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1 -;wyeth. Wyeth Medica reland 0 Newbridge, Co. Kildare, reland Telephone: (045) Facsimile (045) Liz Leacy, Administration Officer, Off ice of Licensing & Guidance, Environmenta Protection Agency, PO Box 3000, Johnstown Castle Estate, Co. Wexford. 27th February 2006 Dear Liz, PC Licence Reaister No. 756 We refer to the telephone discussion between Wyeth Medica reland (WM) personnel Dr Edward Molyneaux and Agency nspector Sean O'Donoghue on 16/02/2005, during which it was agreed that additional supporting information would be forwarded to the Agency as part of the ntegrated Pollution Control (PC) Licence Review Application Register No The following additional information is therefore presented in relation to occupational exposure aspects for Oral Contraceptive (OC) active products. As outlined in WM correspondence of 12/01/2006 the Wyeth Corporate Environment, Health and Safety Department defines the 'Predicted No Adverse Effect Level' (PNAEL) as: 'The PNAEL is a calculated value used to esthnate the human no effect dose level, it is to be used in the absence of a published or rebable 'No Observable Adverse Effect Level' me mlculated PNAEL is designed to provide an order of magnitude safe@ h&r below the lowest effedive daily therapeutk dose (e.g., for a repetitive dosing riime/ if approprhte). The PNAEL for the most potent of the OC actives used at the WM facility namely, Ethinyl Estradiol is 2 pg/day. This PNAEL is derived for an ideal select healthy worker (as used in clinical trials). To calculate a community PNAEL the following is considered:. n calculating the PNAEL for an ideal select healthy worker air breathed in per work day is 20 m3 and a body weight of 70 Kg is used. n calculating a community PNAEL both of these factors are adjusted to account for sensitive human subpopulations i.e. reduced breathing rate and reduced body weight. Managing Directors: F! Jones (USA). E. Lach (USA), W. J. Noonan, J. OConnor (USA), A. M. PloosVan Amstel (Dutch) Wyeth Medica reland is a business name of AHP Manufacturing 8.V.. a company incorporated (Reg. No ) with limited liability in the Netherlands. Registered in reland - Number E3277

2 Wyeth Medica reland Newbridge, Co. Kildare, reland Telephone: (045) Facsimile (045) To account for sensitive human subpopulations in the community (including individuals who may have potentially different health risks), additional risk assessment factors are applied. To provide for potential uncertainty in community hazard determinations, an additional safety or uncertainty factor of lox is indicated. n consideration of these points an extremely conservative community PNAEL of 0.01 < pg/d is generated. a e3 With regard to the predicted ground level value for OC actives presented in Section of Arup Menzies report dated June 2005 [entitled "Wyeth Medica reland PPC Licence Review - Air Dispersion Modelling Assessment" (Report Reference: D4533/19)] as presented in Attachment of the PC Licence review, the model has been rerun (Appendix 1) as one of the assumptions previously made which accounted for a worst-case active concentration of 0.15 mg/m3 modelled for each point can now be more accurately defined as follows and therefore removed as an assumption from the model. Any dust that may discharge to atmosphere will not consist of 100% pharmaceutica active. The concentration of pharmaceutical active used in the manufacturing process is c 10/0 for OC products with the remainder as inert excipient. Results of PC Licence No. 673 monitoring conducted in 2005 indicate total dust in the emissions to atmosphere monitoring locations to be c0.15 mg/m3. t is therefore a reasonable assumption that the OC active content of this duct is c mg/m3. Results of the revised modelling assessment (Appendix 1) indicate that the highest predicted 24-hour ground level value for OC actives at residential property locations Hl - H6 (refer to figure 1 Sensitive Receptors in the Wcinity of the Wyeth Facilityof Arup Menzies Report Reference: D4533/19) located nearest to the WM site varies from pg/m pg/m3. Assuming the normal air intake for an average person is 20 m3/day then pg/day pg/day is the hypothetical, worst case dose range for these locations. To account for sensitive human subpopulations with reduced breathing rates a conservative factor of 0.75 is adopted. The predicted ground level value for the OC actives at these locations is reduced to pg/day pg/day. n addition, as previously referred to in WM correspondence of 11/11/2005 and 16/02/2005 there are a number of broad assumptions which are adopted in the dispersion model which do not reflect WM's actual operations and this must also be considered when assessing the predicted ground level value for OC actives which the model gives us. Specifically these are:. All process points are emitting simultaneously for 365 days per year, 24 hours per day. n reality each of the process emission points emit on a batch basis for 1 to 24 hours per day for between 25 to 343 days per annum.. n relation to the baseline therapeutic dose selected for the OC product family the PNAEL specified for OC is that for the most potent of the OC actives used at the WM facility namely, Ethinyl Estradiol.. All process emission points are simultaneously emitting the OC active Ethinyl Estradiol which will not occur. Managing Directors: F! Jones (USA), E. Lach (USA), W. J. Noonan, J. OConnor (USA), A. M. PloosVan Amstel (Dutch) Wyeth Medica reland is a business name of AHP Manufacturing B.V., a company incorporated (Reg. No ) with limited liability in the Netherlands. Registered in reland - Number E3277

