M ention o f the name o f any company or product does not constitute endorsement by the N ational Institute for Occupational Safety and Health. This document is in the public domain and may b e freely copied or reprinted. C opies o f this and other NIOSH docum ents are available from Publications D issem ination, DSDTT# FOREWORD
The purpose o f the Occupational Safety and Health A ct o f 1970 (Public Law 9 1 -5 9 6 ) is to assure safe and healthful working conditions for every working person and to preserve our human resources. The A ct authorizes the National Institute for Occupational Safety and Health (NIOSH) to develop and recommend occupational safety and health standards and to develop criteria that w ill ensure that no worker w ill suffer dim inished health, functional capacity, or life expectancy as a result o f his or her work experience. Because lim ited data are available from studies in humans, NIOSH bases its recommended exposure lim its (RELs) for EGME, EGEE, and their acetates on data from studies in anim als. The data were adjusted to allow for uncertainties in the extrapolation from anim als to humans. NIOSH recommends that worker exposure to EGME and EGMEA in the workplace be lim ited to 0.1 part per m illion parts o f air (0.1 ppm) (0.3 mg EGME/m^ and 0.

# Through criteria documents, NIOSH communicates recommended standards to regulatory agencies, including the

# SECTION 1.2 EXPOSURE MONITORING
Exposure monitoring shall be conducted as specified in Sections 1.2.1 and 1.2.2. Results o f all exposure monitoring shall be recorded and maintained as specified in Section 1.9.

# Industrial Hygiene Surveys
In work areas where airborne exposures to EGME, EGEE, or their acetates may occur, the em ployer shall conduct initial industrial hygiene surveys to determine the magnitude o f exposure by using personal sam pling techniques for an entire workshift. The em ployer shall keep records o f these surveys. If the em ployer concludes that exposure concentrations for all g lycol ethers are less than one-half the REL, the records must show the basis for this conclusion. Surveys shall be repeated at least annually and w henever any process change is lik ely to increase concentrations o f airborne EGEE, EGME, EGEEA, and EGMEA. The em ployer shall also look for, evaluate, and record the potential for dermal exposure.

# Personal Monitoring
If workers are exposed to any g lyco l ether at or above one-half the REL, a program o f personal monitoring shall be instituted to identify and to measure or calculate the exposure o f each worker (see Section 8.8). Source and area monitoring may be a useful supplement to personal monitoring. In all personal monitoring, sam ples representative o f the TWA exposures to airborne g lycol ethers shall be collected in the breathing zone o f the worker. Procedures for sam pling and analysis shall be in accordance with Section 1.1.2. For each determination o f an occupational exposure concentration, a sufficient number o f sam ples (as determined in Leidel et al. ), shall be collected to characterize each worker's exposure during each workshift. Although not all workers must be monitored, a sufficient number o f sam ples must be collected to characterize the exposure o f all workers. Variations in work and production schedules as w ell as worker locations and job functions shall be considered when determining sam pling locations, tim es, and frequencies.
If a worker is exposed to EGME, EGEE, or their acetates at concentrations below the REL but at or above one-half the REL, the exposure o f that worker shall be monitored at least once every 6 months or more frequently, as indicated by a professional industrial hygienist. If a worker is exposed to one o f these glycol ethers at concentrations exceeding the REL, the worker must wear a respirator until adequate engineering controls and/or work practices are instituted. Controls shall then be initiated, the worker shall be notified o f the exposure and o f the control measures being implemented, and the worker's exposure shall be evaluated at least once a week. Such monitoring shall continue until tw o consecutive determinations at least 1 w eek apart indicate that the worker's exposure no longer exceeds the REL. At that tim e, semiannual monitoring can be resumed; if concentrations o f the g lycol ethers are less than one-half the REL after tw o consecutive sem iannual surveys, sam pling can be conducted annually.
A ll episodes o f skin contact shall be reported to a supervisor. T hese reports and the results o f any investigation or corrective action are to be retained with other records.

# Biological Monitoring
Measurement o f tw o glycol ether m etabolites-ethoxyacetic acid (EAA, the m etabolite o f EGEE and EGEEA) andmethoxyacetic acid (MAA, the metabolite o f EGME and EGM EA)-2 may help characterize occupational exposure to EG EE, EG ME, and their acetates w hen the potential exists for airborne concentrations at or above one-half the REL, or for dermal contact from accidental exposure a breakdown o f chemical protective clothing (see Section 5). G uidelines for biological monitoring are presented in Appendix G.

# SECTION 1.3 MEDICAL MONITORING
The em ployer shall provide the follow ing information to the physician performing or responsible for the m edical monitoring program:
- The requirements o f the applicable standard - A n estim ate o f the worker's potential exposure to g ly co l ethers, including any available results from workplace sampling
- A description o f the worker's duties as they relate to exposure
- A description o f any protective equipment the worker may be required to use

# General
- The em ployer shall institute a m edical monitoring program for all workers who are exposed to airborne concentrations o f EGEE, EGME, or their acetates at or above one-half the REL, or w ho have the potential for dermal exposure.
- If a worker has had a dermal exposure, the em ployer shall provide this information to the physician responsible for or performing the medical monitoring program.
- The em ployer shall ensure that all m edical exam inations and procedures are performed by or tinder the direction o f a licensed physician.
- The em ployer shall provide the required m edical monitoring at a reasonable time and place without loss o f pay or other co st to the workers.
- The em ployer shall institute a biological monitoring program for all workers who are exposed to airborne concentrations o f EGME, EGEE, or their acetates at or above one-half the REL, or w ho have the potential for dermal exposure. Guidelines for b iological monitoring are presented in Appendix G.

# Preplacem ent M edical Exam inations
Preplacement m edical exam inations shall include at least the follow ing:
- A com prehensive m edical, work, and reproductive history that em phasizes iden tification o f existing m edical conditions (e.g., those affecting die reproductive, hem atopoietic, and central nervous system s, skin, liver, and kidneys) and previous occupational exposure to chem ical or physical agents
- A medical examination giving special attention to the reproductive, hematopoietic, and central nervous systems, skin, liver, and kidneys
- Routine urinary monitoring for M AA and EAA before job placem ent, w hich may be a useful adjunct to environmental monitoring because it indicates both airborne and dermal exposures
- A judgment o f the worker's ability to use positive-and negative-pressure respirators

# Periodic Medical Exam inations
Periodic m edical exam inations shall be provided at least annually to all workers occupation ally exposed to airborne concentrations o f EGME, EGEE, and their acetates at or above one-half the REL, and to workers with the potential for dermal exposure. T hese exam ina tions shall include at least the follow ing:
- An update o f medical and work histories
- A m edical examination and tests as outlined above

# Medical Consultation
Workers w ho have a dermal exposure or w ho are exposed to concentrations o f EGME, EGEE, or their acetates above the REL should be given the opportunity to consult with a physician regarding possible adverse health effects, including reproductive and develop mental effects. OSHA Form 2 0 0 shall be m odified to include any reports o f dermal exposure.

# SECTION 1.4 LABELING AND POSTING
A ll labels and warning sign s shall be printed both in English and the predominant language o f workers who do not read English. Workers unable to read the labels and warning signs shall be informed verbally regarding the instructions printed on labels and signs in the hazardous work areas o f the plant.

# Labeling
Containers o f EGME, EGMEA, EGEE, or EGEEA used or stored in the workplace shall carry a permanently attached label that is readily visible. The label shall identify the gly co l ether and give information regarding its effects on human health and em ergency procedures (see Figure 1 -1 ).

# Posting
Signs bearing information about the health effects o f EGME, EGMEA, EGEE, or EGEEA shall be posted in readily visib le positions in work areas and at entrances to work areas or 4 building enclosures where the potential ex ists for exposures at or above the REL or where skin exposures may occur (see Figure 1-2).
If respirators and personal protective clothing are needed during the manufacturing or handling o f these g lycol ethers or during the installation or implementation o f required engineering controls, the follow in g statement shall be added in large letters to the signs required in this section:
Respirators and protective clothing are required in th is area.
In any area where emergency situations may arise, the required sign s shall be supplem ented with em ergency first-aid procedures and the locations o f em ergency show ers and eyew ash fountains.

# SECTION 1.5 PROTECTIVE CLOTHING AND EQUIPMENT
Engineering controls and good w ork practices shall be used to keep the airborne concentra tions o f EGME, EGEE, and their acetates below the REL and to prevent skin and eye contact. W hen protective clothing and equipment are needed, they shall be provided by the em ployer at no cost to the worker.

# Eye and Face Protection
The em ployer shall provide chem ical splash-proof safety goggles or face shields (20-cm minimum) with go ggles and shall ensure that workers wear the protective equipment during any operation in w hich splashes o f these glycol ethers are lik ely to occur. D evices for eye and face protection shall be selected, used, and maintained in accordance with 29 CFR 1910.133 and 30 CFR 56.150004, and 57.150004.

# Skin Protection
- Workers at risk o f dermal exposure to these g ly co l ethers shall be provided with appropriate protective clothing such as g lo v es and disposable clothing. Informa tion presented in Section 8.6.1 provides guidance in the selection o f appropriate materials for g loves and clothing.
- Clothing contaminated with these glycol ethers shall be cleaned before reuse. Anyone w ho handles contaminated clothing or is responsible for its cleaning shall be informed o f the hazards o f these glycol ethers and the proper precautions for their safe handling and use. EGME WARNING! Exposure may be harmful to the reproductive system and blood.

# CAUTION! Combustible
Harmful if Ingested, Inhaled, or absorbed through skin. Irritating to skin, eyes, nose, throat, mouth, and lungs.
- The em ployer shall ensure that all personal protective clothing and equipm ent is inspected regularly and maintained in a clean and satisfactory working condition.
- Protective clothing or gloves shall be evaluated on a routine basis to ensure that they are in good condition and no breakthrough has occurred.

# R espiratory Protection
Engineering controls and good work practices shall be used to control respiratory exposure to airborne contaminants. The use o f respirators is the least desirable method o f controlling worker exposures and should not be used as the primary control method during routine operations. H owever, NIOSH recognizes that respirators may be required to provide protection in certain situations such as implementation o f engineering controls, short-duration maintenance procedures, and em ergencies. Respirator selection guides for protection against EGEE, EGME, and their acetates are presented in Tables 1 -1 through 1 -3 .
- Respirators shall be provided by the em ployer when such equipment is necessary to protect the health o f the worker. The worker shall use the provided respiratory protection in accordance with instructions and training received.
- The em ployer shall ensure that respirators are properly fitted and that workers are instructed at least annually in the proper use and testing for leakage o f respirators assigned to them.
- Workers should not be assigned to tasks requiring the use o f respirators unless it has been determined that they are physically able to perform the work and use the equipment. The respirator user's m edical status should be review ed at least annually or more frequently as recommended by the physician responsible for the physical examination. See Appendix H for additional information about the m edical aspects o f wearing respirators.
- The employer shall be responsible for establishing and maintaining a respiratory protection program as follows:
1. Written standard operating procedures governing selection and use o f respirators shall be established.
2. The worker shall be instructed and trained in the proper use o f respirators and their lim itations.
Where practicable, the respirators should be assigned to individual workers for their exclu sive use.   i Recom m endations f o r Standards Table 1-2  5. Respirators shall be stored in a convenient, clean, and sanitary location.
6 . Respirators used routinely shall be inspected during cleaning. Worn or deteriorated parts shall be replaced. Respirators for emergency use (e.g., self-contained devices) shall be thoroughly inspected at least once a month and after each use.
7. The respiratory protection program shall be regularly evaluated by the employer to determine its continued effectiven ess. The em ployer shall notify the worker when exposure exceeds the REL in the w ork area to which he is assigned.

# Training
The Workers shall also be instructed about their responsibilities for follow in g proper work practices and sanitation procedures to help protect their health and provide for their safety and that o f their fellow workers.
A ll workers in areas where exposure to EGME, EGEE, or their acetates may occur during sp ills or em ergencies shall be trained in proper emergency and evacuation procedures.

# File of W ritten Hazard Communication
Required information shall be recorded on the material safety data sheet (see exam ple in Appendix D ) or on a sim ilar OSHA form that describes the relevant toxic, physical, and chem ical properties o f the g lycol ethers and mixtures o f glycol ethers that are used or otherwise handled in the workplace. T his information shall be kept on file and shall be readily available to workers for examination and copying.

# SECTION 1.7 ENGINEERING CONTROLS AND WORK PRACTICES

# Engineering Controls
Engineering controls shall be used as needed to maintain exposure to airborne g ly co l ethers within the lim its prescribed in Chapter 1.

# Local Exhaust Ventilation
Local exhaust ventilation may be effective when used alone or in com bination w ith process enclosure. When a local exhaust ventilation system is used, it shall be designed and operated to prevent accumulation or recirculation o f airborne glycol ethers in the workplace. Exhaust ventilation system s discharging to outside air shall conform with applicable local, State, and Federal air pollution regulations and shall not constitute a hazard to workers or to the general population. Before maintenance work on control equipment begins, the generation o f airborne g lycol ethers shall be elim inated to the greatest extent feasible.

# Maintaining Design Airflow
Enclosures, exhaust hoods, and ductwork shall be kept in good repair to maintain designed airflow s. Measurements such as capture v elocity, duct velocity, or static pressure shall be made at least sem iannually, and preferably m onthly, to demonstrate the effectiven ess (quantitatively, the ability o f the control system to maintain exposures below the REL) o f the mechanical ventilation system . NIOSH recommends the use o f continuous airflow indicators such as water or o il manometers marked to indicate acceptable airflow . A record shall be kept show ing design airflow and the results o f all airflow measurements. Measure ments o f the effectiven ess o f the system in controlling exposures shall also be made as soon as possible after any change in production, process, or control devices that may increase airborne concentrations o f EGME, EGEE, and their acetates.

# Forced-draft Ventilation
Forced-draft ventilation system s shall be equipped with remote manual controls and should be designed to shut o ff automatically in the event o f a fire.

# General W ork Practices
- Operating instructions for all equipment shall be developed and posted where EGME, EGEE, and their acetates are handled or used.
- Transportation, use, and disposal o f these glycol ethers shall com ply with all applicable lo ca l, State, and Federal regulations.
- These glycol ethers shall be stored in tightly closed containers and in well-ventilated areas.
- Containers shall be m oved only with the proper equipment and shall be secured to prevent loss o f control or dropping during transport.
- Storage facilities shall be designed to prevent contamination o f workroom air and to contain sp ills com pletely within surrounding dikes.
- Ventilation sw itches and em ergency respiratory equipment shall be located outside storage areas in readily accessible locations.
- Process valves and pumps shall be readily accessible and shall not be located in pits or congested areas.
- G lycol ether containers and system s shall be handled and opened with care. Approved protective clothing and equipment as specified in Section 1.5 shall be worn by workers w ho open, connect, and disconnect g ly co l ether containers and system s. Adequate ventilation shall be provided to m inim ize exposures o f such workers to airborne glycol ethers.
- G lycol ether storage equipment and system s shall be inspected daily for signs o f leakage. A ll equipment, including valves, fittings, and connections, shall be checked for leaks imm ediately after glycol ethers are introduced therein.
- When a leak is found, it shall be repaired promptly. W ork shall resume normally only after necessary repair or replacement has been com pleted and the area has been w ell ventilated.

# Confined or Enclosed Spaces
- A permit system shall be used to control entry into confined or enclosed spaces holding containers o f g lyco l ethers (e.g ., tanks, pits, tank cars, and process vessels) where egress is lim ited. Permits shall be signed by an authorized representative o f the em ployer and shall certify that preparation o f the confined space, precautionary measures, and personal protective equipment are adequate and that precautions have been taken to ensure that prescribed procedures w ill be follow ed.
- Confined spaces that hold containers o f EGME, EGEE, and their acetates shall be thoroughly ventilated, inspected, and tested for oxygen deficiency and for airborne concentrations o f these glycol ethers. Every effort shall be made to prevent the inadvertent release o f hazardous amounts o f these g ly co l ethers into confined spaces in w hich work is in progress. G iycol ether supply lines shall be discon nected or blocked o ff before such work begins.
- N o worker shall enter a confined space holding containers o f g ly co l ethers without an entry large enough to admit a worker wearing a safety harness, lifelin e, and appropriate personal protective equipment as specified in Section 1.5.
- C onfined spaces shall be ventilated w hile work is in progress to keep the concentra tion o f g lycol ethers below the RELs, to keep the concentration o f other con taminants below toxic or dangerous lev els, and to prevent oxygen deficiency.
- I f the concentrations o f these glycol ethers in the confined space exceed the RELs, respiratory protective equipment is required for entry.
- A nyone entering a confined space shall be observed from the outside by another properly trained and protected worker. An additional supplied-air or self-contained breathing apparatus with safety harness and lifelin e shall be located outside the confined space for em ergency use. The person entering the confined space shall maintain continuous communication with the standby worker.

# Em ergency Procedures
Emergency plans and procedures shall be developed for all work areas where there is a potential for exposure to EGME, EGEE, and their acetates. T hese plans and procedures shall include those specified below and any others considered appropriate for a sp ecific operation or process. Workers shall be instructed in the effective implementation o f these plans and procedures.
- The follow ing steps shall be taken in the event o f a leak or sp ill o f these g ly co l ethers:
-A ll nonessential personnel shall be evacuated from the leak or sp ill area.
-Persons not wearing the appropriate protective equipment and clothing shall be restricted from the leak or sp ill area until cleanup has been com pleted.
-A ll ignition sources shall be removed.
-The area where the leak or spill occurs shall be adequately ventilated to prevent the accum ulation o f vapor.
-EGME, EGEE, EGMEA and EGEEA shall be contained and absorbed with verm iculite, sand, paper tow els, or equivalent materials.
-Sm all quantities o f absorbed material shall be placed under a fume hood and sufficient tim e shall be allow ed for the liquid to evaporate and for the vapors to clear the ductwork in the hood.
-Large quantities o f absorbed material shall be burned in a suitable com bustion chamber.
-Absorbed materials shall be disposed o f as hazardous w aste.
-The sp ill area shall be cleaned with water.
- Only personnel trained in the emergency procedures and protected against the attendant g lycol ether hazards shall clean up sp ills and control and repair leaks.
- Personnel entering the spill or leak area shall be furnished w ith appropriate personal protective clothing and equipment. Other personnel shall be prohibited from entering the area.
 Safety show ers, eyew ash fountains, and washroom fa cilities shall be provided, maintained in working condition, and made readily accessib le to workers in all areas where skin or eye contact with EGME, EGEE, EGMEA, or EGEEA is likely.
If one o f these g lycol ethers is splashed or spilled on a worker, contaminated clothing shall be removed promptly, and the skin shall be washed thoroughly with soap and water. E yes splashed by these glycol ethers shall be irrigated im m ediately with a copious flow o f water for 15 min. If irritation persists, the worker should seek m edical attention.

