Draft: OPPT Updated Risk Characterization for Occupational Inhalation of PV29 Based on Updated Approach 
Introduction: 
Following the publication of the draft risk evaluation (RE) for C.I. Pigment Violet 29 (PV29), EPA received numerous comments during the public comment period. Many comments related to the screening-level characterization of potential inhalation risks from occupational exposure to PV29. A comment received during that period from the National Institute for Occupational Safety and Health (NIOSH) suggested that, 
      "In developing the margin of exposure (MOE) alternative values that may be more appropriate than the single point estimate of exposure is the NIOSH recommended exposure limit for particles not otherwise regulated (PNOR) of 10 mg/m[3] or the OSHA standard for PNOR (5 mg/m3 for respirable dust and 15 mg/m3 for total dust)."
To provide additional characterization of potential risks from airborne exposures of PV29, EPA has incorporated the OSHA standard for PNOR (5 mg/m3 for respirable dust and 15 mg/m[3] for total dust) into the inhalation risk characterization calculation presented in the draft RE.  In this case, the value of 15 mg/m[3] for total dust was used to calculate the potential dose rate for PV29 to provide a high-end estimate of potential occupational exposure. 
In conjunction to the NIOSH suggested exposures, EPA also utilized the Multiple-Path Particle Dosimetry Model to better understand the % deposition of the PV29 particles in each area of the lung (Head, TB, Alveolar Region) based on the PV29 particle size data submitted by the data owners after the publication of the draft RE (available in the non-confidential report of the Physico-chemical Properties of "Paliogen Violet 5011" https://www.regulations.gov/document?D=EPA-HQ-OPPT-2018-0604-0036) :
          Diameter: 4.620E+1 um
          Sigma_g (GSD): 2.810E+0 (=exp[ln(median/lower bound)/n]
          Mass density: 1.58 g/cm^3
          Aerosol concentration: 15.0 mg/m^3
          Airway deposition fraction calculated by MPPD (v.3.04), based on alveolar deposition: 0.0113 (i.e. 1.13% deposition; see Appendix 1 below for MPPD output)
To incorporate these suggestions, EPA proposes two approaches to characterize the occupational risks of inhalation exposure to PV29: 
 Utilize rat chronic and subchronic toxicity data from an analogous chemical, barium sulfate (BaSO4), a low toxicity fine particulate with low solubility to calculate a POD for portal of entry inhalation toxicity based on lung overload in rats. This POD is then compared to an exposure potential dose rate calculated based on NIOSH-recommended OSHA standard for particles not otherwise regulated (15 mg/m[3]) adjusted for the alveolar deposition fraction of PV29 calculated by MPPD (1.13%) to calculate an MOE. 
 Use particle size information to perform a screening-level analysis of potential for lung overload in workers according to the approach presented in Oberdörster (1994). 



