\
> Flammable limits in air (% by volume): Lower: 1.7 Upper: 8.2\
> Flash point: 44\*c (closed cup)\
> Extinguishing media: Dry chemical, alcohol foam, carbon dioxide\
> Fire and Explosion Hazards: Moderate fire hazard when exposed to heat
> or flame. Forms explosive peroxides in air. Vapors are heavier than
> air and may travel a considerable distance to source of ignition and
> flash back
>
> 2\. Reactivity\
> Conditions contributing to instability: Heat Incompatibilities: Strong
> acids, strong alkalies, strong oxidizers\
> Hazardous decomposition products: Toxic vapors and gases (such as
> carbon monoxide).Thermal decomposition may release acrid smoke or
> irritating fumes

C. Spill Leak and Disposal Procedures

> 1\. Steps to be taken if the material is released or spilled. Remove
> all ignition sources and ventilate the area of spill or leak. Stop
> leak if you can do so without risk. Use water to reduce vapors. For
> small quantities, absorb on paper towels and evaporate in a safe place
> (such as a fume hood). Burn the paper in a suitable location away from
> combustible materials. Large quantities may be collected and atomized
> in a suitable combustion chamber
>
> 2\. Disposal. 2-MEA may be disposed of by absorbing it in vermiculite,
> dry sand, earth or a similar material and disposing it in a secured
> landfill or by atomizing in a suitable combustion chamber

III\. 2-Ethoxyethanol

A. Physical and Chemical Data

> 1\. Substance Identification\
> Chemical name: 2-Ethoxyethanol\
> Formula: C2H20CH2CH2OH\
> Molecular weight: 90.12\
> CAS N0. 110-80-5\
> Synonyms: Cellosolve, Ethylene glycol monoethyl ether
>
> 2\. Physical data\
> Boiling point: 135.6\*c\
> Freezing point: -70\*c\
> Specific Gravity (H20= 1@ 20\*c): .93\
> Vapor Pressure (20\*c): 4mm Hg\
> Vapor Density (air = 1 @ 20\*c): 3.0\
> Solubility in H2O (% by wt @ 20\*c): Miscible in all proportions\
> Appearance and Odor: Colorless liquid with sweetish odor

B. Fire, Explosion and Reactivity Data

> 1\. Fire\
> Flammable limits in air (% by volume): Lower: 1.7 Upper: 15.6\
> Flash point: 43\*c (closed cup)\
> Extinguishing media: Dry chemical, alcohol foam, carbon dioxide\
> Fire and Explosion Hazards: Moderate fire hazard when exposed to heat
> or flame. Vapor air mixtures are explosive above flash point. Forms
> explosive peroxides in air. Vapors are heavier than air and may travel
> a considerable distance to source of ignition and flash back
>
> 2\. Reactivity\
> Conditions contributing to instability: Elevated temperatures\
> Incompatibilities: Strong oxidizers, acid and alkalies\
> Hazardous decomposition products: Toxic vapors and gases (such as
> carbon monoxide)

C. Spill Leak and Disposal Procedures

> 1\. Steps to be taken if the material is released or spilled. Remove
> all ignition sources and ventilate the area of spill or leak. Stop
> leak if you can do so without risk. Use water to reduce vapors. For
> small quantities, absorb on paper towels and evaporate in a safe place
> (such as a fume hood). Burn the paper in a suitable location away from
> combustible materials. Large quantities may be collected and atomized
> in a suitable combustion chamber
>
> 2\. Disposal. 2-EE may be disposed of by absorbing it in vermiculite,
> dry sand, earth or a similar material and disposing it in a secured
> landfill or by atomizing in a suitable combustion chamber

IV\. 2-Ethoxyethanol acetate

A. Physical and Chemical Data

> 1\. Substance Identification\
> Chemical name: 2-Ethoxyethanol acetate\
> Formula: C2H5OCH2CH2OCOCH3\
> Molecular weight: 132.16\
> CAS No.: 111-15-9\
> Synonyms: Cellosolve acetate, ethylene glycol\
> monoethyl ether acetate
>
> 2\. Physical data\
> Boiling point: 156.4\*c\
> Freezing point: -62\*c\
> Specific Gravity (H20 = 1 @ 20\*c): .98\
> Vapor Pressure (20\*c): 2 mm Hg\
> Vapor Density (air = 1 @ 20\*c): 4.6\
> Solubility in H20 (% by wt @ 20\*c): 23\
> Appearance and Odor: Colorless viscous liquid with a\
> mild, non-residual odor

B. Fire, Explosion and Reactivity Data

> 1\. Fire\
> Flammable limits in air (% by volume): Lower: 1.7\
> Upper: 13\
> Flash point: 47\*c (closed cup)\
> Extinguishing media: Dry chemical, alcohol foam, carbon dioxide\
> Fire and Explosion Hazards: Moderate fire hazard when exposed to heat
> or flame. Vapor air mixtures are explosive above flash point. Forms
> explosive peroxides in air. Vapors are heavier than air and may travel
> a considerable distance to source of ignition and flash back
>
> 2\. Reactivity\
> Conditions contributing to instability: Heat\
> Incompatibilities: Nitrates, strong oxidizers, strong alkalies, strong
> acids\
> Hazardous decomposition products: Toxic vapors and gases (such as
> carbon dioxide). Thermal decomposition produces acrid smoke and/or
> irritating toxic fumes

C. Spill Leak and Disposal Procedures

> 1\. Steps to be taken if the material is released or spilled. Remove
> all ignition sources and ventilate the area of spill or leak. Stop
> leak if you can do it without risk. Use water to reduce vapors. For
> small quantities, absorb on paper towels and evaporate in a safe place
> (such as a fume hood). Burn the paper in a suitable location away from
> combustible materials. Large quantities may be collected and atomized
> in a suitable combustion chamber.
>
> **\[page 15624\]**
>
> 2\. Disposal. 2-EEA may be disposed of by absorbing it in vermiculite,
> dry sand, earth or a similar material and disposing it in a secured
> landfill or by atomizing in a suitable combustion chamber

APPENDIX C - Medical Surveillance Guidelines for Glycol Ethers

I. Toxicology

Studies of inhalation exposures to glycol ethers have shown that these
exposures produce adverse reproductive and developmental effects in
several animal species. The effects observed include testicular damage,
reduced fertility, maternal toxicity and developmental abnormalities of
the fetus. Data from experimental animals have also demonstrated that
exposure to glycol ethers may result in a variety of hematologic effects
including hemolysis, bone marrow depression and reduced red and white
blood cell counts. Adverse hematologic and testicular effects have also
been observed in humans exposed to glycol ethers. Among these effects
are testicular degeneration, reduced sperm count, anemia, lowered white
blood cell counts and bone marrow depression. In addition to inhalation
exposure, glycol ethers are also readily absorbed dermally and can also
be swallowed. Exposure to glycol ethers in liquid form or high air
concentrations may cause irritation of the eyes, nose and throat

Ingestion or large does may be fatal. Acute effects from overexposure
also include drowsiness, weakness and shaking

II\. Signs and Symptoms of Acute Overexposure

Glycol ethers are only mildly irritating to the skin. Vapor may cause
conjunctivitis and upper respiratory tract irritation. Temporary corneal
clouding may also result and may last several hours. Acetate derivatives
cause greater irritation than the parent compounds. Acute exposure may
also result in narcosis, pulmonary edema and severe kidney and liver
damage. Symptoms from repeated overexposure to vapors are fatigue and
lethargy, headache, nausea, anorexia, and tremor. Anemia and
encephalopathy have been reported with 2-ME. Acute poisoning by
ingestion resembles glycol ether toxicity, with death from renal failure

III\. Surveillance and Preventative Considerations

As noted above glycol ethers have been connected with adverse
reproductive, developmental and hematologic effects. The physician
should be aware of the findings of these studies in evaluating the
health of employers exposed to glycol ethers

It is also important for the physician to become familiar with the
operating conditions in which exposure to glycol ethers may occur.
Employees with skin diseases may not be able to tolerate the wearing of
whatever protective clothing may be necessary to protect them from
exposure. In addition, employees with chronic respiratory disease may
not be able to tolerate the wearing of respirators. The employer is
required to institute a medical surveillance program for all employees
who are or will be exposed above the action level or above the excursion
limit without regard to the use of respirators. The medical surveillance
program must provide each covered employee with an opportunity for
medical examination. All examinations and procedures must be performed
by or under the supervision of a licensed physician and be provided at a
reasonable place and time at no cost to the employee. The examining
physician is given broad latitude in prescribing specific tests to be
included in the medical surveillance program. However, certain elements
of an examination are suggested as being appropriate by the health data
regarding the reproductive and hematologic effects. These elements
include:

\(i\) Comprehensive medical, work and reproductive histories with
special emphasis directed to the hematologic system and symptoms related
to pulmonary and mucous membrane irritation

\(ii\) A comprehensive physical examination with emphasis given to
hematologic and pulmonary systems, mucous membranes, skin and eyes

\(iii\) A complete blood count to include at least a red cell count, a
white cell count, hemoglobin and hematocrit

In addition, the physician must determine the worker\'s suitability for
respirator use. Workers or job applicants who have medical conditions
that would be aggravated by the use of a respirator need to receive
counseling on the increased risk of impairment of their health. In
certain cases, to provide sound medical advice to the employer and the
employee, the physician must evaluate situations not directly related to
glycol ethers. For example, employees with skin diseases, whether or not
they are glycol ethers related, may be unable to tolerate wearing
protective clothing. In addition, those with chronic respiratory
diseases may not tolerate the wearing of respirators. Additional tests
and procedures that will help the physician determine which employees
are medically unable to wear respirators must include a pulmonary
function test with measurement of the employee\'s forced vital capacity
(FVC), and forced expiratory volume at one second (FEV1). Ratios of FEV1
to FVC as well as measured FVC and measured FEV1 to their expected
values corrected for variations due to age, sex, race, and height must
be calculated. Whether a chest X-ray will provide useful information
should be considered

