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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,

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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),

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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,

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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 radiogaschromatography 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 coadministration 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.

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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 maternaldevelopmental 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,

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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 doseresponse 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 timeweighted 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]