1.0 - Action Requested

The Antimicrobial Division’s (AD) Regulatory Management Branch I has requested an Occupational and Residential Exposure Assessment of a previously unassessed use of phenol that is on the Sporicidin Disinf ectant Solution Label (EPA 8383-3). This use is listed under the heading FOR FOGGING CLEAN ROOMS: See S poricidin Bulletin No. 301. The following directions are included in Bulletin No. 301:

“Sporicidin Brand Disinfectant so lution is recommended for fogging articles and surfaces in sealed rooms and cubicles as an adjunct to ma nual cleaning and disinfecting procedures. Unscrew pump bottle and change [sic] the fogging device with the required volume of solution. Seal all windows and doors. Set ti me for treatment cycle as recommended by device manufacturer. Turn on device, leave room and reseal door. Do not allow anyone to reenter room or cubicle for at least 2 hou rs after fogging cycle has been completed. Upon reentering room or cubicle, follow regul ar cleaning and disinfecting procedures.”

2.0 - Summary of Findings

Because the instructions on Bulletin 301 indicate that Sprocidin is applied by an automatic device, handler exposures occur only when filling the fogger reservoir. These exposures were assessed using the CMA data for the disinfect ant open pouring scenario. This assessment indicated that the estimated de rmal MOE of 300 and the esti mated inhalation MOE of 1500 are above the respective targ et MOEs of 100 and 300, therefore the risks from dermal or inhalation exposures are not of concern.

Post application inhalation exposures can occu r after the fog has been applied and workers re-enter the treated areas. The instructions on Bu lletin 301 indicate that the room must be sealed during application and no one is allowed to re-e nter the room or cubicl e for at least two hours after the fogging cycle is completed. An i nhalation exposure assessment was conducted using the single chamber decay formula from the Mu lti-Chamber Concentra tion and Exposure Model (MCCEM). This assessment indicated that the MO Es rise to the target MOE of 300 after 3.3 air exchanges which takes 50 to 200 minutes depending upon the ventilation rate.

Post application dermal exposures are not expe cted to be significan t because a substantial portion of the applied fog will remain airborne long enough to be removed by ventilation. In addition, Bulletin 301 requires that regular cleaning and disinfecti ng be performed upon entering the room or cubicle which would further reduce su rface residues. Phenol is also fairly volatile and any remaining residues would evaporate rather quickly with a Chinn evaporation time of 5.2 hours.

3.0 - Summary of Toxicological Endpoints:

On March 9, 2004, the Antimicrobials Divisi on Toxicology Endpoint Selection Committee (ADTC) reviewed the available toxicology data for Phenol and discussed endpoint selection for use as appropriate in risk assessments. The conc lusions drawn at this meeting are presented in the ADTC report of March 20, 2004 and the endpoints selected that are relevant for occupational

Page 2 of 6exposure are summarized in Table 1. The hazard based uncertainty f actors and target MOEs are also listed in Table 1. Fo r dermal exposures, only the standard uncertainty fact ors of 10X for inter-species extrapolation and 10X for intra-species variation are required. An additional factor of 3X to is required for short/in termediate term inhalation exposu res to account for the use of a LOAEL and an additional 10X factor is required for long term inhalation exposures to account for the for the lack of a chronic study. Ther e are no concerns regard ing special sensitivity, therefore a data base uncertain ty factor is not required.

Table 1 - Summary of Toxicological Doses fo r Phenol Occupational Exposure Assessment

Exposure Scenario Dose Used in Risk Assessment Hazard Based Uncertainty Factors Study and Toxicological Effects

Dermal AShort and intermediateterm NOAEL = 60 mg/kg/day Target MOE = 100 B Developmental toxicity study in rats (NTP, 1983). Based on significant reductions from the control in mean fetal body weight/litter at 120 mg/kg/day.