The employer is required to provide physical examinations to any
employee exposed to emergency conditions. While little is known about
the effects of high short-term exposures, it appears prudent to monitor
such affected employers closely in light of existing health data

The employer is required to provide the physician with the following
information: a copy of this standard and appendices; a description of
the affected employee\'s duties as they relate to the employee\'s
exposure concentration; the exposure concentration from representative
monitoring along with the employee\'s duration of exposure (e.g., 15
hr/wk, three 8-hour shifts a week, full-time); a description of any
personal protective equipment, including respirators, used by the
employee; and the results of any previous medical determinations related
to glycol ethers exposure for the affected employee that are within the
employer\'s control

The employer is required to obtain the results of the medical
examinations and a written statement from the physician. This statement
must contain the physician\'s opinion as to whether the employee has any
medical condition which would place the employee at increased risk of
impaired health from exposure to glycol ethers or use of respirators.
The physician must also state his opinion regarding any restrictions
that should be placed on the employee\'s exposure to glycol ethers or
upon the use of protective clothing or equipment such as respirators.
The physician\'s opinion must also contain a statement regarding the
suitability of the employee to wear the type of respirator assigned and
a recommendation as to whether or not respirator fit testing should be
conducted

Finally, the physician must inform the employer that the employee has
been informed by the physician of the results of the medical examination
and of any medical conditions which require further explanation or
treatment. This written opinion is not to contain any information on
specific findings or diagnoses unrelated to occupational exposure to
glycol ethers. After the employer has received the physician\'s
statement, the employer is required to make this information available
to the affected employee

The purpose in requiring the examining physician to supply the employer
with a written opinion is to provide the employer with a medical basis
to assist the employer in placing employees initially, in determining
that their health is, or is not, being impaired by glycol ethers, and to
assess the employee\'s ability to use protective clothing and equipment

APPENDIX D (Nonmandatory) - Reproductive History Questionnaire

(Adapted From Appendix B, Office of Technology Assessment Report,
Reproductive Health Hazards in the Workplace, Ex. 5-135)

**REPRODUCTIVE HISTORY**

  --- --------------------------------------------- -----------------------
  1   HAVE THERE BEEN ANY PREGNANCIES WITH YOUR     
      PRESENT                                       

      MATE?                                         YES NO

      If so, when did they                          
      occur?\_\_\_\_\_\_\_\_\_\_                    

  2   HAVE THERE BEEN ANY MISCARRIAGES, ECTOPIC     

      PREGNANCIES OR STILLBIRTHS WITH YOUR PRESENT  

      MATE?                                         YES NO

      If so, when did they                          
      occur?\_\_\_\_\_\_\_\_\_\_\_\_\_              

  3   HAVE YOU EVER HAD OR FATHERED A CHILD THAT    

      RESULTED IN ANY OF THE FOLLOWING?             

      If so, please specify whether it was with     

      your present or a previous mate:              

      \_\_\_Low birth weight baby (less than 5 1/2  

              lbs.)                                 

      \_\_\_Baby born more than 2 weeks early?      

      \_\_\_Twins, triplets, etc                    

      \_\_\_Baby with a birth defect:               

              \_\_\_Cleft palate                    

              \_\_\_Harelip                         

              \_\_\_Limb deformity                  

              \_\_\_Disease or deformity of the     
      heart, lungs,                                 

                       kidney, genitals, urinary    
      tract,                                        

                       gastrointestinal tract,      
      nervous system                                

      **\[page 15625\]**                            

              \_\_\_Malformations of the skull,     
      spine                                         

              \_\_\_Musculoskeletal disorders       
      (e.g., muscular                               

      dystrophy)                                    

  4   HAVE YOU GIVEN BIRTH TO OR FATHERED CHILDREN  
      WHO                                           

      HAVE ANY OF THE FOLLOWING CONDITIONS?         

              Please specify whether these children 
      were                                          

              born to you with your present or a    
      previous                                      

              Mate                                  
  --- --------------------------------------------- -----------------------

  ----- -------------------------------- --------------------------------
        \_\_\_Allergy                    \_\_\_Mental retardation

        \_\_\_Asthma                           or learning problem

        \_\_\_Epilepsy                   \_\_\_Leukemia

        \_\_\_Downs syndrome             \_\_\_Tumor or Cancer

        \_\_\_Cystic fibrosis            \_\_\_Tay-sachs

        \_\_\_Hemophilia                 \_\_\_Other (specify)

        \_\_\_Cerebral palsy             
  ----- -------------------------------- --------------------------------

  ---- ------------------------------------------------------------------ ----------------------
  5    HAVE YOU AND YOUR PRESENT OR ANY PREVIOUS                          

       MATE HAD DIFFICULTY CONCEIVING?                                    YES NO

               (unprotected intercourse for a year                        

               or more with no pregnancy)                                 

  6    HOW LONG HAVE YOU BEEN TRYING FOR A                                

       PREGNANCY WITH YOUR PRESENT MATE?                                  

       \_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_       

  7    HAVE YOU OR YOUR MATE EVER ATTENDED AN                             

       INFERTILITY CLINIC OR HAD PREVIOUS                                 

       TREATMENT FOR INFERTILITY?                                         YES NO

               If so, please give name of the doctor and                  

               the facility:                                              
       \_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_                 

  8    IS THERE ANY HISTORY OF FERTILITY PROBLEMS                         

       IN YOUR FAMILY?                                                    YES NO

               (Difficulty conceiving, miscarriage, still                 

               birth, deformed offspring)                                 

                                                                          
       Parents?\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_   

               Brothers/Sisters?\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_    

               Uncles/Aunts?\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_  

  9    HOW MANY TIMES PER WEEK DO YOU HAVE                                

       SEXUAL INTERCOURSE WITH YOUR PRESENT                               

       MATE?\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_                

  10   DO YOU AND YOUR MATE USE OR HAVE YOU USED ANY OF                   

       THE FOLLOWING TYPES OF CONTRACEPTION?                              
  ---- ------------------------------------------------------------------ ----------------------

  --- ----------------------------------- ----------------------------------
      Oral contraceptive pill\_\_         

      Permanent sterilization\_\_\_       

      Diaphragm\_\_\_\_\_\_               Tubal ligation\_\_\_\_\_\_

      Condom\_\_\_\_\_\_                  Vasectomy\_\_\_

      Spermicidal foam or gel\_\_         

      IUD\_\_\_\_\_                       Coitus interruptus\_\_\_\_

      Other\_\_\_\_\_\_\_\_\_\_\_\_\_\_   
  --- ----------------------------------- ----------------------------------

  -------------- -------------------------------------------------------------------------------- ---------------------------------
  11             WHAT FORM OF CONTRACEPTION, IF ANY, ARE YOU                                      

                         CURRENTLY USING?                                                         

  12             DO YOU TRY TO HAVE INTERCOURSE DURING                                            

                 THE FERTILE TIME OF THE MONTH? YES NO                                            

                         If so, how do you decide the best time?\_\_\_\_\_                        

                                                                                                  
                 \_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_   

  13             DO YOU HAVE ANY PHYSICAL DIFFICULTIES WITH                                       

                 SEX THAT WOULD PREVENT A CONCEPTION?                                             YES NO

                         (e.g., pain during intercourse sufficient to                             

                         Prevent penetration)?                                                    

  14             DO YOU USE LUBRICANTS DURING SEXUAL                                              

                 INTERCOURSE?                                                                     YES NO

  15             HAVE YOU AND YOUR PRESENT MATE EVER HAD A                                        

                 POST COITAL TEST (examination of the cervix                                      

                         for sperm after intercourse)?                                            YES NO

                         If so, was any incompatibility noted?\_\_\_\_                            

  REPRODUCTIVE                                                                                    
  HEALTH                                                                                          

  A              MALE                                                                             

  1              HAVE YOU EVER HAD ANY INJURY OR OPERATION TO                                     

                 THE PENIS OR TESTICLES?                                                          

                         Circumcision                                                             YES NO

                         Other operations on penis                                                YES NO

                         Explain\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_                

                         Varicocele operation                                                     

                         (varicose veins near testicles)                                          YES NO

                         Vasectomy                                                                YES NO

                         Biopsy of the testicle                                                   YES NO

                         Other operations of injuries to                                          

                         the testicles                                                            YES NO

  2              HAVE YOU EVER HAD AN INFECTION OF THE                                            

                         Bladder                                                                  YES NO

                         Urethra                                                                  YES NO

                         Epididymis                                                               YES NO

                         Kidney                                                                   YES NO

                 If so, please give details:                                                      

  3              HAS THERE BEEN ANY RECENT CHANGE IN                                              

                 THE SIZE OF YOUR TESTICLES?                                                      YES NO

                 If so, please give details:                                                      

  4              HAVE YOU EVER HAD A HERNIA OPERATION                                             

                 (Evens as a baby)?                                                               YES NO

                         If so, please give details:                                              

  5              ARE YOU IN THE HABIT OF TAKING VERY                                              

                 HOT BATHS?                                                                       YES NO

  6              ARE YOU IN THE HABIT OF TAKING SAUNAS?                                           

                                                                                                  YES NO

  7              WHAT SORT OF UNDERWEAR DO YOU NORMALLY                                           

                 WEAR?                                                                            

                 \_\_\_Boxer trunks                                                               

                 \_\_\_Jockey shorts                                                              

                 \_\_\_Other                                                                      

  8              HAVE YOU EVER BEEN TOLD BY A DOCTOR                                              

                 HAT YOU HAD A PROSTATE PROBLEM?                                                  YES NO

  9              HAVE YOU EVER GONE THROUGH A PERIOD OF                                           

                 SEVERAL MONTHS WHEN YOU HAD TROUBLE                                              

                 GETTING OR KEEPING AN ERECTION?                                                  YES NO

  10             DO YOU GET SATISFACTORY EJACULATION OF                                           

                 SPERM DURING INTERCOURSE?                                                        YES NO

  11             HAVE YOU EVER GONE THROUGH A PERIOD OF                                           

                 SEVERAL MONTHS WHEN YOU HAD LITTLE                                               

                 INTEREST IN SEX?                                                                 YES NO

                 If so, please give details:                                                      

