### Preface to “ **A PK/PBPK MODEL QUALITY ASSURANCE ASSESSMENT FOR THE TSCA WORKPLAN RISK ASSESSMENT OF**  **N -**  **Methylpyrrolidone ”**  **Prepared by Paul Schlosser, Ph.D. U.S. Environmental Protection**  **Agency National Center for Environmental Assessment**  Poet et al . (2010) developed a PBPK model to reduce uncertainty associated with extrapolating findings from animal toxicity studies to humans. These authors initially developed the model for adult non pr egnant rats and then extrapolated it to pregnancy. The U.S. EPA regularly reviews not only the primary publications describing PBPK models, but performs a quality assurance (QA) review, as described by ( McLanahan et al., 2012 ) . Since the model as described by Poet et al. (2010) appeared to be of sufficient scienti fic quality, the model code was obtained from the principle author, Dr. Torka Poet. The QA process involves checking that the published tables and figures can be reproduced, that the parameters used in the code match those listed in the publication (or at a minimum, are consistent between model simulations and appropriate for the chemical and animal species and/or humans being simulated), and that the equations in the code are correct and match those listed or indicated in the published paper. This review has been conducted by members of the U.S. EPA National Center for Environmental Assessment (NCEA) Pharmacokinetics Workgroup (PKWG), with technical support through an external contract. The contractor’s report and further details from the PKWG NMP team l ead (Paul Schlosser) follow. The initial QA review conducted in the fall of 2012 found several code errors and parameter inconsistencies in the model and the EPA was not able to reproduce all of the figures in Poet et al. (2010) as well as should be possib le. At that point the model was not considered to be of sufficient quality for use in a risk assessment. Subsequently Dr. Torka Poet corrected the model errors originally found by the U.S. EPA and created a set of scripts to aid in reproducing her resul ts (for the NMP Producers Group). As these changes substantially changed some of the model predictions, the revised model results were described in a report that was submitted to the U.S. EPA in April, 2013. **Overall quality:** The U.S. EPA then treated thi s revised model report (Poet, 2013) and code as a new publication and again conducted a QA review. Several more coding and parameter errors were found, as described below in this preface, in the contractor’s report which follows, and in EPA’s appendix to that report. In this case, however, correcting the errors caused only modest changes in the model predictions (fits to data) used to calibrate the model and determine its suitability for risk prediction, subsequent to the changes and corrections described here, in the QA report, and appendix. Since the fits of the model to the various data sets evaluated appears adequate and the parameter values are appropriate and consistent, the model is now deemed to be of sufficient quality for use in this risk assess ment. **Dermal absorption of NMP vapor:** One parameter inconsistency that results in differences in predictions for human exposure scenarios is the assumed surface area (SA) of skin through which vapor can be absorbed. The human model calibration for inhala tion was conducted by Poet (2013) with a SA of 6700 cm 2 , presumed to be face, neck, lower arms, and hands, through which vapor was absorbed, accounting for about 45% of the uptake when exposure is by inhalation only. Since these skin areas would also be exposed to vapors for individuals working with NMP, the model code and parameter files were revised toinclude this route and SA as base assumptions for human exposures, which can occur simultaneous with

dermal liquid absorption. **Oral absorption kinetics i n rats:**  While the oral exposure is not of concern for human workplace and residential scenarios being evaluated by OPPT, the rat PBPK model includes oral dosimetry and calibration to rat oral data was shown by Poet et al. (2010). In order to evaluate pos sible internal dose metrics for their ability to predict developmental effects, oral bioassay data for rats is also evaluated in the dose - response analysis. Hence the ability of the rat model to correctly predict internal doses after oral exposure is also important. However, since this calibration was not carried forward from Poet et al. (2010) to Poet (2013), it was not evaluated in the contractor’s report which follows. When the otherwise revised model was tested by the U.S. EPA for its ability to rep roduce the oral absorption kinetics shown in Figure 5 or Poet et al. (2010) for rats, an error in the coding (revised version provided with Poet (2013)) gave a significant discrepancy between the predictions with the revised model and that figure. In part icular, the total mass of NMP available for oral uptake was not reduced to reflect the oral bioavailability (FRACOR = 68%) reported by Poet et al. (2010) and instead the rate constant for absorption, KAS, was effectively reduced by this extent. Since any material deposited in the model’s stomach lumen compartment is eventually absorbed, irrespective of the value of KAS, the effective bioavailability was therefore erroneously treated as being 100%. When the code was corrected to reduce the mass deposited t o the stomach lumen compartment to 68% and KAS also reduced to 0.92/h (68% of the value in the provided code, 1.36/h), and the incorrect multiplication of KAS and FRACOR removed from the code, fits to the plasma NMP data for rat oral exposures were of a si milar quality to that shown in Figure 5 of Poet et al. (2010), first figure below. Fits to the corresponding data for urinary clearance of 5HNMP in the second plot below (not shown by Poet et al., 2010) are also considered adequate, given that the metabo lite is not considered to be the proximate toxicant. That the NMP plasma levels (middle curve in first plot) observed by Ghantous (1995) for a dose of 57 mg/kg are roughly 50% of those observed by Midgley et al. (1992) for a 112 mg/kg exposur while the 5H NMP levels observed by Ghantous (1995) were 80% of those reported by Midgley et al. (1992) suggests either an experimental discrepancy or a nonlinearity in 5HNMP clearance that is not well captured by the model. It should be noted that the model does desc ribe well the urinary clearance of 5HNMP after a range of IV and inhalation exposures, as validated in the following QA report. Since the U.S. EPA is not using 5HNMP levels as an internal dose metric, this particular discrepancy in the oral data is not co nsidered severe enough to preclude the PBPK model for use.**Revised PBPK Model Simulations vs. Data for Oral Gavage Exposures of NMP to Rats**

**Additional references (not included in following contractor’s report)** Ghantous, H. 1995 . In Oral, Dermal, and Inhalation Pharmacokinetics and Disposition of [2 - 14 C] NMP in the Rat. Report for E.I. du Pont de Nemours and Company, Haskell Laboratory for Toxicology and Industrial Medicine, Wilmington, DE. McLanahan, E.D., El - Masri, H.A., Sweeney, L.M., Kopylev, L.Y., Clewell, H.J., Wambaugh, J.F., Schlosser, P.M. 2012. Physiologically based pharmacokinetic model use in risk assessment -- why being published is not enough. Toxicol Sci 126, 5 - 15. Midgley, I., Hood, A. J., Chasseaud, L. F., Brindley , C. J., Baughman, S., and Allan, G. 199 2. Percutaneous - absorption of co - adm inistered N - methyl - 2 - [C - 14]pyrrolidinone and 2 - [C - 14]pyrrolidinone in the rat. Food Chem. Toxicol. 30, 57

– 64.

### A **PK/PBPK MODEL QUALITY ASSURANCE**  **ASSESSMENT FOR THE**  **TSC A**  **WORKPLAN RISK ASSESSMENT OF**  **N -**  **Methylpyrrolidone (CAS RN**  **872 -**  **50 -**  **4 )** 

**Under Battelle Prime Contract EP -**  **C -**  **09 -**  **006: Physiologically**  **- Based Pharmacokinetic (PBPK) Modeling Technical Support**  **Work Assignment WA 4**  **- 01**  **Prepared By: Michael H. Lumpkin, Ph.D., DABT**  **P. Robinan Gentry, Ph.D., DABT ENVIRON International Corporation** 

**Monroe, Louisiana Prepared for:**  **Paul Schlosser, Ph.D. Work Assignment Manager**  **U.S. Environmental Protection Agency National Center for Environmental Assessment** 

**Submitted through: Rena**  **Thomas Battelle Memorial Institute**  **Prime Contractor Address 505 King Avenue**  **Columbus, OH 43201 September**  **11 , 201**  **3**

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Page 2 **TABLE OF CONTENTS 1**  **QUALITY ASSURANCE ASSESSMENT ................................**  **................................ ..........**  **2 2**  **QA OF NMP MODEL (POET ET AL. 2010) ................................**  **................................ .....**  **3 2.1**  **QA of NMP Model Parameters ................................**  **................................ ............................**  **3 2.2**  **QA and Modification of NMP Model Equations ................................**  **................................ 3**  **3 NMP MODEL OUTPUT**  **................................ ................................**  **................................ ......**  **4 4**  **CONCLUSIONS ................................**  **................................ ................................**  **.................... 5**  **5 REFERENCES**  **................................ ................................**  **................................ ......................**  **6 APPENDIX A. Modified AcslXtreme CSL and M Files Used for the QA Assessment**  **....... 16**  **APPENDIX B. ................................**  **................................ ................................**  **............................. 63**  **LIST OF TABLES** Table 1. Differences between NMP PBPK model parameter values found in the provided model computer code and Poet et al. (2010) ................................ ................................ ................................ ............................ 7 

### LIST OF FIGURES Figure 1. Reproduct ion of Wells and Digenis (1988) and Payan et al. (2002) IV NMP exposures: Plasma profiles ................................ ................................ ................................ ................................ .......................... 8 Figure 2. Reproduction of Payan et al. (2002) IV NMP exposures ................................ .............................. 9 Figure 3. Reproduction of Payan et al. (2003) dermal NMP exposure ................................ ....................... 10 Figure 4. Reproduction of Poet et al. (2010) inhalation NMP exposures: Blood profiles .......................... 11 Figure 5. Reproduction of Poet et al. (2010) inhalation NMP exposures: Urine profiles ........................... 12 Figure 6. Reproduction of Akesson and Paulsson (1997) inhalation NMP exposures ............................... 13 Figure 7. Reproduction of Akes son et al. (2004) dermal NMP exposures ................................ ................. 14 Figure 8. Comparison of Akesson and Paulsson (1997) dermal with inhalation NMP exposures ............. 15 

### 1 **QUALITY ASSURANCE ASSESSMENT** A quality assurance (QA) assessment was conducted for a modified physiologically based pharmacokinetic (PBPK) model for orally ingested, inhaled , or dermally absorbed n - methylpyrrolidone ( NMP ) in rats and humans reported by Poet et al. ( 2010 ) . The e valuation was conducted to i nsure that the model structure and parameter values presented by Poet et al. (2010) are accurately reflected in the computer code implementation . Changes to the model code that would more accurately represent the physiology/biology of NMP pharmacokinetics were discussed and implemented . Simulations of rat and human exposures that were presented by Poe t (2013) were performed and shown here to demonstrate the ability of the current model code to replicate experimental observations .