# Storage
EGME, EGEE, and their acetates shall be stored in cool, w ell-ventilated areas and kept away from acids, bases, and oxidizing agents.

# Waste Disposal
A ll waste material shall be securely packaged in double bags, labeled, and incinerated. The incinerator residue shall be disposed o f in a manner consistent w ith Federal (EPA ), State, and local regulations, or it shall be disposed o f in a licensed hazardous waste landfill.

# SANITATION AND HYGIENE

# Food, Cosmetics, and Tobacco
The follow in g shall be prohibited in areas where EGME, EGEE, EGMEA, or EGEEA is produced or used: the storage, preparation, dispensing, or consumption o f food or beverages; the storage or application o f cosm etics; and the storage or use o f all tobacco products.

# Handwashing
The em ployer shall provide handwashing facilities and encourage workers to use them before eating, sm oking, using the toilet, or leaving the worksite.

# Laundering
- Protective clothing, equipment, and tools shall be cleaned periodically.
- The em ployer shall provide for the cleaning, laundering, or disposal o f con taminated work clothing and equipment.
- A ny person w ho cleans or launders this work clothing or equipment must be informed by the em ployer that it may be contaminated with EGME, EGEE, EGM EA, or EGEEA-chem icals that may cause adverse reproductive, develop mental, hem atologic (blood), and central nervous system (C N S) effects.

# Cleanup of W ork Area
The work area shall be cleaned at the end o f each shift (or more frequently if needed) using vacuum pickup. C ollected wastes shall be placed in sealed containers w ith labels that indicate the contents. Cleanup and disposal shall be conducted in a manner that prevents worker contact with w astes and com plies with all applicable Federal, State, and local regulations.

# Showering and Changing Facilities
Workers shall be provided with quick-drench show er fa cilities and w ith facilities for show ering and changing clothes at the end o f each workshift.

# RECORDKEEPING

# Exposure Monitoring
The em ployer shall establish and maintain an accurate record o f all exposure measurements required in Section 1.2. These records shall include the name o f the worker being monitored, social security number, duties performed and job locations, dates and tim es o f measure m ents, sam pling and analytical methods used, type o f personal protection used (if any), and number, duration, and results o f sam ples taken.

# Medical Monitoring
The em ployer shall establish and maintain an accurate record for each worker subject to the m edical monitoring specified in Section 1.3. Pertinent medical records (Le., the physician's written statement, the results o f m edical examinations and tests, m edical com plaints, reports o f skin exposure, etc.) shall be retained in the m edical files o f all workers subject to airborne concentrations o f EGME, EGEE, EGMEA, or EGEEA in the workplace at or above one-half the REL. C opies o f applicable environmental monitoring data shall also be included in the worker's m edical file.

# Record Retention
In accordance with the requirements o f 29 CFR 1910.20(d) (Preservation o f Records), the em ployer shall retain the records described in Sections 1.2, 1.3, and 1.6 for at least the follow ing periods:
- 30 years for exposure monitoring records, and
- the duration o f employm ent plus 3 0 years for medical surveillance records

# Availability of Records
- In accordance with 29 CFR 1910.20 (A ccess to Em ployee Exposure and M edical Records), the em ployer shall allow examination and copying o f exposure monitor ing records by the subject worker, the former worker, or anyone having the sp ecific written consent o f the subject or former worker.
- Any m edical records required by this recommended standard shall be provided upon request for examination and copying to the subject worker, the former worker, or anyone having the sp ecific written consent o f the subject or former worker.

# Transfer of Records
If the em ployer ceases to do business and no successor is available to receive and retain the records for the prescribed period, the em ployer shall notify the NIOSH has formalized a system for developing criteria on w hich to base standards for ensuring the health and safety o f workers exposed to hazardous chem ical and physical agents. Sim ple com pliance with these standards is not the only goal. The criteria and recommended standards are intended to help management and labor develop better engineer ing controls and more healthful work practices.
Recommended standards for EGEE, EGME, EGEEA, and EGMEA apply on ly to workplace exposures arising from the processing, manufacturing, handling, and use o f these glycol ethers. The recommendations are not designed for the population at large, and any extrapolation beyond the occupational environment may not be warranted. The recommended standards are intended to protect workers from the acute and chronic effects o f EGEE, EGME, EGEEA, and EGMEA. Exposure concentrations are measurable by techniques that are valid, reproducible, and available to industry and government agencies.

# SCOPE
The

# PRODUCTION METHODS AND USES
The ethylene glycol monoalkyl ethers EGME and EGEE are usually produced by a reaction o f ethylene oxide with m ethyl or ethyl alcohol, but may also be made by the direct alkylation o f ethylene glycol with an alkylating agent such as dim ethyl or diethyl sulfate . Temperature, pressure, reactant molar ratios, and catalysts are selected to give the product m ix desired. Ethylene g ly co l monoalkyl ethers are not formed as pure com pounds, but must be separated from the diethers o f diethylene g ly co l, triethylene g ly co l, and the higher glycols. Ethylene glycol monoalkyl ether acetates are prepared by esterifying the particular g ly co l ether with acetic acid, acetic acid anhydride, or acetic acid chloride.
G lycol ethers and their acetates are w idely distributed and have been used com m ercially for more than 50 years.

# PROCESS AND WORKER JOB DESCRIPTIONS
The usefulness o f g lycol ethers and their acetate derivatives can be attributed to their physical properties, particularly their m iscibility or high solubility in water and other organic solvents, and their low vapor pressures. T hese properties allow them to serve a number o f functions in a variety o f products. The follow ing information was obtained during surveys conducted in various industries to determine occupational exposures to g ly co l ethers .

# Paints and Coatings
Although frequently com prising less than 10% o f the final product, g ly co l ethers serve a variety o f important functions in paints and coatings. One function is as a solvent to keep  .
the various paint com ponents in solution. Latex coatings contain g ly co l ethers or their acetate derivatives to enhance the coalescing properties o f the product w hen applied. B y slow ing the evaporation rate, g lycol ethers reduce moisture condensation or "blush." They also improve the penetration and bonding qualities o f paints and coatings. Specialty products, such as aircraft or electrostatic paints, may contain 18% to 35% g ly co l ethers .
The manufacture o f paints and coatings is a batch process. Components are added manually or through a closed piping system to the m ixing tank. B ecause g ly co l ethers generally constitute a sm all percentage o f the total formulation, they are often added manually. After m ixing, the product is packaged according to customer specifications. A variety o f industries use paints and coatings, but as previously noted, these products usually contain a sm all percentage o f g ly co l ethers (i.e ., less than 10%). Lacquer containing less than 1 % glycol ethers is used to coat w ood products. H owever, electrostatic paints used in a spraying process for metal parts may contain 20% to 30% g ly co l ethers. G lycol ethers are also used in the manufacture o f coated fabrics. These fabrics pass through a dip pan to pick up the coating and then rise through a ventilated drying tower .

# Cleaners and Cleaning Solvents
Cleaning agents that contain glycol ethers are spot removers, carburetor cleaners, metal cleaners, and glass cleaners. In these products, glycol ethers function as surface active agents, enhancing the penetration o f the product, clarifying the appearance, and in glass cleaners, increasing the viscosity. The percentage o f glycol ethers in these products is less than 5% .

# NUMBER OF WORKERS POTENTIALLY EXPOSED
Based on information from the National Occupational Exposure Survey (NOES) , the estim ated number o f workers potentially exposed to g ly c o l ethers in the workplace during the period 1981 to 1983 is as shown in  Both children underwent surgery in the follow ing years. The perineal and the penile hypospadias were corrected, chordee was removed in both children, and the undescended testes were removed to the scrotum. 'Hie older child was treated with chronic gonadotrophin, w hich led to norm al-sized testes.
The authors stated that the risk o f isolated hypospadia was betw een 1 in 300 and 1 in 1,800, w hile the risk for a boy w hose brother has hypospadia w as 1 in 24. T hey indicated that both the family history and medical examinations showed no overt risks other than the pronounced exposure o f the mother to EGMEA during fetal development. The authors concluded that the hypospadias were actually caused by exposure to EGMEA.
There is only one case report that describes the effects o f EGEE [Fucik 1969   N o statistically significant differences were found in hem atology test results, hormone lev els, or sperm counts between the exposed workers and the controls. The investigators suggested that testicular size may have been reduced; how ever, the decrease in size approached but did not reach statistical significance (P < 0.05) in either length (F -0 .1 9 ) or width (P -0 .0 8 ).

# Market a n d M oody 
In

# Boiano 
NIOSH conducted a health hazard evaluation in 1983 to evaluate worker exposure to two solvent cleaners, an im age remover, and the paint remover used in a silk screening process . The silk screener using the im age remover was monitored for exposure to EGEEA and cyclohexanone, w hile the worker using the paint remover was monitored for a variety o f organic solven ts, one o f which was EGEEA. A lthough the workers were primarily exposed by inhalation, they may have also been exposed by skin absorption because personal protective clothing was not alw ays worn. The workers com plained o f headaches, lethargy, sinus problems, nausea, and heartburn. When they were away from work, their symptom s improved. The silk screener using im age remover had TW A ex posures to EGEEA ranging from 1.3 to 3.3 ppm, with short-term excursions to 3.8 ppm. The silk screener using paint remover had TW A exposures to EGEEA ranging from 0 .5 to 3.9 ppm, with a short-term excursion to 4 .0 ppm. Measured airborne exposures thus were 32 below occupational standards, but absorption through the skin may have contributed to the workers' overall exposure . 4.1.2.5 G u n te r  In 1985, NIOSH conducted a health hazard evaluation o f production areas at a plant that manufactured solid-state electronic circuits [Gunter 1985
Ratctiffe e ta l.  NIOSH conducted an evaluation for possible adverse effects on testicular function in male workers potentially exposed to EGEE during the preparation o f ceram ic sh ells used to cast metal parts

# Welch etal.
, Sparer etal. , and  The effect o f com bined EGME and EGEE exposure on the reproductive potential o f men w ho worked in a large shipbuilding facility was recently studied . This site was selected for study because o f a previous health hazard evaluation     , which demonstrated that ADH has a higher affinity for ethanol than for the gly co l ethers . This finding confirmed the hypothesis that EGEEA is first converted to EGEE by esterases [Groeseneken et al. 1987a A detailed description o f the preceding studies may be found in Appendix B.

# EFFECTS ON ANIMALS
Although kidney and liver dam age, hem atologic, CN S, reproductive, and teratogenic effects have been observed in experimental animals exposed to glycol ethers and their acetates, the type and severity o f the response induced by each g ly co l ether are not identical. Therefore, each glycol ether and its corresponding acetate w ill be discussed separately follow ing Section 4.3.1.

# Acute Toxicity
Many experim ents investigating the acute toxicity o f glycol ethers to anim als have been performed. These investigations led to the establishm ent o f a lethal concentration or lethal dose for 50% o f the exposed animals (LC50 or LDjq) in a variety o f sp ecies by a variety o f routes (inhalation, oral, dermal, injection). A summary o f the available data by animal species is presented in Table 4 -1 .

# O ral Adm inistration
The toxicity o f glycol ethers has been studied more extensively by oral administration than by any other route. concentrations ranged from 500 to 6,0 0 0 ppm and were administered over a period o f 1 to 24 hr. Guinea pigs exposed to 6 ,0 0 0 ppm for 24 hr exhibited inactivity, w eakness, and dyspnea, and died by the end o f the exposure; 3,0 0 0 ppm for 24 hr caused death within 24 hr follow in g exposure; and exposure to 6,0 0 0 ppm for 10 hr, and 3,000 ppm or 1,000 ppm for 18 hr, caused death 1 to 8 days follow ing exposure. Exposure to 6,0 0 0 ppm for 1 hr, 3 .000 ppm for 4 hr, and 500 ppm for 14 hr caused no apparent harm. G ross pathological exam inations o f anim als that died during and up to tw o days after exposure revealed congestion and edema o f the lungs, distended and hemorrhagic stom achs, and congested kidneys. Ten male and ten fem ale rats and tw o male and tw o fem ale rabbits were exposed to 2.000 ppm EGEEA for 4 hr . O nly in rabbits w as there a slight and transient hemoglobinuria or hematuria; no gross pathological lesion s w ere noted in either species.

# D erm al Exposure
A m odified Draize "slee v e " technique was used to study the acute dermal toxicity o f EGEEA in rabbits . Death generally occurred 24 to 48 hr after the application o f 10,500 m g EGEEA/kg. Although hemoglobinuria and/or hematuria were observed, there w as little variation in Hb concentration and the number o f RBCs (less than 15% to 20%) in blood; how ever, there was a considerable decrease in the number o f W BCs (50% to 70%). In surviving anim als, the WBC counts gradually returned to normal. Necropsy revealed bloody kidneys and blood in the bladder. W hen survivors were exam ined after the 2-w eek observation period, no gross lesions were noted.       . In another study , EGEEA caused an increase in W BC levels.

# EGM E and EGMEA
The

# EGME, EGEE, and Their Acetates

# Mutagenicity

# In Vitro Toxicity
The

# EGME, EGEE, and Their Acetates

# Cytotoxicity
The in vitro cytotoxicities o f EGME, EGEE, and their corresponding alkoxyacetic acids (M AA and EAA) were studied using CHO cells . CHO ce lls were seeded into culture flasks, and after 4 to 5 hr test material was added to the medium. After 16 hr the medium w as renewed and the cells were allow ed to grow in colon ies for 6 to 7 days prior to counting.

# RECOGNITION OF THE HAZARD
Each em ployer who manufactures, transports, packages, stores, or u ses EGME, EGEE, or their acetates in any capacity should determine the potential for occupational exposure o f any worker at or above the action level (one-half the REL). - The charcoal in the sam pling tube is transferred to a sm all, stoppered sample container, and the analyte is desorbed. EGME, EGEE, EGMEA, and EGEEA may be desorbed from the charcoal with m ethylene chloride and 5% (v/v) methanol.

# ENVIRONMENTAL SAMPLING
- An aliquot o f the desorbed sample is injected into a gas chromatograph w ith a flam e ionization detector.
- The area o f the resulting peak is determined and compared with areas obtained from the injection o f standards.
The detailed analytical method is described in Appendix A .   - Periodic medical examinations. The aforementioned m edical exam inations should be performed annually for all workers occupationally exposed to EGEE, EGME, or their acetates at or above the action lev els, and for all w ho have the potential for significant skin exposure.

# E G M E E G M E A E G E E E G E E

# BIOLOGICAL MONITORING
B iological monitoring may be a useful adjunct to environmental monitoring in assessing worker exposure to EGME, EGEE, and their acetates. B iological monitoring includes the influence o f workload and percutaneous absorption.

# Justification for Biological Monitoring
Human experimental inhalation studies have demonstrated the uptake o f EGEE , EGEEA , and EGME .
Studies that included different workloads in the experimental design  demonstrated a linear relationship betw een the workload and uptake o f each glycol ether; a linear relationship was also found for the exposure concentration and uptake.
Table 5 - Nakaaki et al.  demonstrated that 10 tim es more EGME w as absorbed through the forearm than acetone or methanol.
Johanson 

# Selection of Monitoring Medium
A variety o f biological monitoring media can be used to assess uptake (e.g ., expired air, blood, urine). Groeseneken et al. [1986bGroeseneken et al. [ , 1987aGroeseneken et al. [ , 1989a  - Expected concentrations for these metabolites at the proposed RELs can also be measured by the recommended analytical method (see Appendix F).
- The acid metabolites are associated with the reproductive and hem atologic toxicity o f EGEE, EGME, and their acetates, and may reflect the concentration o f the "active agent" at the target sites.
- The half-lives o f the acid m etabolites in urine are suitable for exposure monitoring and can reflect integrated exposures over a workweek [Groeseneken et al. 1989a[Groeseneken et al. , 1988. The half-life for MAA is 77 hr and for EAA is 42 to 48 hr.
- C ollection o f urine sam ples is a noninvasive procedure.      Full-shift personal breathing zone exposures o f EGEE ranged from 3 to 14.5 ppm for workers in the investing areas. R atcliffe et al.  reported that recoveries o f EGEE in three quality control sam ples w ere as low as 69% indicating that the measured airborne concentrations could have been underestimated.

# Limitations of Biological Monitoring
Urine sam ples were collected as voided during a 24-hr period from three EGEE-exposed workers and two controls (unexposed workers). In the June survey, area sam ples averaged 2 .4 to 14.9 ppm. Personal breathing zone sam ples averaged 8.1 ppm for grabber operators, 4.5 ppm for shell processors, and 5 .0 ppm for investm ent room supervisors. In this case, spot urine sam ples were collected at random over a 7-day period. Table 5 -     A wide range of EAA concentrations was noted in workers using EGEE-containing paints; this was probably caused by variation in work assignments, work areas, work practices, and in the use of personal protective equipment. The author concluded that there appeared to be a relationship between urinary EAA excretion and the use of paints containing EGEE .
The health hazard evaluation demonstrated that the potential existed for exposure of painters to EGEE and EGME. Because of the complexity of the work environment and the variable use of personal protective equipment, no dose-response relationship could be developed. However, at the exposure concentrations measured, painters who used paints with EGEE did excrete more EAA in the urine than painters who did not use EGEE-containing paints. Sparer et al.  and  examined some of the same workers from the health hazard evaluation. (These studies are discussed in detail in Section 4.1.) The authors concluded that exposure to EGEE and EGME lowered sperm counts in the painters. In addition, they concluded that when smoking was controlled the painters had an increased odds ratio for a lower sperm count per ejaculate ],
However, it would be inappropriate to conclude that the EGEE and EGME exposure concentrations presented in the health hazard evaluation  were representative of the chronic exposure of shipyard workers who participated in the semen study ]. In addition, it cannot be concluded that marginally (but not statistically significant) lowered sperm counts were caused by exposure concentrations measured in the health hazard evaluation .