Inhalation All durations LOAEL = 0.1 mg/L (26 mg/kg/day) E Target MOE = 300 C (ST, IT)

MOE = 1000 D (LT) Dalin and Kristofferson: Ph ysiological Effects of a Sub-lethal Concentration of Inhaled Phenol on the Rat. Ann. Zool. Fennici 11: 193-199, 1974 LOAEL of 0.1 mg/L, based on alterations in sliding angle from tilting plane test, and significant increases in liver enzymes

Cancer data inadequate for assessment of human carcinogenic potential (USEPA, 2002)

A A dermal absorption factor of 50% is used since an oral endpoint was selected. Dermal abso rption data were available from the IRIS Toxicological profile for phenol . From the available data, dermal abso rption percentages of 20-50% have been observed from in vivo and in vitro studies . The ADTC selected the 50% dermal absorption value for phenol for use in risk assessments as a conservative valu e. This value also takes into account the ir ritant properties of ph enol which may increase its dermal absorption. B. Includes the standard uncertainty factors of 10X for inte r-species extrapolation and 10X for intra-species variation. C. Includes the standard uncertain ty factors and an additional factor of 3X to account for the use of a LOAEL. D. Includes the standard uncertainty factors and an additi onal factor of 10X to account for lack of a chronic study. E. 26 mg/kg/day = (0.1 mg/L * 10.26 L/hr/kg * 6 hrs/day) / 0.236 kg

4.0 - Residential Exposures

The existing Sporicidin label in dicates that Sporidic in is used for fogging clean rooms. By definition, clean rooms are specia lized production or research f acilities that are designed to minimize product contamination and are not consider ed residential areas, therefore residential exposures are not anticipated.

5.0 - Occupational Handler Exposures

Because the instructions on Bulle tin 301 indicate that Sprocidin is applied by an automatic device, handler exposures occur only when filling the fogger reservoir. These exposures were assessed using the CMA data for the disinfectant open pouring scenario. Th is data was collected as workers poured a 2 percent solution of glutaraldehyde from one gallon containers into pans

Page 3 of 6for disinfection of medical instruments.

The phenol handler exposures were asse ssed using the following assumptions.

• Given that one gallon of Sporicidin can tr eat 30,000 square feet (or 240,000 cubic feet assuming an eight foot ceiling) it is likely that a handler would load at most five gallons of Sporocidin per day.

• Sporicidin contains 0.13 lb act ive ingredient (ai) per gallon based upon the ai concentration of 1.56% and a density of 8.35 lbs per gallon.

• Dermal exposures are assessed using the dermal unit exposure value of 36.5 mg/lb ai handled from the CMA database. This is the value for the disinfectant liquid pou r scenario and is the mean of two samples. The handlers wore protective gloves during the sampling period.

• Inhalation exposures are assessed using the inhalation unit exposure va lue of 1.89 mg/lb ai handled from the CMA database. This is the value for the disinfectan t liquid pour scenario and is the mean of two samples.

• The exposures would be short and intermediate term in duration because fogging is not done every day.

The calculations and MOEs are included in Ta ble 2. The dermal MOE of 300 exceeds the target MOE of 100 and the inhalation MOE of 1500 exceeds the target MOE of 300, therefore the risks from dermal or inhalati on exposures are not of concern.
Table 2 - Occupational Handler Risk Summary
Exposure Scenario Amount ai Handled

per Day A Exposure Pathway Unit Exposure B (mg/lb ai) Exposure C (mg/day) Dose D,E (mg/kg/day) MOE F,G

Dermal 36.5 23.7 0.20 300 Loading Fogger – Liquid pour 0.65 lb Inhalation 1.89 1.23 0.0176 1500 A. Amount ai handled per day = 0.13 lb ai per gallon * 5 gallons handled per day B. Unit exposures are from CMA, dermal exposures represent chemical resistant gloves being worn. C. Exposure (mg/lb) = Amount ai handled pe r day (lb) * Unit Exposure (mg/lb ai) D. Dermal dose (mg/kg/day) = [Expos ure (mg/day) * Dermal Ab sorption Factor (0.5)] / Body weight (60 kg). E. Inhalation dose (mg/kg/day) = [Expos ure (mg/day) * Inhalation Absorption Factor (1.0)] / Body weight (70 kg). F. Dermal MOE = NOAEL/ Dose where NOAEL = 60 mg/kg/day. Target MOE = 100 G. Inhalation MOE = LOAEL / Dose; wher e LOAEL = 26 mg/kg/day. Target MOE = 300