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Page 3 **2 QA OF**  **NMP MODEL (**  **POET ET AL.**  **2010 )**  T he initial PBPK model computer code relied upo n for the QA assessment was supp lied by Battelle/ Pacific Northwest National Laboratories . The model code was written in the ACSL programming language and was modified/assessed using the acslXtreme software package (version 3.0. 2 . 1 , Aegis Technologies, Inc.). Separate code files were provided for the rat and human models. 

### 2.1 **QA of NMP**  **Model Parameter s**  The NMP model parameter values in the provided model code were checked against the values published in Poet et al. ( 2010 ) , as well as with Brown et al. (1997) for physiological values and Gentry et al. (2002) for pregnancy - related growth rates . R at and human model parameter values were assigned in acsl command files (m files), which set parameter values (including exposure conditions), invoke simulation runs, and plot the resulting simulations. Sev eral rat model parameter values included in the acsl model code were different from the values provided in Tables 1, 2, and 5 of Poet et al. (2010). Difference s in rat model parameters included the molecular weight for the modeled metabolite, 5 - hydroxy - N - methyl - 2 - pyrrolidone (5 - HNMP), fractional blood flow to the mammary glands, uterus, and skin, lung tissue volume, first order urinary elimination rate of 5 - HNMP, and equilibrium tissue:blood partition coefficients for NMP in the lung and slowly - perfused lu mped tissues compartments (Table 1). The reference for the rat tissue:blood partition coefficient s for NMP used in the model code for the placenta ( 0.309 ) and for 5 - HNMP for placenta and rest - of - body (1.07 and 0.73, respectively) were not provided in the model code or cannot be estimated based on the information provided in Table 5 of the Poet et al. (2010) paper. Similarly, the human model command files assigned parameter values that were different from published values for molecular weight for NMP, fractional blood flow to the skin and uterus, NMP vapor permeability constant, and fat:blood partition coefficient for 5 - HNMP (Table 1). Additionally, source references for tissue:blood partition coefficient values for NMP in the placenta and rapidly - perfused tissues (0.31 and 0.94) and 5 - HNMP in the rapidly - and slowly - perfused tissues and rest - of - body (6.5 and 1.0) were not provided in the model code or cannot be determined based on the information provided in Table 5 of Poet et al. (2010) paper. 

### 2.2 **QA and Modification**  **of NMP**  **Model Equations** The equations used in the model code to calculate rates of change, amounts, concentrations, and area under - the - curve (concentration x time) of NMP and 5 - HNMP absorption, dis tribution, metabolism, and elimination in blood and tissues were examined to assure that they accurately represented the model structure and relationships described by Poet et al. (2010). Poet et al. (2010) implemented equations for pregnancy - related chan ges in body weight, tissues volumes, pulmonary ventilation, and cardiac output used by Gentry et al. (2002) . The only differences identified in the pregnancy - related growth equations were for the fet al compartment in rats. Gentry et al. (2002) described fetal growth as having three different phases beginning on the gestation days 0, 11, and 18 , whereas the provided NMP model code implemented these changes in fetal growth rates on gestation days 0, 10, and 17 . It was not clear if these differences in mode led fetal growth phases may be due to differences between the Poet et al. (2010) and Gentry et al. (2002) in defining time for onset of gestation in rats.

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Page 4 Two modifications were made by EPA staff to the code prior to the QA assessment and included : a) Changing the body weight scaling exponent from 0.74 to 0.75 for all allometrically - scaled parameters, and b) Correcting the rate equation for dermal absorption of liquid NMP (RADL and RASL for rat and human models, respectively) of NMP from

RADL = ((KPL × S A / 1000) × CSURF) - (CSK/PSK) to RADL = (KPL × SA / 1000) × (CSURF - (CSK/PSK)) in the rat model, and from

RASL = ((PVL × SA/1000) × CSURF) - (CVSK/PSKL) to RASL = (PVL × SA/1000) × (CSURF - (CVSK/PSKL)) in the human model. In addition, several errors in parameters for skin volumes (total body skin or exposed skin only) and equations calculating tissue - specific NMP concentrations in the human model were identified by the EPA WAM, Paul Schlosser , and were corrected. The corrections include selection of an exposure - specific skin volume to use in calculating NMP vapor absorption, introducing a term in the vapor absorption rate that accounts for evaporative NMP loss from the skin (after e xposure cessation), corrections in calculating NMP concentration leaving the skin and entering the venous circulation, correction in the calculation of cardiac output and tissue volume of the slowly - perfused compartment by removing the skin volume term, and introduction of spray - on NMP dermal exposures. Also, the human model c ode was modified to remove discontinuities in placental blood flow at time zero (causing the model to crash) and fat, ma mmar y, and uterine volumes. Pregnancy - related cardiac output and volume growth changes for 5 - HNMP in fat were not properly reflected in the slowly - perfused compartment . This res ult ed in a blood flow mismatch and an artificial loss of 5 - HNMP. A detailed description of all of these changes is provided in Appendix B . In the human NMP model, the parameter for rate of daily NMP ingestion in drinking water (DRINK, mg/kg/day) is included in the equation for rate of NMP change in the liver (RALiv), but should more appropriately be placed in the equation for rate of NMP change in the stomach (RSTOM). As a practical matter, the differences in NMP dose metrics from average daily drinking water doses being introduced in the liver compartment versus the stomach are likely to be negligible. 

### 3 **NMP M**  **ODEL O**  **UTPUT** Select simulations in rats and humans were run using the code with modification as outlined i n Section 2 (referred to hereafter as the modified EPA model). The resulting output was compared with output from the same simulations presented in the Poet (2013) report, which presented a metabolism re - optimized version of the model code relied upon in Poet et al. (201 0 ), as well as experimental observations, where available. Figure 1 shows the comparative simulations of the Poet (2013) model, the modified EPA

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Page 5 model to the concentrations of NMP measured in blood following a single IV injection of 0.1 ( Payan et al. 2002) or 45 mg/kg (Wells and Digenis 1988) . Figure 2 provides model estimates of 5 - HNMP concentrations in blood and urine , as well as the corresponding measured concentrations, following single IV injections of 0.1

– 500 mg/kg NMP (Payan et a l. 2002). In both Figures, minimal differences were seen between the Poet (2013) and modified EPA models in predicting blood or urine levels of NMP and 5 - HNMP. Figure 3 shows measured and model estimated concentrations from both the Poet (2013) and modi fied EPA models of plasma NMP in rats following a single dermal application of 200 μL neat NMP (Payan et al. 2003). The Poet (2013) and modified EPA models replicated the experimental observations equally well, with slight over - and under - predictions of t he plasma profiles, respectively. Thus, the modified EPA NMP model code is capable of reproducing plasma and urine profiles of NMP and 5 - HNMP in rats. The Poet (2013) and modified EPA models for NMP in humans were used to simulate acute inhalation and der mal exposures. Figures 4 and 5 provide the measured and model estimated concentrations (for both the Poet and modified EPA models) of NMP or 5 - HNMP in blood or urine of volunteers inhaling 10

- 80 mg NMP/m 3 for six hours (Poet et al. 2010). Model - predicted NMP levels in plasma and 5 - HNMP levels in plasma and urine using the modified EPA code were slightly closer to experimental observations at 39 and 80 mg/m 3 than were predictions using the Poet (2013) code. However, the Poet (2013) code predicted NMP in u

rine levels that were closer to experimental observations than predicted by the modified EPA model. The output from both model codes (Figure 6) produce very similar simulations of plasma NMP in human volunteers inhaling 10

– 53 mg/m 3 NMP (Akesson and Paulsson 1997). For human dermal exposure simulations ( Figures 7 and 8 ) , t he estimated plasma 5 - HNMP concentrations from the modifi ed EPA model code replicated the profiles of the experimental observations (Akesson et al. 2004), which was not the case fo r urinary 5 - HNMP, in which model predictions using the modified EPA model for both males and females were approximately 25 - 30% lower than experimental observations (Figure 7 ). The lower model predictability of the urinary data may be due to lower urine pro duction in the volunteers, compared to the assumed 2 L/day production used in the model. Lower urine volume in the experimental subjects could result in higher 5 - HNMP levels, compared to model predictions. Finally, the dermal simulations of the Akesson et al. (2004) experiments using modified EPA code (Figure 9) comport with statements by Akesson et al. (2004) that 6 - hour dermal exposures to neat NMP would likely result in similar plasma NMP levels to those seen previously following 10 mg/m 3 inhalation ex posures (Akesson and Paulsson 1997). 