  12             DO YOU HAVE ANY PROBLEMS URINATING?                                              YES NO

  13             HAVE YOU EVER BEEN EXAMINED BY A                                                 

                 UROLOGIST?                                                                       YES NO

                 If so when?\_\_\_\_\_\_\_ For what reason?\_\_\_\_\_\_\_\_\_                     

                 Were any problems identified? \_\_\_\_\_\_\_\_\_\_\_\_\_\_                       

  14             HAVE YOU HAD GENITAL HERPES?                                                     YES NO

  15             HAVE YOU HAD SEXUALLY TRANSMITTED                                                

                 DISEASE?                                                                         YES NO

  16             HAS YOUR SEMEN BEEN EVALUATED BEFORE?                                            

                                                                                                  YES NO

                 How many times?\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_                                    

                 When most recently?\_\_\_\_\_\_\_\_\_\_                                          

                 What were the results?\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_                 

                 Have any other tests (e.g. antibody, mucous                                      

                 penetration) been done with your semen?                                          

                                                                                                  YES NO

                 If so, when?\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_       

                 What were the results?\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_                 

  17             HAVE ANY ENDOCRINE (HORMONE) STUDIES BEEN                                        

                         DONE WITH YOUR BLOOD?                                                    YES NO

                         If so, when?\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_           

                         What were the results?\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_                     

  18             HAVE YOU EVER HAD A FERTILITY INVESTIGATION?                                     

                                                                                                  YES NO

                         If so, what was the diagnosis?                                           

                         \_\_\_\_\_\_\_\_Anatomical defect                                        

                         \_\_\_\_\_\_\_\_Hormonal/Glandular disorder                              

                         \_\_\_\_\_\_\_\_Other                                                    

                         \_\_\_\_\_\_\_\_No abnormality found                                     

  19             HAVE YOU EVER HAD SURGERY FOR INFERTILITY?                                       

                                                                                                  YES NO

                         If so, give details:                                                     

  B              FEMALE                                                                           

  MENSTRUAL                                                                                       
  HISTORY                                                                                         

  1              HOW OLD WERE YOU WHEN YOU BEGAN TO                                               

                 MENSTRUATE?\_\_\_\_\_\_\_                                                        

  2              ARE YOUR PERIODS REGULAR?                                                        

                                                                                                  Yes\_\_\_ No\_\_\_

  3              WHAT IS THE AVERAGE LENGTH OF YOUR                                               

                 CYCLE?\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_                     

  4              GIVE THE DATE OF THE 1st DAY OF YOUR                                             

                 LAST PERIOD:\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_                         

  5              GIVE THE DATE OF THE 1st DAY OF THE PERIOD                                       

                 BEFORE LAST:\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_             

  6              FOR HOW MANY DAYS DO YOU                                                         

                 BLEED?\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_                                         

  7              IF YOU EXPERIENCE ANY OF THESE SYMPTOMS,                                         

                 NOTE HOW MANY DAYS BEFORE ONSET OF BLEEDING                                      

                 THE SYMPTOM BEGINS:                                                              

                 Premenstrual:                                                                    
  -------------- -------------------------------------------------------------------------------- ---------------------------------

  --- ----------------------------------------------- -------------------------------------------------
      Abdominal Bloating\_\_\_\_ Urinary Tract        
      Symptoms\_\_\_                                  

      Swelling of face, hands                         
      Headache\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_      

      or feet\_\_\_\_\_\_\_\_\_\_\_\_\_\_             

      Irritability\_\_\_\_\_\_\_\_\_                  Breast Tenderness\_\_\_\_\_

      Weight Gain\_\_\_\_\_\_\_\_\_\_\_\_\_\_         

      Bowel Changes\_\_\_\_\_\_\_\_\_                 

      Other\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_   

      During Period:                                  

      Cramps\_\_\_\_\_\_\_                            Hot Flashes\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_

      Nausea\_\_\_\_\_\_\_                            Fever\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_

      Diarrhea\_\_\_\_\_                              Sweats\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_

      Chills\_\_\_\_\_\_\_                            Constipation\_\_\_\_\_\_\_\_\_\_\_\_\_\_

      Headaches\_\_\_\_                               Rectal Pain\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_

      Fainting\_\_\_\_\_\_                            Other\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_

      Dizziness\_\_\_                                 
  --- ----------------------------------------------- -------------------------------------------------

  ------------- ----------------------------------- ---------------------------------
  8             DO YOU HAVE ANY BLEEDING OR BLOODY  
                DISCHARGE:                          

                Between Periods                     YES NO

                After Intercourse                   YES NO

                After Douching                      YES NO

  GYNECOLOGIC                                       
  HISTORY:                                          

  1             DO YOU HAVE ANY PAIN OR DISCOMFORT  
                ASSOCIATED                          

                WITH INTERCOURSE?                   YES NO

  2             DO YOU HAVE ANY PROBLEMS OR         
                DIFFICULTY RELATED                  

                TO SEXUAL ACTIVITY                  YES NO

  3             HAVE YOU EVER GONE THROUGH A PERIOD 
                OF                                  

                SEVERAL MONTHS WHEN YOU HAD LITTLE  

                INTEREST IN SEX? YES NO             

                If so, give details:                

  4             HAVE YOU HAD GENITAL HERPES?        YES NO

  5             HAVE YOU HAD SEXUALLY TRANSMITTED   

                        DISEASE?                    YES NO

  6             HAVE YOU EVER HAD AN ABNORMAL PAP   
                SMEAR?                              

                                                    YES NO

  7             HAVE YOU HAD OR DO YOU RECURRENT    
                VAGINAL                             

                        INFECTION?                  YES NO

                **\[page 15626\]**                  

  8             HAVE YOU HAD OR DO YOU HAVE         
                PROBLEMS WITH                       

                VAGINAL DISCHARGE?                  YES NO

  9             DID YOUR MOTHER TAKE                
                Diethylstilbestrol(DES)             

                WHILE PREGNANT WITH YOU?            YES NO

                DISEASE, ABNORMALITY OR SURGERY OF  
                THE                                 
  ------------- ----------------------------------- ---------------------------------

  ---- ---------------------- ---------------------- ----------------------
  10   HAVE YOU HAD ANY TYPE                         
       OF PELVIC INFECTION,                          

       Vulva\_\_\_            Vagina\_\_\_           Cervix\_\_\_

       Uterus\_\_             Tubes\_\_\_\_          Ovaries\_\_

       Urinary Tract\_\_\_    Anus\_\_\_             Rectum\_\_\_
  ---- ---------------------- ---------------------- ----------------------

  ---- --------------------------------------------- ----------------------
  11   HAVE YOU EVER HAD ENDOMETRIOSIS?              YES NO

       If so, when?\_\_\_\_\_\_\_ How was it         

               Treated?\_\_\_\_\_\_\_\_              
  ---- --------------------------------------------- ----------------------

  ---- ------------------------------------------------------ ----------------------
  12   DO YOU KNOW WHETHER OR NOT YOUR FALLOPIAN              

       TUBES ARE OPEN?                                        YES NO

  13   HAS EITHER TUBE BEEN REMOVED?                          YES NO

  14   HAVE YOU EVER HAD A HYSTEROSALPINGOGRAM                

       (Tubal dye study)?                                     YES NO

       If so, when?\_\_\_\_\_ What were the                   

               results?\_\_\_\_\_\_                           

  15   HAVE YOU EVER HAD A LAPAROSCOPY?                       YES NO

       If so, when\_\_\_\_ What were the                      

               results?\_\_\_\_\_\_\_\_                       

  16   HAVE ANY ENDOCRINE (HORMONE) STUDIES BEEN DONE         

       WITH YOUR BLOOD?                                       YES NO

       If so, when?\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_     

       What were the                                          
       results?\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_   

  17   HAVE YOU EVER HAD A FERTILITY INVESTIGATION?           

                                                              YES NO

       If so, what was the diagnosis?                         

       \_\_\_\_\_Anatomical defect                            

       \_\_\_\_\_Hormonal/Glandular disorder                  

       \_\_\_\_\_Other                                        

       \_\_\_\_\_No abnormality found                         

  18   HAVE YOU EVER HAD SURGERY FOR INFERTILITY?             

                                                              YES NO

       If so, give details:                                   
  ---- ------------------------------------------------------ ----------------------

APPENDIX E- Sampling and Analytical Methods for 2- Methoxyethanol,
2-Ethoxyethanol, and their Acetates

This appendix describes the method presently used at the OSHA Analytical
Laboratory in Salt Lake City for measurement of 2-Methoxyethanol,
2-Ethoxyethanol and their acetates. The method is the most sensitive
method presently available for measurement of employee exposure.
Inclusion of this method in the appendix does not imply that it is the
only one which will be satisfactory. Other methods may also be
acceptable provided they can determine these glycol ethers at the
permissible exposure limit within + 25% of the \"true\" value at the 95%
confidence level. Where applicable, the method must also be able to
measure glycol ethers at the action level to + 35% of the \"true\" value
with 95% confidence

The following is extracted from the OSHA Analytical Laboratory Method
No. 79. For a more complete copy of the method see Exhibit 5-139

Method number: 79 Matrix: Air

Procedure: Samples are collected by drawing air through standard size
cocunut shell charcoal tubes. Samples are desorbed with 95/5 (v/)
methylene choride/methonal and analyzed by gas chromatography using a
flame inonization detector

Recommended air48 L at 0.1 L/min for TWA samples volume and sampling 15
L at 1.0 L/min for STEL samples rate:

  ----------------------- ------------------------------------------------------------------------------------------ ----------- ----------- ------------
                          \_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_                           

                          2ME                                                                                        2MEA        2EE         2EEA

  Target conc.:                                                                                                                              

   ppm (mg/m3)            0.1                                                                                        0.1         0.5         0.5

                          (0.3)                                                                                      (0.5)       (1.8)       (2.7)