# EGME
No studies have evaluated the relationship between EGME exposure in the workplace and urinary MAA concentration. Results of the study by Groeseneken et al.  have provided the following information regarding MAA excretion in urine.
- The relatively long urinary elimination half-life of MAA (77 hr) suggests that MAA would be expected to accumulate during the workweek. If biological monitoring were done, urine specimens collected at the end of the week, or possibly prior to the first shift of the week, would be appropriate.
- Sixty percent of the urine specimens from this study contained MAA at concentra tions below 2 mg/liter. If 4-hr exposures are extrapolated to 8~hr exposures, based on linear kinetics, then subjects exposed to 5.1 ppm at rest would be expected to have 60% of their urine samples with MAA concentrations below 4 mg/liter. If exposures were 1/10 of those from this study (i.e., 0.5 ppm) then 6096 of the urine specimens would be expected to have less than 0.4 mg/liter of MAA , The limit of quantitation for MAA was reported to be 0,1 mg/liter . Higher concentrations of MAA would be expected with exercise.
Although dermal absorption was not studied, dermal uptake of EGME is a potential route of exposure. Dugard et al.  demonstrated in vitro absorption of EGME through human abdominal skin. Nakaaki et al.  also demonstrated dermal penetration of EGME through the forearm of human volunteers. Johanson  suggested that dermal uptake of EGME is possibly the major route of exposure.
Thus, in spite of the lack of quantitative relationships between EGME exposure and MAA excretion in urine, measurement of MAA in urine is warranted. The potential for extensive skin absorption, and the potential buildup of the active urinary metabolite MAA during the workweek, are reasons to measure MAA in urine as an exposure index. In addition, measurement of MAA in urine may be useful as an indicator of the potential for adverse reproductive effects.

# Methods fo r Analyzing Urinary EAA and MAA
A variety of methods have been developed for the analysis of EAA and MAA in human urine. Gas chromatographic procedures are based on either fluoranhydride derivatization following the extraction of the acid tetrabutylammonium ion-pair . Groeseneken etal.  developed a method that combined the best attributes of the two basic existing models. Detailed descriptions of the above methods are presented in Appendix H.

# Summary
EGEE, EGME, and their acetates are metabolized to their respective alkoxyacetic acid metabolites, EAA and MAA, which are excreted in the urine. EAA and MAA have produced reproductive and hematotoxic effects noted for glycol ethers. These glycol ethers can also be absorbed through the skin. In fact, the major route of exposure to EGME and EGEE may be through the skin . Thus, monitoring of these acids may serve not only as a measure of exposure or uptake, but also as a measure of potential adverse health effects.
The alkoxyacetic acid metabolites may be analyzed by a variety of sensitive and specific methods. The recently developed method of Groeseneken et al.  has sufficient sensitivity to monitor excretion of these metabolites at the recommended RELs.
Results from human laboratory inhalation exposure studies indicated that EAA in urine could be used to monitor uptake of EGEE and EGEEA .
Investigations of occupational exposure also revealed a correlation between urinary EAA excretion and repeated daily inhalation exposure of workers to a mixture of EGEE and EGEEA . Data showed the accumulation of EAA following repeated daily exposures to EGEE and EGEEA. The estimated elimination half-life of EAA was 48 hr.
Two other worksite investigations of occupational exposure to EGEE demonstrated the utility of EAA in urine to assess uptake of EGEE regardless of the route of exposure [Ratcliffe et al. 1986;Clapp et al. 1987;Lowry 1987;McManus et al. 1989;Sparer et al. 1988;.
Experimental studies were conducted in which humans were exposed to EGME. Results of these studies indicated that measurement of urinary MAA could be used to assess uptake of EGME. The concentration of MAA peaked several hr after exposure ended, and MAA was eliminated with a half-life of 77 hr. Examination of the elimination kinetics showed that MAA would accumulate following repeated daily exposures, and could also accumulate over extended exposure periods.
Insufficient information is available at present to construct a dose-response plot that would provide statistically sound guidelines for the concentration of alkoxyacetic acid metabolites in urine that would correspond to an airborne exposure to glycol ethers. Table 5-11 presents a summary of the laboratory and occupational dose-response data. In 1971, OSHA adopted the current Federal standards for worker exposure to EGME, EGMEA, EGEE, and EGEEA, which are based on the American Conference of Governmen tal Industrial Hygienists (ACGEH) 1968 Threshold Limit Values (TLVs). These TLVs were based on the hematotoxic and neurotoxic effects and exposure concentrations reported in the early case reports of human health effects . The OSHA PELs include a "skin'' notation, indicating the potential for skin absorption of toxic amounts of these glycol ethers.
The OSHA PELs for occupational exposure to the glycol ethers are as follows: 25 ppm (80 mg/m3) for EGME, 25 ppm for EGMEA (120 mg/m3), 200 ppm (740 mg/m3) for EGEE, 100 ppm (540 mg/m3) for EGEEA, as TWAs for an 8 -hr workshift [29 CFR 1910[29 CFR .1000. OSHA is considering a revision of these PELs.
NIOSH has previously recommended that EGME and EGEE 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 female, and that occupational exposure to them should be reduced to the lowest extent possible . These recommendations were based on the results of animal studies that demonstrated dose-related embryotoxicity and other reproductive effects in several species of animals exposed by different routes of administration .
In 1946, ACGIH established maximum allowable concentrations (m.a.c.s) of 100 ppm for EGME, EGMEA, and EGEEA, and 200 ppm for EGEE , In 1947, the m.a.c.s for EGME and EGMEA were lowered to 25 ppm because of the Greenburg et al.  study in which neurologic and hematologic changes were observed in men exposed to EGME at concentrations estimated to be as low as 25 ppm. The m.a.c. for EGMEA was lowered because the toxic effects caused by it were likely to be similar to those caused by EGME as a result of EGMEA's metabolism to EGME and then to the active metabolite [ACGIH 1962[ACGIH ,1984. Although the values remained unchanged, the term "threshold limit value" was substituted for m.a.c. in 1948.
In 1968, the notation "skin" (indicating the potential for skin absorption of toxic amounts of a compound) was added to the TLVs for EGME, EGEE, EGMEA, and EGEEA. In 1971, ACGIH lowered the TLV for EGEE from 200 to 100 ppm to prevent irritation of the nose and eyes . In 1981, the ACGIH adopted TLVs of 50 ppm for EGEE and EGEEA, each with a short-term exposure limit (STEL) of 100 ppm; in 1987-88, the STELs were deleted . The TLVs were lowered because of adverse hematologic effects observed in laboratory animals . Changes in rat erythrocyte fragility were produced by 125 ppm EGEE but not by 62 ppm. ACGIH deemed it prudent to maintain chemical exposures below levels found to cause blood changes in experimental animals. Because the TLV of 100 ppm for EGEEA was based on analogy with EGEE, it was logical to establish a similar TLV of 50 ppm for its acetate .
Reports of adverse testicular effects in experimental animals treated with EGME, EGEE, and their acetatesJNagano et al. 1979] led ACGIH to lower the TLVs for these compounds. The 5-ppm TLV for EGME, EGMEA, EGEE, and EGEEA as an 8 -hr TWA was adopted in 1984, and the "skin" notation was retained.  The principal health effects documented in humans exposed to EGEE, EGME, and their acetates involve the blood, central nervous and hematopoietic systems, liver, and kidneys. These effects include headache, drowsiness, dizziness, forgetfulness, personality change, loss of appetite, tremors, hearing loss, slurred speech, hematuria, hemoglobinuria, anemia, and leukopenia.
Only limited direct evidence indicates that exposure to EGEE, EGME, or their acetates causes adverse reproductive effects in humans. However, experimental studies in animals provide strong evidence of adverse reproductive and developmental effects related to these exposures. Summaries of the developmental and reproductive toxicity of EGEE, EGEEA, and EGME are presented in Tables 7-1 through 7-3. Because humans and the animal species studied metabolize these glycol ethers in the same way, the animal data are considered to be highly predictive of the hazard for humans.

# CORRELATION OF EXPOSURE AND EFFECTS

# EGEE

# Studies in Humans
No epidemiologic studies describe the effects of EGEE in humans, and only one case report exists. A 44-year-old woman who mistakenly drank 40 ml of EGEE (Section 4.1.1) experienced chest pains and vertigo, and lost consciousness shortly after the ingestion . Upon hospitalization, the following signs and symptoms were observed: restless ness, cyanosis, tachycardia, swelling of the lungs, tonoclonic spasms, and breath smelling of acetone. The urine tested positive for protein, acetone, and RBCs; the liver became enlarged and jaundice developed. After 44 days, the woman's condition improved, but insomnia, fatigue, and paresthesia of the extremities persisted for 1 year.
Several cases of anemia were reported in shipyard workers exposed to EGEE and EGME, and all cases were suspected to have been caused by the exposure .
A detailed description of this study is provided in Chapter 4.
Few data are available on the reproductive effects of EGEE in humans. Ratcliffe et al.  concluded that EGEE may have affected the semen quality by lowering the sperm counts of male workers exposed to this chemical during the preparation of ceramic shells for casting  ------------------------------------------------------------------------------------ ------------------------------------------------------------------------------------ -------------------------- ------------------------------------------------------------------------------------ ------------------------------------------------------------------------------------ ------------------------------------------------------------------------------------  ]. The potential also existed for skin absorption. In addition, the shipyard painters had been exposed to EGME, lead, and epichlorohydrin, all of which have been reported to affect semen quality. Airborne concentrations of lead were well below those known to depress sperm count. Most blood lead concentrations were below 20 pg%, with the highest single concentration being 40 g%. Epichlorohydrin was not detected in the air sampling during the study .

# Studies In Animals
Studies in animals have provided evidence of adverse reproductive and developmental effects from EGEE exposure (see Appendix B). The LOAELs and the NOAELs of the following studies were used in determining the REL for EGEE.
Testicular atrophy occurred in mice given oral doses of EGEE (1,000 mg/kg of body weight per day or more), for 5 days/wk during a 5-wk period. The NOAEL noted in this study was 500 mg EG EE/kg per day ], Decreased testis weight, spermatocyte depletion and degeneration, and microscopic testicular lesions were observed in rats treated with 500 or 1,000 mg EGEE/kg per day for 11 days ; no effects were observed at 250 mg/kg. Decreased sperm counts, abnormal sperm morphology, and decreased epididymal weights were found in rats given oral doses of 936, 1,872, or 2,808 mg EGEE/kg per day for 5 days . A no-effect level was not included in this study. Stenger et al.  treated male rats orally with 46.5, 93, or 186 mg EGEE/kg per day for 13 wk. Microscopic testicular lesions were found only at doses of 186 mg EGEE/kg per day.
Rats and rabbits of both sexes were exposed to 0,25,100, or 400 ppm EGEE for 6 hr/day, 5 days/wk over a 13-wk period . At the highest exposures (400 ppm EGEE), reduced testicular weights and microscopic testicular lesions were observed in rabbits, and reduced pituitary weights were observed in male rats. Reduced body weights were observed in male and female rabbits at 25 and 400 ppm EGEE, and reduced spleen weights were found in nonpregnant female rats at 100 and 400 ppm EGEE.
Studies have demonstrated adverse effects on the dam and the developing fetus. Stenger et al.  treated rats orally with 11.5, 23,46.5,93, 186, or 372 mg EGEE/kg per day on g.d. 1 through 21. Decreased fetal body weights and skeletal defects were demonstrated at 93, 186, and 372 mg/kg per day. No effects were noted at 11.5, 23, or 46.5 mg/kg per day.
In rabbits exposed to EGEE for 7 hr/day on g.d. 1 through 18, maternal toxicity and embryolethality were observed at 615 ppm, and embryolethality (22%), skeletal variations, renal and cardiovascular defects, and decreased maternal food consumption were observed at 160 ppm . No effects were apparent on fertility or pregnancy outcome when female rats were exposed to 150 or 650 ppm EGEE for 7 hr/day, 5 days/wk during the 3 wk before breeding. Toxic signs were noted in female rats exposed at 650 ppm, but none were observed at 150 ppm. However, when pregnant rats were exposed to 765 ppm EGEE for 7 hr/day on g.d. through 19, 100% intrauterine death occurred. Similar exposure at 200 ppm EGEE significantly increased fetal cardiovascular and skeletal defects. These effects on development were not influenced by exposures to filtered air or EGEE before pregnancy .
In rats exposed 6 hr/day to 250 ppm EGEE on g.d. 6 through 15, investigators observed increased postimplantation loss, retarded fetal growth, decreased ossification, and increased skeletal variations; they found no effects on fetuses at 50 or 10 ppm EGEE , Fetal skeletal variations were found in rabbits exposed 6 hr/day to 175 ppm EGEE on g.d. 6 through 18; no effects were found in fetuses at 10 or 50 ppm EGEE .
Exposure of pregnant rats to 100 ppm EGEE on g.d. 14 through 20 caused extended gestation (0.7 day), and exposure to 100 ppm EGEE on g.d. 7 through 13 or 14 through 20 caused altered behavioral responses and altered brain neurochemical concentrations in offspring .
Effects on the fetus were also demonstrated in a dermal application study of EGEE . Four daily doses of 0.25 or 0.50 ml EGEE were applied to rats on g.d. 7 through 16. The higher dose resulted in decreased maternal body weight gain, ataxia, and 100% fetolethality; the lower dose produced fetotoxicity, 75% fetolethality, and malformations.

# Basis for Selecting the No Observable Adverse Effect Level (NOA EL)
Acute toxicity data for EGEE (Table 4-2) indicate that CNS and kidney effects occurred at higher EGEE concentrations than adverse reproductive and developmental effects. Smyth et al.  reported narcosis, digestive tract irritation, and kidney damage in guinea pigs and rats exposed to 1,400 or 3,000 mg EGEE/kg. Dyspnea damaged lungs, and toxic effects on WBCs were reported in mice exposed to 1,130 to 6,000 ppm EGEE , and the LC50 was 1,820 ppm EGEE.
Adverse effects on the blood and hematopoietic system also occurred at higher EGEE concentrations than adverse reproductive and developmental effects. Data in Table 4-9 indicate that EGEE adversely affects the blood and hematopoietic system at concentrations of 125 to 2,000 ppm. These effects include decreased Hb, Hct, RBCs, WBCs, and increased osmotic fragility of erythrocytes .
Limited human data correlate adverse reproductive effects with EGEE exposure .
Table 7-1 presents the reproductive and developmental effects resulting from exposure to EGEE. In rabbits, the LOAEL for male reproductive effects was 400 ppm . This concentration caused decreased testis weight and micro scopic testicular lesions, but 100 ppm and 25 ppm had no effect on the male reproductive system. In the male rat, the LOAEL (500 mg/kg) caused decreased testis weight and micro scopic testicular lesions ; the NOAEL was250mg/kg.
Adverse developmental effects (behavioral and neurochemical alterations) were observed in rats exposed at 100 ppm EGEE in a study that did not demonstrate an NOAEL for these effects . The NOAEL for structural malformations in rats and rabbits was 50 ppm EGEE . Carpenter et al.  had previously established a 62-ppm NOAEL for osmotic fragility.
Adverse developmental effects occur at lower EGEE concentrations than reproductive, hematotoxic, CNS, and kidney effects. Thus, limiting exposures to control adverse develop mental effects will also control reproductive, hematotoxic, CNS, and kidney effects.
The LOAELs and NOAELs in Table 7-1 indicate that 50 ppm is the highest NOAEL  in rats that is also lower than the lowest LOAEL in rats . Because of the lack of human data and because the rat is the species most sensitive to EGEE, it is reasonable to use the rat NOAEL to extrapolate an equivalent dose for humans. NIOSH therefore deems it appropriate to use 50 ppm as the NOAEL for EGEE and to use the body freights of rats  for calculating their daily NOAEL and extrapolating an equivalent dose for humans.

# EGEEA
No information is available about the toxic effects of EGEEA in humans.

# .1.2.1 Studies fn Animais
In mice administered EGEEA orally 5 days/wk for 5 wk, testicular atrophy occurred at 1,000, 2,000, and 4,000 mg/kg per day, and depletion and degeneration of spermatocytes occurred at 4,000 mg/kg per day ], When doses were expressed as mmoles/kg per day, the dose-response relationships of EGEE and EGEEA were equivalent. No effects appeared at 500 mg EGEEA/kg per day. Testicular atrophy and spermatocyte depletion developed in rats fed 726 mg EGEEA/kg per day for 11 days . Nelson et al.  examined the effects of EGEEA on rat embryo-fetal development by exposing pregnant rats to 130,390, or 600 ppm EGEEA for 7 hr/day on g.d. 7 through 15.
The highest concentration (600 ppm) caused 100% fetolethality. A 56% increase in resorptions occurred at 390 ppm EGEEA, and fetal weights were significantly reduced at 130 and 390 ppm EGEEA. Visceral malformations of the heart and umbilicus occurred in fetuses at 390 ppm, and one fetus from dams exposed to 130 ppm EGEEA had a heart defect.
In another study, rabbits were exposed to 25, 100, or 400 ppm EGEEA on g.d. 6 through 18 . Adverse effects on the fetus included decreased fetal body weights and retarded ossification at 100 ppm EGEEA, and vertebral column malformations at 400 ppm EGEEA. Decreased maternal body weight gain and food consumption, and increased resorptions also occurred at 400 ppm EGEEA. No adverse maternal effects developed at 25 or 100 ppm EGEEA, and no adverse effects on the fetus appeared at 25 ppm EGEEA.
These studies in animals provide ample evidence of adverse reproductive and developmental effects from EGEEA exposure. The following studies, including the LOAEL and the NOAEL of each, were used in determining the REL for EGEEA. Tyl et al.  found evidence of maternal toxicity and fetotoxicity in rabbits exposed by inhalation to 100, 200, and 300 ppm EGEEA for 6 hr/day on g.d. 6 through 18. A 100% incidence of malformations occurred at 300 ppm EGEEA, and external, visceral, and skeletal malformations increased significantly at 200 ppm EGEEA. No effects were observed on dams or fetuses at 50 ppm EGEEA. Tyl et al.  found evidence of maternal toxicity (i.e., decreased body weight gain and food consumption, and increased liver weight) in rats exposed by inhalation to 100, 2 0 0 , and 300 ppm EGEEA for 6 hr/day on g.d. 6 through 15. Fetotoxicity was also found at 100, 200, and 300 ppm EGEEA, with an increased incidence of visceral, skeletal, and external malformations at 200 and 300 ppm EGEEA. Dams and fetuses showed no effects at 50 ppm EGEEA.
Dermal treatment of pregnant rats on g.d. 7 through 16 with 1.4 ml EGEEA/day caused decreased maternal body weights and adverse developmental effects in offspring, including visceral malformations and skeletal variations ,

# 7A .2.2 Basis for Selecting the N o Observable Adverse Effect Level (NOAEL)
Reports in the literature indicate that EGEEA exerts adverse hematologic effects in ex perimental animals at 62 to 4,000 ppm . These effects include hemolysis, reduced RBC and WBC counts, and a reduction in Hb, Hct, and MCV.
Acute toxicity data for EGEEA (Table 4-2) indicate that CNS and kidney effects occur at higher EGEEA concentrations than adverse reproductive and developmental effects. Smyth et al.  reported narcosis and damaged kidneys in guinea pigs and rats treated with 1,910 or 5,100 mg EGEEA/kg. Hemoglobinuria, hematuria, and renal lesions were reported in rats treated with 2,900 to 3,900 mg EGEEA/kg , and transient hemoglobinuria and/or hematuria were reported in rabbits exposed to 2,000 ppm EGEEA for 4 hr.
Adverse reproductive and developmental effects generally occur at lower concentrations than hematotoxic, CNS, and kidney effects. Thus, limiting exposures to prevent adverse reproductive and developmental effects will also prevent hematotoxic, CNS, and kidney effects.
Table 7-2 presents reproductive and developmental effects resulting from exposure to EGEEA. These data include the LOAEL for mice (1,000 mg/kg), rats (130 ppm), and rabbits (100 ppm). In the study by Tyl et al. , 50 ppm EGEEA caused no effects in rabbits.
The LOAELs and NOAELs presented in Table 7-2 indicate that 50 ppm is the highest NOAEL in rabbits that is also lower than the lowest LOAEL in rabbits .
Because human data are lacking and because the rabbit is the animal species most sensitive to EGEEA, it is reasonable to use the rabbit NOAEL to extrapolate an equivalent dose for humans. NIOSH therefore deems it appropriate to use 50 ppm as the NOAEL for EGEEA and to use the body weights of rabbits studied by Tyl et al.  for calculating their daily NOAEL and extrapolating an equivalent dose for humans.