### 4 **CONCLUSIONS** The NMP PBPK model code of Poet et al. ( 2010 ), as re - optimized by Poet (2013) , for rats and humans, was modified by EPA and provided to ENVIRON for use in a Q A assessment of the model for use in risk assessm ent. The modified EPA model code and the Poet (2013) models generally produced very similar simulations following IV and dermal exposures in rats and inhalation and dermal exposures in humans. The modified EPA model provide s predictions of plasma NMP lev els in both species that were closer to experimental observations than were urinary metabolite predictions. Thus, the modified EPA model code is capable of predicting parent compound and metabolite profiles from multiple data sets providing blood and urin e measurements in rodents and humans exposed to NMP by multiple routes of exposure (IV, dermal and inhalation).

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Page 6 **5 R**  **EFERENCES** Akesson, B., Carnerup , M. A. and Jonsson, B. A. (2004). Evaluation of exposure biomarkers from percutaneous absorption of N - methyl - 2 - pyrrolidone. Scand.J.Work Environ.Health **30** , 306 - 312 . Akesson, B. and Paulsson, K. (1997). Experimental exposure of male volunteers to N - methy l - 2 - pyrrolidone (NMP): acute effects and pharmacokinetics of NMP in plasma and urine. Occup.Environ.Med. **54** , 236 - 240 . Brown , R. P., Delp, M. D., Lindstedt, S. L., Rhomberg, L. R., Beliles, R. P. (1997) . Physiological parameter values for physiologically based pharmacokinetic models. Tox icol Ind Health 13, 407 - 484. Gentry , P. R., Covington, T. R., Andersen, M. E., and Clewell, H. J. III. (2002) . Application of physiologically based pharmacokinetic model for Isopropanol in the derivation of a reference dose and reference concentration. Reg Toxicol Pharm 36, 51 - 68. Payan, J. P., Beydon, D., Fabry, J. P., Boudry, I., Cossec, B., and Ferrari, E. (2002). Toxicokinetics and metabolism of N - [14C]methylpyrrolido ne in male Sprague - Dawley rats. A saturable NMP elimination process. Drug Metab. Dispos . **30** , 1418

– 1424. Payan, J. P., Boudry, I., Beydon, D., Fabry, J. P., Grandclaude, M. C., Ferrari, E. and Andre, J. C. (2003). Toxicokinetics and metabolism of N - [(14)C] N - methyl - 2 - pyrrolidone in male Sprague - Dawley rats: in vivo and in vitro percutaneous absorption. Drug Metab Dispos. **31** , 659 - 669 . Poet, T. S., Kirman, C. R., Bader, M., van Thriel, C., Gargas, M. L. and Hinderliter, P. M. (2010). Quantitative Risk Analysi s for N - Methyl Pyrrolidone Using Physiologically Based Pharmacokinetic and Benchmark Dose Modeling. Toxicol Sci **113** , 468 - 482 . Poet 

### .	( 2013 

### ). Internal Dose, as Derived from Updated PBPK Model, Should Be Basis for NMP Toxicity Assessment . Battelle Memorial Institute Pacific Northwest Division . Wells, D. A., and Digenis, G. A. (1988). Disposition and metabolism of double - labeled [3h and 14c] N methyl - 2 - pyrrolidinone in the rat. Drug Metab. Dispos . **16** , 243

– 249.

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Page 7 **Table 1**  **. Differences**  **between NMP PBPK model parameter values found in the provided model computer code and Poet et al. (2010)**  Species Parameter Parameter name Value provided in

model computer code Value published by

Poet et al. (2010) Rat Molecular weight for 5 - HNMP MWHP 116.14 115.13 Rat Percent cardiac output to skin QSKNC 5.8 1.0 Rat Percent cardiac output to ma mmar y gland QMAMC 0 . 1 0.2 Rat Percent cardiac output to uterus QUTRC 0.1 0.5 Rat First - order urinary elimination rate of NMP (L/hr) KLC 3.9 4.9 Rat Slowly - perfused tissue:blood NMP partition coefficient PS 0.74 0.57 Rat Lung tissue:blood NMP partition coefficient PLU 0.10 0.13 Human Molecular weight for 5 - HNMP (g/mol) MWHP 116.14 115.13 Human Percent cardiac output to

skin QSKNC 5.8 3.0 Human Percent cardiac output to uterus QUTRC 0.5 0.62 Human NMP vapor permeability coefficient (cm/hr) PV 32 23

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Page 8 **Figure 1**  **. Reproduction of Wells and Digenis (1988) and Payan et al. (2002) IV NMP exposures: Plasma profiles** 

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Page 9 **Figure 2**  **. Reproduction of Payan et al. (2002) IV NMP exposures**

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Page 10 **Figure 3**  **. Reproduction of Payan et al. (2003) dermal NMP exposure**

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Page 11 **Figure 4**  **. Reproduction of Poet et al. (2010) inhalation NMP exposures: Blood profiles** 

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Page 12 **Figure 5**  **. Reproduction of Poet et al. (2010) inhalation NMP exposures: Urine profiles**

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Page 13 **Figure 6**  **. Reproduction of Akesson and Paulsson (1997) inhalation NMP exposures** 

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Page 14 **Figure 7**  **. Reproduction of Akesson et al. (2004) dermal NMP exposures**

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Page 15 **Figure 8**  **. Comparison of Akesson and Paulsson (1997) dermal with inhalation NMP exposures** 

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Page 16 **A PPENDIX**  **A. Modified**  **AcslXtreme CSL and M**  **Files Used**  **for the QA Assessment**  **NMPPREG_RAT .CSL**  PROGRAM NMP.ACSL !PBPK MODEL FOR N - METHYL PYRROLIDONE !FINAL RAT MODEL (5/ 09) !T.S. POET,P HINDERL ITER. CHEMICAL DOSIM ETRY GROUP, PNNL, RICHLAND, WA !MODEL TRANSFERRED F ROM SIMUSOLV TO ACSL XTREME FORMAT IN 08 !MODEL CONFIGURED FO R INHALATION (OPEN, WHOLE BODY/NOSE ONLY ) ! IV, ORAL, DERMA L, AND IP ROUTES OF ADMINISTRATION. !MODEL TRACKS DISPOS ITION OF NMP A ND 5 - HNMP. !ASSUMPTIONS: ! (1) FLOW - LIMITED (ALL COMPART MENTS) ! (2) METABOLISM OF NMP BY A SAT PATH WAY TO FORM 5HNP ! (3) METABOLISM OF HNP BY SATU RABLE PATHWAY TO ETC . ! (5) METABOLISM OCCURS ONLY IN THE L IVER ! (6) TISSUE:BLOO D PART. COEFF. = H UMAN = KRISHNAN EQN ! UPDATED IN CMD FILE TO MEASURED IN - HOUSE ! (7) 5HNP ELIMIN FROM MIXED VENOUS - 1ST ORDER ! THIS DI FFERS FROM 02: URINE BY *GFR CLEARANCE FR OM KIDNEY ! METAB RATE CONST . FROM REPORT - UPDATED WITH LIT VAL UES IN CMD FILE ! PREG ADDED - OTHER PARAMETERS CHA NGED NOMINALLY TO HA RMONIZE WITH FETAL I PA MODEL OF ! GENTRY ET AL. REGU TOX PHARM 36:51 - 68 , 2002 INITIAL ! MODEL UNITS ! CONCENTRATION, MG/ L ! FLOW, L/HR ! BODY WT, KG CONSTANT BWINIT=0. ! PRE - PREGNANCY BODY WEIGH T (KG) CONSTANT RATS=1. !NUMBER OF ANIMALS I N EXPT. NOT USED IN HUMAN MODEL CONSTANT MWNMP=99.1 3 !MOL. WT. NMP, MG/MMOL CONSTANT MWHP= 116. 14 !MOL. WT. 5 - HNP, MG/MMOL !BLOOD FLOWS !FROM BROWN ET AL TO X IND HEALTH 97 !AND/OR FROM IPA MOD EL OF GENTRY ET AL., ! BLOOD FLOWS (FRACT ION OF CARDIAC OUTPU T) CONSTANT QCC = 0 ! CARDIAC OUTPUT (L/ HR FOR 1 KG ANIMAL) CONSTANT QPC = 0 ! ALVEOLAR VENT. RAT E CONSTANT QFATC = 0 ! FAT (NON - PREGNANT)