     Reliable quanti-     6.7                                                                                        1.7         2.1         1.2

  tation limit:           \(21\)                                                                                     (8.4)       (7.8)       6.5)

   ppb(ug/m3)                                                                                                                                

     Standard error of                                                                                                                       

  estimate at the         6.0%                                                                                       5.7%        6.2%        5.7%

  target concentra-                                                                                                                          

  tion:                                                                                                                                      

  (Section 4.7)                                                                                                                              
  ----------------------- ------------------------------------------------------------------------------------------ ----------- ----------- ------------

Special requirements: As indicated in OSHA Method 53 (Ref. 5.1.),
samples for 2MEA and 2EEA should be refrigerated upon receipt by the
laboratory to minimize hydrolysis

Status of method: Evaluated method. This method has been subjected to
the established evaluation procedures of the Organic Methods Evaluation
Branch

1\. General Discussion 1.1. Background

1.1.1. History An air sampling and analytical procedure for 2ME, 2MEA,
2EE, and 2EEA (OSHA Method 53) was previously evaluated by the Organic
Methods Evaluation Branch of the OSHA Analytical Laboratory. (Ref. 5.1.)
The target concentration for all four analytes in that method was 5 ppm.
OSHA is now in the process of 6(b) rulemaking to consider reducing
occupational exposure to these glycol ethers. Because the proposed
exposure limits may be significantly lower than the target
concentrations in Method 53, the methodology was re-evaluated at lower
levels

A number of changes were made to Method 53 to accommodate the lower
target concentrations

\(1\) The recommended air volume for TWA samples was increased from 10 L
to 48 L. This allows for lower detection limits and increases the TWA
sampling time to a more convenient 480 min (8 h) when sampling at 0.1
L/min

\(2\) A capillary GC column was substituted for a packed column to
attain higher resolution. This was especially helpful in achieving
better separation of 2ME and methylene chloride, a major component of
the desorption solvent

\(3\) It was found that the desorption efficiency from wet charcoal was
significantly lower for 2ME, and to a lesser extent for 2EE, at these
lower concentrations. This problem was overcome by adding about 125 mg
of anhydrous magnesium sulfate to each desorption vial to remove the
desorbed water. Because charcoal will always collect some water from
sampled air, all 2ME and 2EE air samples must be treated in this manner

Utilizing these three major modifications of Method 53, a successful
evaluation was performed for these glycol ethers at the lower target
concentrations. Also, a minor modification was made in the determination
of desorption efficiencies. Aqueous instead of methanolic stock
solutions were used to determine the desorption efficiencies for 2MEA
and 2EEA. It was found that at these lower levels, when stock methanolic
solutions are spiked on dry Lot 120 charcoal, part of the 2MEA and 2EEA
react with the methanol to form methyl acetate and 2ME and 2EE
respectively. The reaction, which is analogous to hydrolysis, is called
transesterification (alcoholysis) and is catalyzed by acid or base. The
surface of dry Lot 120 charcoal is basic and the reaction was verified
to occur by quantitatively determining methyl acetate and the
corresponding alcohol (2ME for 2MEA samples, 2EE for 2EEA samples) from
spiked samples. Transesterification was not observed when methanolic
stock solutions were spiked onto wet charcoal. Therefore,
transesterification is not expected to occur for samples collected from
workplace air containing methanol as well as 2MEA or 2EEA because
workplace atmospheres are seldom completely dry

Because of the number of modifications and the extensive amount of data
generated in this evaluation, the findings are presented as a separate
method instead of a revision of Method 53. This method supersedes Method
53, although Method 53 is still valid at the higher analyte
concentrations. Although hydrolysis of 2MEA and 2EEA does not appear to
be a problem at lower concentrations, as a precautionary measure, the
special requirement that 2MEA and 2EEA samples should be refrigerated
upon receipt by the laboratory was retained from Method 53

1.1.2. Toxic effects (This section is for information only and should
not be taken as the basis of OSHA policy.)

As reported in the Documentation of Threshold Limit Values (Refs.
5.2.-5.5.), all four analytes were investigated by Nagano et al. (Ref.
5.6.) in terms of potency for testicular effects. They concluded that on
an equimolar basis, the respective acetate esters were about as potent
as 2ME and 2EE in producing testicular atrophy and leukopenia (an
abnormally low number of white blood cells) in mice. Based on this study
and because 2MEA and 2EEA hydrolyze to 2ME and 2EE respectively in the
body, ACGIH suggests lowering the time-weighted TLVs for all four
analytes to 5 ppm

The following is quoted from NIOSH Current Intelligence Bulletin 39.
(Ref. 5.7.)

The National Institute for Occupational Safety and Health (NIOSH)
recommends that 2-methoxyethanol (2ME) and 2-ethoxyethanol (2EE) be
regarded in the workplace as having the potential to cause adverse
reproductive effects in male and female workers. These recommendations
are based on the results of several recent studies that have
demonstrated dose-related

**\[page 15627\]**

embryotoxicity and other reproductive effects in several species of
animals exposed by different routes of administration. Of particular
concern are those studies in which exposure of pregnant animals to
concentrations of 2ME or 2EE at or below their respective Occupational
Safety and Health Administration (OSHA) Permissible Exposure Limits
(PELs) led to increased incidences of embryonic death, teratogenesis, or
growth retardation. Exposure of male animals resulted in testicular
atrophy and sterility. In each case the animals had been exposed to 2ME
or 2EE at concentrations at or below their respective OSHA PELs.
Therefore, appropriate controls should be instituted to minimize worker
exposure to both compounds.

On May 20, 1986, EPA referred these four analytes to OSHA in accordance
with the Toxic Substances Control Act (TSCA). On April 2, 1987, OSHA
issued an Advanced Notice of Proposed Rulemaking (ANPR) which summarized
the information currently available to OSHA concerning the uses, health
effects, estimates of employee exposure and risk determinations for
these glycol ethers. OSHA invited comments from interested parties and
based on the gathered information will decide on appropriate action.
(Ref. 5.8.) 1.1.3. Workplace exposure

2ME- It is used as a solvent for many purposes: cellulose esters, dyes,
resins, lacquers, varnishes, and stains; and as a perfume fixative and
jet fuel deicing additive. (Ref. 5.2.)

2MEA- It is used in photographic films, lacquers, textile printing, and
as a solvent for waxes, oils, various gums and resins, cellulose
acetate, and nitrocellulose. (Ref. 5.3.)

2EE- It is used as a solvent for nitrocellulose, natural and synthetic
resins, and as a mutual solvent for the formulation of soluble oils. It
is also used in lacquers, in the dyeing and printing of textiles, in
varnish removers, cleaning solutions, in products for the treatment of
leather, and as an anti-icing additive for aviation fuels. (Ref. 5.4.)

2EEA- It is used as a blush retardant in lacquers; as a solvent for
nitrocellulose, oils and resins; in wood stains, varnish removers, and
in products for the treatment of textiles and leathers. (Ref. 5.5.)

  ------------ ----------------------- -----------------------------------
  1.1.4.                               
  Physical                             
  properties                           
  (Refs.                               
  5.2.-5.5.)                           

                                       
  chemical                             
  formulae:                            

               2ME- CH3OCH2CH2OH       2MEA- CH3OCH2CH2OOCCH3

               2EE- CH3CH2OCH2CH2OH    2EEA- CH3CH2OCH2CH2OOCCH3
  ------------ ----------------------- -----------------------------------

synonyms: (Ref. 5.9.)

2ME- methyl Cellosolve; glycol monomethyl\
ether; ethylene glycol monomethyl ether; methyl\
oxitol; Ektasolve; Jeffersol EM;

2MEA- methyl Cellosolve acetate; glycol\
monomethyl ether acetate; ethylene glycol\
monomethyl ether acetate

2EE- Cellosolve solvent; ethylene glycol\
monoethyl ether

2EEA- Cellosolve acetate; glycol monoethyl\
ether acetate; ethylene glycol monoethyl ether\
acetate

  --------------- ------------------------------------------------------------------------------------------------------------------ ----------- ----------- ------------------ ----
                  \_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_                                              

                  2ME                                                                                                                2MEA        2EE         2EEA               

                  \_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_                                              

  CAS number:     109-86-4                                                                                                           110-49-6    110-80-5    11-15-9            

  Molecular Wt.:  76.09                                                                                                              118.13      90.11       132.16             

  Boiling Point:  124.5oC                                                                                                            145oC       135.6oC     156.4oC            

  Color:          colorless                                                                                                          colorless   colorless   colorless          

  Specific                                                                                                                                                                      

  Gravity:        0.9663f                                                                                                            1.005       0.931       0.975              

  Vapor Press-                                                                                                                                                                  

  ure at 20oC:    0.8 kPa                                                                                                            0.3 kPa     0.49 kPa    0.3 kPa            

  Flash Point,                                                                                                                                                                  

  closed cup:     43oC                                                                                                               49oC        40oC        49oC               

  Odor:           mild,                                                                                                              mild,       sweetish    mild               

  (Ref. 5.9)      nonresid-                                                                                                          ether-                  nonresid-          

                  ual                                                                                                                like                    ual                

  Explosive                                                                                                                                                                     

  Limits:                                                                                                                                                                       

  (ref. 5.9)                                                                                                                                                                    

  Lower:          2.5%                                                                                                               1.1%        1.8%        1.7%               

  Upper:          19.8%                                                                                                              8.2%        14%         ?                  
  --------------- ------------------------------------------------------------------------------------------------------------------ ----------- ----------- ------------------ ----

The analyte air concentrations throughout this method are based on the
recommended TWA-sampling and analytical parameters. Air concentrations
listed in ppm and ppb are referenced to 25 C and 101.3 kPa (760 mm Hg.)
1.2. Limit defining parameters 1.2.1. Detection limit of the analytical
procedure

The detection limits of the analytical procedure are 0.10, 0.04, 0.04,
and 0.03 ng per injection (1.0-L injection with a 10:1 split) for 2ME,
2MEA, 2EE, and 2EEA respectively. These are the amounts of each analyte
that will give peaks with heights approximately 5 times the height of
baseline noise. (Section 4.1.) 1.2.2. Detection limit of the overall
procedure. The detection limits of the overall procedure are 1.0, 0.40,
0.37, and 0.31 g per sample for 2ME, 2MEA, 2EE, and 2EEA respectively.
These are the amounts of each analyte spiked on the sampling device that
allow recovery of amounts of each analyte equivalent to the detection
limits of the analytical procedure. These detection limits correspond to
air concentrations of 6.7 ppb (21 g/m), 1.7 ppb (8.4 g/m), 2.1 ppb (7.8
g/m), and 1.2 ppb (6.5 g/m) for 2ME, 2MEA, 2EE, and 2EEA respectively.
(Section 4.2.) 1.2.3. Reliable quantitation limit

The reliable quantitation limits are the same as the detection limits of
the overall procedure because the desorption efficiencies are
essentially 100% at these levels. These are the smallest amounts of each
analyte that can be quantitated within the requirements of recoveries of
at least 75% and precisions (+/- 1.96 SD) of +/- 25% or better. (Section
4.3.)