 Use of BaSO4 Analogue Data: 
PV29 is a relatively large (MMD=46.9 um), poorly respirable, poorly absorbed particle, which is not metabolized not inherently toxic, and exhibits a low solubility. As a result, the most relevant endpoint of interest to determine an inhalation POD is lung overload. Limited appropriate analogues were identified. From the identified analogues, BaSO4 is proposed as an analogue because it is a relatively large particle, has a low solubility, it is not inherently toxic, and it is very poorly absorbed (USEPA, 2005). Compared to Titanium Dioxide (TiO2), a similar poorly soluble analogue, , BaSO4 was considered more appropriate because it has a larger particle size (MMAD 4.3 μm vs 2.1 μm) that is more representative of the particle size of PV29 (MMD=46.9 um), as particles with larger diameter and smaller surface area require a larger dose to cause symptoms of lung overload (Tran et al., 1999). In addition, TiO2 may demonstrate surface reactivity depending on the surface characteristics (NIOSH, 2011). 
For the PV29 risk characterization, a NOAEC of 40 mg/m[3] was used as a POD. This NOAEC value is based on the level for BaSO4 where lung overload would not occur based on the impairment of clearance, increase in the rate of inflammatory recruitment of PMN (Polymorphonuclear Cells) and dust translocation to the lymph nodes for the average animal (Tran et al., 1999). This NOAEC is comparable to that reported in other inhalation toxicity studies with BaSO4, where sub chronic inhalation exposure to BaSO4 up to 50 mg/m3 resulted in no treatment related effects, and sub-chronic inhalation exposures above 75 mg/m[3] did not result in increased PMN counts (Landsiedel et al., 2014). There are uncertainties related to the use of BaSO4 as an analogue due to the difference in particle size. To account for the difference in particle size between BaSO4 (MMAD= 4.3 μm) and PV29 (MMD= 46.9 um), the deposition fraction of PV29 in the alveolar region was estimated using the Multiple-Path Particle Dosimetry Model (v.3.04) and the EPA proposes applying this deposition fraction to the potential dose rate to calculate an exposure value that accounts for particle size differences between PV29 and the analogues (1.13% deposition to the alveolar region only, see Table 1 for MPPD output (ARA, inc, 2015). 
The inputs, outputs and results of this approach are presented below and in Table 1:
MOE Equation and Inputs for Analogue approach (See Table 1 for calculator tool inputs and outputs):
MOE =PODConc*PODHOURSExposureperiodhoursPDRTotalVolumeBreathed*DurationAnimalDaysDurationHumanDays* DefaultBRWorkerBR
 PODConc =Point of Departure (POD) in mg/m3. Based on symptoms of lung overload data for:
 Fine (4.3 μm for BaSO4) particles of BaSO4 NOAEC= 40 mg/m[3] based on symptoms of particle overload in rats (Tran et al., 1999).
 PODHOURS =Duration of the POD experiment in hours/day. 7 hours of exposure hours for animal study (Tran et al., 1999)
 Exposureperiodhours =Worker exposure duration in hours/day. Generally this will be 8 hours
 PDR= Updated Potential Dose Rate of 1.7 mg/day was calculated based on information provided by NIOSH
 Potential Dose Rate of 1.7 mg/day was calculated using the OSHA standard for PNOR (15 mg/m3 for total dust.
 15 mg/m[3] : Using NIOSH-recommended OSHA standard for particles not otherwise regulated instead of 0.5 mg/m3 provided by Sun Chemical.
 1.25 m[3]/hour : EPA default inhalation rate.
 8 hours/day : NIOSH default assumption.
 15 mg/m3 x1.25 m[3]/hr x 8 hr/day = 150 mg/day. 
 1.7 mg/day based on the OSHA standard for particles not otherwise regulated (150 mg/day*0.0113 (based on 1.13% alveolar deposition predicted by MPPD))
 TotalVolumeBreathed= Worker breathing rate. The default for the worker used by the engineering staff is 10 m[3]/8 hours of exposure
 DurationAnimalDays/DurationHumanDays= 1 based on a exposure duration of 5 days for humans and rats. 
 DefaultBR= Default human breathing rate. The default for the general population used by the exposure staff is 0.61 m[3]/hr = 4.9 m[3]/8 hours 
 WorkerBR= The default for the worker used by the engineering staff is 10 m[3]/8 hours of exposure
Conclusion based on use of analogous chemicals: 
(See Table 1 below for MOE inputs and outputs) Based on the deposition fraction outputs provided by the MPPD model, our revised potential dose rates and MOEs for PV29 are: 
 Using a POD of 40 mg/m3 for BaSO4 (Based on NOAEC= 40 mg/m[3] based on predicted level where lung overload would not occur based on the (i) impairment of clearance, increase in the rate of inflammatory recruitment of PMN (Polymorphonuclear Cells) and dust translocation to the lymph nodes for the average animal (Tran et al., 1999). This is based on 2-year chronic inhalation data with rats with an exposure for 5 days/week, 7 hours/day.
 New PDR of 1.7 mg/day based on the OSHA standard for particles not otherwise regulated {150 mg/day*0.0113 (based on 1.13% alveolar deposition predicted by MPPD)}
 MOE=101 based on BaSO4
 Risks were not identified based on BaSO4
            
 Use of screening-level lung overload calculation from Oberdorster (1994)
The purpose of this simple analysis is to integrate basic information about typical alveolar macrophage (AM)-mediated lung clearance rates and predicted alveolar deposition of nuisance dusts such as PV29 in order to provide an estimated occupational exposure level that provides protection from lung overload. The output of this equation estimates the airborne concentration where the deposition rate of inhaled particles overwhelms the alveolar clearance rate of the lungs.  
 Screening level calculation presented in Oberdörster (1994) includes the following variables: 
 Maximum particulate lung burden= 2000 mg/g lung
 Weight of human lung= 1000 g 
 Average fractional clearance rate= 0.0015 mg/day
 Avg. daily clearance rate= 3 mg/day (based on 0.0015 mg/day * 2000 mg/lung particulate burden)
 Total deposition fraction in alveolar region for PV29 is predicted to be 1.13% (calcualted with MPPD)
            
 Maximum inhalable concentration to avoid lung overload: 
 Assuming 1.13% (from MPPD, based on the alveolar deposition only)
 (3 mg/day)/(0.0113)= 265.5 mg particles can be inhaled daily to avoid overload (Oberdörster, 1994).
 Assuming that 10 m[3] air is inhaled during work shift (EPA default).
 Airborne concentrations of PV29 of 26.55 mg/m3 or greater are predicted to overwhelm lung clearance mechanisms and result in lung overload in humans. The OSHA standard for PNOR of 15 mg/m3 is below 26.55 mg/m3 and it therefore protective of lung overload for PV29.
                  