# EGME

# Studies in Humans
As reported in Chapter 4 (Section 4.3), adverse CNS effects (headache, forgetfulness, fatigue, personality change, nausea, and neurologic abnormalities) and hematotoxic effects (anemia and lymphopenia) were observed in workers exposed to EGME-containing solvents in shirt factories . Greenburg et al.  studied workers fusing shirt collars at the same factory as Parsons and Parsons  and observed similar effects (i.e., anemia, neurologic abnormalities, drowsiness, and fatigue). Industrial hygiene measurements taken after the report of adverse health effects in workers indicated that the airborne concentration of EGME was about 25 ppm with windows open and 75 ppm with windows partially closed. Greenburg et al.  stated that worker exposures to EGME had been higher than the measured concentrations because improvements had been made to exhaust and ventilation systems after the report of adverse health effects in workers.
Severe anemia , major encephalopathy, and bone marrow depression  were observed in workers exposed to EGME dermally and by inhalation in the printing and microfilm industries. In one study , EGME was used as a cleaning agent and as a solvent, but the workers seldom wore gloves. No means were available to measure possible dermal absorption. Workers were exposed to 60 to 3,960 ppm EGME during the various cleaning operations, but after airborne EGME concentrations were reduced to the order of 20 ppm EGME, no further ill effects were noted. No mention was made about preventing skin exposure.
Nitter-Hauge  reported general weakness, disorientation, nausea, and vomiting in two men who had each ingested about 0.1 liter of pure EGME, believing it to be ethyl alcohol. Upon admittance to the hospital, the men were suffering from cerebral confusion, pronounced hyperventilation, and profound metabolic acidosis. After i.v. treatment with sodium bicar bonate and ethyl alcohol, both patients made an uneventful recovery over a 4-wk period.
Limited evidence shows the adverse effects of EGME on the male reproductive system. Data suggest that testicle size may have been reduced in male workers with potential exposure to EGME (see Section 4.1.2.2) .  noted lowered sperm counts in shipyard painters exposed to EGME and EGEE; airborne EGME ranged from nondetectable concentrations to 5.6 ppm. Details of this study, which are presented in Chapter 4, indicated that lead and epichlorohydrin (also present in the work environment) had no effect on semen quality.
When hematologic parameters were studied in the same group of shipyard painters , several cases of anemia were reported. Exposure to EGME and EGEE was suspected as the cause of the hematologic disorders, but no dose -response relationship was established.

# Studies In Anim als
Chapter 4 summarizes experimental studies demonstrating reproductive and developmental toxicity resulting from EGME exposure (see Appendix B for the complete studies). Doses of 62.5, 125, 250, 500, 1,000, or 2,000 mg EGME/kg per day were administered to mice 5 days/wk for 5 wk ]. Testicular atrophy was found at 250, 500,1,000, and 2,000 mg EGME/kg per day, but not at lower doses.
In a study to determine temporal development and the site of the testicular lesion, rats were treated orally with 50,100,250, or 500 mg EGME/kg per day for up to 11 days . Testis weights were significantly reduced after 2 days at 500 mg/kg per day and after 7 days at 250 mg/kg per day. The lesion appeared localized in the primary spermatocyte 24 hr after a single dose of 100 mg/kg. Partial depletion and degeneration of spermatids and spermatocytes were also observed in rats treated with 100 mg EGME/kg per day for 11 days. No effects were noted over the 11-day treatment period at 50 mg EGME/kg per day.
Treatment of rats with 50 mg EGME/kg per day for 5 days in another study caused a reduction in epididymal sperm counts  and the appearance of abnormal sperm morphology at wk 4, followed by recovery at wk 8 .
Adverse reproductive effects were noted in male rats exposed to >100 ppm EGME by inhalation for 6 hr/day, 5 days/wk during a 10-day to 13-wk period , testicular atrophy , microscopic testicular lesions, and decreased testis weights ; at 100 ppm, male rats showed no effects. Miller et al.  observed testicular effects in rabbits exposed to 100 or 300 ppm EGME and slight microscopic changes in testicular tissue in 1 of 5 rabbits exposed to 30 ppm EGME. These investigators considered 30 ppm to be the NOAEL in rabbits.
The effects of EGME on rat reproductive performance were studied by exposing males or females to 30, 100, or 300 ppm EGME for 6 hr/day, 5 days/wk for 13 wk before mating with unexposed animals . At 300 ppm, EGME completely suppressed male fertility for 2 wk after exposure; fertility was partially restored 13 to 19 wk after exposure ended. No effects were observed on female reproductive performance at any concentration of EGME, or on male reproductive performance at 30 or 100 ppm. No neonatal effects were found in this study at any EGME concentration.
Nagano et al.  administered doses of 31.25, 62.5, 125, 250, 500, or 1,000 mg EGME/kg per day to rats on g.d. 7 through 14. Skeletal variations consisting of bifurcated and split cervical vertebrae were observed at the lowest dose, and increased malformations (spina bifida occulta) occurred at 62.5 mg EGME/kg per day.

# Ill
Heart function was also evaluated in rat fetuses from dams treated orally on g.d. 7 through 13 with 25 or 50 mg EGME/kg per day . At 25 mg/kg per day, EGME caused a significant increase in the number of fetuses with abnormal QRS wave complexes; and at 50 mg/kg per day, it caused an increase in cardiovascular defects.
Oral treatment of nonhuman primates with 36 mg EGME/kg during gestation resulted in one embryo that was missing a digit on each forelimb , Three of thirteen pregnancies (23%) at the 12-mg/kg dose ended in embryonic death.
Rats and rabbits were exposed by inhalation to 3,10, or 50 ppm EGME for 6 hr/day on g.d. 6 through 15 (rats) or 6 through 18 (rabbits) . Maternal toxicity (decreased body weight) in dams of both species was noted at 50 ppm EGME. A significant increase in the resorption rate was also noted in pregnant rabbits exposed to 50 ppm EGME. Significant increases in the incidence of two minor skeletal variations (i.e., lumbar spurs and delayed ossification) indicated slight fetotoxicity in rat fetuses from dams exposed to 50 ppm EGME. Rabbit fetuses from dams exposed to 50 ppm EGME exhibited a significant increase in the incidence of malformations of all organ systems and a significant decrease in the mean body weight. No effects were noted in either species for dams and fetuses at 3 or 10 ppm EGME. Hanley et al.  found minimally decreased body weight gains in mice exposed to 50 ppm EGME 6 hr/day on g.d. 6 through 15. Examination of fetuses from dams exposed to 50 ppm EGME revealed statistically significant increases in the incidence of extra lumbar ribs and of unilateral testicular hypoplasia. No adverse effects were noted in dams or fetuses at 10 ppm EGME.
In another study, pregnant rats were exposed to 100 or 300 ppm EGME for 6 hr/day on g.d. 6 through 17, and males were exposed to 100 or 300 ppm EGME for 6 hr/day during a 10-day period . At 100 ppm, EGME increased gestation time and decreased the number of pups and live pups. At 300 ppm, EGME decreased maternal body weight and produced 100% fetolethality. Male rats showed testicular effects after 10 exposures to 300 ppm, but not after exposures to 100 ppm EGME.
In a dominant lethal study, male rats were exposed by inhalation to 25 or 500 ppm EGME for 6 hr/day over 5 days . Rats exposed to 500 ppm showed decreased fertility during wk 3 through 8 , and rats exposed to 25 ppm EGME showed no adverse effects on fertility. Nelson et al.  exposed male rats to 25 ppm EGME for 7 hr/day, 7 days/wk during a 6 -wk period. These rats were then mated with untreated females that were allowed to deliver and rear their young. In the same study, pregnant females were exposed to EGME for 7 hr/day on g.d. 7 through 13 or 14 through 20 and allowed to deliver and rear their young. Significant differences in avoidance conditioning were observed in offspring of dams exposed on g.d. 7 through 13, but not in offspring of dams exposed on g.d. 14 through 20. Brain neurochemical deviations were noted in offspring from the paternally exposed group and in offspring from both maternally exposed groups.
In a dermal exposure study, female rats were exposed to solutions of 3%, 10%, 30%, or 100% EGME (10 ml/kg) in physiological saline , Reduced litter sizes were observed at the 10% concentration, 100% fetolethality occurred at the 30% concentra tion, and 10 0 % maternal death was observed at the 1 0 0 % concentration.
A single dermal application of 500, 1,000, or 2,000 mg EGME/kg on g.d. 12 caused statistically significant increases (P<0.05) in external, visceral, and skeletal malformations . In the same study, dermal exposure of female rats to EGME ( 1 ,0 0 0 mg/kg on g.d. 12 or 2 ,0 0 0 mg/kg on g.d. 10 and 12) caused a statistically significant decrease in fetal body weights (P<0.05). The investigators determined 250 mg EGME/kg to be the NOAEL for adverse developmental effects.

# Basis for Selection o f N o Observable Adverse Effect Level (NOAEL)
Adverse CNS effects (encephalopathy) and hematotoxic effects (bone marrow depression, anemia, and leukopenia) were observed in workers exposed to EGME . However, there is limited evidence of an adverse effect on the male reproductive system as a result of EGME exposure ].
Acute toxicity data for EGME (Table 4-2) indicate that CNS, liver, and kidney effects occur at higher EGME concentrations than adverse reproductive and developmental effects. Wiley et al.  reported tissue damage to the kidneys and liver in dogs and rabbits exposed to 2,130 mg EGME/kg. Narcosis, lung, and kidney damage were reported in rats (3,250 to 3,400 mg/kg), rabbits (890 mg/kg), and guinea pigs (950 mg/kg) , and digestive tract irritation and damaged kidneys were reported in rats and guinea pigs exposed to 246 and 950 mg EGME/kg, respectively.
Adverse effects on the blood and hematopoietic system also occurred at higher EGME concentrations than adverse reproductive or developmental effects. Data in Table 4-9 indicate that 32 to 2,000 ppm EGME adversely affects the blood and hematopoietic system. These effects include increased osmotic fragility, decreased Hb, Hct, RBC and WBC counts .
Table 7-3 presents the reproductive and developmental effects caused by exposure to EGME. In rats, the LOAEL of 50 mg EGME/kg per day caused decreased sperm counts and abnormal sperm morphology in two separate studies that did not demonstrate a NOAEL , In rabbits, the LOAEL (100 ppm EGME) caused microscopic testicular lesions and decreased testis weights, and the NOAEL was 30 ppm EGME . In mice, the LOAEL (250 mg/kg per day) caused testicular atrophy, and the NOAEL was 125 mg/kg per day ].
Behavioral defects and neurochemical deviations were observed in the offspring of rats exposed to 25 ppm EGME . Retarded fetal ossification was observed in the offspring of mice treated with 31.25 mg EGME/kg per day (LOAEL) . Adverse developmental effects were observed in the offspring of rats, rabbits, and mice exposed to an LOAEL of 50 ppm EGME ; the NOAEL for these species was 10 ppm EGME. In the same study, the NOAEL for maternal effects in these species was 10 ppm EGME. Feuston et al.  observed an increase (P<0.05) in external, visceral, and skeletal malformations in the fetuses of rats exposed to single dermal applications of 500,1,000, or 2,000 mg EGME/kg on g.d. 12. The authors determined 250 mg EGME/kg to be the NOAEL for adverse developmental effects in this study.
Adverse developmental effects occur at lower EGME concentrations than reproductive, hematotoxic, CNS, liver, and kidney effects. Thus, limiting exposure to control adverse developmental effects will also control reproductive, hematotoxic, CNS, liver, and kidney effects.
The data that demonstrate reproductive and developmental toxicity, and the LOAELs and NOAELs presented in Table 7-3 indicate that in several species (rats, rabbits, and mice), 10 ppm is the highest NOAEL that is also lower than the lowest LOAEL . Because of the lack of human data, it is reasonable to use the NOAEL of 10 ppm  to extrapolate an equivalent dose for humans.

# EGMEA
Few data are available on the toxicity of EGMEA. Bolt and Golka  reported the occurrence of hypospadias at birth in two boys whose mother had been exposed to EGMEA during her pregnancies. The authors concluded that the hypospadias were caused by exposure to EGMEA. Testicular atrophy was observed in mice exposed orally for 5 days/wk during a 5-wk period to 500,1,000, or 2,000 mg EGMEA/kg per day; no reproductive effects were noted at 62.5, 125, or 250 mg EGMEA/kg per day

# BASIS FOR RECOMMENDED STANDARDS FOR EGEE, EGME, AND THEIR ACETATES

# Data Available from Studies in Humans and Anim als
Toxic effects of human exposure to EGEE and EGME include personality change, memory loss, drowsiness, blurred vision, hearing loss, anemia, and leukopenia. However, data are limited on possible adverse reproductive and developmental effects of worker exposure to EGEE, EGME, and EGMEA, and no human data are available on EGEEA exposure. Cook et aL  suggested that testicle size in males may have been reduced because of EGME exposure.  concluded that exposure to EGEE and EGME caused functional impairment in males by lowering sperm counts. The occurrence of hypospadias in two boys at birth was attributed to the mother's exposure to EGMEA during her pregnancies . Ballew and Hattis  performed a quantitative risk analysis under contract to NIOSH to determine the risk of developmental effects in the offspring of pregnant women exposed to EGEE and EGME. Although data for humans are limited, ample evidence from studies in animals indicates that EGEE, EGME, and their acetates adversely affect reproduction and development. In the absence of sufficient human data, NIOSH deems it appropriate to base the RELs for EGEE, EGME, and their acetates on animal data. The following procedure was therefore used to calculate equivalent human doses from animal data.