6.0 - Occupational Post Application Exposures

Inhalation Exposures

Post Application inhalation exposures can occu r after the fog has been applied and workers re-enter the treated areas. The instructions on Bu lletin 301 indicate that the room must be sealed during application and no one is allowed to re-e nter the room or cubicl e for at least two hours after the fogging cycle is completed. An i nhalation exposure assessment was conducted using the single chamber decay formula from the Mu lti-Chamber Concentra tion and Exposure Model (MCCEM v1.2). This assessment was based upon th e application parameters listed in the revised version of the Bulletin 301. The following assumptions were made:

Page 4 of 6• The application is treated as an instant release scenario where the product becomes airborne as an aerosol and either remains airborne as an aerosol until it is removed by ventilation or it evaporates from the aerosol before it settle s. Although it is acknowledged that some portion of the aerosol would settle onto horizontal surfaces, th is fact is ignored for simplicity in the calculations and results in a c onservative estimate of exposure.

• The application rate is 1 ga llon per 240,000 cubic feet (ft 3 ) based upon listed rate of 1 gallon

per 30,000 square feet and assuming an 8 foot ceiling.

• The product contains 0.13 lb ai per gallon ba sed upon the ai concentration of 1.56% and a

density of 8.35 lbs per gallon.

• The initial concentration is 8.7 mg/m 3 based upon the following:

(0.13 lb ai * 454,000 mg per lb) / (240,000 ft 3 * 0.0283 m 3 per ft 3 )

• All openings such as windows and doors are closed and the ventil ation system is turned off

during the application of the fog.

• After the fog has been applied and given time to penetrate, the ventilation system is

activated.

• The ventilation system provides an air excha nge rate of 1.0 to 4.0 air changes per hour.

The calculations are included in Appendix A a nd a summary of the results is included in Table 3. The MOEs rise to the target MOE of 300 after 3.3 air excha nges which takes 50 to 200 minutes depending upon the ventilation rate.

Table 3 – Phenol Air Concentrations Following Fogging Application

Initial Concentration Ventilation Rate (Air Changes per hour) Time to Reach MOE of 300 (Minutes) Number of Air Changes

1 200 2 100 8.7 mg/m 3

4 50 3.3

Dermal Exposures

Post application dermal exposures are not expe cted to be significan t because a substantial portion of the applied fog will remain airborne long enough to be removed by ventilation. In addition, Bulletin 301 requires that regular cleaning and disinfecti ng be performed upon entering the room or cubicle which would further reduce su rface residues. Phenol is also fairly volatile and has a short Chinn evaporation time. The Ch inn evaporation time is the time needed for 90 percent of a substance applied as a thin film to evaporate and is based on the molecular weight and vapor pressure as outlined in the Resident ial SOPs. The Chinn formula is given below:

Page 5 of 6D = 145/[(mw * vp) 0.9546 ]

Where:

D = Chinn evaporation time (hours) mw = molecular weight (unitless) vp = vapor pressure in torr

Given that phenol has molecular weight of 94.1 and a vapor pressure of 0.35 mm hg at 25 C, the Chinn evaporation time for phenol is 5.2 hours at 25 C.

7.0 - Occupational Risk Characterization

The assessment of the occupational handler risk s are based on the CMA data for the liquid pour disinfectant scenario which consists of only two monitoring units. This scenario was chosen, however, because the chemical handled, glut araldehyde, is similar in volatility to phenol and because glutaraldehyde, like Sporicidin, was handled in one gallon containers. The other liquid pour CMA data were either collected from operations, where la rger containers that ranged in size from 5 gallon to 55 gallons, were hand led and/or where chemical s that are less volatile than phenol were handled.