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Page 17 CONSTANT QLIVC = 0 ! LIVER CONSTANT QMAMC = 0 ! MAMMARY TIS SUE (NON - PREGNANT) CONSTANT QSKNC = 0 ! SKIN CONSTANT QUTRC = 0 ! UTERUS (NON - PREGNANT) CONSTANT QRAPC = 0 ! RAPID USE STATIC R APID FOR RATS (MUST BE CHANGED FOR HUMAN ) ! PERMEABILITY - AREA PRODUCT (L/HR) CONSTANT PA FC = 0.1 ! DIFFUSION ON FETAL S IDE OF PLACENTA ! NOTE 0.1 IS THE VA LUE SUPPLIED BY ENVI RON AND USED FOR IPA , IT IS UNSURE WHERE THE VALUE COMES FROM ! GRAPHING OUT TRANS PORT TO FETUS, 0.1 R ESULTS IN A MAX FOR NMP, MAYBE FOR IPA A S WELL ! TISSUE V OLUMES (FRACTION OF BODY WEIGHT) !FROM BROWN ET AL TO X IND HEALTH 97 FOR RATS !OR FROM GENTRY ET A L CONSTANT VLUC = 0 ! LUNG CONSTANT VFATC = 0 ! FAT (NON - PREGNANT) CONSTANT VLIVC = 0 ! LIVER CONSTANT VMAMC = 0 ! MAMMARY TISSUE (NO N - PREGNANT) CONSTANT VRAPC = 0 ! RAPIDLY PERFUSED CONSTANT VUTRC = 0 ! UTERUS (NON - PREGNANT) CONSTANT VBLC = 0 ! TOTAL BLOOD ! FOR PARENT MODEL, SKIN COMPARTMENT I S ONLY DEFINED AS DO SED SKIN CONSTANT VSKC = 0 .19 ! SKIN CONSTANT SA = 0 .01 !SURFACE AREA EXPOSED, SQ.CM TSA = 906.*BWINIT**( 2./3.) !TOTAL BODY SURFACE AREA, SQ.CM. !MCDOUGAL ET AL. T.A .P. 85 (1996)286 IF (CONCL.GT.0.0) TH EN

VSKCC = VSKC*SA/TSA QSKCC = QSKNC*SA/TSA ELSE VSKCC = VSKC*SA/TSA QSKCC = QSKNC*SA/TSA ENDIF ! SLOWLY PERFUSED (D EFINED AS BALANCE OF TISSUES AND FLOWS) VSC = 0.91 - (VLUC + VFATC + VLIV C + VMAMC + VRAPC + VUTRC + VBLC + VSKCC) ! NOTE: 0.91 IS APPR OX WHOLE BODY LESS B ONE QSC = 1. - (QFATC + QLIVC + QMA MC + QRAPC + QUTRC + QSKCC) ! SCALED BLOOD FLOWS (L/HR) QCINIT = QCC * (BWIN IT**0.75) ! CHANGED 0.74 TO 0. 75; PMS 8 - 19 - 13 QFATI = QFATC * QCIN IT QLIV = QLIVC * QCINI T QMAMI = QMAMC * QCIN IT QRAP = QRAPC * QCINI T QSKN = QSKCC * QCINI T

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Page 18 QSLW = QSC * QCINIT QUTRI = QUTRC * QCIN IT ! SCALED TISSUE VOLU MES (L) VLU = VLUC * BWINIT VFATI = VFATC * BWIN IT VLIVI = VLIVC * BWIN IT VRAP = VRAPC * BWINI T VSLW = VSC * BWINIT VMAMI = VMAMC * BWIN IT VUTRI = VUTRC * BWIN IT VSK = VSKCC * BWINIT VBL = VBLC * BWINIT ! TOTAL BLOOD VA = 0.25*VBL !ARTERIAL BLOOD VV = 0.75*VBL !VENOUS BLOOD ! PREGNANCY PARAMETE RS CONSTANT NUMFET = 7 .0 ! NUMBER OF FETUSES (NOT USED FOR HUMAN, ASSUME 1) CONSTANT PUPBW = 4 500. ! BIRTH WEIGHT (MG) CONSTANT VFETD18 = 1 0 51.254 ! VOLUME OF FETUS AT DAY 18 ( ) OF PREGNANCY ! CONVERSION FACTORS CONSTANT MGKG = 1 .0E6 ! CONVER SION FACTOR FROM MG TO KG !PARTITION COEFFICIE NTS !EXPERIMENTALLY MEAS URED VALUES CONSTANT PB=0. !NMP BLOOD:AIR CONSTANT PF=0 !NMP FAT:BLOOD - MEASURED CONSTANT PL=0 !MEASURED CONSTANT PR=0 !MEASURED LIVER CONSTANT PS=0 !NOT MEASURED MUSCLE - CORRECTED FOR FILTER ERROR USING SKIN PROPORTIONALITY CONSTANT PSKL=0 !MEASURED CONSTANT PLU=0 !NMP LUNG:BLOOD CONSTANT PSKA= 0 !NMP SKIN:AIR

CONSTANT PSKB=0 ! NMP SKIN:BLOOD ! CODE FOR SKIN - AIR TRANSFER IS COMM ENTED OUT BELOW, HEN CE PSKA IS NOT USED; PAUL SCHLOSSER, U.S. EPA 5 - 17 - 13 ! CONSTANT PSKL=0 !MEASURED CONSTANT PM=0 !MAMMARY, E STIMATED FORM LIVER CONSTANT PPLA=0 CONSTANT PUTR=0 !EXPERIMENTALLY MEAS URED VALUES CONSTANT PLHNP=0 ! LIVER MEASURED CONSTANT PBHNP=0 !ESTIMATED AVG OF "O THER" TISSUES CONSTANT PFHNP=0 !MEASURED

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Page 19 CONSTANT PPLHNP=0 !METABOLIC RATE CONS TANTS !**THESE ARE FROM PA YAN ET AL !NMP TO 5HNP CONSTANT KM=0 !MICHAELIS CONSTANT, MG/L CONSTANT VMAXC=0 !MAX. ENZ. ACT., MG/ HR/L VMAX1 = VMAXC*BWINIT **0.75 !5HNP TO OTHER METAB S CONSTANT KM2=0 !MICHAELIS CONSTANT, MG/L CONSTANT VMAX2C=0 !MAX. ENZ. ACT., MG/ HR/L VMAX2 = VMAX2C*BWINI T**0.75 !URINARY ELIMINATION OF 5 - HNMP - CLEARED FROM BLOOD !NOTE FIRST ORDER RA TE COMMENTED OUT, SA TURABLE FITS BETTER CONSTANT KLC=0 KL=KLC/( BWINIT**0.25) CONSTANT KLNC=0 !URINARY LOSS OF NMP , L/HR KLN=KLNC/(BWINIT**0. 25) !FRACTIONAL ABSORPTI ON CONSTANT FRACIN = 1 !FRACTIONAL UPTAKE O F NMP BY INHAL,START AT 65% !OF ALVEOLAR - AS IN AKESSON ET AL 1997 CONSTANT FRACOR = 1 .0 !FRACTION AB SORBED ORALLY, INITA LLY 100% CONSTANT FRACF=1 ! INITIAL CONDITIONS FOR CLOSED CHAMBER I NHALATION CONSTANT VCHC = 9 E9 ! VOLUME OF CLO SED CHAMBER (L),STAR T LARGE FOR OPEN CONSTANT KLOSS = 0 .0 ! CHAMBER LOSS RATE /HR !TIMING COMMANDS CONSTANT TCHNG=6.0 !END OF INHAL EXPOSU RE, HR CONSTANT TSTOP=24.0 !END OF EXPERIMENT/S IMULATION, HR CONSTANT MAXT=0.01 !MAXIMUM STEP SIZE, HR THIS MAY NEED SET LOWER FOR NEW VERSION OF ACSL TO RUN CONSTANT MINT=1E - 7 CONSTANT CINT = 0.2 !DATA LOGGING RATE / HR CONSTANT GDDAYS=0.0 ! OFFSET FOR GESTATI ONAL DAY SIMULATION CONSTANT GDMONTHS=0 .0 !OFFSET FOR HUMA N GD SIMULATION !INITIAL EXPOSURE CONDITIONS ! EXPOSURE CONDITION S BASED ON USER DEFI NED INITIAL AMOUNTS OF CHEMICAL (MG) CONSTANT CONCPPM = 0.0 !AIR CONCENTRATION I N PPM!

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Page 20 CONSTANT CONCMGS = 0 .0 ! USED TO SET AIR CO NC'N AS MG/M3, PMS, 8 - 13 - 13 VCH = VCHC - (RATS*BWINIT) !VOLUME OF OCCUPIED CHAMBER CONCMG = CONCMGS/100 0 + CONCPPM*MWNMP/24 451. !CONVERT PPM TO MG/LITER! CONSTANT DOSEINTER VAL=24 !TIME BETWEEN DAILY DOSES

CONSTANT CONCCHPPM0 = 0 ! INITI AL PPM IN CLOSED CHA MBER CONCHMG0= CONCCHPPM0 *MWNMP/24451. ACHO = CONCHMG0 * VC H !INIT . AMT IN CHAMBER, MG ! !ORAL CONSTANT KAS=1.0 !1ST ORDER RATE CONS T FOR ORAL ABS,HR - 1 CONSTANT DOSE=0.0 !ORAL DOSE IN MG/KG BW ODOSE = DOSE*BWINIT !CONVERT MG/KG BW TO MG TOTAL(ORAL) !**NOTE - CONSIDER ADDING ZERO ORDER FOR HUMAN HED

CONSTANT DOSE2=0.0 ! ORAL DOSE IN MG/KG BW, BUT TOTAL DOSE I NCREASES W/ BW !FEED CONSTANT KASF =1.0 !1ST O RDER RATE CONST FOR ORAL ABS,HR - 1 CONSTANT DOSEF=0.0 !ORAL DOSE IN MG/KG BW ! TABLE FEEDDOSE 1 ,10 /10*24.,10*1./ !IV CONSTANT IVDOSE=0.0 !IV DOSE, MG/KG NMP CONSTANT TINF=0.01 !DUR ATION OF IV INFUSION , HR, SET TCHNG=TINF !DERMAL CONSTANT CONCL = 0.0 !CONC OF NMP IN LIQU ID, MG/L CONSTANT KPL = 0.0 !PERM COEFF FOR LIQU ID, CM/HR CONSTANT VLIQ = 1.0E - 99 !INITIAL VOLUME APPL IED, L CONSTANT DENSITY= 1 .03