# Procedure for Calculating Equivalent Human Doses from Animal Data
No mechanistic models exist to describe the relationship of reproductive and developmental toxicity to exposure; only empirical models are available to use in a quantitative risk assessment (QRA). Because a threshold is assumed to exist for reproductive and develop mental toxicity, a QRA model is inappropriate since these models assume a no-threshold effect. Therefore, the following method was used to determine the RELs for EGEE, EGME, and their acetates.
Both humans and animals were assumed to retain 100% of inhaled EGEE, EGME, or their acetates. The retained dose for animals exposed at the NOAEL was calculated as follows by using the inhalation rate and the average body weights of the animals (see Table 7-5):

# Retained dose for animals  N O A E L ( m g / m 3) x inhaja^onrate (m /day) x q 2 5 ay (1 ) animal body weight
That dose was converted to an equivalent exposure for humans by assuming a 70-kg body weight and an inhalation rate of 10 m3 in an 8-hr workday : t, . , .
" , retained dose for animals (mg/ k g per day) x 70 kg Equivalent exposure for humans - ----------------\ a -a r j-l----e.
(2) 1 0 m /day Adapted from Ballew and Hattis . Concentrations of EGEE or EGME associated with the indicated effect under a more pessimistic assumption about the degree of interindividual variability in susceptibility of the human population (log probit slope of 1). 1 Bast-estimate assumption of the degree of interindividual variability in susceptibility for the quantal developmental effects (log probit slope of 2). sDeath in the first year after birth. In the case of this hypothesized effect, only best estimates have been made. To allow for potential interspecies variability, an uncertainty factor of 10 was applied to the equivalent exposure for humans. An additional uncertainty factor of 10 was then applied to allow for potential intraspecies variability. The resulting concentration was converted to parts per million:
Equivalent exposure for humans __________ 24.45__________ _ 100 mol wt of particular glycol ether

# .2 .2 .1 REL fo r EGEE and EGEEA
Although limited data in humans have shown adverse reproductive or developmental effects from exposure to EGEE  and EGEEA Doe 1984a;Foster et al. 1984;Nelson et al. 1984b;Tyl et al. 1988]. These animal data provide the basis for determining the RELs for worker exposure to EGEE and EGEEA and for instituting controls to reduce worker exposure. On the basis of the calculations presented in Equations 4 through 12, NIOSH recommends that occupational exposure to EGEE and EGEEA be limited to 0.5 ppm as a TWA for up to a 10-hr workshift during a 40-hr workweek. Because both EGEE and EGEEA can be absorbed percutaneously , dermal contact is prohibited. The data in

# REL for EG M E a n d EGM E A
Case reports and clinical studies demonstrated adverse CNS and hematotoxic effects on workers exposed to EGME , but data demonstrating adverse reproductive and developmental effects in offspring of EGME-exposed workers are limited . Bolt and Golka reported hypospadias at birth in two boys whose mother was exposed to EGMEA during her pregnancies.
Sufficient evidence in animal studies indicates that EGME exerts adverse reproductive and developmental effects Nagano et al. 1981;Foster et al. 1983;McGregor etal. 1983;Miller etal. 1983a;Raoetal. 1983;Hanley etal. 1984a;Nelson etal. 1984a;Chapin et al. 1985a;Chapin etal. 1985b;Toraason et al. 1985;Scott et al. 1989; Wickramaratne 1986]. EGMEA was also shown to have such effects by , who found that this glycol ether caused testicular atrophy in mice. Data from these animal studies warrant concern that EGME and EGMEA are capable of inducing similar adverse effects in exposed workers.
Based on information presented in Table 7-3, a 10-ppm NOAEL was determined for EGME in rats, rabbits, and mice . Any effects that EGMEA might cause would be likely to occur through the initial conversion of EGMEA to EGME (see Section 4.2). Therefore, it is reasonable to propose the same REL for both compounds. An equivalent human dose was determined for EGME using the information presented in the study by Hanley et al. , On the basis of the calculations presented in Equations 13 through 21, NIOSH recommends that occupational exposure to EGME and EGMEA be limited to 0.1 ppm as a TWA for up to a 10-hr workday during a 40-hr workweek. Because EGME and EGMEA can be absorbed percutaneously , dermal contact is prohibited. The data in Table 7-5 were used in Equations 13 through 21 to calculate the human equivalents to the daily animal NOAELs for EGME and EGMEA as follows: The hazard communication program is to be written and made available to workers and their designated representatives.
Chemical manufacturers, importers, and distributors are required to ensure that containers of hazardous chemicals leaving their workplaces are labeled, tagged, or marked to show the identity of the chemical, appropriate hazard warnings, and the name and address of the manufacturer or other responsible party. Employers must ensure that labels on incoming containers of hazardous chemicals are not removed or defaced unless they are immediately replaced with other labels containing the required information.
Each container in the workplace must be prominently labeled, tagged, or marked to show the identity of any hazardous chemical it contains and the hazard warnings appropriate for worker protection. If a work area has a number of stationary containers that have similar contents and hazards, the employer may post hazard signs or placards rather than label each container. Employers may use various types of standard operating procedures, process sheets, batch tickets, or other written materials as substitutes for individual container labels on stationary process equipment. However, these written materials must contain the same information that is required on the labels and must be readily accessible to workers in the work areas. Pipes or piping systems are exempted altogether from the OSHA labeling requirements, although NIOSH recommends that filler ports and outlets be labeled. In addition, NIOSH recommends that a system be set up to ensure that pipes containing hazardous materials are identified to avoid accidental cutting and discharge of their contents.
Employers are not required to label portable containers holding hazardous chemicals that have been transferred from labeled containers and that are intended only for the immediate use of the worker who performs the transfer. According to the OSHA definition of "immediate use," the container must be under the control of the worker performing the transfer and must be used only during the workshift in which the chemicals are transferred.
The OSHA Hazard Communication standard requires chemical manufacturers and importers to develop an MSDS for each hazardous chemical they produce or import. Employers in the manufacturing sector (which includes paint and allied coating products) are required to obtain or develop an MSDS for each hazardous chemical used in the workplace. The MSDS is required to provide information such as the chemical and common names for the hazardous chemical. For hazardous chemical mixtures, the MSDS must list each hazardous component that constitutes 1 % or more of the mixture. NIOSH suggests that any potential occupational carcinogen be listed. Ingredients present in concentrations of less than 1 % must also be listed if there is evidence that the PEL may be exceeded or that the ingredients could present a health hazard in those concentrations. Workers should also be trained in methods for detecting the presence or release of hazardous chemicals (e.g., monitoring conducted by the employer, continuous monitoring devices, visual appearance or odor of hazardous chemicals when released, etc.). Training should include information about measures workers can take to protect themselves from exposure to hazardous chemicals (e.g., the use of appropriate work practices, emergency procedures, and personal protective equipment).

# W ORK PRACTICES

# W orker Isolation
If feasible, workers should be isolated from direct contact with the work environment by the use of automated equipment operated from a closed control booth or room. The control room should be maintained at a positive pressure so that air flows out of rather than into the room. However, when workers must perform process checks, adjustments, maintenance, or other related operations in work areas where EGME, EGEE, or their acetates are present, personal protective clothing and equipment may be necessary, depending on exposure concentrations and the potential for dermal contact.

# Storage and Handling
Containers of EGME, EGEE or their acetates should be stored in a cool, dry, well ventilated location away from any area containing a fire hazard. Outside or detached storage is preferred. These glycol ethers should be isolated from materials with which they are incompatible; contact with strong oxidizing agents may cause fires and explosions. Con tainers of solvents, including those that contain EGME, EGEE, or their acetates, should be tightly covered at all times except when material is transferred. Working amounts of these solvents should be stored in containers that (1) hold no more than 5 gal, (2) have springclosing lids and spout covers, and (3) are designed to safely relieve internal pressure in case of fire. Because small amounts of residue may remain and present a fire hazard, containers that have held solvents should be thoroughly cleaned with steam and then drained and dried before reuse. Fittings should not be struck with tools or other hard objects that may cause sparks. Special spark-resistant tools of nonferrous materials should be used where flam mable gases, highly volatile liquids, or other explosive substances are used or stored . In addition, all sources of ignition such as smoking and open heaters should be prohibited except in specified areas. Fire hazards around tank trucks and cars can be reduced by keeping motors turned off during loading or unloading operations.
Specific OS HA requirements for the storage and handling of flammable and combustible liquids are given in 29 CFR 1910.106.

# Sanitation and Hygiene
The preparation, storage, or consumption of food should not be permitted in areas where there is exposure to EGME, EGEE or their acetates. The employer should make handwash ing facilities available and encourage the workers to use them before eating, smoking, using the toilet, or leaving the worksite. Tools and protective clothing and equipment should be cleaned as needed to maintain sanitary conditions. Toxic wastes should be collected and disposed of in a manner that is not hazardous to workers or the environment. Vacuum pickup or wet mopping should be used to clean the work area at the end of each workshift or more frequently if needed to maintain good housekeeping practices. Collected wastes should be placed in sealed containers that are labeled as to their contents. Cleanup and disposal should be conducted in a manner that enables workers to avoid contact with the waste.
Tobacco products should not be smoked, chewed, or carried uncovered in work areas.
Workers should be provided with and advised to use facilities for showering and changing clothes at the end of each workshift. Work areas should be kept free of flammable debris. Flammable work materials (rags, solvents, etc.) should be stored in approved safety cans.

# Spills and W aste Disposal
Procedures for decontamination and waste disposal should be established for materials or equipment contaminated with EGME, EGEE, or their acetates. The following procedures are recommended in the event of a spill of these glycol ethers :
- Exclude persons not wearing protective clothing and equipment from areas of spills or leaks until cleanup has been completed.
- Remove all ignition sources.
- Ventilate the area of a spill or leak.
- Absorb small spills on paper towels. Allow the vapors to evaporate in a suitable place such as a fume hood, allowing sufficient time for them to clear the hood ductwork. Bum the paper towels in a suitable location away from combustible materials.
- Absorb large quantities with sand or other noncombustible absorbent material and atomize the contaminated material in a suitable combustion chamber.

# LABELING AND POSTING
In accordance with 29 CFR 1910.1200 (Hazard Communication), workers must be informed of chemical exposure hazards, of their potential adverse health effects, and of methods to protect themselves. Labels and signs also provide an initial warning to other workers who may not normally work near processes involving hazardous chemicals such as EGME, EGEE, or their acetates. Depending on the process, warning signs should state a need to wear eye protection or a respirator, or they may be used to limit entry to an area without protective equipment. For transient nonproduction work, it may be necessary to display warning signs at the worksite to inform other workers of the potential hazards.
All labels and warning signs should be printed in both English and the predominant language of workers who do not read English. Workers who cannot read labels or posted signs should be identified so that they may receive information about hazardous areas and be informed of the instructions printed on labels and signs.

# EMERGENCIES
The employer should formulate a set of written procedures covering fire, explosion, asphyxiation, and any other foreseeable emergency that may arise during the use of materials that may contain EGME or EGEE, or their acetates. All potentially affected workers should receive training in evacuation procedures to be used in the event of fire or explosion. All workers who are using materials containing these glycol ethers should be thoroughly trained in proper work practices that reduce the potential for starting fires and causing explosions.

# ENGINEERING CONTROLS
Engineering controls should be the principal method for minimizing exposure to airborne EGME, EGEE, or their acetates in the workplace. To achieve and maintain reduced airborne concentrations of these glycol ethers, adequate engineering controls are necessary (e.g., properly constructed and maintained closed-system operations and ventilation). Control technology applicable to spray painting is discussed in a NIOSH document ,
Airborne concentrations of these glycol ethers can be most effectively controlled at the source of contamination by enclosure of the operation and use of local exhaust ventilation. Enclosures, exhaust hoods, and ductwork should be kept in good repair so that designed airflows are maintained. Measurements of variables such as capture velocity, duct velocity, or static pressure should be made at least semiannually, and preferably monthly, to demonstrate the effectiveness of the mechanical ventilation system. The use of continuous airflow indicators (such as water or oil manometers marked to indicate acceptable airflow) is recommended. The effectiveness of the system should also be made as soon as possible after any change in production, process, or control that may result in any increase in airborne contaminants.
It is essential that any scheme for exhausting air from a work area also provide a positive means of bringing in at least an equal volume of air from the outside, conditioning it, and evenly distributing it throughout the exhausted area. The ventilation system should be designed and operated to prevent the accumulation or recirculation of airborne contaminants in the workplace. To evaluate the use of these materials with EGMEA or EGEEA, users should consult the best available performance data and manufacturer's recommendations. Significant differen ces have been demonstrated in the chemical resistance of generically similar PPE materials (e.g., butyl) produced by different manufacturers . In addition, the chemical resistance of a mixture may be significantly different from that of any of its neat components . Users should therefore test the candidate material with the chemicals to be used.
The worker should be trained in the proper use and care of the chemical protective clothing.
After this clothing is in routine use, it should be examined along with the workplace to ensure that nothing has occurred to invalidate the effectiveness of these materials. The NIOSH publication A Guide fo r Evaluating the Performance o f Chemical Protective Clothing  may be helpful. Safety showers and eye wash stations should be located close to operations that involve EGME, EGEE, or their acetates.
Splash-proof chemical safety goggles or face shields (20 to 30 cm minimum) should be worn during any operation in which a solvent, caustic, or other toxic substance may be splashed into the eyes.
In addition to the possible need for wearing protective outer apparel (e.g., aprons, encap sulating suits), workers should wear work uniforms, coveralls, or similar full-body coverings that are laundered each day. Employers should provide lockers or other closed areas to store work and street clothing separately. Employers should collect work clothing at the end of each workshift and provide for its laundering. Laundry personnel should be informed about the potential hazards of handling contaminated clothing and instructed about measures to minimize their health risk.
Employers should ensure that protective clothing is inspected and maintained to preserve its effectiveness. Clothing should be kept reasonably free of oil or grease.
Workers and persons responsible for worker health and safety should be informed that protective clothing may interfere with the body's heat dissipation, especially during hot weather or in hot industries or work situations (e.g., confined spaces). Additional monitoring is required to prevent heat-related illness when protective clothing is worn under these conditions.

# Respiratory Protection
Engineering controls should be the primary method used to control exposure to airborne contaminants. Respiratory protection should be used by workers only in the following circumstances:
- During the development, installation, or testing of required engineering controls The actual respirator selection should be made by a qualified individual, taking into account specific use conditions, including the interaction of contaminants with the filter medium, space restrictions caused by the work location, and the use of any required face and eye protective devices. Respirator selection tables are presented in Chapter 1.

# CHEMICAL SUBSTITUTION
The substitution of less hazardous materials can be an important measure for reducing worker exposure to hazardous materials.

# EXPOSURE MONITORING
An occupational health program designed to protect workers from adverse effects caused by exposure to EGME, EGEE, or their acetates should include the means for thoroughly identifying all potential hazards. Routine environmental sampling as an indicator of worker exposure is an important part of this program, as it provides a means of assessing the effectiveness of work practices, engineering controls, personal protective clothing and equipment, etc.
Prior knowledge of the presence of certain types of inteifering compounds in the sampled environment will greatly help the analyst in the selection of the appropriate analytical conditions for sample analysis. This list of compounds can be compiled from the material safety data sheets for the compounds that are used in or around the process where the sampling will take place.
Initial and routine worker exposure surveys should be made by competent industrial hygiene and engineering personnel. These surveys are necessary to characterize worker exposures and to ensure that controls already in place are operational and effective. Each worker's exposure should be estimated, whether or not it is measured by a personal sampler.
Therefore, the sampling strategy should allow reasonable estimates of each worker's exposure. The NIOSH publication Occupational Exposure Sampling Strategy Manual may be helpful in developing efficient programs to monitor worker exposure .
In work areas where airborne exposures to EGME, EGEE or their acetates may occur, an initial survey should be done to determine the extent of worker exposure. In general, TWA exposures should be determined by collecting samples over a full shift. Measurements to determine worker exposure should be taken so that the average 8 -hr exposure is based on a single 8-hr sample or on two 4-hr samples. Several short-term interval samples (up to 30 min) may also be used to determine the average exposure concentration.
When the potential for exposure to these glycol ethers is periodic, short-term samples may be needed to replace or supplement full-shift sampling. Personal sampling (i.e., samples collected in the worker's breathing zone) is preferred over area sampling. If personal sampling is not feasible, area sampling can be substituted only if the results can be used to approximate worker exposure. Sampling should be used to identify the sources of emissions so that effective engineering controls or work practices can be instituted.
If a worker is found to be exposed to EGME, EGEE, or their acetates at concentrations below the REL but at or above one-half the REL, the exposure of that worker should be monitored at least once every 6 months or as otherwise indicated by a professional industrial hygienist When the work environment contains concentrations exceeding the respective RELs for these glycol ethers, workers must wear respirators for protection until adequate engineering controls or work practices are instituted; exposure monitoring is recommended at 1-wk intervals. Such monitoring should continue until consecutive determinations at least 1 wk apart indicate that the workers' exposure no longer exceeds the REL.
When workers' exposures are greater than one-half the REL but less than the REL, sampling should be conducted after 6 months; if the concentrations of these glycol ethers are lower than one-half the REL after two consecutive biannual surveys, sampling can then be conducted annually. Exposure monitoring should be conducted whenever changes in production, process, controls, work practices, or weather conditions may result in a change in exposure conditions.

# MEDICAL MONITORING

# General Requirem ents
Workers exposed to EGME, EGEE, or their acetates are at risk of suffering adverse health effects. Medical monitoring as described below should be made available to all workers. The employer should provide the following information to the physician responsible for the medical monitoring program:
- Any requirements of the applicable OSHA standard or NIOSH recommended standard
- Identification of and extent of exposure to physical and chemical agents that may be encountered by the worker - Any available workplace sampling results that characterize exposures for job categories previously and currently held by the worker - A description of any protective devices or equipment the worker may be required to use
- The frequency and nature of any reported illness or injury of a worker
- The results of any monitoring of urinary MAA or EAA for any worker exposed to unknown concentrations of EGME or EGMEA during a spill or emergency (see Appendix G).

# M edical Exam inations
The objectives of a medical monitoring program are to augment the primary preventive measures, which include industrial hygiene monitoring of the workplace, the implementa tion of engineering controls, and the use of proper work practices and personal protective equipment. Medical monitoring data may also be used for epidemiologic analysis within large plants and on an industrywide basis; they should be compared with exposure data from industrial hygiene monitoring.
Medical examinations are conducted before job placement and periodically thereafter. The preplacement medical examination allows the physician to assess the applicant's functional capacity and inform him or her of how it relates to the physical demands and risks of the job. Furthermore, such an examination provides baseline medical data that can be compared with subsequent health changes. The preplacement examination should also provide information about prior occupational exposures. Periodic medical examinations after job placement are intended to detect work-related changes in health at an early stage.
The following factors should be considered during the preplacement medical examination and any periodic medical examinations of the worker: (a) exposure to chemical and physical agents that may produce interdependent or interactive adverse effects on the worker's health (including exacerbation of pre-existing health problems and nonoccupational risk factors such as tobacco use), and (b) potentially hazardous characteristics of the worksite (e.g., confined spaces, heat, and proximity to hazards such as explosive atmospheres and toxic chemicals). The type of information that should be gathered is discussed in the following subsections.

# Preplacem ent m edical examination

# Medical history
The medical history should contain information about occupational history, including the number of years worked in each job. Special attention should be given to any history of occupational exposure to hazardous chemical and physical agents .

# Clinical examination
The preplacement clinical examination should determine the fitness of the worker to perform the intended job assignment. Appropriate pulmonary and musculoskeletal evaluation should be done for workers whose jobs may require extremes of physical exertion or stamina (e.g., heavy lifting), especially these who must wear personal respiratory protection. Because the standard 12-lead electrocardiogram is of little practical value in monitoring for asymptomatic cardiovascular disease, it is not recommended. More valuable diagnostic information is provided by physician interviews of workers that elicit reports of the occurrence and work-relatedness of angina, breathlessness, and other symptoms of chest illnesses. Special attention should also be given to workers who require the use of eyeglasses. These workers must be able to wear simultaneously any equipment needed for respiratory protection, eye protection, and visual acuity, and they must be able to maintain their concurrent use during work activities.
The worker's duties may be performed near unrelated operations that generate potentially harmful exposures (e.g., asbestos or cleaning or degreasing solvents). The physician must be aware of these potential exposures to evaluate possible hazards to the individual worker.