3 Wyeth Medica reland Newbridge, Co. Kildare, reland Telephone: (045) Facsimile (045) n consideration of all of these factors the overall conclusion of the Air Dispersion Modelling Assessment that the predicted OC active concentration is of no significance is further reinforced. An original and 2 hard copies and 2 electronic copies on CD-ROM of this information are enclosed. Trusting this is to the satisfaction of the Agency. queries please do not hesitate in contacting me. Should you, however, have any Yours sincerely, A Senior Environmenta Officer Managing Directors: F! Jones (USA), E. Lach (USA), W. J. Noonan, J. OConnor (USA), A. M. PloosVan Amstel (Dutch) Wyeth Medica reland is a business name of AHP Manufacturing B.V., a company incorporated (Reg. No ) with limited liability in the Netherlands. Registered in reland - Number E3277

4 Wyeth Wyeth Medica reland Appendix 1 Air Dispersion Modelling of OC Emission

5 Arup Consulting Engineers Wyeth Medica reland ~~ PPC Licence Review ~ Air Dispersion Modelling of OC Emission SSUE

6 . Arup Consulting Engineers Wyeth Medica reland PPC Licence Review Air Dispersion Modelling of OC Emission February 2006 Arup Consulting Engineers 10 Wellington Road, Dublin 4 reland Tel Fax This report takes into account the particular instructions and requirements of our client. t is not intended for and should not be relied upon by any third party and no responsibility is undertaken to any third party Job number D

7 ~ ~ ~, Arup Consulting Engineers Document Verification Page 1 of 1 Job title PPC Licence Review Job number D Document title Air Dispersion Modelling of OC Emission File reference Document ref Revision late Filename Draft 1!7/02/06 Description First draft Name Prepared by Checked by Approved by ~~ Maire OSullivan Sinead Whyte Don Menzies Signature ssue!7/02/06 Filename Description OC emissions report ssue.doc Prepared by Checked by Approved by Name Maire OSullivan Sinead Whyte Don Menzies Signature Filename Description Name Prepared by Checked by Approved by Qi) Prepared by Checked by Approved by ssue Document Verification with Document i J\D4500-D4599W533W) DESGNUJ\OC EMSSONS REPORT SSUE DOC Amp Consultlng Engineers ssue 27 February 2008

8 Wyeth Medica reland PPC Licence Review Air Dispersion Modelling of OC Emission Contents 1 ntroduction 2 Scope 3 Air Quality Guidelines 4 Dispersion Modelling 4.1 Emission data 4.2 Building Wake Effect 4.3 Receptors 4.4 Scenario Meteorological Data 5 Results 5.1 Scenario Scenario 2 6 Conclusions 7 References Page J:u)4500D4599\D4533W) DESGNVJ\OC EMSSONS REPORT SSUE DOC Amp Consulting Engineers ssue 27 February 2006

9 Wyeth Medica reland PPC Licence Review Air Dispersion Modelling of OC Emission 1 ntroduction Wyeth Medica reland (WMl) operates a pharmaceutical plant at Newbridge, CO Kildare. This study assesses the impact of emissions of OC (oral contraceptive) from the plant to atmosphere on the air quality of the surrounding area. Emissions to atmosphere also occur from the tablet manufacturing process. These emissions include Active Pharmaceutical ngredients (APls), one of which is OC. 2 Scope Air dispersion modelling was carried out to determine the impact of emissions from the main emission points on concentrations of OC. The modelling described in this report used hourly meteorological data from Met Eireann s station at Dublin Airport. The model was used to predict ground level concentrations (GLCs) at receptors up to 10 km from the site. -hour average, 24-hour average and annual average GLCs were calculated for the emissions. The model was run for 2 scenarios, as follows: Scenario 1 : Using a number of grids to determine the GLCs at the worst-case receptor within a 10km x 10km area Scenario 2: Placing receptor points at the six sensitive receivers nearest to the site (refer to Figure 1). These scenarios are described in more detail in Section Air Quality Guidelines There are currently no guidelines for ambient levels of APls. n order to establish the potential impact of OC on the receiving environment an assessment was conducted using the Maximum At Risk ndividual (MAR) Risk Assessment Concept. This is used by the US EPA for assessment of health impacts of emissions from industrial processes. The Mari Calculation is as follows: 24 - hour average GLC of OC x average volume of air inhaled by a human therapeutic dose for OC actives x 100 = %dose This calculation is based on the following assumptions: All process points are emitting for 365 days per year, 24 hours per day. However, the PC Licence restricts emissions to between 25 and 343 days per annum for each of the process emission points. A worst-case active concentration of mg/m3 is modelled for each point An individual will spend a fraction of the time spent by the MAR1 at this worst-case location, not the 24 hours that is assumed. The worst 24 hour concentration occurring over a 5 year period has been calculated. 4 Dispersion Modelling The emissions from the plant were analysed by the computer model AERMOD. J:D4500D4599\D4533W) DESGNV3\0C EMSSONS REPORT SSUE.DOC Amp Consulting Engineers ssue 27 February 2006

