IX. APPENDIX I -Sampling Procedure for Collection of Dioxane 169 X. APPENDIX II -Analytical Procedure for Determination of Dioxane 172 XI. APPENDIX III -Material Safety Data Sheet 181 XII. TABLES 191 x I. RECOMMENDATIONS FOR A DIOXANE STANDARD The National Institute for Occupational Safety and Health (NIOSH) recommends that worker exposure to dioxane (p-dioxane, 1,4-dioxane, diethylene dioxide, glycol ethylene ether) in the workplace be controlled by adherence to the following sections. The standard is designed to protect the health and provide for the safety of employees for up to a 10hour workday, 40-hour workweek, during their working lifetime. Compliance with all sections of the standard should minimize adverse effects of exposure to dioxane on the health and safety of employees. The recommended environmental limit presented should be regarded as the upper limit of exposure, and every effort should be made to maintain exposure as low as is technically feasible. The standard is measurable by techniques that are valid and available to industry and government agencies. Sufficient technology exists to permit compliance with the recommended standard. The criteria and standard will be subject to review and revision as necessary. Dioxane is a volatile liquid which can readily penetrate intact skin to cause systemic effects, which include adverse renal and hepatic changes. Exposure to dioxane may also cause cancer, a conclusion interpreted from experimental studies with animals, and much of the recommended standard is based on this conclusion. Because of the carcinogenic action of dioxane and its ability to penetrate the skin, occupational exposure to dioxane is defined as any work in workplaces where dioxane is handled, manufactured, or otherwise used, except where it is present as an unintentional contaminant in other chemical substances at less than 1% by weight or where it is only stored in leak-proof containers. The recommended exposure limit, based on the belief that dioxane can be tumorigenic, is the lowest concentration reliably measureable by the sampling and analytical methods selected. Section 1 -Environmental (Workplace Air) (a) Concentration Occupational exposure to dioxane shall be controlled so that employees are not exposed at airborne concentrations greater than 1 ppm (3.6 mg/cu m) based on a 30-minute sampling period. (b) Sampling and Analysis Procedures for sampling and analysis of workroom air shall be as provided in Appendices I and II or by any method shown to be at least equivalent in sensitivity, accuracy, and precision. Section 2 -Medical Medical surveillance shall be made available as outlined below to all workers subject to occupational exposure to dioxane. (a) Preplacement examinations shall include at le a s t : (1) Comprehensive medical and work histories with special emphasis directed toward disorders of the upper respiratory system, and hepatic and renal functions. (2) Physical examination giving particular attention to nares, and the hepatic and renal systems. (3) Specific clinical tests to include at least liver and kidney function tests such as SGOT, SGPT, and a complete urinalysis. 2 (4) A judgment of worker's ability to use positive pressure respirators. (b) Periodic examinations shall be made available at least annually. These examinations shall include at least: (1) An interim medical and work history. (2) A physical examination as outlined in (a)(2) and (3) above. (c) Initial examinations shall be made available to all workers occupationally exposed to dioxane within six months after the promulgation of a standard based on these recommendations. (d) Pertinent medical records shall be maintained for all employees exposed to dioxane in the workplace. Such records shall be kept for at least 30 years after termination of employment. These records shall be made available to the designated medical representatives of the >  Secretary of Health, Education, and Welfare, of the Secretary of Labor, of the employer, and of the employee or former employee. Section 3 -Labeling and Posting All labels and warning signs shall be printed both in English and in the predominant language of non-English-reading employees. Employees unable to read the language used on labels and posted signs shall be appropriately Informed of the location of hazardous areas and of the instructions on labels and signs. (a) Labeling The following warning label shall be affixed in a readily visible location on dioxane processing or other equipment and on dioxane storage tanks or containers: 3 DIOXANE warning: CANCER-SUSPECT AGENT BREATHING VAPOR MAY BE HAZARDOUS TO HEALTH HARMFUL IF ABSORBED THROUGH SKIN OR IF INHALED Avoid breathing vapor. Avoid contact with skin or eyes. Use only with adequate ventilation. Keep containers closed when not in use. Wash thoroughly after using. Extremely flammable. May explode. Keep away from heat, sparks, open flame and oxidizing materials. First a i d : In case of skin or eye contact, immediately flush eyes or skin with water for at least 15 minutes. Call a physician. If swallowed, induce vomiting immediately if patient is conscious. Call a physician. (b) Posting Areas in which dioxane is present shall be posted with a sign reading: DIOXANE WARNING! CANCER-SUSPECT AGENT HARMFUL IF ABSORBED THROUGH SKIN OR IF INHALED Extremely flammable. May explode. Do not use near open flame or oxidizing materials. (b) All employees occupationally exposed to dioxane shall be informed that dioxane has induced cancer in experimental animals after repeated oral ingestion and that, because of this finding, it is concluded that dioxane is a potential human carcinogen. (c) Employers shall institute a continuing education program to ensure that all employees have current knowledge of job hazards and procedures for maintenance, cleanup, emergency, and evacuation. This program should include at least the following: Emergency procedures and drills. Instruction in handling spills and leaks. Decontamination procedures. Firefighting equipment location and use. First-aid procedures, equipment location, and use. Rescue procedures. Confined space entry procedures, if relevant. Inadequacy of odor as a means of detection. The training program shall include a description of the general