# $.9.2.2 Periodic m edical examination
A periodic medical examination should be conducted annually or more frequently, depend ing on age, health status at the time of a prior examination, and reported signs or symptoms associated with exposure to EGME, EGEE, or their acetates. The physician should note any trends in health changes revealed by epidemiologic analyses of examination results. The occurrence of an occupationally related disease or other work-related adverse health effects should prompt an immediate evaluation of industrial hygiene control measures and an assessment of the workplace to determine the presence of a previously unrecognized hazard.
The physician's interview with the worker is an essential part of a periodic medical examination. The interview gives the physician the opportunity to leam of (1) changes in the work setting (e.g., confined spaces), and (2 ) potentially hazardous workplace exposures that are in the vicinity of the worker but are not related to the worker's job activities.
During the periodic medical examination, the physician should re-examine organ systems at risk to note changes from the previous examination.

# BIOLOGICAL MONITORING
Urinary concentrations of the metabolites of EGME, EGEE, and their acetates may be useful biological indicators of worker exposure to these glycol ethers. Biological monitoring accounts not only for environmental concentrations and actual respiratory uptake, but also for absorption through the skin. Information about biological monitoring appears in Section S.4 of this document and guidelines for biological monitoring are given in Appendix G.
Biological monitoring is suggested when the potential exists for (1) airborne exposure to EGME, EGEE, or their acetates at or above their respective RELs, or (2) skin contact as a result of accidental exposure or breakdown of chemical protective clothing (see Section 8 .6 .1). Monitoring of urinary MAA or EAA (see Appendix G) should be made available to any worker exposed to unknown concentrations of EGME, EGEE, or their acetates during a spill or other emergency. In the absence of skin exposure, a urinary MAA concentration of 0.8 mg/g creatinine or an EAA concentration of 5 mg/g creatinine approximates the concentration that would result from exposure to the REL for EGME (0.1 ppm) or EGEE (0.5 ppm) during an 8 -hr workshift. If a worker's urinary MAA or EAA suggests exposure to EGME, EGEE, or their acetates above their respective RELs, an effort should be made to ascertain the cause (e.g., failure of engineering controls, poor work practices, or nonoccupational exposures).

# RECORDKEEPING
Medical records as well as exposure and biological monitoring results must be maintained for workers as specified in Section 1.9 of this document. Such records must be kept for at least 30 years after termination of employment. Copies of environmental exposure records for each worker must be included with the medical records. These records must be made available to the past or present workers or to anyone having the specific written consent of a worker, as specified in Section 1.9.4 of this document.

# RESEARCH NEEDS
The following research is needed to further reduce the risk of adverse developmental and reproductive effects from occupational exposure to EGME, EGEE, or their acetates:
- Investigations should be conducted in the workplace to relate glycol ether exposure to concentrations of metabolites in urine and toxic effects such as reduction in testis size, semen quality, etc.
- Additional studies are needed to define more accurately the human reproductive hazards posed by EGME, EGEE, and their acetates.
- Evaluations of exposed populations are needed to correlate dermal absorption of EGME, EGEE, and their acetates with concentrations of metabolites in urine.
- Additional data should be collected to quantify airborne and dermal exposures to EGME, EGEE, and their acetates under actual conditions of use in the workplace.
- Other glycol ethers should be evaluated to identify any that have effects similar to those of EGME, EGEE, and their acetates (see Appendix E for a list of glycol ethers).
- Physiologically based pharmacokinetic models for EGME, EGEE, and their acetates need to be developed and validated in both human beings and the animal species in which NOAELs were determined.
- Methods are needed for quantitative monitoring of dermal exposure.
- Epidemiologic studies are needed to determine the effects of occupational exposure to EGME, EGEE, and their acetates.
- The method of Groeseneken et al.  should be validated.
APPENDIX A

# METHODS FOR SAMPLING AND ANALYSIS OF EGME, EGEE, EGMEA, AND EGEEA IN AIR- A.1 General Requirem ents fo r Sampling
Air samples are collected that represent the air a worker breathes while performing each job or specific operation. It is advisable to maintain records of the date, time, rate, duration, volume, and location of sampling.

# A.2 Collection and Shipping o f Samples
1. Immediately before sampling, break the ends of the sampling tube to provide an opening at least one-half the internal diameter of the tube (2 mm).
2. Attach the sampling tube to the sampling pump with flexible tubing. The smaller section of charcoal is used as a backup and should be positioned nearest the sampling pump.
3. The charcoal tube should be placed in a vertical direction during sampling to minimize channeling through the charcoal.
4. Air being sampled should not be passed through any hose or tubing before entering the charcoal tube.
5. The flow rate of sampling should be known with an accuracy of at least +5 %. Calibrate each sampling pump with a representative charcoal tube in line.
9. Capped charcoal tubes should be packed tightly and padded before they are shipped to minimize tube breakage during shipping.
10. A sample of the bulk material should be submitted to the laboratory in a glass container with a Teflon-lined cap. This sample should not be transported in the same container as the charcoal tubes. A number of changes were made to Method 53 to accommodate the lower target concentrations.
(1) The recommended air volume for TWA samples was increased from 10 liters to 48 liters. This allows for lower detection limits and increases the TWA sampling time to a more convenient 480 min (8 hr) when sampling at 0.1 liter/m in.
(2) A capillary GC column was substituted for a packed column to attain higher resolution. This was especially helpful in achieving better separa tion of 2ME and methylene chloride, a major component of the desorption solvent.
(3) It was found that the desorption efficiency from wet charcoal was significantly lower for 2ME, and to a lesser extent for 2EE, at these lower concentrations. This problem was overcome by adding about 125 mg of anhydrous magnesium sulfate to each desorption vial to remove the desorbed water. Because charcoal will always collect some water from sampled air, all 2ME and 2EE air samples must be treated in this manner.
Utilizing these three major modifications of Method 53, a successful evaluation was performed for these glycol ethers at the lower target concentrations. Also, a minor modification was made in the determination of desorption efficiencies. Aqueous instead of methanolic stock solutions were used to determine the desorption efficiencies for 2MEA and 2EEA. It was found that at these lower levels, when stock methanolic solutions are spiked on dry Lot 120 charcoal, part of the 2MEA and 2EEA react with the methanol to form methyl acetate and 2ME and 2EE, respectively. The reaction, which is analogous to hydrolysis, is called transesterification (alcoholysis) and is catalyzed by acid or base. The surface of dry Lot 120 charcoal is basic and the reaction was verified to occur by quantitatively determining methyl acetate and the corresponding alcohol (2ME for 2MEA samples, 2EE for 2EEA samples) from spiked samples. Transesterification was not observed when methanolic stock solutions were spiked onto wet charcoal. Therefore, transesterification is not expected to occur for samples collected from workplace air containing methanol as well as 2MEA or 2EEA because workplace atmospheres are seldom completely dry.
Because of the number of modifications and the extensive amount of data generated in this evaluation, the findings are presented as a separate method instead of a revision of Method 53. This method supercedes Method 53, although Method 53 is still valid at the higher analyte concentrations.
Although hydrolysis of 2MEA and 2EEA does not appear to be a problem at lower concentrations, as a precautionary measure, the special require ment that 2MEA and 2EEA samples should be refrigerated upon receipt by the laboratory was retained from Method 53.
1.1.2 Toxic effects (This section is for information only and should not be taken as the basis of OSHA policy.)
As reported in the Documentation of Threshold Limit Values (Refs. 5.2 to 5.5), all four analytes were investigated by Nagano et al. (Ref. 5.6)  The detection limits of the analytical procedure arc 0.10,0.04, 0.04, and 0.03 ng per injection (1.0-^iL injection with a 10:1 split) for 2ME, 2MEA, 2EE, and 2EEA respectively. These are the amounts of each analyte that will give peaks with heights approximately 5 times the height of baseline noise (Section 4.1).

# Detection limit of the overall procedure
The detection limits of the overall procedure are 1.0,0.40,0.37, and 0.31 fig per sample for 2ME, 2MEA, 2EE, and 2EEA respectively. These are the amounts of each analyte spiked on the sampling device that allow recovery of amounts of each analyte equivalent to the detection limits of the analytical procedure. These detection limits correspond to air concentra tions of 6.7 ppb (21 jig/m3), 1.7 ppb (8.4 jig/m3), 2.1 ppb (7.8 fig/ m3), and 1.2 ppb (6.5 jig/m ) for 2ME, 2MEA, 2EE, and 2EEA respectively (Section 4.2).

# Reliable quantitation limit
The reliable quantitation limits are the same as the detection limits of the overall procedure because the desorption efficiencies are essentially 1 0 0 % at these levels. These are the smallest amounts of each analyte that can be quantitated within the requirements of recoveries of at least 75% and precisions (1.96 SD) of 25% or better (Section 4.3).
The reliable quantitation limits and detection limits reported in the method are based upon optimization of the GC for the smallest possible amounts of each analyte. When the target concentration of an analyte is exception ally higher than these limits, they may not be attainable at the routine operating parameters unless one optimizes parameters of instruments.

# Instrument response to the analyte
The instrument response over the concentration ranges of 0.5 to 2 times the target concentrations is linear for all four analytes (Section 4.4).

# Recovery
The recovery of 2ME, 2MEA, 2EE, and 2EEA from samples used in a 15-day storage test remained above 84, 87, 84, and 85% respectively when the samples were stored at ambient temperatures. The recovery of analyte from the collection medium after storage must be 75% or greater. (Section 4.5, from regression lines shown in Figures 4. 5.1.2, 4.5.2.2, 4.5.3.2, and 4.5.4.2) 1.2.6 Precision (analytical procedure)
The pooled coefficients of variation obtained from replicate determinations of analytical standards at 0.5, 1, and 2 times the target concentrations are 0.022,0.004,0.002, and 0.002 for 2ME, 2MEA, 2EE, and 2EEA respec tively (Section 4.6).

# Precision (overall procedure)
The precisions at the 95% confidence level for the ambient temperature 15-day storage tests are 11.7, 11.1, 12.3, and 11.2% for 2ME, 2MEA, 2EE, and 2EEA respectively. These include an additional 5% for sam pling error. The overall procedure must provide results at the target concen tration that are 25% or better at the 95% confidence level (Section 4.7).

# Reproducibility
Six samples for each analyte collected from controlled test atmospheres and a draft copy of this procedure were given to a chemist unassociated with this evaluation. The samples were analyzed after 12 days of refrigerated storage. No individual sample result deviated from its theoreti cal value by more than the precision reported in Section 1.2.7 (Section 4.8).

# Advantages
1.3.1 Charcoal tubes provide a convenient method for sampling.
The analysis is rapid, sensitive, and precise.

# Disadvantage
It may not be possible to analyze co-collected solvents using this method. Most of the other common solvents which are collected on charcoal are analyzed after desorption with carbon disulfide. 3.1.3 An electronic integrator or some other suitable means of measuring peak areas or heights. A Hewlett-Packard 18652A A/D converter interfaced to a Hewlett-Packard 3357 Lab Automation Data System was used in this evaluation.
3.1.4 Two-milliliter vials with Teflon-lined caps.
3.1.5 A dispenser capable of delivering 1.0 mL to prepare standards and samples. If a dispenser is not available, a 1.0-mL volumetric pipet may be used.
3.1.6 Syringes of various sizes for preparation of standards.
3.1.7 Volumetric flasks and pipets to dilute the pure analytes in preparation of standards. 3.2.5 A suitable internal standard, reagent grade. "Quant Grade" 3-methyI-3pentanol from Polyscience Corporation was used in this evaluation.
The desorption solvent consists of methylene chloride/methanol, 95/5 (v/v) containing an internal standard at a concentration of 20 pL/liter.
3.2.7 GC grade nitrogen, air, and hydrogen.

# R eliable quantitation lim it
The reliable quantitation lim its were determined by analyzing charcoal tubes spiked with loadings equivalent to the detection lim its o f the analytical procedure.

# Precision (analytical procedure)
The precision o f the analytical procedure for each analyte is the pooled coefficien t o f variation determined from replicate injections o f standards.
The precision o f the analytical procedure for each analyte is given in Tables 4.6.1 to 4 .6 .4 . T hese tables are based on the data presented in Section 4.4.

# .1 0 Stability o f desorbed sam ples
The stability o f desorbed samples was checked by reanalyzing the target concentra tion sam ples from Section 4 .9 one day later using fresh standards. The sample vials were resealed with new septa after the original analyses and were allow ed to stand at room temperature until reanalyzed. The results are given in

# Range, Stability and Interference
This method has been validated for sam pling air concentrations o f the stated glycol ethers and their acetates from 2 to 25 ppm by volum e in air. The method can be used for higher concentrations; how ever, the higher range has not been validated by U nion Carbide. B ecause som e o f the compounds may becom e hydrolyzed when sampled in high humidity atmospheres, the analysis o f the charcoal tube sam ples must be com pleted within 24 hours _ _ o f the sampling. H owever, in the case o f CELLOSOLVE solvent, sam ples can be stored for up to 14 days in a refrigerator but should be analyzed within 9 0 minutes after desorption.
In the case o f passive dosim eters, the sample may be refrigerated for up to fiv e days prior to analysis w ithout any significant le ss.
The presence o f other glycol ether vapor with sim ilar m olecular w eights and vapor pressure may result in interference. In addition to the 3M #3500 Organic Vapor M onitoring Badge, passive dosim eter badges from other manufacturers, such as Dupont's Pro-Tek Organic B adge, may also be used for monitoring g lycol ethers. Please contact the manufacturer for information concerning the suitability o f their monitors for specific glycol ethers or glycol ether acetates.

# Instrument Parameters

# Chromatograph
Som e firms are also known to provide analytical services for these m onitors for specific chem icals, including g lycol ethers. T his may be useful for som e o f the sm aller locations which do not have air sam pling equipment and/or on-site analytical capabilities o f their own. Further information about the NIOSH methods or passive monitors may be obtained from the NIOSH regional o ffice or equipment manufacturer. In the EGME-treated m ice, the mean testes w eights were significantly low er than those o f the control group at wk 2 to 5, and apjp>eared to increase again towards the end o f the study (statistics not given); there w as also a tendency towards a dose-response relationship in the incidence o f abnormal sperm (statistics not given).
In the rat dominant lethal study, the total implant numbers among fem ales mated at wk 5 to EGM E-dosed rats were reduced in a dose-dependent manner ( P 0 .0 0 1 ) . A lthough there w as a rise in preimplantation lo ss rate, there w as no statistically significant evidence for the

# B.2.1.3 Inhalation
In inhalation studies , pregnant N ew Zealand white rabbits were exposed 7 hr/day on g. (rabbits). This study indicated that exposure o f rabbits to EGEEA during organogenesis resulted in maternal toxicity at 100 to 300 ppm. Signs o f this included significantly decreased w eight gain and reduced gravid uterine w eight (P <0.001) and elevated absolute liver w eight (P < 0.05). In rats, significantly (P <0.001) reduced w eight gain and reduced food consumption were noted at 2 0 0 and 300 ppm EGEEA; significantly elevated relative liver w eights were noted at 1 0 0 ,2 0 0 , and 300 ppm EGEEA (no statistics given). In rabbits, an increased incidence o f totally resorbed litters at 200 ppm (P < 0.05) and 300 ppm (P < 0.001), an increase in nonviable fetuses at 300 ppm (P < 0.05), and a decrease in viable fetu ses per litter at 200 ppm and 300 ppm EGEEA (P <0.05) w ere observed. Fetotoxicity (reduced ossification) was observed at 100, 200, and 300 ppm EGEEA. The incidence o f external visceral and skeletal malform ations was increased at 2 0 0 ppm and 300 ppm (P < 0 .0 5 ). In rats, em bryo/fetotoxicity w as observed at 1 0 0 ,2 0 0 , and 3 0 0 ppm EG EEA. O bservations included increased nonviable im plantations/litter at 3 0 0 ppm (P < 0 .0 5 ), reduced fetal body w eight/litter at 2 0 0 and 300 ppm (P < 0.05), and increased incidence (P<0 .0 5 ) o f external variations at 300 ppm and visceral and skeletal variations at 100, 200, and 300 ppm. There w as no evidence o f maternal, embryonic, or fetal toxicity (including teratogenicity) at 50 ppm EGEEA in either species. T yl e t al. [ 1988J concluded that 50 ppm EGEEA was the no observable effect lev el.

# B .2 .1.4 Derm al Exposure
The effects o f dermal exposure to EGEE on pregnant Sprague-Dawley rats have been investigated by Hardin et al. .

# B.2.2 EGME and EGMEA

# B.2.2.1 O ral Adm inistration

# B.2.2.2 Inhalation

# B.2.2.3 D erm al Exposure
The teratogenic potential o f dermal exposure to EGME was estim ated using the C hem off and K avlock in v iv o assay. Groups o f 10 pregnant Alpk/AP (W istar derived) rats were exposed to 3%, 10%, 30%, or 100% EGME in physiological saline at 10 mL/kg . The test compound was applied for 6 hr (occluded exposure) on g.d. 6 through 17. Rats were then allow ed to deliver litters normally and rear their litters until day 5 post-partum. The application o f 100% EGME w as lethal to all dams and 30% was lethal to all developing fetuses. A t 10% EGME, the litter size w as reduced by 26% as was survival at day 5 (neither statistically significant). N o adverse effects w ere seen in the 3% group. The results were evaluated using "rules" generated from the C hem off and K avlock in vivo teratology screen assay. The authors concluded that the data demonstrated a clear doseresponse and that a 10% solution o f EGME is lik ely to be a rat teratogen . Exposure o f N ew Zealand white rabbits and Fischer 344 rats to 0 ,5 0 ,1 0 0 ,2 0 0 , or 300 ppm EGEEA 6 hr/day on g.d. 6 through 18 (rabbits) and 6 through 15 (rats) resulted in adverse hem atologic parameters in both species . In rabbits, there was evidence o f enlarged erythrocytes (elevated MCV) at 300 ppm EGEEA (P < 0.01) and significant dose-related decreases in the number o f platelets at 100 (P < 0.05), 200 (P < 0.01) and 300 ppm EGEEA (P <0.001). In rats, the W BC count was significantly increased (P < 0.001) at 200 and 300 ppm EGEEA. Statistically significant reductions in rat RBC count (P < 0.0), Hb level (P < 0.01), and Hct and RBC volum e (0.05) were seen at the three highest exposures (1 0 0 , 2 0 0 , and 3 0 0 ppm EG EEA). P latelet counts were a lso sig n ifica n tly reduced at 2 0 0 ppm (P <0.001) and 300 ppm EGEEA (P <0.01) in the rat.