10 ~~ Wyeth Medica reland PPC Licence Review Air Dispersion Modelling of OC Emission The model predicts the ground level concentration caused by emission of OC. The model requires data on: 0 Emission sources Neighbouring buildings Location and elevation of receptors Meteorological data The model was used to calculate -hour, 24-hour and annual average ground level concentrations (GLCs) of OC. 4.1 Emission data The relevant emission data input into the air dispersion model is outlined in Table 1 below. This data is based on the following sources: PC licence 0 nformation provided by Wyeth. Process emissions points are located throughout the site. Emissions of AP (OC active) were modelled from these points. n order to assess the impact of AP on the receiving environment, an emission limit value of mg/nm3 has been assumed. This represents an absolute worst-case scenario. 4.2 Buildina Wake Effect Data on the building comprises of the length, width and height of each section or tier. A software utility called BPP was used, in conjunction with the location and height of emission sources, to calculate direction-specific building downwash factors from the building data. The dimensions, roof heights and location of the buildings were taken from site plans. 4.3 Receptors Scenario 1 For this modelling situation, three nested Cartesian receptor grids were used. The first grid extends for 10 km in each direction from the facility, with receptors at 2 km intervals. The second grid extends for 5 km in each direction from the facility, with receptors at 1 km intervals. The fine grid extends for 1 km in each direction, with receptors at 100 m intervals. On-site receptors were eliminated. Elevations were taken from Ordnance Survey maps at 6 and 1" to 1 mile scales. 4.4 Scenario 2 For this modelling situation, the model was run only with the inclusion of receptor points located at the six sensitive receivers shown in Figure 10.1 of the ES assessment (ref. Wyeth Medica reland Proposed PNFX Development ES, AWN Consulting, planning reference 04/1713)', see Figure 1. Elevations were taken from Ordnance Survey maps at 6' and 1" to 1 mile scales. 4.5 Meteorological Data Five years ( ) of meteorological data from Met Eireann's station at Dublin Airport was used. J:\D450C-D4599\D4533W) DESGNUJ\OC EMSSONS REPORT SSUE.DOC AN^ Consulting Engineers ssue 27 February 2006

11 Wyeth Medica reland PPC Licence Review Air DisDersion Modelling of OC Emission The meteorological data includes hourly values of wind speed, wind direction, atmospheric stability, ambient temperature and mixing heights. Results There are currently no guidelines for ambient levels of APls. n order to establish the potential impact of such emissions on the receiving environment an assessment was conducted using the Maximum At Risk ndividual (MAR) Risk Assessment Concept. This is used by the US EPA for assessment of health impacts of emissions from industrial processes'. To demonstrate the effect of the OC results, an assessment of the effect of the emission on an individual at a point of maximum risk to the emission. The therapeutic dose for OC actives is advised by WM to be 50 pg/day. The average air volume inhaled by an adult male or female is given as 20Nm3 of air per day. 5.1 Scenario 1 Emissions of OC were modelled from process emission points, the results of which are shown in Table 2. Table 2 shows the highest predicted 24-hour average GLC of OC is pg/m3. The location of this maximum concentration is shown in Figure 2. sopleths showing areas of equal 24-hour ground level concentrations are shown in Figure 3. The OC active dose for the MAR1 is therefore calculated to be: x 20 = 0.064pg 0*064x100=0.128% 50 The theoretical OC dose to the MAR1 is therefore calculated to be 0.128% of the therapeutic OC dose. 5.2 Scenario 2 Table 3 shows the highest predicted 24-hour average GLC of OC is pg/m3 (Receptor H4). The OC active dose for the MAR1 is therefore calculated to be: x 20 = 0.024pg 0'024 x 100 = 0.048% 50 The theoretical OC dose to the MAR1 is therefore calculated to be 0.048% of the therapeutic OC dose. t can therefore be concluded that the predicted OC active concentration is of no significance. 6 Conclusions OC active concentrations will pose no significant impact to individuals in the vicinity of the WM facility. J:U)4500D4599\C4533W) DESGNU3\OC EMSSONS REPORT SSUE.DOC Amp Consulting Engineers ssue 27 Februaly 2008