CONSTANT DSK=0.0 ! INITIAL AMOUNT (MG /KG BW) RUBBED INTO SKIN; PMS 8 - 14 - 13 ASKO=DSK*BWINIT ! PMS, 8 - 14 - 13

CONSTANT TWASH=8.0 ! WASH TIME IN BECCI ET AL. (1982) EXPOSU RES !CONSTANT RESID=0 !AMOUNT STICKING TO EXPOSURE SYSTEM, MG ! DDN = CONCL*VLIQ CONSTANT FAD=0.222 !FRAC NO ABSORBED IN PAYAN ET AL

!IN VITRO HUMAN VAN DYK ET AL. AIHA J 56 : 651 - 660 !START WITH SMALL SA SO VSKE IS NON - ZERO (USED IN DENOMI NATOR OF CSK CALCULA TION) !IP CONSTANT IPDOSE = 0 .0 !IP DOSE, MG/KG NMP CONSTANT KIP=1.0 !1ST ORDER RATE OF A BS, HR - 1 PDOSE = IPDOSE*BWINI T !TOTAL IP DOSE, MG !DOSING SCHEDULE

IF (DSK.GT.0.0) THEN SCHEDULE SKWASH.AT.T WASH ENDIF SCHEDULE OFFD.AT.TCH NG !TURN OFF EXPOSURE AT TCHN G CIZONE = 1.0 !START WITH INHALATI ON ON

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Page 21 IVZONE = 1.0 !START WITH IV ON IF (CONCL.GT.0.0) TH EN DZONE = 1.0 !START WITH DERMAL O N ELSE DZONE = 0.0 ENDIF CONSTANT TSTART=0.2 ! OFFSET START - TIME FOR GAVAGE DOSI NG

SCHEDULE GAVD.AT.TST ART ALGORITHM IALG=2 !GEAR ALGORITHM END DYNAMIC DERIVATIVE !===============FETA L AND BW CHANGES W/P REGNANCY============ =========== GDMONTH=GDMONTHS/0.6 4 !TO WAG HUMAN GROWTH, THIS SETS HU MAN FETAL !AT BIRTH ~3.5 KG AN D MOTHER GAINING ~ 8 .7 KG !ACTUAL HUMAN AT BIR TH AVERAGE IS 3.5 KG !MOTHER AT BIRTH GAI NS 13.6 KG HOURS = T MINUTES = T * 60.0 DAYS = T / 24.0 + GD DAYS +GDMONTH ! VOLUME OF FAT (L) VFAT = VFATI * (1.0 + (0.0165 * DAYS)) ! VOLUME OF FETUS (K G) ! ADDED 1.0E - 8 TO VARIOUS VOLUMES TO AVOID DIVIDE - BY - ZERO PROBLEMS; PMS 8 - 13 - 13 IF (DAYS.LT.10.0) TH EN VFET = (1.0E - 8 + NUMFET * ((0.120 6 * DAYS)**4.53)) / MGKG ELSE IF (DAYS.LT.17. 0) THEN VFET = (1.0E - 8 + NUMFET * ((1.5 * (DAYS - 9))**2.8)) / MGKG ELSE VFET = (1.0E - 8 + NUMFET * (VFETD1 8 + (((PUPBW - VFETD18) / 4.0) * (D AYS - 17)))) / MGKG ENDIF ! VOLUME OF MAMMAR Y TISSUE (L) VMAM = VMAMI * (1.0 + (0.27 * DAYS)) ! VOLUME OF PLACEN TA (L) IF (DAYS.LT.6.0) THE N VPLA = 1.0E - 8 ELSE IF (DAYS.LT.10. 0) THEN VPLA = (1.0E - 8 + NUMFET * (8. * ( DAYS - 6.))) / MGKG ELSE

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Page 22 VPLA = (1.0E - 8 + NUMFE T * ((32 * EXP( - 0.23 * (DAYS - 10)))+ (40 * (EXP(0. 28 * (DAYS - 10)) - 1)))) / MGKG ENDIF ! VOLUME OF UTERUS (L) IF (DAYS.LE.3.0) THE N VUTR = VUTRI ELSE VUTR = VUTRI * (1.0 + (0.077 * ((DAYS - 3.)**1.6))) ENDIF !VOLUME OF LIVER INC REASE !CORLEY ET A L CRC 03,BUELKE - SAM ET AL '82 AND OT HERS IF (DAYS.LT.5.0) THE N VLIV=VLIVI ELSE VLIV= VLIVI * (1.0 + (0.0455 * ((DAYS - 5.0)))) ENDIF ! INCREASE IN BODY WEIGHT (KG) ! WATER=(0.0033*DAY S)+(9.2E - 5*(DAYS**2)) !CORLEY ET AL CRC 03 ,

BW = BWINIT + (VFAT - VFATI) + VFET + (VMA M - VMAMI) + VPLA + (VUT R - VUTRI)+(VLIV - VLIVI) ! SCALED ALVEOLAR VENTILATION (L/HR) QP = QPC * ((BW - VFET - VPLA)**0.75) ! CHANGED 0.74 TO 0. 75; PMS 8 - 19 - 13 ! INCREASE IN BLOOD FLOWS (L/HR) QFAT = QFATI * (VFAT / VFATI) QMAM = QMAMI * (VMAM / VMAMI) QUTR = QUTRI * (VUTR / VUTRI) !!!!!! NOTE THAT THE BLOOD FLOWS NO LONGE R BALANCE. QP HAS IN CREASED BY THE ADDIT IONAL !!!!!! FETAL AND PLA CENTAL VOLUMES BUT THE COMP ARTMENTAL FLOWS HAVE NOT CHANGED. !!!!!! QRECOV WILL S TART AT 100 AND DECR EASE THRU PREGNANCY (PMH 25 - APR - 2007) ! TOTAL BODY FOR HNM P QB = QRAP+QSLW+QSKN+ QMAM+QUTR ! +QPLA ! PLACENTA IS A SEPARA TE COMPARTMENT; PMS 8 - 19 - 13 VB = VRAP+VSLW+VLU+V SK+VMAM+VUTR ! +VPLA ! DITTO; PMS 8 - 19 - 13 ! BLOOD FLOW TO PL ACENTA (L/HR) IF (DAYS.LT.6.0) THE N QPLA = 0.0 ELSE IF (DAYS.LT.10. 0) THEN QPLA = (NUMFET * (0. 55 * (DAYS - 6.0))) / 24 ELSE IF (DAYS .LE.12.0) THEN QPLA = (NUMFET * (2. 2 * EXP( - 0.23 * (DAYS - 10)))) / 24 ELSE

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Page 23 QPLA = (NUMFET * ((2 .2 * EXP( - 0.23 * (DAYS - 10)))+ ((0.1207 * (D AYS - 12.0))**4.36))) / 24 ENDIF ! INCREASED CARDIA C OUTPUT (L/HR) !QC = QC INIT + (QFAT - QFATI) + (QMAM - QMAMI) + QPLA+ (QUTR - QUTRI) QC = QFAT+QLIV+QSLW+ QRAP+QSKN+QMAM+QPLA+ QUTR ! PMS, 8 - 13 - 13 ! SCALED PERMEABILIT Y - AREA PRODUCT PAF = PAFC * (VFET** 0.75)

!==================F IRST MODEL FOR TRACK ING NMP======== ================= !EQUATIONS FOR ORAL GAVAGE DOSING RAO = KAS * AO*FRACO R AO = INTEG( - RAO,ODOSE) !AMT REM AINING TO BE ABS, MG ! OABS = INTEG(RAO,0.0 )

!ODOSE - AO !AMT ABSORBED ORALLY , MG! !EQUATIONS FOR FEED DOSING FDOSE = DOSEF*BW !CONVERT MG/KG BW TO MG TOTAL(ORAL) RAF = KASF * AF*FRAC F AF = FDOSE - INTEG(RAF,0.0) !AMT REMAINING TO BE ABS, MG! FABS = INTEG(RAF,0.0 ) !AL = AMOUNT NMP IN LIVER COMPARTMENT (M G) RAL = QLIV*(CA - CVL)+ RAIP + RAO + RAF - RAML AL = INTEG(RAL, 0.0) CVL = AL/(VLIV*PL) RAML = (VMAX1*CVL)/( KM+CVL) !SATURABLE METABOLIS M, MG/HR AML = INTEG(RAML,0.0 ) !AMT NMP METAB BY SA TURABLE PATH, MG AML1B = RATS*AML*MWH P/MWNMP !TOT AMT HNP PRODUCED IN LIVE R, MG !EQUATIONS FOR IP DO SING RAIP = KIP * AIP AIP = INTEG( - RAIP,PDOSE) !AMT RE MAINING TO BE ABS, M G! IPABS = INTEG(RAIP,0 .0) !EQUATIONS FOR IV IN FUSION IVR = IVZONE*IVDOSE* BW/TINF !RATE OF IN FUSION, MG/HR TIV = INTEG(IVR,0.0) !TOTAL AMOUNT INJECT ED, MG ! ARTERIAL BLOOD RAAB = (QC * (CVLU - CA)) - RAUNP AAB = INTEG(RAAB, 0. 0) !AMOUNT, MG CA = AAB / VA !CONCENTRATION, MG/L AAUCB = INTEG(CA, 0. 0) !AUC, HR*MG/L RAUNP = KLN*CA*VV !FIRST ORDER RATE OF LOSS (URINE