# B.3.1.3 D erm al Exposure
In a study by Truhaut et al. , rabbits were exposed to a sin g le 24-hr dermal application (10,500 m g/kg) o f EGEEA; death follow ed betw een 1 and 4 days after application. The reduction in RBC count did not exceed 15% to 20% and blood Hb lev els show ed little variation; however, a 50% to 70% decrease in W BC count was noted.
In a study by Carpenter et al. , hem olytic effects in the rat erythrocyte were demonstrated by a single 4-hr inhalation exposure o f six fem ale rats to EGME or EGMEA. The low est concentrations causing significant osm otic fragility w ere 2,0 0 0 ppm EGME and 32 ppm EGMEA.
In a study by M iller et al. , Fischer 344 rats and B 6C 3F1 m ice were exposed by inhalation to 0, 100, 300, or 1,000 ppm EGME 6 hr/day for a total o f 9 days in an 1 1-day period. WBC counts o f both rats and m ice exposed to 1,000 ppm EGME were statistically lower than those o f the controls (P < 0.05). M CV, RBC counts, and Hb lev els o f male and fem ale rats and male m ice in the 1,000 ppm EGME-exposure group were also statistically depressed (*<0.05). A t 300 ppm EGME, sim ilar but less severe effects were seen in rats; statistically lower (P <0.05) WBC counts in both sex es and Hb and RBC counts in fem ales were noted. H em atologic parameters in m ice exposed at 300 ppm EGME were stated to be sim ilarly affected, but data were not presented. Histopathology was performed on rats only, revealing reduced bone marrow cellularity, lymphoid depletion in the cortex o f the thymus, and reduced numbers o f lymphoid cells in the spleen and in the m esenteric lymph nodes in the 1,000-ppm EGME group. Both m yeloid and erythroid elem ents o f the bone marrow were markedly reduced in all rats exposed to 1,000 ppm EGME, and m egakaryocytes were present in decreased numbers and were smaller than those o f controls. The entire thymic cortical lymphoid population was depleted, with less dramatic reductions in the lymph nodes and spleen. Lymphoid organ toxicity persisted at 300 ppm EGME, but to a much lesser extent. In addition, serum total protein, albumin (m ales only), and globulin values in the 1,000 ppm EGM E-exposure group (rats) were significantly reduced (P < 0.05).
In
This study show ed that in man, EGEE is rapidly absorbed through the lungs. About 64% o f the inhaled vapor w as retained at rest, and retention increased as physical exercise w as performed during exposure. The absorbed dose was apparently proportional to the inhaled concentration, and a linear relation was observed between uptake rate and exposure concentration. The rate o f uptake increased when physical exercise w as performed during exposure. The rate o f uptake was higher as exposure concentration, or pulmonary ventilation rate, or both increased. Individual uptake rates seemed dependent only on transport mechanism s (pulmonary ventilation, or cardiac output, or both) and not on anthropometric data or body fat content. Respiratory elim ination o f unchanged EGEE accounted for 0.4% o f the total body uptake and occurred rapidly after cessation o f exposure, follow ed by a much slow er decrease. This slow decrease indicated that tw o pharm acological compart ments were involved. Groeseneken et al.  also studied the urinary excretion o f EA A in the 10 male volunteers w ho inhaled various concentrations o f EGEE for 4 hr both at test and during physical exercise in the previously described study . The subjects, divided into tw o groups o f fiv e , were either exposed at rest to concentrations o f 2 .7 ,5 .4 , or 10.8 ppm EGEE (1 0 ,2 0 , or 40 mg/m3, respectively) or were exposed to 5 .4 ppm EGEE at rest and during physical exercises (see Table B -2  were still detectable. On a number of days, the preshift EAA concentrations were even higher than the immediate postshift values on the preceding and same day. For this reason, and because of the more constant exposure profiles, an estimation of the maximum EAA levels after prolonged daily exposure was made on the basis o f the results of the first exposure period. A linear correlation (r-0.92) was found between average exposure to EGEE and EGEEA over the 5 exposure days and EAA excretion at the end of the 5-day workweek. EAA estimate of 150 mg  35 mg/g creatinine was found to correspond with repeated 5-day full-shift exposures to 5 ppm of EGEE or 5 ppm of EGEEA. Groeseneken et al.  compared urinary EAA excretion in man and the rat after experimental exposure to EGEE. The human data were drawn from the previously men tioned inhalation study  in which five subjects had been exposed to 2.7 ppm, 5.4 ppm, or 10.8 ppm EGEE. Urine samples collected at short intervals were pooled into 12-hr groups for comparison with rat data. Groups o f five male Wistar rats were treated by oral intubation with 0.5, 1 ,5 , 10, 50, or 100 mg EGEE/kg. Rat urine samples were collected before EGEE exposure and then at 12-hr intervals up to 60 hr after the dosing. The maximal excretion rate of EAA in human and rat urine was found within 12 hr after exposure or dosing. Afterwards, the decline of urinary EAA was much slower in man than in the rat. In man, the half-life o f EAA was on average 42.0 + 4.7 hr, a longer half-life than reported in the original study (21 to 24 hr) . The author attributes the longer half-life to the use o f 12-hr pooled urine specimens in this study  rather than to specimens collected at 1-to 2-hr intervals in the previous study . In the previous study, half-lives were calculated from the peak exposure time (8 hr after the start o f exposure). Examination of the excretion curves from the previous paper showed that elimination between 8 and 12 hr was more rapid than at longer time intervals, leading to a shorter calculated elimination half-life . The authors concluded that the longer elimination half-life was more consistent with half-lives seen in occupational exposure, which were as high as 48 hr . The recovery o f EAA in human urine after 48 hr averaged 23%. Based on the half-life of EAA elimination o f 42 hr, the authors estimated total recovery of EAA as 30% to 35% of the absorbed dose.
In the rat, the half-life of EAA was 7.20  1.54 hr. On the average, 27.6% + 6.1 % of urinary EAA in rats was present as the glycine conjugate, with the extent of conjugation being independent o f the dose. The extent of conjugation demonstrated a diumal variation; the lowest extent of conjugation was found during the night EAA glycine conjugates were absent in human urine. In man, the recovery of EAA was higher than in the rat for equivalent low doses of EGEE (0.5 and 1 mg/kg). When urinary excretion data for the lower dose range were normalized for body weight in both species, rats excreted EAA at a higher rate than did man for equivalent doses. The authors concluded, that although nonlinear kinetics had been observed in some animal studies at high doses, the elimination kinetics seen at low doses in this study were not dose-dependent in either rats or humans . Groeseneken et al.  studied the pulmonary absorption and elimination o f EGEEA in 10 male subjects under various conditions of exposure and physical workload; subjects were 23.6 1.8 hr. However, 3hrafterthe first peak EAA excretion, a second maximum excretion of EAA was observed; this second peak was especially pronounced after exposure during physical exercise. Redistribution of EGEEA, or EAA, or both from a peripheral to central compartment could explain this phenomenon. Urinary EAA excretion was dependent on the EGEEA uptake rate, as a consequence of higher exposure (.PO.OOl), and on the uptake rate of EGEEA at constant exposure, as a consequence o f physical workload (P<0.001). On average, 22.2%  0.9% of the absorbed EGEEA was metabolized and excreted in the urine as EAA within 42 hr. The total excretion of EAA in 42 hr was related both to total uptake from increasing concentrations of EGEEA (P<0.001) and to total uptake, at constant exposure, with increasing workload (P<0.001). Total EAA excretion was correlated to EGEEA concentration, uptake rate, and transport mechanisms (pulmonary ventilation, oxygen consumption, respiratory rate, etc.). In addition, EAA excretion was correlated to body fat (r=0.40, /*<0.001). Groeseneken et al.  concluded that the metabolism of EGEEA proceeded through EGEE via esterases and then continued through the same excretion pathway as EGEE. Indeed, the kinetics of EAA excretion after exposure to EGEEA were very similar to these found after exposure to EGEE .
Workers from a shipyard painting operation who applied paint containing EGEE were evaluated for EGEE exposure . Work conditions and practices varied consid erably between brush and spray painters. Some workers were in confined spaces below deck, whereas others were in the open. The study was conducted in the winter, and the temperatures varied greatly depending on the painters' work areas. Information on work practices such as the number of hours spent painting, the type of paint used, the work area locations, and the use of personal protective equipment was gathered from questionnaires.
Environmental breathing zone samples were collected for each worker for 3 days. Urine samples were collected every day for 1 wk, at the beginning and end o f each workday, and EAA levels were measured. A wide range o f EAA levels was noted in workers using EGEE-containing paints; this was probably due to variation in work assignments, work areas, and use of personal protective equipment. This study has not gone through extensive evaluation to determine the importance of the many variables on the levels o f EAA in urine. The author could only conclude that there appeared to be a relationship between urinary EAA excretion and the use of paints containing EGEE . Clapp et al.  investigated EGEE exposure o f workers engaged in casting precision metal parts. The 8-hr TWAs of EGEE ranged from nondetectable to 23.8 ppm. EGEE was not detected in any of the blood samples from the EGEE-exposed workers, but exposed workers were found to have measurable levels of EAA in urine (163 mg/g creatinine). EAA was not detected in the urine of unexposed control subjects.

# B.4.2 EGME and EGMEA
EGME has been shown to be a possible substrate for alcohol dehydrogenase (ADH) , and thus oxidation of EGME via ADH and aldehyde dehydrogenase to methoxyacetic acid (MAA) is a potential route o f metabolism . second major urinary metabolite was identified as methoxyacetylglycine (approximately 20% o f radioactivity). Analysis o f radioactivity in the plasma demonstrated rapid disap pearance (tl/2 = 0.56 hr) o f EGME between 0 and 4 hr after dosing with a corresponding appearance o f MAA. Radioactivity clearance from plasma (tl/2 ) was estimated to be 19.7 hr.
In the rats pretreated with pyrazole, the metabolism o f EGME to MAA was inhibited. Analysis of radioactivity in plasma showed a slower disappearance o f EGME (tl/2 " 42.6  5 .6 hr) and radioactivity clearance from plasma (tl/2 -51.0 + 7.8 hr) than in the controls. The percentage o f the dose found in urine after 24 hr (9.8%  2.4%) and 48 hr (7.9% + 2.2%) showed urinary excretion not to be the major route o f elimination. MAA was not a major urinary component, and methoxyacetylglycine was not found in urine from these rats. Pretreatment with the aldehyde dehydrogenase inhibitor disulfiram had no significant effect on plasma or urinary metabolic profiles. Yonemoto et al.  used an in vitro culture system  to determine the effects of EGME and MAA on the development of post-implantation rat embryos. On g.d. 9, conceptuses were removed from the dams (Wistar-Porton strain) and placed in pairs in bottles that contained 3 mL of heat-inactivated male rat serum and 1 mL o f test compound. Ten to 15 conceptuses per group were cultured for 48 hr in 381 mg EGME or in 90, 180, 270, or 450 mg MAA and then examined under a stereoscopic dissecting microscope. EGME had no significant effects on embryonic growth and development when compared with that of the controls. MAA, however, produced statistically significant reductions in morphological development, crown-rump length, head length, number of somites, and yolk sac diameter when compared with those o f the controls (P<0.001). These effects demonstrated a dose response, as all were seen at 450 mg MAA; all but yolk sac diameters were affected at 270 mg, and only head length and morphological development were affected at 180 mg. No significant effects were seen at 90 mg MAA. The predominant abnormalities seen in affected conceptuses were irregular fusion of the neural tube (wavy or open neural suture line) and irregular segmentation of the somites. The authors  concluded that the data demonstrated that MAA or its metabolites are the proximal toxins in vivo and that, at the organogenesis stage, the rat fetus in vitro lacks alcohol dehydrogenase activity.
The in vitro culture system used by Yonemoto et al.  was used by Rawlings et al.  to study the mechanism of teratogenicity o f EGME. Conceptuses were explanted from pregnant Wistar-Porton rats at embryonic age 9.5 days and cultured for 48 hr with 2 or 5 mM MAA. At the end of the culture period, crown-rump length, head length, and yolk sac diameter were measured, and the degree of differentiation and development was evaluated by a morphological scoring system. MAA at the 5 mM concentration had an adverse effect on fetal development. MAA-exposed embryos had statistically significant reductions (P<0.01) in morphological score, crown-rump length, head length, and yolk sac diameter compared with those of the controls. MAA also produced statistically significant reductions (P<0.05) in the protein content of the embryo. No statistically significant reductions in growth parameters were seen at the 2 mM level. However, irregularity of the neural suture line was seen in 100% o f the MAA-exposed embryos. Other abnormalities observed in the MAA-exposed groups included abnormal otic and somite development, turning failure, open cranial folds, and abnormal yolk sac .
As has been demonstrated, the induction of paw malformations following in utero  as well as in vitro  exposure to EGME appears to depend on the oxidation o f EGME to MAA. Sleet et al.  investigated the relationship between the induction of paw malformations and the disposition of EGME in the maternal and embryonal compartments. Pregnant C D -1 mice were dosed by gavage on g.d. 11 with either EGME (1.3 to 6.6 mmol/kg, 100 to 500 mg/kg, or 5.2 fil/g) or MAA (1.1 to 7.7 mmol/kg, 100 to 693 mg/kg, or 4.9 pl/g) and were sacrificed on g.d. 18. Fetuses were delivered by laparotomy and weighed before external examination for paw defects. The embryotoxic potencies o f EGME and MAA were determined by comparing the dosedependent incidence o f digit anomalies. EGME and MAA were equipotent in causing digit malformations. The ADH inhibitor 4-methylpyrazole administered orally 1 hr before EGME reduced the incidence of malformations 60% to 100%, depending on the dosing regimen. Oxidation of EGME to MAA was nearly complete after 1 hr when approximately 90% o f ( I4C) in maternal compartment and conceptus coeluted with authentic ( 14C)-MAA on HPLC. Embryonic ( 14C)-MAA levels were 1.2 times those in plasma 1 hr and 6 hr after dosing; by 6 hr, however, concentrations in the embryo had declined to approximately 50% of 1-hr values. Dams treated i.v. with ( 14C) MAA had higher ( 14C) blood levels than did dams treated orally, but the offspring of the former had fewer digit malformations. The authors concluded that peak and steady-state plasma levels of MAA, as well as embryonic MAA levels, do not appear to determine the embryotoxic outcome whereas further metabo lism of MAA does . EGME uptake and urinary MAA excretion were examined in seven male subjects exposed at rest to 5.1 ppm EGME (16 mg/m3) by mask for four 50-min periods . There was a short 10-min break at the end o f each 50-min period to allow for urine collection. Urine samples were collected immediately before the beginning of the experi ment and at hourly intervals until the fourth hour after exposure. Collections were taken until the morning of the fifth day after the exposure period (four 2-hr collections, one 8-hr collection, and eight 12-hr collections). Urinary MAA was then measured by the method of Groeseneken et al. . Retention o f EGME was 76% during the 4-hr exposure period. The uptake rate showed no significant variation because of constant pulmonary ventilation and a fixed exposure concentration. On average, 19.4  2 .1 mg EGME was inhaled during the 4-hr exposure period. MAA was detected in the urine during and up to 120 hr after exposure. The elimination half-life averaged 77.1  9.5 hr. On average, 54.9 %  4.5% o f inhaled EGME was excreted within 120 hr o f the start o f exposure; half o f this amount was excreted within 48 hr. By extrapolation, the total amount of MAA was estimated at 85.5%  4.9% o f inhaled EGME.   as "aromatic amine," "safety solvent," or "aliphatic hydrocarbon" when the specific name is known.
The " % " may be the approximate percentage by weight or volume (indicate basis) that each hazardous ingredient o f the mixture bears to the whole mixture. This may be indicated as a range or maximum amount (i.e., 10% to 40% vol. or 10% max. wt.) to avoid disclosure of trade secrets.

# D.3 SECTION III. PHYSICAL DATA
The data in Section III should be for the total mixture. Include the boiling point and melting point in degrees Fahrenheit (Celsius in parenthesis); vapor pressure, in conventional millimeters of mercury (mm Hg); vapor (tensity of gas or vapor (air " 1); solubility in water, in parts/hundred parts of water by weight; specific gravity (water = 1); percent volatiles (indicated if by weight or volume) at 70F (21.1C); evaporation rate for liquids or sublimable solids, relative to butyl acetate; and appearance and odor. These data are useful for the control of toxic substances. Boiling point, vapor density, percent volatiles, vapor pressure, and evaporation are useful for designing proper ventilation equipment This information is also useful for designing and deploying adequate fire and spill containment equipment The appearance and odor may facilitate identification of substances stored in improperly marked containers or spilled substances.

# D.4 SECTION IV. FIRE AND EXPLOSION DATA
Section IV should contain complete fire and explosion data for the product. Include flashpoint and autoignition temperature in degrees Fahrenheit (Celsius in parentheses), flammable limits in percent by volume in air, suitable extinguishing media or materials, special fire-fighting procedures, and unusual fire and explosion hazard information. If the product presents no fire hazard, insert "NO FIRE HAZARD" on the line labeled "Extinguishing Media."