The reliable quantitation limits and detection limits reported in the
method are based upon optimization of the GC for the smallest possible
amounts of each analyte. When the target concentration of an analyte is
exceptionally higher than these limits, they may not be attainable at
the routine operating parameters. 1.2.4. Instrument response to the
analyte

The instrument response over the concentration ranges of 0.5 to 2 times
the target concentrations is linear for all four analytes. (Section
4.4.) 1.2.5. Recovery

The recovery of 2ME, 2MEA, 2EE, and 2EEA from samples used in a 15-day
storage test remained above 84, 87, 84, and 85% respectively when the
samples were stored at ambient temperatures. The recovery of analyte
from the collection medium after storage must be 75% or greater.
(Section 4.5., from regression lines shown in Figures 4.5.1.2.,
4.5.2.2., 4.5.3.2. and 4.5.4.2.) 1.2.6. Precision (analytical procedure)

The pooled coefficients of variation obtained from replicate
determinations of analytical standards at 0.5, 1, and 2 times the target
concentrations are 0.022, 0.004, 0.002, and 0.002 for 2ME, 2MEA, 2EE,
and 2EEA respectively. (Section 4.6.) 1.2.7. Precision (overall
procedure)

The precisions at the 95% confidence level for the ambient temperature
15-day storage tests are +/- 11.7, +/- 11.1, +/- 12.3, and +/- 11.2% for
2ME, 2MEA, 2EE, and 2EEA respectively. These include an additional +/-
5% for sampling error. The overall procedure must provide results at the
target concentration that are +/-25% or better at the 95% confidence
level. (Section 4.7.) 1.2.8. Reproducibility

Six samples for each analyte collected from controlled test atmospheres
and a draft copy of this procedure were given to a chemist unassociated
with this evaluation. The samples were analyzed after 12 days of
refrigerated storage. No individual sample result deviated from its
theoretical value by more than the precision reported in Section 1.2.7.
(Section 4.8.)

1.3. Advantages

1.3.1. Charcoal tubes provide a convenient method for sampling

1.3.2. The analysis is rapid, sensitive, and precise

1.4. Disadvantage

> It may not be possible to analyze co-collected solvents using this
> method. Most of the other common solvents which are collected on
> charcoal are analyzed after desorption with carbon disulfide

2\. Sampling Procedure

**\[page 15628\]**

2.1. Apparatus

2.1.1. Samples are collected using a personal sampling pump calibrated
to within +/- 5% of the recommended flow rate with a sampling tube in
line

2.1.2. Samples are collected with solid sorbent sampling tubes
containing coconut shell charcoal. Each tube consists of two sections of
charcoal separated by a urethane foam plug. The front section contains
100 mg of charcoal and the back section, 50 mg. The sections are held in
place with glass wool plugs in a glass tube 4-mm i.d. x 70-mm length.
For this evaluation, SKC Inc. charcoal tubes (catalog number 226-01, Lot
120) were used. 2.2. Reagents None required 2.3. Technique

2.3.1. Immediately before sampling, break off the ends of the charcoal
tube. All tubes should be from the same lot

2.3.2. Connect the sampling tube to the sampling pump with flexible
tubing. Position the tube so that sampled air first passes through the
100-mg section

2.3.3. Air being sampled should not pass through any hose or tubing
before entering the sampling tube

2.3.4. Place the sampling tube vertically (to avoid channeling) in the
employee\'s breathing zone

2.3.5. After sampling, seal the tubes immediately with plastic caps and
wrap lengthwise with OSHA Form 21

2.3.6. Submit at least one blank sampling tube with each sample set.
Blanks should be handled in the same manner as samples, except no air is
drawn through them

2.3.7. Record sample volumes (in liters of air) for each sample, along
with any potential interferences

2.3.8. Ship any bulk sample(s) in a container separate from the air
samples. 2.4. Sampler capacity

2.4.1. Sampler capacity is determined by measuring how much air can be
sampled before breakthrough of analyte occurs, i.e., the sampler
capacity is exceeded. Individual breakthrough studies were performed on
each of the four analytes by monitoring the effluent from sampling tubes
containing only the 100-mg section of charcoal while sampling at 0.2
L/min from atmospheres containing 10 ppm analyte. The atmospheres were
at approximately 80% relative humidity and 20-25 C. No breakthrough was
detected in any of the studies after sampling for at least 6 h (\>70 L).
(This data was collected in the evaluation of OSHA Method 53, Ref. 5.1.)

2.4.2. A similar study as in 2.4.1. was done while sampling an
atmosphere containing 10 ppm of all four analytes. The atmosphere was
sampled for more than 5 h (\>60 L) with no breakthrough detected. (This
data was collected in the evaluation of OSHA Method 53, Ref. 5.1.) 2.5.
Desorption efficiency

2.5.1. The average desorption efficiencies of 2ME, 2MEA, 2EE, and 2EEA
from Lot 120 charcoal are 95.8, 97.9, 96.5, and 98.3% respectively over
the range of 0.5 to 2 times the target concentrations. Desorption
samples for 2MEA and 2EEA must not be determined by using methanolic
stock solutions since a transesterification reaction can occur. (Section
4.9.)

2.5.2. Desorbed samples remain stable for at least 24 h. (Section 4.10.)
2.6. Recommended air volume and sampling rate

2.6.1. For TWA samples, the recommended air volume is 48 L collected at
0.1 L/min (8-h samples)

2.6.2. For short-term samples, the recommended air volume is 15 L
collected at 1.0 L/min (15-min samples)

2.6.3. When short-term samples are required, the reliable quantitation
limits become larger. For example, the reliable quantitation limit is 21
ppb (67 ug/m3) for 2ME when 15 L is sampled. 2.7. Interferences
(sampling)

2.7.1. It is not known if any compound(s) will severely interfere with
the collection of any of the four analytes on charcoal. In general, the
presence of other contaminant vapors in the air will reduce the capacity
of charcoal to collect the analytes

2.7.2. Suspected interferences should be reported to the laboratory with
submitted samples. 2.8. Safety precautions (sampling)

2.8.1. Attach the sampling equipment to the employee so that it will not
interfere with work performance or safety

2.8.2. Wear eye protection when breaking the ends of the charcoal tubes

2.8.3. Follow all safety procedures that apply to the work area being
sampled

3\. Analytical Procedure 3.1. Apparatus

3.1.1. A GC equipped with a flame ionization detector. For this
evaluation, a Hewlett-Packard 5890 Series II Gas Chromatograph equipped
with a 7673A Automatic Sampler was used

3.1.2. A GC column capable of separating the analyte of interest from
the desorption solvent, internal standard and any interferences. A thick
film, 60-m X 0.32-mm i.d., fused silica RTx-Volatiles column (Cat. no.
10904, Restek Corp., Bellefonte, PA) was used in this evaluation

3.1.3. An electronic integrator or some other suitable means of
measuring peak areas or heights. A Hewlett-Packard 18652A A/D converter
interfaced to a Hewlett-Packard 3357 Lab Automation Data System was used
in this evaluation. 3.1.4. Two-milliliter vials with Teflon-lined caps

3.1.5. A dispenser capable of delivering 1.0 mL to prepare standards and
samples. If a dispenser is not available, a 1.0-mL volumetric pipet may
be used

3.1.6. Syringes of various sizes for preparation of standards

3.1.7. Volumetric flasks and pipets to dilute the pure analytes in
preparation of standards. 3.2. Reagents

3.2.1. 2-Methoxyethanol, 2-methoxyethyl acetate, 2-ethoxyethanol, and
2-ethoxyethyl acetate, reagent grade. Aldrich Lot HB062777 2ME, Eastman
Lot 701-2 2MEA, Aldrich Lot DB040177 2EE, and Aldrich Lot 04916HP 2EEA
were used in this evaluation

3.2.2. Anhydrous magnesium sulfate, reagent grade. Chempure Lot M172
KDHM was used in this evaluation

3.2.3. Methylene chloride, chromatographic grade. American Burdick and
Jackson Lot AQ098 was used in this evaluation

3.2.4. Methanol, chromatographic grade. American Burdick and Jackson Lot
AT015 was used in this evaluation

3.2.5. A suitable internal standard, reagent grade. \"Quant Grade\"
3-methyl-3-pentanol from Polyscience Corporation was used in this
evaluation

3.2.6. The desorption solvent consists of methylene chloride/methanol,
95/5 (v/v) containing an internal standard at a concentration of 20
uL/L. 3.2.7 GC grade nitrogen, air, and hydrogen. 3.3. Standard
preparation

3.3.1. Prepare concentrated stock standards by diluting the pure
analytes with methanol. Prepare working standards by injecting
microliter amounts of concentrated stock standards into vials containing
1.0 mL of desorption solvent delivered from the same dispenser used to
desorb samples. For example, to prepare a stock standard of 2ME, dilute
195 uL of pure 2ME (sp gr = 0.9663) to 50.0 mL with methanol. This stock
solution would contain 3.769 ug/uL. A working standard of 15.08
ug/sample is prepared by injecting 4.0 uL of this stock into a vial
containing 1.0 mL of desorption solvent