nature of the environmental and medical surveillance procedures and why it is advantageous for the worker to participate in these procedures. Records of such training should be kept for at least 5 years. This training program shall be held at least annually, or whenever there is a process change, for all employees with occupational exposure to dioxane. (d) Workers shall be informed that cancer has been induced in animals treated with dioxane at concentrations considerably higher than work environment exposures. (e) Information as required shall be recorded on US Department of Labor Form 0SHA-20, "Material Safety Data Sheet," or similar form approved by the Occupational Safety and Health Administration, US Department of Labor. Section 6 -Work Practices (a) Emergency Procedures Procedures for emergencies, including fires, shall be established to meet foreseeable potential events. Necessary emergency equipment shall be kept in readily accessible locations. Where appropriate, respirators shall be available for use during evacuation. (b) Control of Airborne Dioxane (1) Suitable engineering controls designed to limit exposure to dioxane to that prescribed in Section 1(a) shall be used. The use of completely enclosed processes is the recommended method for control of dioxane. Local exhaust ventilation may also be effective, used alone or in combination with process enclosure. When a local exhaust ventilation system is used, it shall be designed to prevent the accumulation or recirculation of dioxane in the workroom, to maintain dioxane concentrations below the limit of the recommended standard, and to remove dioxane from the breathing zones of employees. Exhaust systems discharging into outside air must conform with applicable local, state, and federal air pollution regulations. Ventilation systems shall be subjected to regular preventive maintenance and cleaning to ensure effectiveness, which shall be verified by periodic airflow measurements at least every 3 months. Measurements of system efficiency shall also be made immediately by personnel properly attired in any needed protective equipment and clothing when any change in production, process, or control might result in increased concentrations of airborne dioxane. Tempered makeup air shall be provided to work areas in which exhaust ventilation is operating.(2) Forced-draft ventilation systems shall be equipped with remote manual controls and shall be designed to turn off automatically in the event of a fire in the work area. (3) Exhaust vents to the outside shall be so located as to prevent the return of the exhausted air via air-intakes. Buildings in which dioxane is used and where it could form an explosive air-mixture shall be explosion-proof. Explosion vents are available and are effective on windows, roof and wall panels, and skylights as a safeguard against destruction of buildings and equipment in which flammable vapors may accumulate. Stair enclosures shall also be fire-resistant and shall have self-closing fire doors. (c) General Work Practices (1) Safety showers and eyewash fountains shall be installed in areas where dioxane is handled or used. The employer shall ensure that the equipment is in proper working order through regularly scheduled inspections performed by qualified maintenance personnel. (2) Transportation and use of dioxane shall comply with all applicable local, state, and federal regulations. (3) When dioxane containers are being moved, or when they are not in use and are disconnected, valve protection covers shall be in place. Containers shall be moved only with the proper equipment and shall be secured to prevent dropping or loss of control while moving. (4) Process valves and pumps shall be readily accessible and shall not be located in pits or congested areas. (5) Containers and systems shall be handled and opened with care. Approved protective clothing as specified in Section 4 shall be worn 10 while opening, connecting, and disconnecting dioxane containers and systems. Adequate ventilation shall be provided to prevent exposure to dioxane when opening containers and systems. (6) Personnel shall work in teams when dioxane is first admitted to systems, while repairing leaks, or when entering a confined or enclosed space. (7) Containers of dioxane shall be bonded and grounded to prevent ignition by static electrical discharge. (8) Smoking shall not be permitted in work areas where there is dioxane. (d) Work Areas (1) Dioxane Hazard Areas A hazard area is any space with physical characteristics and sources of dioxane that could result in air concentrations in excess of the recommended limit. Exits shall be plainly marked and shall open outward. Emergency exit doors shall be conveniently located and shall open into areas which will remain free of contamination in an emergency. At least two separate means of exit shall be provided from each room or building in which dioxane is stored, handled, or used in quantities that could create a haz a r d . (2) Confined or Enclosed Spaces Entry into confined spaces, such as tanks, pits, process vessels, tank cars, sewers, or tunnels where there may be limited egress, shall be controlled by a permit system. Permits shall be signed by an authorized employer representative certifying that proper preventive and protective measures have been followed. (b) Recordkeeping Environmental monitoring records shall be maintained for at least 30 years. These records shall include methods of sampling and analysis used, types of respiratory protection used, and concentrations found. Each employee shall be able to obtain information on his own environmental exposures. Environmental records shall be made available to designated representatives of the Secretary of Labor and of the Secretary of Health, Education, and Welfare. Pertinent medical records shall be retained for 30 years after the last occupational exposure to dioxane. Records of environmental exposures applicable to an employee should be included in that employee's medical records. These medical records shall be made available to the designated medical representatives of the Secretary of Labor, of the Secretary of Health, Education, and Welfare, of the employer, and of the employee or former employee.# CRITERIA DOCUMENT:

# RECOMMENDATIONS FOR AN OCCUPATIONAL EXPOSURE STANDARD FOR DIOXANE

# Table of Contents

# PREFACE iii

# REVIEW COMMITTEE vi NIOSH REVIEW CONSULTANTS vii I. RECOMMENDATIONS FOR
There is also equivocal evidence of carcinogenesis from dioxiane when applied dermally, but this evidence has not been judged persuasive. While experimental inhalation studies and limited epidemiologic studies have not supported the implications that dioxane is carcinogenic, these studies have not been considered to be sufficient to negate the implications of the studies of dioxane administered at higher doses in the drinking water. Since a safe limit for this chemical substance, judged to be carcinogenic, is not known, a limit based on the sensitivity of the analytical and sampling methods has been recommended.
Concern for the carcinogenic and other toxic properties of dioxane by manufacturers may stimulate action to replace dioxane, for example, as a stabilizer for trichloroethane, by chemicals presumed or known to be much less toxic. Such manufacturers are urged to ensure that the substitutes are known, rather than presumed, to pose more acceptable toxicity properties.        3, or 5 ml of 80% dioxane diluted with saline to a total volume of 10 ml.

# III. BIOLOGIC EFFECTS OF EXPOSURE
Extent
Three other rabbits each were given two 5-ml injections of dioxane mixed with 5 ml of saline with an interval of 48 hours between injections. One rabbit, used as a control, received 10 ml of saline. The immediate effect of dioxane injection in all the rabbits was violent struggling, which began as soon as the first few drops were injected. With doses of 4 or 5 ml of dioxane, the struggling was followed by convulsions and collapse; then the rabbits rapidly returned to normal.
The four rabbits given the single doses of 80% dioxane were killed 1 month later. Degeneration of the renal cortices with hemorrhages was observed by microscopic examination.
In the rabbit administered the 3-ml dioxane dose, the degenerative changes extended into the medulla, and the liver showed extensive and gross cellular degeneration starting at the periphery of the lobules. No abnormality was found in other organs. The livers of the rabbits given the 1-and 5-ml doses showed no microscopic abnormalities, and areas of cloudy swelling were seen in the liver of the rabbit given 2 ml of dioxane.
One of three rabbits given two 5-ml doses of 80% dioxane was killed for necropsy when it seemed acutely ill, 5 days after the second injection.
The two remaining rabbits appeared to be ill on the 7th day when one died    The blood urea rose to 81 mg/100 ml after the administration of 4 ml dioxane on day 42 and increased to mg/100 ml after a 5-ml dose was administered on day 47, which produced a terminal uremia.
The ig administration to a dog of 25 ml of commercial dioxane in 75 ml water followed 50 minutes later by 100 ml of a 50% solution was reported    affected at 2,500 ppm and its responses were not consistent from day to day. In the group exposed at 3,000 ppm, the avoidance reaction was delayed in two to three rats/exposure. About 75% of the rats showed delay of the avoidance response after one exposure at 6,000 ppm, but the escape response was unaffected.
After two exposures, the avoidance reaction was blocked in all animals and the escape response was blocked in three of eight rats.
Three or more exposures completely blocked the avoidance response in 37-62% of the rats; the escape response was not affected.
It was noted from these experiments that the delay in avoidance response increased with increase in concentration and, in multiple exposures, the escape responses were also blocked in many cases. The rats were killed with ether at 16 months or earlier if the nasal cavity tumors were clearly observable.
Autopsies were performed on all rats.  In another report, apparently of the same experiment, Argus et al  reported that the hepatocarcinogenicity of dioxane in male rats was a function of the total oral dose administered.