# D.5 SECTION V. HEALTH HAZARD INFORMATION
For the "Health Hazard Data" line, use a combined estimate o f the hazard o f the total product. This can be expressed as a TWA concentration, as a permissible exposure, or by some other indication of an acceptable standard. Other data are acceptable, such as lowest LD50 if multiple components are involved.     (3) gas chromatography analysis using name ionization detection (FID). Urine (1 ml) was adjusted to pH 2 with HC1 and extracted three times with methylene chloride. Phase transfer catalysis (a combination of ion-pair extraction and nuoroanhydride derivitization) was done by adding alkaline tetrabutylammonium hydrogen sulfate and PFBB to the methylene chloride extract. The mixture was rotated for 2 hr. Gas chromatography was employed to analyze 5 (jl of the methylene chloride layer (bottom layer) using FID and a 6 ft x 1/4 in (4-mm id) glass column (packed with 1.95% QF-1 and 1.5% OV-17 on 80/100 mesh Supelcoport). Detection limits for MAA and EAA were 11.4 and 5.0 mg/liter of urine, respectively. Average recoveries (and relative standard deviations) were 78% (0.17) for MAA and 91 % (0.14) for EAA. Groeseneken et al.  developed a method for determining MAA and EAA in urine based on lyophilization of urine samples followed by derivitization with diazomethane. After adjustment of urine specimens to pH 8 to 8.5 with KOH, 1 ml of urine and 50 fig of 2-furonic acid (FA) (internal standard) were added, and the sample was lyophilized. The dry residue was redissolved in 1 ml methylene chloride with added HC1 and derivitized with diazomethane in methylene chloride. Gas chromatographic analysis using FID was performed on a fused silica capillary column (CP WAX 57 CB, 25 m x 0.33 mm id) with a split ratio of 10:1. The detection limits of MAA and EAA were 0.15 and 0.07 mg/liter of urine, respectively. Mean recoveries of MAA, EAA, and FA added to "blank" urine samples were 31.4%, 62.5%, and 58.4%, respectively; the recoveries of MAA and EAA were well correlated with those of the internal standard. Day-to-day variability for MAA and EAA was 6.0% and 6.4%, respectively; the corresponding within-day variability was 6.2% and 8.9%. Smallwood et al.  developed and validated a method for analysis of EAA in urine. Two ml of urine, along with potassium carbonate, tetrabutylammonium hydrogen sulfate, methylene chloride, and PFBB were added to a screw-top culture tube. After 2 hr of mixing on a rotator at 60 rpm, the tube was heated for 20 min in a 50C water bath. Additional mixing at room temperature, removal of the upper aqueous layer, and washing o f the lower methylene chloride layers with distilled water removed unreacted reagents. The methylene chloride extract was dried with anhydrous sodium sulfate and loaded into an autosampler vial. Automated gas chromatographic analysis using FID was conducted with the use of a 6 ft x 4 mm id glass column packed with 4% SE-30 and 6% OV-210 on 100/120 mesh Chromosorb WHP. Standards were prepared in pooled urine. The analytical range for EAA was 5 to 100 mg/liter of urine; the limit o f detection was 4 mg/liter; and the limit of quantitation was 7 mg/liter. Within-day variation was 0.5% to 1.8%, and day-to-day variation was 3.0% to 4.7%. Sample stability was confirmed for at least 8 months when specimens were stored at -20C. The authors stated that the method could also be used for MAA and butoxyacetic acid (BAA) in urine. Preliminary data were presented in the paper indicating that the technique has the potential for assessing EGEE exposure in shipyard painters who use paints containing EGEE. Groeseneken et al.  observed that MAA appeared in the chromatogram of control subjects not exposed to EGME. Further investigation revealed that the diazomethane procedure was producing MAA by reacting with the hydroxyl group of naturally occurring glycolic acid. Groeseneken et al.  further evaluated the existing methods for determining alkoxyacetic acids and concluded that the phase transfer catalysis procedures had the required specificity, without the production of artifacts, but lacked sufficient sensitivity to detect these metabolites at low occupational exposure concentrations. On the other hand, the methods utilizing diazomethane derivitization had the required sensitivity but lacked the specificity. Therefore, Groeseneken et al.  developed an improved method that combined the best attributes of the two basic existing methods.
The procedure developed by Groeseneken et al.  was described as follows. Urine was adjusted to pH 7; l-ml aliquots were placed in small vials with 3-chloropropionic acid (internal standard) and lyophilized overnight. The dry residue was redissolved in methanol containing PFBB, and the vials were capped. The vials were heated at 90C for 3 hr. After cooling, sample cleanup was done by adding distilled water and extracting the pentafluorobenzyl-esters (PFB-esters) with methylene chloride. The methylene chloride extract was analyzed by gas chromatography using FID. A fused silica capillary column was used (CP Sil 5,25 m x 0.32 mm id, 0.21 pm film thickness) with a split ratio of 5:1. Temperature programming was employed. All PFB-esters showed baseline resolution; retention times of 6.53 min (MAA), 7.77 min (EAA), and 8.59 min (internal standard) were observed. A typical gas chromatographic run, including cool-down and equilibration times, required about 30 min.
Optimization studies were done for reagent concentrations as well as for urinaiy pH and reaction time. After correction for the partial solubility of methylene chloride in the 50:50 methanol: urine phase, recoveries of alkoxyacetic acids from urine averaged 95.0% (MAA), 94.8% (EAA), and 95.1 % (BAA). The yield for the derivitization reaction averaged 99.5% (MAA) and 101.8% (EAA). Standard curves were set up for urine and were linear over the range of 0.1 to 200 mg/liter. The limit of detection, at a signal-to-noise ratio o f 5, for the two acids was 0.03 mg/liter. Precision of the method, calculated from triplicate injections of 40 urine samples, averaged 3.5% (RSD), ranging from 1.1% at 25 mg/liter to 20% at 0.1 mg/1 iter. Groeseneken et al. methods [1986aGroeseneken et al. methods [ , 1989b, 1. The presence o f EAA in urine specimens (collected as specified) above a concentra tion of approximately 5 mg EAA/g creatinine is evidence for a single EGEE and/or EGEEA inhalation exposure corresponding to an 8-hr exposure to 0.5 ppm EGEE and/or EGEEA at 60 W of exercise. This value was extrapolated from 4-hr experimental exposures at 5 ppm at 60-W workload to an 8-hr exposure at 0.5 ppm at 60-W workload [Groeseneken et al. 1986c[Groeseneken et al. , 1987b

# NIOSH has not validated the

# G.2 Justification For Recommendations
Biological monitoring for glycol ether exposure is recommended, even though no validated guidelines can be provided as to the relationship between airborne exposure to glycol ethers and the alkoxyacetic acid urinary metabolites. The alkoxyacetic acid metabolites (EAA and MAA) are not only an index of exposure or uptake of EGEE or EGME by the worker, but they are also an index of potential adverse health effects from these glycol ethers.
Dermal absorption may be a major route o f exposure to EGME and EGEE and their respective acetates. The potential exists for absorption of glycol ether vapors through wet skin.
The influence of workload is significant for inhalation exposure. Doubling the workload results in twice the uptake of the glycol ethers. The potential for adverse effects, particularly decreased cardiac output, from the positive pressure feature o f some respirators has been reported . However, several recent studies suggest that this is not a practical concern, at least not in healthy individuals .
Theoretically, the increased fluctuations in thoracic pressure caused by breathing with a respirator might constitute an increased risk to subjects with a history o f spontaneous pneumothorax. Few data are available in this area. While an individual is using a negative-pressure respirator with relatively high resistance during very heavy exercise, the usual maximal-peak negative oral pressure during inhalation is about 15 to 17 cm of water . Similarly, the usual maximal-peak positive oral pressure during exhalation is about 15 to 17 cm of water, which might occur with a respirator in a positive-pressure mode, again during very heavy exercise . By comparison, maximal positive pressures such as those during a vigorous cough can generate 200 cm of water pressure . The normal maximal negative pleural pressure at full inspiration is -4 0 cm o f water , and normal subjects can generate -8 0 to -1 6 0 cm o f negative water pressure . Thus vigorous exercise with a respirator does alter pleural pressures, but the risk of barotrauma is substantially less with exercise than with coughing.
In some asthmatics, an asthmatic attack may be exacerbated or induced by a variety of factors including exercise, cold air, and stress, all of which may be associated with wearing a respirator. Although most asthmatics who are able to control their condition should not have problems with respirators, a physician's judgment and a field trial may be needed in selected cases.

# H.1.2 Cardiac Effects
The added work of breathing from respirators is small and could not be detected in several studies . A typical respirator might double the work of breathing (from 3% to 6% of the total oxygen consumption), but this is probably not of clinical significance [Gee et al. 1968

# H.1.5 Psychologic Effects
This important topic is discussed in recent reviews by Morgan . However, some individuals are likely to remain psychologi cally unfit for wearing respirators.

# H.1.6 Local Irritation Effects
Allergic skin reactions may occur occasionally from wearing a respirator, and skin occlusion may cause irritation or exacerbation of preexisting conditions such as pseudofolliculitis barbae. Facial discomfort from the pressure of the mask may occur, particularly when the fit is unsatisfactory.

# H.1.7 Miscellaneous Health Effects
In addition to the health effects (described above) associated with wearing respirators, specific groups of respirator wearers may be affected by (1) Corneal irritation or abrasion Comeal irritation or abrasion might occur with the exposure. This would, of course, be a problem primarily with quarter-and half-face masks, especially with particulate exposures. However, exposures could occur with full-face respirators because of leaks or inadvisable removal of the respirator for any reason. Although corneal irritation or abrasion might also occur without contact lenses, their presence is known to substantially increase this risk.
(2) Loss or misplacement of a contact lens
The loss or misplacement of a contact lens by an individual wearing a respirator might prompt the wearer to remove the respirator, thereby resulting in exposure to the hazard as well as to the potential problems noted above.

# 3) Eye irritation from respirator airflow
The constant airflow of some respirators, such as powered air-purifying respirators (P APR's) or continuous flow air-line respirators, might irritate the eyes of a contact lens wearer.

# H.2 SUGGESTED MEDICAL EVALUATION AND CRITERIA FOR RESPIRATOR USE
The following NIOSH recommendations allow latitude for the physician in determining a medical evaluation for a specific situation. More specific guidelines may become available as knowledge increases regarding human stresses from the complex interactions o f worker health status, respirator usage, and job tasks. Although some of the following recommen dations should be part of any medical evaluation of workers who wear respirators, others are applicable for specific situations.
- A physician should determine fitness to wear a respirator by considering the worker's health, the type of respirator, and the conditions of respirator use.
The recommendation above leaves the final decision of an individual's fitness to wear a respirator to the person who is best qualified to evaluate the multiple clinical and other variables. Much of the clinical and other data could be gathered by other personnel. It should be emphasized that the clinical examination alone is only one part o f the fitness determination. Collaboration with foremen, industrial hygienists, and others may often be needed to better assess the work conditions and other factors that affect an individual's fitness to wear a respirator.
- A medical history and at least a limited physical examination are recommended.
The medical history and physical examination should emphasize the evaluation of the cardiopulmonary system and should elicit any history of respirator use. The history is ah important tool in medical diagnosis and can be used to detect most problems that might require further evaluation. Objectives of the physical examination should be to confirm the clinical impression based on the history and to detect important medical conditions (such as hypertension) that may be essentially asymptomatic.
- Although chest X-ray and/or spirometry may be medically indicated in some fitness determinations, these should not be routinely performed.
In most cases, the hazardous situations requiring the wearing o f respirators will also mandate periodic chest X-rays and/or spirometry for exposed workers. When such information is available, it should be used in the determination of fitness to wear respirators.
Data from routine chest X-rays and spirometry are not recommended solely for determining if a respirator should be worn. In most cases, with an essentially normal clinical examination (history and physical), these data are unlikely to influence the respirator fitness determina tion; additionally, the X-ray would be an unnecessary source of radiation exposure to the worker. Chest X-rays in general do not accurately reflect a person's cardiopulmonary physiologic status, and limited studies suggest that mild to moderate impairment detected by spirometry would not preclude the wearing of respirators in most cases. Thus it is recommended that chest X-rays and/or spirometry be done only when clinically indicated.
- The recommended periodicity of medical fitness determinations varies according to several factors but could be as infrequent as every 5 years.
Federal or other applicable regulations shall be followed regarding the frequency o f respirator fitness determinations.   This trial period should also be used to evaluate the ability and tolerance o f the worker to wear the respirator . This trial period need not be associated with respirator fit testing and should not compromise the effectiveness of the vital fit testing procedure.
- Examining physicians should realize that the main stress of heavy exercise while using a respirator is usually on the cardiovascular system and that heavy respirators (e.g., SCBA) can substantially increase this stress. Accordingly, physicians may want to consider exercise stress tests with electrocardiographic monitoring when heavy respirators are used, when cardiovascular risk factors are present, or when extremely stressful conditions are expected. also wish to consider the following conditions in selecting or permitting the use of respirators:
- History of spontaneous pneumothorax
The authors  concluded that although the low dose o f EGME w as designed to be a n o-effect le v el, there were sligh t, previously noted [Chapin et al. 1985a
This method was reprinted from OSHA .
Further information on this subject or the U nion Carbide method may be obtained from U nion Carbide Corporation Saw M ill R iver Road Route 100 C Tarrytown, NY 10591 (9 1 4 )7 8 9 -2 2 3

# B .1 .1.2 Oral Adm inistration
Twenty male albino rats were fed 1.45% EGEE in their basic diet for 2 yr . U pon histological examination, testicular enlargement and edema and tubular atrophy were observed in two-thirds o f the animals that had received EGEE. These changes were not seen in untreated controls. The testicular lesion s were more often bilateral than unilateral and consisted o f marked interstitial edema.
Oral administration o f 46.5 or 93 mg EGEE/kg per day for 13 w eeks to m ale dogs (three per group) had no adverse effect . On the other hand, oral administration o f 186 m g EGEE/kg per day for 13 w k caused degenerative changes in the te ste s o f a ll *References for Appendix B can be found beginning on page 262.

# B.3.2 EGME and EGMEA

# B .3.2.1 Oral Adm inistration
Oral administration o f EGME and EGMEA has induced hem atologic changes in laboratory anim als.  found a statistically significant decrease (P < 0.01) in W BC counts follow in g oral administration o f 500 mg EGME/kg or 1,000 m g EGME A/kg to m ale JCL-ICR m ice 5 tim es/w k for 5 wk. Statistically significant decreases were also observed in RBC and Hb values for the 1,000 mg EGME/kg group (P<0 .0 1 ) and in Hb values for the 2,000 mg EGMEA/kg group (P <0.01). Treatment o f fem ale JCL-ICR m ice with 1,000 mg EGME/kg on g.d. 7 through 14 also significantly decreased the leukocyte counts (P < 0.01) . Grant et al.  investigated the effects o f subchronic oral exposure to EGME on the hem atopoietic system o f rats and the reversibility o f such effects. Groups o f 2 4 male F344 rats were orally dosed with EGME at 0 , 100, or 500 m g/kg per day for 4 consecutive days. S ix animals from each group w ere then sacrificed 1 ,4 ,8 , and 22 days after the last treatment. Rats in the high-dose group displayed severely hemorrhagic femoral bone marrow with major loss o f the normal nucleated tissue and damage o f sinus endothelial cells on day 1. The normal architecture o f the marrow w as restored by day 4 post-treatment. Treatment with 500 m g EGME/kg for 4 days abolished extramedullary hem opoiesis (EMH) in the spleen; partial recovery w as seen on day 4 , follow ed by marked improvement on day 8, and a return to control values by day 22. The high-dose group also show ed m ild anemia characterized by reductions o f the Hct and Hb values at day 4 (P <0.05 and P < 0.001, respectively), and RBC, Hct, and Hb values at day 8 (P <0.05, P <0.05, and P <0.01, respec tively). Leukocyte counts (neutrophils and lym phocytes) were significantly reduced in this group on day 1 (P <0.001) and did not return to control values by the end o f the recovery period. Low dose (100 m g EGME/kg per day) rats also had reduced leukocyte counts on day 1 (P < 0.05). The authors  concluded that the major hem atological effect o f EGME was leukopenia characterized by reductions in lym phocytes and neutrophils. Changes in the circulating blood together with reduced splenic EMH and bone marrow toxicity suggested an inhibitory action on erythropoiesis. The toxicity o f MAA will be discussed next to evaluate the importance o f metabolism as a detoxification or bioactivation mechanism for EGME. In a study by Miller et al. , groups o f five male F344 rats were given daily doses o f 0, 3 0 ,1 0 0 , or 300 mg MAA/kg per day orally on 8 days out o f 10 and were then sacrificed 24 hr after the final dose. Rats given the high dose had significantly lower body weights on the fifth day and again when recorded on the tenth day (P<0.05 The role o f metabolism in EGME-induced testicular toxicity was investigated by Moss et al.  using groups o f nine male Sprague-Dawley rats pretreated i.p. with 400 mg pyrazole/kg, an alcohol dehydrogenase (ADH) inhibitor, or pretreated with 300 mg disulfiram/kg, an aldehyde dehydrogenase inhibitor. One hr after pretreatment with pyrazole or 24 hr after pretreatment with disulfiram, animals were injected i.p. with 250 mg o f labeled EGME/kg. Controls with no pretreatment also received 250 m g(14C) EGME/kg i.p. Urinary excretion was the major route of elimination o f EGME metabolites after 24 hr (40.4%  3.6% o f dose) and 48 hr (14.8%  0.6% o f dose) in controls. High performance liquid chromatography (HPLC) analysis identified MAA as the major urinary metabolite at 0 to 24 hr (63% of the radioactivity) and at 24 to 48 hr (50% of the radioactivity). The

# B.3.2.2 Inhalation

# APPENDIX C O CCUPATIO N AL EXPOSURES TO TH E G LYC O L ETHERS BY W ORKSITE OR PR O C ESS

# APPENDIX D M ATERIAL S A FE T Y DATA SH EET
The following sections describe the information that must be supplied for each product or material in the appropriate blocks of the Material Safety Data Sheet (MSDS).
To

# D.2 SECTION II, HAZARDOUS INGREDIENTS
The "materials" listed in Section II shall be those substances that are part of the hazardous product covered by the MSDS and that individually meet any o f the criteria defining a hazardous material. Thus, one component of a multicomponent product might be listed because of its toxicity, another component because of its flammability, and a third com ponent for both its toxicity and its reactivity. Note that a MSDS for a single component product must have the name of the material repeated in this section to avoid giving the impression that there are no hazardous ingredients.

# TRADE NAME

# SYNONYMS II HAZARDOUS INGREDIENTS

# H.1 BACKGROUND INFORMATION
Brief descriptions of the health effects associated with wearing respirators are summarized below. More detailed analyses of the data are available in recent reviews by James  and Raven et al. .

# H.1.1 Pulmonary Effects
In general, the added inspiratory and expiratory resistances and dead space of most respirators cause an increase in tidal volume and a decrease in respiratory rate and ventilation (including a small decrease in alveolar ventilation). These respirator effects have usually been small both among healthy individuals and, in limited studies, among individuals with impaired lung function . This generalization is applicable to most respirators when resistances (particularly expiratory resistance) are low .
Although most studies report minimal physiologic effects during submaximal exercise, the resistances commonly lead to reduced endurance and reduced maximal exercise perform ance . The physiological responses of mild pulmonary impaired subjects while using a "demand" respirator during rest and work. Am Ind Hyg Assoc J 42(4):247-257.

# Raven