The assessment of post applicati on inhalation risk can be consid ered conservative because it is based entirely on contaminant removal by ventilation and does not consider removal by aerosol settling. This conservatism is reduced, however, by the fact that phenol is fairly volatile and will be emitted from the settled aerosols.

Page 6 of 6Appendix A - ORE Assessment for the Existing Cleanroom Use of Phenol (Sporicidin) Spreadsheet 1 - Phenol Fogger Post Application Exposures Estimated Using MCCEM

Time (minutes) Phenol (mg/m3) MOE Input Value Units 0 8.71 11 Amount Product Applied 1 Gallon 10 7.37 14 Percent ai 1.56 percent 20 6.24 16 Product Density 8.35 lb/ga 30 5.28 19 Amount ai Applied 0.13 lb 40 4.47 22 Amount ai 59138 mg 50 3.78 26 60 3.20 31 Treated Area 30000 sq feet 70 2.71 37 Ceiling Height 8 feet 80 2.29 44 Treated Volume 240000 cubic feet 90 1.94 51 Treated Volume 6792 cubic meters 100 1.64 61 Applied Concentration 8.71 mg/m3 110 1.39 72 120 1.18 85 Ventilation Rate 4000 CFM 130 1.00 100 Air Exchange Rate 1 ACH 140 0.84 118 150 0.71 140 EPA LOAEL 100 mg/m3 160 0.60 165 UF 300 170 0.51 195 EPA LOC 0.33 mg/m3 180 0.43 231 190 0.37 273 200 0.31 322 (1 Air Change per Hour)

0 1 2 3 4 5 6 7 8 9 10

0 30 60 90 120 150 180 210 Elasped Ventilation Time in MinutesPhenol (mg/m3)Appendix A - ORE Assessment for the Existing Cleanroom Use of Phenol (Sporicidin) Spreadsheet 2 - Phenol Fogger Post Application Exposures Estimated Using MCCEM

Time (minutes) Phenol (mg/m3) MOE Input Value Units 0 8.71 11 Amount Product Applied 1 Gallon 10 6.24 16 Percent ai 1.56 percent 20 4.47 22 Product Density 8.35 lb/ga 30 3.20 31 Amount ai Applied 0.13 lb 40 2.29 44 Amount ai 59138 mg 50 1.64 61 60 1.18 85 Treated Area 30000 sq feet 70 0.84 118 Ceiling Height 8 feet 80 0.60 165 Treated Volume 240000 cubic feet 90 0.43 231 Treated Volume 6792 cubic meters 100 0.31 322 Applied Concentration 8.71 mg/m3

Ventilation Rate 8000 CFM Air Exchange Rate 2 ACH

EPA LOAEL 100 mg/m3 UF 300 EPA LOC 0.33 mg/m3 (2 Air Changes per Hour)

0 1 2 3 4 5 6 7 8 9 10

0 30 60 90 120 150 180 210 Elasped Ventilation Time in MinutesPhenol (mg/m3)Appendix A - ORE Assessment for the Existing Cleanroom Use of Phenol (Sporicidin) Spreadsheet 3 - Phenol Fogger Post Application Exposures Estimated Using MCCEM

Time (minutes) Phenol (mg/m3) MOE Input Value Units 0 8.71 11 Amount Product Applied 1 Gallon 10 4.47 22 Percent ai 1.56 percent 20 2.29 44 Product Density 8.35 lb/ga 30 1.18 85 Amount ai Applied 0.13 lb 40 0.60 165 Amount ai 59138 mg 50 0.31 322 Treated Area 30000 sq feet Ceiling Height 8 feet Treated Volume 240000 cubic feet Treated Volume 6792 cubic meters Applied Concentration 8.71 mg/m3

Ventilation Rate 16000 CFM Air Exchange Rate 4 ACH

EPA LOAEL 100 mg/m3 UF 300 EPA LOC 0.33 mg/m3 (4 Air Changes per Hour)

0 1 2 3 4 5 6 7 8 9 10

0 30 60 90 120 150 180 210 Elasped Ventilation Time in MinutesPhenol (mg/m3)