# Five groups of 28-32 Charles
River CD strain male rats, 2-3 months old, and weighing 110-230 g at the beginning of the experiment, were used in each group. The rats were housed two to a cage. The experimental animals were given drinking water containing 0.75, 1.0, 1.4 or 1.8% dloxane for 13 months with one group used as a control. Fresh dioxane solutions were prepared daily. The weights of the rats were recorded weekly, and all rats that survived for 16 months were killed with ether.
Autopsies were performed on all rats. The exact number of animals used in each group was not stated and hence the number of animals having tumors or the number of tumors/animal could not be determined.
Four "incipient" tumors were found in the livers in the group that received 0.75% dioxane and nine in the group that received 1% dioxane.
These so-called "incipient" tumors were described as nodules with the histologic characteristics of hepatomas.
Thirteen "incipient" liver tumors and three hepatomas were found in the 1.4% group and 11 "incipient" liver tumors and 12 hepatomas were found in the group administered 1.8% dioxane. In their earlier studies, the authors  had observed nasal tumors at all the four levels, 0.75, 1.0, 1.4 and 1.8% dioxane, one tumor at each of the two lower levels and two each at the two higher levels of dioxane.

# The total dioxane doses
In the present study, no nasal tumors were reported and, although lung tumors were not found in any of the rats, the lungs of one rat given 1.4% dioxane in drinking water showed early peripheral adenomatous change of the alveolar epithelium; papillary hyperplasia of the bronchial epithelium was found in another rat receiving the same level of dioxane.
For electron microscopic studies, the investigators  administered 1% dioxane in drinking water to 10 male Sprague-Dawley rats. Five of them were killed after 8 months and the other five after 13 months of treatment.
Although microscopic examination revealed no evidence of liver tumors in any of the rats killed after 8 months, "incipient" liver tumors, which they termed precancerous changes, were seen in two rats consuming dioxane for 13 m o n t h s .  The sodium salts of oxalic acid and diglycolic acid were administered iv to rabbits, and ethyl oxalate was applied to the skin of rabbits and guinea pigs.
Renal and hepatic changes were similar to those seen with dioxane.         given to rats at doses greater than 2,000 mg/cu m by the respiratory route, above 3,000 mg/kg by the dermal route, and above 500 mg/kg/day by the oral route for a lifetime, which is equivalent to 100 g total dose for the rat.

# VI REACTIVITY D A T A C O N D IT IO N S C O N T R IB U T IN G T O IN S T

# C E N T E R F O R D IS E A S E C O N T R O L N A T I O N A L IN S T IT U T E FO R O C C U P A T I O N A L S A F E T Y A N D H E A L T H R O B E R T A. T A F T L A B O R
Neoprenecoated gloves, boots, overshoes, and bib-type aprons that cover boot tops will sometimes be necessary. Impervious supplied-air hoods or suits should be worn when entering confined spaces, such as pits or tanks, unless they are known to be safe.
If skin comes into contact with dioxane, promptly wash or shower to remove dioxane from the skin, thereby preventing penetration of dioxane through the skin.
Clothing that is wet with dioxane can be easily ignited; hence, wet clothing must be removed immediately. This clothing must not be reworn until the dioxane is removed from the clothing. The employer should ensure that all personal protective clothing is inspected regularly for had been damaged previously.
Penetration of skin to cause systemic effects is probably more Important than local skin effects in the case of dioxane.
As was discussed in Chapter III, dioxane can cause skin irritation and can penetrate skin readily. Hence, protective clothing that will prevent skin contact should be used whenever liquid dioxane is handled.    There is no information available on possible mutagenic effects of dioxane. This is another area where research is needed.

# Irritation of the eyes and nose has been

# T h e p a t h w a y s of m e t a b o l i c t r a n s f o r m a t i o n , d i s t r i b u t i o n , and e l i m i n a t i o n of d i o x a n e as a f u n c t i o n of t h e d o s e , rate, a n d r o u t e of a d m i n i s t r a t i o n , h a v e n o t b e e n a d e q u a t e l y i n v e s t i g a t e d in a n i m a l s a n d in man. O n e i m p o r t a n t f a c t o r is to d e t e r m i n e w h e t h e r it is u n c h a n g e d d i o x a n e o r a n y of its m e t a b o l i t e s t h a t i n d u c e s c ancer.
Those studies most indicative of dioxane as a carcinogen have  "safety solvent," or "aliphatic hydrocarbon" when the specific name is known.