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Page 24 AUNP = INTEG(RAUNP,0 .0) ! CHAMBER CONCENTRAT ION (MG/L) RACH = (RATS * QP * CLEX) - (FRACIN * RATS * QP * CI) - (KLOSS * ACH) ACH = INTEG(RACH, AC HO) ! THE FOLLOWING CALC ULATION YIELDS AN AI R CONCENTRATION EQUA L TO ! THE CLOSED CHAMBER VALUE IF A CLOSED CH AMBER RUN IS IN PLAC E AND ! A SPECIFIED CONSTA NT AIR CONCENTRATION IF AN OPEN CHAMBER R UN IS IN PLACE CCH = (ACH / VCH)! * CIZONE) + (CONCMG * (1.0 - CLON)) CCPPM = CCH *2445 1/MWNMP CLOSS = INTEG(KLOSS * ACH,0.0) CI = CCH*PULSE(0., D OSEINTERVAL,TCHNG) + CIZONE*CONCMG ! MG /L ! ADDED CIZONE*CO NCMG, PMS, 8 - 13 - 13 ! LUNGS !RALU = (QP * ((FRAC IN * CI) - CLEX)) + (QC * (CV - CVLU)) RALU = (QP * ((FRACI N * CI) - CLEX)) + RVV - (QC * CVLU) ! PMS, 8 - 13 - 13 ALU = INTEG(RALU, 0. 0) CLU = ALU / VLU !CONCENTRATION, MG/L CVLU = CLU / PLU !EXITING CONCENTRATI ON, MG/L ! AMOUNT INHALED RINH = FRACIN * QP * CCH *CIZONE AINH = INTEG( RINH, 0.0) ! MG PE R AINHC = AINH * RATS ! MG FOR A GROUP OF RATS ! AMOUNT EXHALED CLEX = CV / PB ! CONCENTRATION, MG/ L RAEX = QP * CLEX AEX = INTEG(RAEX, 0. 0) ! AMOUNT, MG PE R AEXC = AEX * RATS ! AM OUNT, MG, FOR A GROU P OF RATS !ASK = AMOUNT NMP IN SKIN TISSUES (MG) AN D DERMAL DOSING RASK = QSKN*(CA - CSKV) + RADL ! NOW MINUS CSKV, NO T CSK; PMS 8 - 21 - 13 ASK = INTEG(RASK,ASK O) ! INITIAL VALUE, ASK O, ADDED FOR BECCI E T AL. (1982) EXPOSUR ES; PMS 8 - 14 - 13 CSK = ASK/VSK !'NMP IN SKIN, MG/L'

CSKV = CSK/PSKB ! NMP IN VENOUS BLOOD, PMS 8 - 22 - 13 CVSK3 = CSK*1000/MWN MP !'NMP IN CVSK , MICROMOL/L' ! RADL = (KPL*SA/100 0)*(CONC2 - (CSK/PSKA))*DZONE !R EPLACE CONCL W CONC2 IF LIQUID ABSORPTION NEEDED ! ADL = INTEG(RADL, 0.0) !'AMT NMP ABSORBED D ERMAL,MG' ! DDA=DDN - RESID !'LESS AMT NMP RECOV ERED ON PATCH

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Page 25 ! ADLA = INTEG( - RADL,DDA) ! ADL2 = ADL*1000/MW NMP !'AMT ABSOR BED, MICROMOLES' ! CONC2= RSW(VLIQABS1.LE.VLIQ ,ADLA/(VLIQ - VLIQABS1),0.01) ! VLIQABS1=ADL/1000/ DENSITY/1000 CONCL2=CONCL*FAD CSURF=(CONCL2 - (ADL/VLIQ))*DZONE !RADL=((KPL*SA/1000) *CSURF) - (CSK/PSK) ! INCORREC T FORM; PMS 8 - 13 - 13 RADL=(KPL*SA/1000.0) *((CSURF - (CSK/PSKL))*DZONE - (1.0 - DZONE)*(CSK/PSKA)) ! CORRECT FORM; PMS 8 - 13 - 13 ! 2ND TERM, (1.0 - DZONE)*(CSK/PSKA), A LLOWS FOR EVAPORATIV E LOSS WHEN DZONE=0; PMS 8 - 14 - 13 ADL=INTEG(RADL,0.0) ! NOTE - NO LOSS TERM. TRY WI THOUT OR ADD LOSS UP - FRONT BY SUBTRACTING ! AMOUNT RECOVER ED FOR EACH STUDY WI TH AMOUNT (CONC) ORI GINALLY APPLIED ! "LOSS" OR STICKING PROBABLY ESSENTIALLY IMMEDIATE AND NOT KI NETIC ! REPORTS OF ~11 - 24% STICKING TO DRES SING ! AMOUNT IN FAT (MG) RAFAT = QFAT * (CA - CVFAT) AFAT = INTEG(RAFAT, 0.0 ) CFAT = AFAT / VFAT CVFAT = CFAT / PF ! AMOUNT IN FETUSES (MG) RAFET = PAF * (CPLA - CFET) AFET = INTEG(RAFET, 0.0) !IF (DAYS.GT.6.0) CF ET = AFET / VFET

CFET = AFET / VFET ! PMS, 8 - 13 - 13 AUCCFET = INTEG(CFET , 0.0) ! AMOUNT IN UTERUS (MG ) RAUTR = QUTR * (CA - CVUTR) AUTR = INTEG(RAUTR, 0.0) CUTR = AUTR / VUTR CVUTR = CUTR / PUTR ! AMOUNT IN MAMMARY TISSUE (MG) RAMAM = QMAM * (CA - CVMAM) AMAM = INTEG(RAMAM, 0.0) CMAM = AMAM / VMA M CVMAM = CMAM / PM ! AMOUNT IN PLACENTA (MG) RAPLA = (QPLA * (CA - CVPLA)) + (PAF * (CF ET - CPLA)) APLA = INTEG(RAPLA, 0.0) ! IF (DAYS.GT.6.0) C PLA = APLA / VPLA

CPLA = APLA / VPLA ! PMS, 8 - 13 - 13

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Page 26 CVPLA = CPLA / PPLA !AS = A MOUNT IN SLOWLY PERF USED TISSUES (MG) RAS = QSLW*(CA - CVS) AS = INTEG(RAS, 0.0) CVS = AS/(VSLW*PS) CS = AS/VSLW !AR = AMOUNT IN RAPI DLY PERFUSED TISSUES (MG) RAR = QRAP*(CA - CVR) AR = INTEG(RAR, 0.0) CVR = AR/(VRAP*PR) CR = AR/VRAP !MIXED VENOUS BLOOD !RV=(QFAT*CVFAT+QLIV *CVL+QSLW*CVS+QRAP*C VR+QSKN*CSK+CVMAM*QM AM+CVPLA*QP LA+QUTR*CVUTR+IVR) - QC*CV RVV = QC*CV ! PMS, 8 - 13 - 13 RV=(QFAT*CVFAT+QLIV* CVL+QSLW*CVS+QRAP*CV R+QSKN*CSKV+CVMAM*QM AM +CVPLA*QP LA+QUTR*CVUTR+IVR) - RVV ! PMS, 8 - 13 - 13 AV=INTEG(RV,0.0) CV=AV/VV AUCBB=INTEG(CV,0.0) !AUC, HR*MG/L ! ----------- MASS BALANCE NMP -------------- BODY = (AFAT+AR+AS+A L+ASK+AV+ALU+AAB+APL A+AMAM+AUTR) TMASS = RATS*(BODY + AML + AEX+AUNP+AFET) !CO MPARE TO

!AINH FOR OC MASS BA L !OR OABS FOR ORAL MA SS BAL !OR TIV FOR IV MASS BAL !OR ADL FOR DERMAL L IQUID MASBAL=TMASS/( AINH+OABS+TIV+ADL+1E - 9) ! CHECK BLOOD FLOWS QTOT = QFATI + QLIV + QRAP + QSKN + QSLW + QUTRI +QMAM+QPLA QRECOV = 100.0 * (QT OT / QC) !===============SECO ND MODEL FOR TRACKIN G HNP=============== ====== !ALHP = AMOUNT HNMP IN LIV ER COMPARTMENT (MG) RALHP = QLIV*(CAHP - CVLHP)+ RAML1 - RAMLH RAML1=RAML*MWHP/MWNM P AML2B=INTEG(RAML1,0. 0) ALHP = INTEG(RALHP,0 .0) !AMT IN MG HNMP, COR RECTED FOR MW CVLHP = ALHP/(VLIV*P LHNP) !TOTAL HNMP RAMLH = (VMAX2*CVLHP )/(KM2+CVLHP) !SATURABLE METABOLIS M, MG/HR AMLH = INTEG(RAMLH,0 .0) !AMT HNMP METAB BY S ATURABLE PATH, MG RDOSE=RAMLH/(BW**0.7 5)