3.3.2. Bracket sample concentrations with working standard
concentrations. If samples fall outside of the concentration range of
prepared standards, prepare and analyze additional standards to
ascertain the linearity of response. 3.4. Sample preparation

3.4.1. Transfer each section of the samples to separate vials. Discard
the glass tubes and plugs

3.4.2. For 2ME and 2EE samples, add about 125 mg of magnesium sulfate to
each vial

3.4.3. Add 1.0 mL of desorption solvent to each vial using the same
dispenser as used for preparation of standards

3.4.4. Immediately cap the vials and shake them periodically for about
30 min

3.5. Analysis

  ------- ----------------- ----------------------------------------------
  3.5.1   GC conditions     

          zone              column-80 C for 4 min
          temperatures:     

          10 C/min to 125 C 

          125 C for 4 min   

          injector-150 C    

          detector-200 C    

          gas flows:        hydrogen (carrier)- 2.5 mL/min

                            (80 kPa head pressure)

                            nitrogen (makeup)-20 mL/min

                            hydrogen (flame)-65 mL/min

                            air-400 mL/min

          injection volume: 1.0 uL (with a 10:1 split)

          column:           60-m X 0.32-mm i.d. fused silica,

                            RTx-Volatiles, thick film

          retention times:  2ME- 5.0 min

                            2MEA- 10.0 min

                            2EE- 6.7 min

                            2EEA- 11.9 min

                            (3-methyl-3-pentanol- 7.5 min)
  ------- ----------------- ----------------------------------------------

3.5.2. Peak areas (or heights) are measured by an integrator or other
suitable means

3.5.3. An internal standard (ISTD) calibration method is used.
Calibration

**\[page 15629\]**

curves are prepared by plotting micrograms of analyte per sample versus
ISTD-corrected response of standard injections. Sample concentrations
must be bracketed by standards. 3.6. Interferences (analytical)

3.6.1. Any compound that responds on a flame ionization detector and has
the same general retention time of the analyte or internal standard is a
potential interference. Possible interferences should be reported to the
laboratory with submitted samples by the industrial hygienist. These
interferences should be considered before samples are desorbed

3.6.2. GC parameters (i.e. column and column temperature) may be changed
to possibly circumvent interferences

3.6.3. Retention time on a single column is not considered proof of
chemical identity. Analyte identity should be confirmed by GC/mass
spectrometer if possible. 3.7. Calculations The analyte concentration
for samples is obtained from the appropriate calibration curve in terms
of micrograms of analyte per sample, uncorrected for desorption
efficiency. The air concentration is calculated using the following
formulae. The back (50-mg) section is analyzed primarily to determine if
there was any breakthrough from the front (100-mg) section during
sampling. If a significant amount of analyte is found on the back
section (e.g., greater than 25% of the amount found on the front
section), this fact should be reported with sample results. If any
analyte is found on the back section, it is added to the amount found on
the front section. This total amount is then corrected by subtracting
the total amount (if any) found on the blank

  --------------------- --------------------------- -------------------------------------------
                        (ug of                                analyte per sample)

   mg/m3 =           (L                             
  of air                                            
  sampled)(desorption                               
  efficiency)                                       

                        where desorption            0.958 for 2ME
                        efficiency=                 

                                                    0.979 for 2MEA

                                                    0.965 for 2EE

                                                    0.983 for 2EEA

                         ppm =                      
                        (mg/m3)(24.46)/(molecular   
                        weight of analyte)          

                        where 24.46 is the molar    
                        volume at 25 C and 101.3    
                        kPa                         

                                  (760 mmHg)        

                        and molecular weights       
                        =76.09 for 2ME, 118.13 for  
                        2MEA                        

                                  90.11 for 2EE,    
                        132.16 for 2EEA             
  --------------------- --------------------------- -------------------------------------------

3.8 Safety precautions (analytical)

3.8.1. Avoid skin contact and inhalation of all chemicals

3.8.2. Restrict the use of all chemicals to a fume hood when possible

3.8.3. Wear safety glasses and a lab coat at all times while in the lab
area

4\. Backup Data

(For backup data see Section 4 of OSHA Analytical Method Number 79,
Exhibit 5-139)

5\. References

  ------ ----------- ----------------------------------------------------
         5.1         \"OSHA Analytical Methods Manual\" U.S. Department

                     of Labor, Occupational Safety and Health

                     Administration; OSHA Analytical Laboratory: Salt

                     Lake City, UT, 1985; Method 53; American

                     Conference of Governmental Industrial Hygienists

                     (ACGIH): Cincinnati, OH, ISBN: 0-936712-66-X

         5.2         \"American Conference of Governmental Industrial

                     Hygienists: Documentation of the Threshold Limit

                     Values, Supplemental Documentation for 1982\",

                     pp. 259-260, Cincinnati, OH (1982)

         5.3         \"American Conference of Governmental Industrial

                     Hygienists: Documentation of the Threshold Limit

                     Values, Supplemental Documentation for 1982\", p

                     260, Cincinnati, OH (1982)

         5.4         \"American Conference of Governmental Industrial

                     Hygienists: Documentation of the Threshold Limit

                     Values, Supplemental Documentation for 1982\", p

                     171, Cincinnati, OH (1982)

         5.5         \"American Conference of Governmental Industrial

                     Hygienists: Documentation of the Threshold Limit

                     Values, Supplemental Documentation for 1982\", p

                     172, Cincinnati, OH (1982)

         5.6         Nagano, K.; Nakayama, E.; Koyano, M.; Oobayaski,

                     H.; Adachi, H.; Yamada, T. Jap. J. Ind. Health

                     1979, 21, 29-35

         5.7         \"Current Intelligence Bulletin 39, Glycol

                     Ethers\"; May 2, 1983, U.S. Department of Health

                     and Human Services, Public Health Service,

                     Center for Disease Control, NIOSH

         5.8         Fed. Regist. 1987, 52 (No. 63, Thursday, April

                     2), 10586-10593

         5.9         \"Pocket Guide to Chemical Hazards\", NIOSH/OSHA,

                     Sept. 1978, DHEW (NIOSH) Publ. No. 78-210
  ------ ----------- ----------------------------------------------------

APPENDIX F - Qualitative and Quantitative Fit Testing
Procedures-Mandatory

I. Fit Test Protocols

A. The employer shall include the following provisions in the fit test
procedures. These provisions apply to both qualitative fit testing
(QLFT) and quantitative fit testing (QNFT)

1\. The test subject shall be allowed to pick the most comfortable
respirator from a selection including respirators of various sizes from
different manufacturers. The selection shall include at least three
sizes of elastomeric facepieces of the type of respirator that is to be
tested, i.e., three sizes of half mask; or three sizes of full
facepiece; and units from at least two manufacturers

2\. Prior to the selection process, the test subject shall be shown how
to put on a respirator, how it should be positioned on the face, how to
set strap tension and how to determine a comfortable fit. A mirror shall
be available to assist the subject in evaluating the fit and positioning
the respirator. This instruction may not constitute the subject\'s
formal training on respirator use, as it is only a review

3\. The test subject shall be informed that he/she is being asked to
select the respirator which provides the most comfortable fit. Each
respirator represents a different size and shape, and if fitted and used
properly, will provide adequate protection

4\. The test subject shall be instructed to hold each facepiece up to
the face and eliminate those which obviously do not give a comfortable
fit

5\. The more comfortable facepieces are noted; the most comfortable mask
is donned and worn at least five minutes to assess comfort. Assistance
in assessing comfort can be given by discussing the points in item 6
below. If the test subject is not familiar with using a particular
respirator, the test subject shall be directed to don the mask several
times and to adjust the straps each time to become adept at setting
proper tension on the straps

6\. Assessment of comfort shall include reviewing the following points
with the test subject and allowing the test subject adequate time to
determine the comfort of the respirator: (a) position of the mask on the
nose (b) room for eye protection (c) room to talk (d) position of mask
on face and cheeks

7\. The following criteria shall be used to help determine the adequacy
of the respirator fit: (a) chin properly placed; (b) adequate strap
tension, not overly tightened; (c) fit across nose bridge;

\(d\) respirator of proper size to span distance from nose to chin; (e)
tendency of respirator to slip;

\(f\) self-observation in mirror to evaluate fit and respirator position

8\. The test subject shall conduct the negative and positive pressure
fit checks as described below or ANSI Z88.2-1980. Before conducting the
negative or positive pressure test, the subject shall be told to seat
the mask on the face by moving the head from side-to-side and up and
down slowly while taking in a few slow deep breaths. Another facepiece
shall be selected and retested if the test subject fails the fit check
tests

(a). Positive pressure test. Close off the exhalation valve and exhale
gently onto the facepiece. The face fit is considered satisfactory if a
slight positive pressure can be built up inside the facepiece without
any evidence of outward leakage of air at the seal

For most respirators this method of leak testing requires the wearer to
first remove the exhalation valve cover before closing off the
exhalation valve and then carefully replacing it after the test

(b). Negative pressure test. Close off the inlet opening of the canister
or cartridge(s) by covering with the palm of the hand(s) or by replacing
the filter seal(s), inhale gently so that the facepiece collapses
slightly, and hold the breath for ten seconds. If the facepiece remains
in its slightly collapsed condition and no inward leakage of air is
detected, the tightness of the respirator is considered satisfactory

9\. The test shall not be conducted if there is any hair growth between
the skin and the facepiece sealing surface, such as stubble beard
growth, beard, or long sideburns which cross the respirator sealing
surface. Any type of apparel which interferes with a satisfactory fit
shall be altered or removed

10\. If a test subject exhibits difficulty in breathing during the
tests, she or he shall be referred to a physician trained in respiratory
disease or pulmonary medicine to determine whether the test subject can
wear a respirator while performing her or his duties