12 Wyeth Medica reland PPC Licence Review Air Dispersion Modelling of OC Emission 7 References 1 Human Health And Ecological Risk Assessment Support To The Development Of Technical Standards For Emissions From Combustion Units Burning Hazardous Waste, EPA Contract No W6-0053, US EPA, Washington, July Wyeth Medica reland ES for PNFX Building 3C, A Three Storey Extension to the Existing 38 Manufacturing Facility ncluding Office Accommodation, Ancillary Site Buildings, Structures and services Prepared by Fluor Ltd. and AWN Consulting Ltd., July J:\D45OO-D4599\D4533W) DESGNVB\OC EMSSONS REPORT SSUE.DOC Arup Consulting Engineers ssue 27 February 2006

13 Wyeth Medica reland PPC Licence Review Air Dispersion Modelling of OC Emission Arup Consulting Engineers Appendix A Tables ' J:U)4500D4599\D4533W) DESGNUB\OC EMSSONS REPORT SSUE.DOC AN^ Consulhng Engineers ssue 27 February 2006 EPA Export :18:18:59

14 ~~ -- Wyeth Medica reland, Air Dispersion Modelling Study of Emissions of OC 7 Table 1 Emission Data for OC Emission Points Volume Flow Exit Stack Reference Stack Height Temperature Concentration Mass Emission Diameter Sectional Area New Ref (Old Ref.) (m) ( C) (NmYhr) (mglnm ) (@a ~-.- - (mw A2-8 (TB 0) , A2-9 (TB11) A2-12 (TB14) A2-18 (TBl9) 11, , , A2-19 (TB20) , A2-29 (TB32) , A249 Laboratory Emission Plant for ~- A249 Levo Continuous Use ~~~ A2-70 Levo Continuous Use A2-71 Levo Continuous Use A2-72 Levo Continuous Use A2-73 Levo Continuous Use A2-74 Levo Continuous Use A2-75 Glatt Coater Exhaust Levo , Continuous Use A2-76 Central Dust Collector Levo Continuous Use , A2-91 Charging solator Levo Continuous Use A2-92 Vacuum Lifter Levo Continuous Use , J:D \04533!4) DESGNUWOC EMSSONS REPORT SSUE.DOC A6 AN^ Consulting Engineers Draft 1 24 February 2006 EPA Export :18:18:59

15 Wyeth Medica reland Air Dispersion Modelling Study of Emissions of OC Desiccant Wheel Levo Continuous ce , J:\D4500-D4599\D4533!4) DESGNUB\OC EMSSONS REPORT SSUE.DOC A7 Amp Consulting Engineers Drafl 1 24 February 2006 EPA Export :18:18:59

16 ~~ ' Wyeth Medica reland Air Dispersion Modelling Studv of Emissions of OC Table 2 Scenario 1, Dispersion Modelling Results for OC - Pollutant Parameter Ground level OS Easting (m) OS Northing (m) concentration hj@ma) Oral Contraceptive (OC) 1 hour Average hour Average Annual Average hour 24-hour Annual OS Easting OS Northing Pollutant Receptor Average Average Average No. GLC (pglm3) GLC (pg/m3) GLC (pg/ma) (m) (m)., Table 3 Scenario 2, Dispersion Modelling Results for OC (Refer to Figure 1) Oral Contraceptive (OC) H H H H H5 H J:D W533W) OESGN\23\0C EMSSONS REPORT SSUEDOC page 1 Amp Consulbng Engineers ssue 27 February 2006 EPA Export :18:18:59

17 6 Figure 1 Sensitive Receptors in the Vicinity of the Wyeth Facility EPA Export :18:18:59

18 Figure 2: Location of Maximum OC Active Concentration EPA Export :18:18:59

19 s P FGURE 3: OC ACTVE 24-HOUR GLC (ug/m3) WETH MEDCA NEWBRDGE 2 Ordnance Survey reland Licence No. EN c Ordnance Survey reland and Government of reland EPA Export :18:18:59