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Page 27 TDOSE=INTEG(RDOSE,0. 0) !ABHP = AMOUNT HNMP IN TISSUES (MG) RABHP = QB*(CAHP - CBSHP) ABHP = INTEG(RABHP,0.0) CBSHP = ABHP/(VB*PBH NP) !AFHP = AMOUNT HNMP IN FAT (MG) RFSHP = QFAT*(CAHP - CVFHP) AFHP = INTEG(RFSHP,0 .0) CVFHP = AFHP/(VFAT*P FHNP) !CVHP = MIXED VENOUS BLOOD CONC TOTAL HNM P (MG/L) CRHP = (QLIV*CVLHP + QB*CBSHP + QFAT*CVFHP + QPLA*CV PLHP) - QC*CVHP - RAUHP ! ** ADDED QPLA*CVPL HP TO ABOVE; PMS 8 - 19 - 13 AVHP = INTEG (CRHP,0 .0) CVHP = AVHP/VBL CAHP = CVHP CVHP2 = CVHP*1000/MW HP !VENOUS BLOO D TOT CONC HNMP IN M ICROM AUCVHP = INTEG(CVHP2 ,0.0) !AUC HNMP VEN. BLOOD, MICROMOL*HR/L ! AMOUNT IN PLACENTA (MG) RAPLHP = (QPLA * (CA HP - CVPLHP)) + (PAF * (C FETHP - CPLHP)) APLHP = INTEG(RAPLHP , 0.0) !IF (DAYS.GT.6.0) CP LHP = APLHP / VPLA

CPLHP = APLHP / VPLA ! PMS, 8 - 13 - 13 CVPLHP = CPLHP / PPLHNP ! AMOUNT IN FETUSES (MG) RAFETHP = PAF * (CPL HP - CFETHP) AFETHP = INTEG(RAFET HP, 0.0) ! IF (DAYS.GT.6.0) C FETHP = AFETHP / VFE T CFETHP = AFETHP / VF ET ! PMS, 8 - 13 - 13 AUCFETHP = INTEG(CFE THP, 0.0) !RATE OF ELIM IN THE URINE, RAUHP, FROM M IXED BLOOD RAUHP = KL*CAHP*VA !FIRST ORDER RATE AUHP = INTEG(RAUHP,0 .0) !CUMULATIVE A MT HNMP IN URINE (MG ), NOT MGEQ ! ----------- MASS BALANCE -------------- ! ----------- MASS BALANCE 5 - HNMP SUBMODEL -------------- !COMMENT OUT EQUATIO NS WHEN NOT USING TO ELIM. UNESSESARY INT EG BODYHP = (AFHP+ABHP+ ALHP+AVHP+AFETHP+APL HP)*RATS !+AABH TMASHP = RATS*(AUHP + BODYHP +AMLH) !COMPARE TO AML1B ! CHECK BLOOD FLOWS 5 HNMP COMPARTMENT QTOTH = QLIV + QFAT + QB+QPLA

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Page 28 QRECOVH = 100.0 * (Q

TOTH / QC) TERMT(T .GE. TSTOP) ! ---- STATEMENT TO STOP EX ECUTION --- END !END OF DERI VATIVE DISCRETE GAVD AO = AO + DOSE2*BW SCHEDULE GAVD .AT. ( T+24.0) END !EXPOSURE CONTROL DISCRETE SKWASH ! PMS, 8 - 14 - 13 ASK = 0.0 ! ASSUME SKIN WASHIN G IN BECCI ET AL. (1 982) REMOVES ALL NMP FROM SKIN IF (DAYS.LT.15.0) SC HEDULE REAPPLY.AT.(T +DOSEINTERVAL - TWASH) END DISCRETE REAPPLY ! PMS, 8 - 14 - 13 IF (ROUND(DAYS).EQ.9 .0) AS KO=DSK*BW IF (ROUND(DAYS).EQ.1 2.0) ASKO=DSK*BW IF (ROUND(DAYS).EQ.1 5.0) ASKO=DSK*BW ASK = ASK+ASKO SCHEDULE SKWASH.AT.( T+TWASH) END DISCRETE OFFD IVZONE=0.0 !TURN IV OFF CIZONE=0.0 !TURN INHAL EXPOSURE OFF DZONE=0.0 !TURN OFF DERMAL SCHEDULE O ND.AT.(T+DOSEINTERVA L - TCHNG) ! PMS, 8 - 13 - 13 END DISCRETE OND ! PMS, 8 - 13 - 13 CIZONE=1.0 !TURN INHAL EXPOSURE ON SCHEDULE OFFD.AT.(T+ TCHNG) END END !END OF DYNA MIC END !END OF PROG RAM

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Page 29 **HUMPREGRETRIEVE_REST ORED_1.CSL**  PROGRAM NMPHUMPG.ACS L !PBPK MODEL FOR N - METHYL PYRROLIDONE I N PREGNANT WOMEN !T.S. POET,P HINDERL ITER. CHEMICAL DOSIM ETRY GROUP, PNNL, RI CHLAND, WA !FIRST CREATED 8.8.0 8 !FINAL REPORT FROM I NITIAL RAT MODEL DEV ELOPMENT SUBMITTED 9 .02 !MODEL CONFIGURED FO R INHALATION (OPEN, WHOLE BODY/NOSE ONLY) ! IV, ORAL, DERMA L, AND IP ROUTES OF ADMINISTRATION. !MODEL TRACKS DISPOS ITION OF NMP AND 5 - HNMP. !ASSUMPTIONS: ! (1) FLOW - LIMITED (ALL COM PARTMENTS) ! (2) METABOLISM OF NMP BY A SAT PATH WAY TO FORM 5HNP ! (3) METABOLISM OF HNP BY SATURABLE PATHWAY TO ETC. ! (5) METABOLISM OCCURS ONLY IN THE L IVER ! (6) TISSUE:BLOO D PART. COEFF. R AT = HUMAN = KRISHNA N EQN ! UPDATED IN CMD FILE TO MEASURED IN - HOUSE ! (7) 5HNP ELIMIN FROM MIXED VENOUS - 1ST ORDER ! THIS DIFFERS FROM 02 : URINE BY *GFR CLEA RANCE FROM KIDNEY ! METAB RATE CONST . FROM REPORT - UPDATED WITH LIT VAL UES IN CMD FILE ! OTHER PARAMETERS CHANGED NOMINALLY TO HARMONIZE WITH FETAL IPA MODEL OF ! GENTRY ET AL. REGU TOX PHARM 36:51 - 68, 2002 ! GENTRY MODEL NOTES : ! - CODING FOR PREGNANCY IS FROM MEHGFAT.CSL WITH SOME MINOR CHAN GES ! - PHYSIOLOGICAL PARAME TERS ARE FROM ME HGFAT.CSL (AJUSTED A S NEEDED) ! - NON - PREGNANT MAMMARY TIS SUE AND UTERINE VOLU ME IS FROM ICRP ! - NON - PREGNANT MAMMARY TIS SUE AND UTERINE BLOO D FLOWS ARE BASED ON THE ! - RATIOS OF MAMMARY AN D UTERINE TISSUE VOL UMES TO RAPIDLY PERF USED ! - TISSUE VOLUME AND BLOOD FLOW TO RAPIDL Y PERFUSED TISSUE WH ERE RAPIDLY ! - PERFUSED TISSUE INCL UDES LIVER, LUNG, ET C. ! - ((VMAMC/VRAPC)*QRAPC ) AND ((VUTRC/VRAPC) *QRAPC) ! - DATA USED TO FIT CUR VE FOR GROWING RAPID LY PERFUSED TISSUE I N ! - MEHGFAT.CSL WAS REFI T SEPARATELY TO FIT CURVES FOR GROWI NG UTERUS ! - AND MAMMARY TISSUE I N THIS MODEL ! - BODY WEIGHT AND CARD IAC OUTPUT ARE CALCU LATED AS THE INITIAL VALUES ! - PLUS THE CHANGE IN T HE GROWING COMPARTME NTS ! - INCREASE IN BLOOD FL OW TO FAT, MAMMARY T ISSUE, AND UTERUS AR E MODEL ED ! - AS BEING PROPORTIONA L TO THE INCREASE IN VOLUME IN THOSE COMP ARTMENTS ! - BASED ON THE DATA IN THORESEN AND WESCHE, 1988 (UTERUS AND MAM MARY ! - TISSUE) INITIAL TABLE RESLVL, 1, 144 1 / 1441*0.0, 1441*0 .0 / ! HUMAN TOTAL PULMON ARY VENTILATION RATE (L/HR FOR 1 KG ANIMAL)