11\. The test subject shall be given the opportunity to wear the
successfully fitted

**\[page 15630\]**

respirator for a period of two weeks. If at any time during this period
the respirator becomes uncomfortable, the test subject shall be given
the opportunity to select a different facepiece and to be retested

12\. The employer shall certify that a successful fit test has been
administered to the employee. The certification shall include the
following information: (a) Name of employee; (b) Type, brand and size of
respirator; and (c) Date of test;

\(e\) Where QNFT is used, the fit factor, strip chart, or other
recording of the results of the test, shall be retained with the
certification. The certification shall be maintained until the next fit
test is administered

13\. Exercise regimen. Prior to the commencement of the fit test, the
test subject shall be given a description of the fit test and the test
subject\'s responsibilities during the test procedure. The description
of the process shall include a description of the test exercises that
the subject will be performing. The respirator to be tested shall be
worn for at least 5 minutes before the start of the fit test

14\. Test Exercises. The test subject shall perform exercises, in the
test environment, in the manner described below:

\(a\) Normal breathing. In a normal standing position, without talking,
the subject shall breathe normally

\(b\) Deep breathing. In a normal standing position, the subject shall
breathe slowly and deeply, taking caution so as to not hyperventilate

\(c\) Turning head side to side. Standing in place, the subject shall
slowly turn his/her head from side to side between the extreme positions
on each side. The head shall be held at each extreme momentarily so the
subject can inhale at each side

\(d\) Moving head up and down. Standing in place, the subject shall
slowly move his/her head up and down. The subject shall be instructed to
inhale in the up position (i.e., when looking toward the ceiling)

\(e\) Talking. The subject shall talk out loud slowly and loud enough so
as to be heard clearly by the test conductor. The subject can read from
a prepared text such as the Rainbow Passage, count backward from 100, or
recite a memorized poem or song

\(f\) Grimace. The test subject shall grimace by smiling or frowning

\(g\) Bending over. The test subject shall bend at the waist as if
he/she were to touch his/her toes. Jogging in place shall be substituted
for this exercise in those test environments such as shroud type QNFT
units which prohibit bending at the waist

\(h\) Normal breathing. Same as exercise 1. Each test exercise shall be
performed for one minute except for the grimace exercise which shall be
performed for 15 seconds

The test subject shall be questioned by the test conductor regarding the
comfort of the respirator upon completion of the protocol. If it has
become uncomfortable, another model of respirator shall be tried

B. Qualitative Fit Test (QLFT) Protocols

1\. General

\(a\) The employer shall assign specific individuals who shall assume
full responsibility for implementing the respirator qualitative fit test
program

\(b\) The employer shall ensure that persons administering QLFT are able
to prepare test solutions, calibrate equipment and perform tests
properly, recognize invalid tests, and assure that test equipment is in
proper working order

\(c\) The employer shall assure that QLFT equipment is kept clean and
well maintained so as to operate at the parameters for which it was
designed

2\. Isoamyl Acetate Protocol

\(a\) Odor threshold screening. The odor threshold screening test,
performed without wearing a respirator, is intended to determine if the
individual tested can detect the odor of isoamyl acetate. (1) Three
1-liter glass jars with metal lids are required

\(2\) Odor free water (e.g. distilled or spring water) at approximately
25 degrees C shall be used for the solutions

\(3\) The isoamyl acetate (IAA) (also known at isopentyl acetate) stock
solution is prepared by adding 1 cc of pure IAA to 800 cc of odor free
water in a 1 liter jar and shaking for 30seconds. A new solution shall
be prepared at least weekly

\(4\) The screening test shall be conducted in a room separate from the
room used for actual fit testing. The two rooms shall be well ventilated
but shall not be connected to the same recirculating ventilation system

\(5\) The odor test solution is prepared in a second jar by placing 0.4
cc of the stock solution into 500 cc of odor free water using a clean
dropper or pipette. The solution shall be shaken for 30 seconds and
allowed to stand for two to three minutes so that the IAA concentration
above the liquid may reach equilibrium. This solution shall be used for
only one day

\(6\) A test blank shall be prepared in a third jar by adding 500 cc of
odor free water

\(7\) The odor test and test blank jars shall be labeled 1 and 2 for jar
identification. Labels shall be placed on the lids so they can be
periodically peeled, dried off and switched to maintain the integrity of
the test

\(8\) The following instruction shall be typed on a card and placed on
the table in front of the two test jars (i.e., 1 and 2): \"The purpose
of this test is to determine if you can smell banana oil at a low
concentration. The two bottles in front of you contain water. One of
these bottles also contains a small amount of banana oil. Be sure the
covers are on tight, then shake each bottle for two seconds. Unscrew the
lid of each bottle, one at a time, and sniff at the mouth of the bottle.
Indicate to the test conductor which bottle contains banana oil.\"

\(9\) The mixtures used in the IAA odor detection test shall be prepared
in an area separate from where the test is performed, in order to
prevent olfactory fatigue in the subject

\(10\) If the test subject is unable to correctly identify the jar
containing the odor test solution, the IAA qualitative fit test shall
not be performed

\(11\) If the test subject correctly identifies the jar containing the
odor test solution, the test subject may proceed to respirator selection
and fit testing. (b) Isoamyl acetate fit test

\(1\) The fit test chamber shall be similar to a clear 55-gallon drum
liner suspended inverted over a 2-foot diameter frame so that the top of
the chamber is about 6 inches above the test subject\'s head. The inside
top center of the chamber shall have a small hook attached

\(2\) Each respirator used for the fitting and fit testing shall be
equipped with organic vapor cartridges or offer protection against
organic vapors. The cartridges or masks shall be changed at least weekly

\(3\) After selecting, donning, and properly adjusting a respirator, the
test subject shall wear it to the fit testing room. This room shall be
separate from the room used for odor threshold screening and respirator
selection,and shall be well ventilated, as by an exhaust fan or lab
hood, to prevent general room contamination

\(4\) A copy of the test exercises and any prepared text from which the
subject is to read shall be taped to the inside of the test chamber

\(5\) Upon entering the test chamber, the test subject shall be given a
6-inch by 5-inch piece of paper towel, or other porous, absorbent,
single-ply material, folded in half and wetted with 0.75 cc of pure IAA.
The test subject shall hang the wet towel on the hook at the top of the
chamber

\(6\) Allow two minutes for the IAA test concentration to stabilize
before starting the fit test exercises. This would be an appropriate
time time to talk with the test subject; to explain the fit test, the
importance of his/her cooperation, and the purpose for the head
exercises; or to demonstrate some of the exercises

\(7\) If at any time during the test, the subject detects the banana
like odor of IAA, the test has failed. The subject shall quickly exit
from the test chamber and leave the test area to avoid olfactory fatigue

\(8\) If the test has failed, the subject shall return to the selection
room and remove the respirator, repeat the odor sensitivity test, select
and put on another respirator, return to the test chamber and again
begin the procedure described in (1) through (7) above. The process
continues until a respirator that fits well has been found. Should the
odor sensitivity test be failed, the subject shall wait about 5 minutes
before retesting. Odor sensitivity will usually have returned by this
time

\(9\) When a respirator is found that passes the test, its efficiency
shall be demonstrated for the subject by having the subject break the
face seal and take a breath before exiting the chamber

\(10\) When the test subject leaves the chamber, the subject shall
remove the saturated towel and return it to the person conducting the
test. To keep the test area from becoming contaminated, the used towels
shall be kept in a self sealing bag so there is no significant IAA
concentration build-up in the test chamber during subsequent tests

3\. Saccharin Solution Aerosol Protocol

The saccharin solution aerosol QLFT protocol is the only currently
available, validated test protocol for use with

**\[page 15631\]**

particulate disposable dust respirators not equipped with
high-efficiency filters. The entire screening and testing procedure
shall be explained to the test subject prior to the conduct of the
screening test

\(a\) Taste threshold screening. The saccharin taste threshold
screening, performed without wearing a respirator, is intended to
determine whether the individual being tested can detect the taste of
saccharin

\(1\) Threshold screening as well as fit testing subjects shall wear an
enclosure about the head and shoulders that isapproximately 12 inches in
diameter by 14 inches tall with at least the front portion clear and
that allows free movements of the head when a respirator is worn. An
enclosure substantially similar to the 3M hood assembly, parts \# FT 14
and \# FT 15 combined, is adequate

\(2\) The test enclosure shall have a 3/4-inch hole in front of the test
subject\'s nose and mouth area to accommodate the nebulizer nozzle

\(3\) The test subject shall don the test enclosure. Throughout the
threshold screening test, the test subject shall breathe through his/her
wide open mouth with tongue extended

\(4\) Using a DeVilbiss Model 40 Inhalation Medication Nebulizer the
test conductor shall spray the threshold check solution into the
enclosure. This nebulizer shall be clearly marked to distinguish it from
the fit test solution nebulizer

\(5\) The threshold check solution consists of 0.83 grams of sodium
saccharin USP in 1 cc of warm water. It can be prepared by putting 1 cc
of the fit test solution (see (b)(5) below) in 100 cc of distilled water

\(6\) To produce the aerosol, the nebulizer bulb is firmly squeezed so
that it collapses completely, then released and allowed to fully expand

\(7\) Ten squeezes are repeated rapidly and then the test subject is
asked whether the saccharin can be tasted

\(8\) If the first response is negative, ten more squeezes are repeated
rapidly and the test subject is again asked whether the saccharin is
tasted

\(9\) If the second response is negative, ten more squeezes are repeated
rapidly and the test subject is again asked whether the saccharin is
tasted

\(10\) The test conductor will take note of the number of squeezes
required to solicit a taste response

\(11\) If the saccharin is not tasted after 30 squeezes (step 10), the
test subject may not perform the saccharin fit test

\(12\) If a taste response is elicited, the test subject shall be asked
to take note of the taste for reference in the fit test

\(13\) Correct use of the nebulizer means that approximately 1 cc of
liquid is used at a time in the nebulizer body