 References: 
 Applied Research Associates, Inc. (2015). Multiple Path Particle Dosimetry Model (MPPD v 3.04) Applied Research Associates, Inc., Raleigh, NC (2015) Available at: https://www.ara.com/products/multiple-path-particle-dosimetry-model-mppd-v-304 
 Landsiedel, R., Ma-Hock, L., Hofmann, T., Wiemann, M., Strauss, V., Treumann, S., Wendel, W., Sibylle G., Karin W., van Ravenzwaay, B. (2014). Application of short-term inhalation studies to assess the inhalation toxicity of nanomaterials. Particle and fibre toxicology, 11(1), 16.
 NIOSH. (2011). Current Intelligence Bulletin 63; Occupational Exposure to Titanium Dioxide. Department of Health and Human Services, Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health. Publication No. 2011 - 160. https://www.cdc.gov/niosh/docs/2011-160/pdfs/2011-160.pdf
 Oberdörster, G. (1994). Lung particle overload: implications for occupational exposures to particles. Regulatory Toxicology and Pharmacology, 21(1), 123-135.
 Tran, C. L., Cullen, R. T., Buchanan, D., Jones, A. D., Miller, B. G., Searl, A., Davis, J.M.G., Donaldson, K. (1999). Investigation and prediction of pulmonary responses to dust. Part II. Investigations into the pulmonary effects of low toxicity dusts. Parts I and II. Contract Research Report, 216, 1999.
 USEPA (US Environmental Protection Agency). (2005). Toxicological review of barium and compounds (CAS No. 7440-39-3). In Support of Summary Information on the Integrated Risk Information System (IRIS). Washington, DC. https://cfpub.epa.gov/ncea/iris/iris_documents/documents/toxreviews/0010tr.pdf


Table 1. Inputs and Outputs of the OPPT Risk Estimation Tool Using BaSO4. 

Appendix 1. MPPD Output
  MPPD v3.04 (C) 2016 by Applied Research Associates, Inc.
  --> Lung morphometry  <--
  Lung Geometry: Humansymmetric
  Number of segments: 24
  Scaling tree by (TLC ---> FRC): 0.840
  TLC = 5558.09  ml
  FRC = 3300.00  ml
  Scaling tree by ((1+TV/2FRC)^1/3): 1.031
  Calculated FRC  =       3300.00  ml
  Lung (distal) volume = 3612.50 ml
  Volume of conducting airways: 160.75 ml
   
  -----> Breathing Parameters and Times <-------
  Breathing Frequency: 12.0 #/min     Tidal volume: 625.0 ml
  Nasopharyngeal dead space: 50.0 ml
  --> Regional Deposition <--
    
  Inhalation time: 2.50 sec    Exhalation time: 2.50 sec
  Volumetric inhalation flow rate at trachea: 250.0 ml/sec
  Volumetric exhalation flow rate at trachea: 250.0 ml/sec
  Time spent in the head during inhalation: 0.200 sec
  Time spent in the head during exhalation: 0.200 sec
      
  -->  Particle properties  <--
  Diameter: 4.690E+1 um
  Sigma_g (GSD): 2.810E+0
  Mass density: 1.58 g/cm^3
  
  Aerosol concentration: 15.0 mg/m^3
      
  Inhalable fraction: 0.5221
  Breathing route: oral
     
  -->  Inhalation  <--
  Inspiratory Fraction: 0.5
      
  -->  Pause  <--
  Pause Fraction: 0.0
      
  
  Total head deposition fraction: 0.4623
  Total TB deposition fraction: 0.0323
  Total pulmonary deposition fraction: 0.0113
  Total deposition fraction: 0.5059
      
  Head deposited mass rate: 5.201E+1 ug/min
  TB deposited mass rate: 3.635E+0 ug/min
  Pulmonary deposited mass rate: 1.274E+0 ug/min
  Total deposited mass rate: 5.692E+1 ug/min
   
  Head deposited mass rate per unit area: 3.359E-1 ug/min/cm^2
  TB deposited mass rate per unit area: 8.186E-4 ug/min/cm^2
  Pulmonary deposited mass rate per unit area: 1.777E-6 ug/min/cm^2
  Total deposited mass rate per unit area: 7.885E-5 ug/min/cm^2
  
  Lobe: Entire Lung
  Number of segments: 24
  Number of terminal airways (alveolar regions): 65536
  Lobe volume: 3612.50 ml
  Volume of conducting airways: 160.75 ml
  Total deposition fraction in conducting airways: 0.0323
  Total deposition fraction in conducting airways during inhalation: 0.0420
  Total deposition fraction in conducting airways during pause: 0.0000
  Total deposition fraction in conducting airways during exhalation: 0.0202
  Total deposition fraction in alveolar region: 0.0113
  Total deposition fraction in alveolar region during inhalation: 0.0667
  Total deposition fraction in alveolar region during pause: 0.0000
  Total deposition fraction in alveolar region during exhalation: 0.0624
  