\(14\) The nebulizer shall be thoroughly rinsed in water, shaken dry,
and refilled at least each morning and afternoon or at least every four
hours. (b) Saccharin solution aerosol fit test procedure

\(1\) The test subject may not eat, drink (except plain water), or chew
gum for 15 minutes before the test

\(2\) The fit test uses the same enclosure described in (a) above

\(3\) The test subject shall don the enclosure while wearing the
respirator selected in section (a) above. The respirator shall be
properly adjusted and equipped with a particulate filter(s)

\(4\) A second DeVilbiss Model 40 Inhalation Medication Nebulizer is
used to spray the fit test solution into the enclosure. This nebulizer
shall be clearly marked to distinguish it from the screening test
solution nebulizer

\(5\) The fit test solution is prepared by adding 83 grams of sodium
saccharin to 100 cc of warm water

\(6\) As before, the test subject shall breathe through the open mouth
with tongue extended

\(7\) The nebulizer is inserted into the hole in the front of the
enclosure and the fit test solution is sprayed into the enclosure using
the same number of squeezes required to elicit a taste response in the
screening test

\(8\) After generating the aerosol the test subject shall be instructed
to perform the exercises in section I. A. 14 above

\(9\) Every 30 seconds the aerosol concentration shall be replenished
using one half the number of squeezes as initially

\(10\) The test subject shall indicate to the test conductor if at any
time during the fit test the taste of saccharin is detected

\(11\) If the taste of saccharin is detected, the fit is deemed
unsatisfactory and a different respirator shall be tried

4\. Irritant Fume Protocol

\(a\) The respirator to be tested shall be equipped with high-efficiency
particulate air (HEPA) filters

\(b\) The test subject shall be allowed to smell a weak concentration of
the irritant smoke before the respirator is donned to become familiar
with its characteristic odor

\(c\) Break both ends of a ventilation smoke tube containing stannic
oxychloride, such as the MSA part No. 5645, or equivalent. Attach one
end of the smoke tube to a low flow air pump set to deliver 200
milliliters per minute

\(d\) Advise the test subject that the smoke can be irritating to the
eyes and instruct the subject to keep his/her eyes closed while the test
is performed

\(e\) The test conductor shall direct the stream of irritant smoke from
the smoke tube towards the face seal area of the test subject. He/She
shall begin at least 12 inches from the facepiece and gradually move to
within one inch, moving around the whole perimeter of the mask

\(f\) The exercises identified in section I. A. 14 above shall be
performed by the test subject while the respirator seal is being
challenged by the smoke

\(g\) Each test subject passing the smoke test without evidence of a
response shall be given a sensitivity check of the smoke from the same
tube once the respirator has been removed todetermine whether he/she
reacts to the smoke. Failure to evoke a response shall void the fit test

\(h\) The fit test shall be performed in a location with exhaust
ventilation sufficient to prevent general contamination of the testing
area by the test agent

C. Quantitative Fit Test (QNFT) Protocol

1\. General

\(a\) The employer shall assign specific individuals who shall assume
full responsibility for implementing the respirator quantitative fit
test program

\(b\) The employer shall ensure that persons administering QNFT are able
to calibrate equipment and perform tests properly, recognize invalid
tests, calculate fit factors properly and assure that test equipment is
in proper working order

\(c\) The employer shall assure that QNFT equipment is kept clean and
well maintained so as to operate at the parameters for which it was
designed

2\. Definitions

\(a\) Quantitative fit test. The test is performed in a test chamber.
The normal air-purifying element of the respirator is replaced by a
high-efficiency particulate air (HEPA) filter in the case of particulate
QNFT aerosols or a sorbent offering contaminant penetration protection
equivalent to high-efficiency filters where the QNFT test agent is a gas
or vapor

\(b\) Challenge agent means the aerosol, gas or vapor introduced into a
test chamber so that its concentration inside and outside the respirator
may be measured

\(c\) Test subject means the person wearing the respirator for
quantitative fit testing

\(d\) Normal standing position means standing erect and straight with
arms down along the sides and looking straight ahead

\(e\) Maximum peak penetration method means the method of determining
test agent penetration in the respirator as determined by strip chart
recordings of the test. The highest peak penetration for a given
exercise is taken to be representative of average penetration into the
respirator for that exercise

\(f\) Average peak penetration method means the method of determining
test agent penetration into the respirator utilizing a strip chart
recorder, integrator, or computer. The agent penetration is determined
by an average of the peak heights on the graph or by computer
integration, for each exercise except the grimace exercise. Integrators
or computers which calculate the actual test agent penetration into the
respirator for each exercise will also be considered to meet the
requirements of the average peak penetration method

\(g\) \"Fit Factor\" means the ration of challenge agent concentration
outside with respect to the inside of a respirator inlet covering
(facepiece or enclosure)

3\. Apparatus

\(a\) Instrumentation. Aerosol generation, dilution, and measurement
systems using corn oil or sodium chloride as test aerosols shall be used
for quantitative fit testing

\(b\) Test chamber. The test chamber shall be large enough to permit all
test subjects to perform freely all required exercises without
disturbing the challenge agent concentration or the measurement
apparatus. The test chamber shall be equipped and constructed so that
the challenge agent is effectively isolated from the ambient air, yet
uniform in concentration throughout the chamber.

**\[page 15632\]**

\(c\) When testing air-purifying respirators, the normal filter or
cartridge element shall be replaced with a high-efficiency particulate
filter supplied by the same manufacturer

\(d\) The sampling instrument shall be selected so that a strip chart
record may be made of the test showing the rise and fall of the
challenge agent concentration with each inspiration and expiration at
fit factors of at least 2,000. Integrators or computers which integrate
the amount of test agent penetration leakage into the respirator for
each exercise may be used provided a record of the readings is made

\(e\) The combination of substitute air-purifying elements, challenge
agent and challenge agent concentration in the test chamber shall be
such that the test subject is not exposed in excess of an established
exposure limit for the challenge agent at any time during the testing
process

\(f\) The sampling port on the test specimen respirator shall be placed
and constructed so that no leakage occurs around the port (e.g. where
the respirator is probed), a free air flow is allowed into the sampling
line at all times and so that there is no interference with the fit or
performance of the respirator

\(g\) The test chamber and test set up shall permit the person
administering the test to observe the test subject inside the chamber
during the test

\(h\) The equipment generating the challenge atmosphere shall maintain
the concentration of challenge agent inside the test chamber constant to
within a 10 percent variation for the duration of the test

\(i\) The time lag (interval between an event and the recording of the
event on the strip chart or computer or integrator) shall be kept to a
minimum. There shall be a clear association between the occurrence of an
event inside the test chamber and its being recorded

\(j\) The sampling line tubing for the test chamber atmosphere and for
the respirator sampling port shall be of equal diameter and of the same
material. The length of the two lines shall be equal

\(k\) The exhaust flow from the test chamber shall pass through a
high-efficiency filter before release

\(l\) When sodium chloride aerosol is used, the relative humidity inside
the test chamber shall not exceed 50 percent

\(m\) The limitations of instrument detection shall be taken into
account when determining the fit factor

\(n\) Test respirators shall be maintained in proper working order and
inspected for deficiencies such as cracks, missing valves and gaskets,
etc

4\. Procedural Requirements

\(a\) When performing the initial positive or negative pressure test the
sampling line shall be crimped closed in order to avoid air pressure
leakage during either of these tests

\(b\) An abbreviated screening isoamyl acetate test or irritant fume
test may be utilized in order to quickly identify poor fitting
respirators which passed the positive and/or negative pressure test and
thus reduce the amount of QNFT time. When performing a screening isoamyl
acetate test, combination high-efficiency organic vapor
cartridges/canisters shall be used

\(c\) A reasonably stable challenge agent concentration shall be
measured in the test chamber prior to testing. For canopy or shower
curtain type of test units the determination of the challenge agent
stability may be established after the test subject has entered the test
environment

\(d\) Immediately after the subject enters the test chamber, the
challenge agent concentration inside the respirator shall be measured to
ensure that the peak penetration does not exceed 5 percent for a half
mask or 1 percent for a full facepiece respirator

\(e\) A stable challenge concentration shall be obtained prior to the
actual start of testing

\(f\) Respirator restraining straps shall not be overtightened for
testing. The straps shall be adjusted by the wearer without assistance
from other persons to give a reasonable comfortable fit typical of
normal use

\(g\) The test shall be terminated whenever any single peak penetration
exceeds 5 percent for half masks and 1 percent for full facepiece
respirators. The test subject shall be refitted and retested. If two of
the three required tests are terminated, the fit shall be deemed
inadequate

\(h\) In order to successfully complete a QNFT, three successful fit
tests are required. The results of each of the three independent fit
tests must exceed the minimum fit factor needed for the class of
respirator (e.g. half mask respirator, full facepiece respirator). (i)
Calculation of fit factors

\(1\) The fit factor shall be determined for the quantitative fit test
by taking the ratio of the average chamber concentration to the
concentration inside the respirator

\(2\) The average test chamber concentration is the arithmetic average
of the test chamber concentration at the beginning and of the end of the
test

\(3\) The concentration of the challenge agent inside the respirator
shall be determined by one of the following methods:

\(i\) average peak concentration

\(ii\) Maximum peak concentration

\(iii\) Integration by calculation of the area under the individual peak
for each exercise. This includes computerized integration

\(j\) Interpretation of test results. The fit factor established by the
quantitative fit testing shall be the lowest of the three fit factor
values calculated from the three required fit tests

\(k\) The test subject shall not be permitted to wear a half mask, or
full facepiece respirator unless a minimum fit factor equivalent to at
least 10 times the hazardous exposure level is obtained

\(l\) Filters used for quantitative fit testing shall be replaced at
least weekly, or whenever increased breathing resistance is encountered,
or when the test agent has altered the integrity of the filter media.
Organic vapor cartridges/canisters shall be replaced daily (when used)
or sooner if there is any indication of breakthrough by a test agent

\[FR Doc. 93-1277 Filed 1-26-93; 8:45

**Billing Code 4510-26-M**