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Page 30 CONSTANT QPC = 2 7.75 ! HUMAN BLOOD FLOWS (FRACTION OF CARDIAC OUTPUT) CONSTANT QCC = 1 2.9 ! CARDIAC OUTPUT (L/HR FOR 1 K G ANIMAL) CONSTANT QFATC = 0 .052 ! FAT (N ON - PREGNANT FEMALE) CONSTANT QLIVC = 0 .227 ! LIVER CONSTANT QMAMC = 0 .027 ! MAMMAR Y TISSUE (NON - PREGNANT FEMALE) CONSTANT QRAPC = 0 .325 ! RAPIDLY PERFUSED CONSTANT QSKC = 0. 058 ! SKIN CONSTANT QUTRC = 0 .0062 ! UTERUS (NON - P REGNANT FEMALE) ! GENTRY MODEL HAS 0 .249, BUT ADDING THE SE =0.944, SO BE AWA RE CAN REPLACE WITH EQN ! PERMEABILITY - AREA PRODUCT (L/HR) CONSTANT PAFC = 0 .01 ! DIFFUS ION ON FETAL SIDE OF PLACENTA ! NOT SURE WHERE OPT IMIZED PARAMETER COM E S FROM VISAVIS GENTRY ! HUMAN TISSUE VOLUM ES (FRACTION OF BODY WEIGHT) CONSTANT BWINIT = 6 7.8 ! PRE - PREGNANCY BODY WEIGH T (KG) CONSTANT VALVC = 0 .0079 ! ALVEOL AR BLOOD CONSTANT VBLC=0.06 CONSTANT VFATC = 0 .273 ! FAT (N ON - P REGNANT FEMALE) CONSTANT VLIVC = 0 .026 ! LIVER CONSTANT VMAMC = 0 .0062 ! MAMMAR Y TISSUE (NON - PREGNANT FEMALE) CONSTANT VRAPC = 0 .1044 ! RAPIDL Y PERFUSED !CONSTANT VSLWC = 0.35 ! SLOWL Y PERFUSED IN GENTRY MODEL, TH IS MODEL IS CALCULAT ED BELOW CONSTANT VUTRC = 0 .0014 ! UTERUS (NON - PREGNANT FEMALE) CONSTANT VSKC=0.19 ! HUMAN DERMAL EXPOS URE PARAMETERS CONSTANT P = 0 .0016 ! PER MEABILITY CONSTANT ( KP) (CM/HR) CONSTANT PV=31.0 ! PERMEABILITYT CONSTA NT (CM/HR) FOR VAPOR !FOR PARENT MODEL, S KIN COMPARTMENT IS O NLY DEFINED AS DOSED SKIN CONSTANT SAL = 0.01 !SURFAC E AREA EXPOSED TO LI QUID, SQ.CM CONSTANT SAV = 6700 !SURFAC E AREA EXPOSED TO GA S/VA POR, SQ.CM CONSTANT HT=170.0 !HEIGHT (OR LENGTH) OF REFERENCE MAN TSA = 71.81*(BWINIT* *0.425)*(HT**0.725) !FOR HUMANS, DUBOIS AND DUBOIS, 1916, AS REPORTED IN REFERENC E MAN VSKLC = VSKC*SAL/TSA QSKLC = QSKC*SAL/TSA VSKVC = VSKC*SAV/TS A QSKVC = QSKC*SAV/TSA ! CONSTANT DERM=0 ! DERMAL DOSE - MG (AMOUNT) ! DERM NOT USED IN R EST OF CODE; PAUL SC HLOSSER, U.S. EPA (P S), 5 - 17 - 2013

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Page 31 CONSTANT FAD = 0.0 !FRACTION ABSORBED - FROM BADER ET AL, CA LCULATE FROM AMNT REMAINING ON GAUZE CONSTA NT PVL=0.0 ! SLOWLY PERFUSED (D EFINED AS BALANCE OF TISSUES AND FLOWS) VSLWC = 0.91 - ( VFATC + VLIVC + VM AMC + VRAPC + VUTRC + VSKVC + VSKLC) !VL UC + ! PMS 8 - 20 - 13, REMOVED + VALVC ! NOTE: 0.91 IS APPR OX WHOLE BODY LESS B ONE VSLWC5=0.91 - (VFATC + VLIVC + VRA PC) ! PMS 8 - 20 - 13, REMOVED + VALVC QSLWC = 1.0 - (QFATC + QLIVC + QMA MC + QRAPC + QUTRC + QSKVC + QSKLC) QSLWC5 = 1.0 - (QFATC + QLIVC + QRA PC)! + QSKCC) ! MOLECULAR WEIGHTS CONSTANT MW=99.13 !MOL. WT. NMP, MG/MM OL CONSTANT MW1= 116.1 4 !MOL. WT. 5 - HNP, MG/MMOL STOCH = MW1/MW ! HUMAN NMP/BLOOD PA RTITION COEFFICIENTS !EXPERIMENTALLY MEAS URED RATVALUES CONSTANT PB = 450 .0 ! BLOOD/AI R CONSTANT PFAT = 0 .61 ! FAT CONSTANT PLIV = 1 .00 ! LIVER CONSTANT PMAM = 1 .0 ! MAMMAR Y TISSUE, ESTIMATED FROM LIVER CONSTANT PPLA = 0 .31 ! PLACEN TA CONSTANT PRAP = 1 .0 ! RAPIDLY PERFUSED TISS UE, LIVER CONSTANT PSLW = 0 .30 ! SLOWLY PERFUSED TISSUE, MUS CLE CONSTANT PUTR = 0 .34 ! UTERUS CONSTANT PSKA = 4 4.5 !450.0 ! USE (BLOOD/AIR)*(R AT SKIN:LIQUID)/(HUM AN BLOOD:LIQUID) CONSTANT PSKL = 0 .42 ! MEASURED SKIN ;LIQUID (RAT) CONSTANT PSKB = 0.099 ! (RAT SKIN:LIQUID)/ (HUMAN BLOOD:LIQUID) CONSTANT PLU= 0.1 ! LUNG:BLOOD !METABOLIC RATE CONS TANTS !**THESE ARE FROM PA YAN ET AL !NMP TO 5HNP CONSTANT KM=198.0 !MICHAELIS CONSTANT, MG/L CONSTANT VMAXC=2.67 !MAX. ENZ. ACT., MG/ HR/L ! HUMAN 5HNMP TISSUE /BLOOD PARTITION COE FFICIENTS ! MEASURED CONSTANT PB1=5.0 CONSTANT PLIV1=3.0 ! LIVER MEASURED CONSTANT PFAT1=0.40 !MEASURED CONSTANT PRAP1=0.93 CONSTANT PSLW1=0.40 !NO FETAL COMPARTMENT FO R METABOLITE, NMP IS CONSIDERED THE ACTIV E MOIETY

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Page 32 !5HNP TO OTHER METAB S CONSTANT KM2=22.8 !MICHAELIS CONSTANT, MG/L CONSTANT VMAX2C=1.0 !MAX. ENZ. ACT., MG/ HR/L ! HUMAN UPTAKE AND C LEARANCE PARAMETERS !URINARY ELIMINATION OF 5 - HNMP - CLEARED FROM BLOOD !NOTE FIRST ORDER RA TE COMMENTED OUT, SA TURABLE FITS BETTER CONSTANT KAS=5.0 CONSTANT KME=8.0 !MICHAELIS CONSTANT, MG/L CONSTANT VMAXEC=8.0 !MAX. ENZ. ACT., MG/ HR/L CONSTANT KMNE=8.0 !MICHAELIS CONSTANT FOR NMP IN URINE CONSTANT VMXNEC=1.0 ! INITIALIZE HUMAN C ONCENTRATIONS IN TIS SUES (MG/L) CONSTANT ICART = 0 .0 ! BLOOD CONSTANT ICFAT = 0 .0 ! FAT CONSTANT ICLIV = 0 .0 ! LIVER CONSTANT ICRAP = 0 .0 ! RAPIDL Y PERFUSED CONSTANT ICSKN = 0 .0 ! SKIN CONSTANT ICSLW = 0 .0 ! SLOWLY PERFUSED ICMAM = ICSLW ! MAMMARY TISSUE ICUTR = ICRAP ! UTERUS ! DOSING PARAMETERS CONSTANT CONCPPM = 0.0 ! INH ALED CONCENTRATION ( PPM) CONSTANT CONCMGM = 0.0 ! INHALED CONCENTRAT ION (MG/M3) CONSTANT IVDOSE = 0 .0 ! IV DOS E (MG/KG) CONSTANT PDOSE = 0 .0 ! ORAL D OSE (MG/KG) CO NSTANT PDOSE2=0.0 CONSTANT PDOSE3=0.0 CONSTANT PDRINK = 0 .0 ! DRINKI NG WATER DOSE (MG/KG /DAY) CONSTANT TCHNG = 2 4.0 ! LENGTH INH. EXPOSURE OR IV INJ.(HRS) CONSTANT DAYSWK = 5 .0 ! NUMBER OF EXPOSURE DAYS PER WEEK CONST ANT TMAX = 24.0 ! MAXIMUM TIME FOR E XPOSURES CONSTANT S2=0.0 !INHALATION ON CONSTANT P2=3.0 !INHALATION EXPOSURE CONSTANT S3=3.16 !INHALTION RESUME (HANOVER STUD Y) CONSTANT P3=3.0 !SECOND DAILY EXPOSU RE PERIO D CONSTANT ON3=1.0 ! SET TO ZERO TO TUR N OFF 2ND DAILY PULS E; PMS 8 - 20 - 13 CONSTANT FULLWEEK=16 8.0 ! HRS IN A FULLWEEK; PMS 8 - 20 - 13 HRSWEEK=24.0*DAYSWK ! HRS/WEEK IN WORKPL ACE; PMS 8 - 20 - 13 ! STARTDS IS ADDED T O TCHNG TO ALLOW FOR DOSING THAT DOES NOT START AT T=0 !INITIAL EXPOSURE CO NDITIONS !DERMAL

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Page 33 CONSTANT CONCL = 0.0 !CONC OF NMP IN LIQU ID, MG/L

CONSTANT SRATE = 0.0 ! MG/HR DELIVERED TO SKIN BY SPRAY APPLICATION; PMS 8 - 20 - 13 CONSTANT VLIQ = 1.0E - 99 !INITIAL VOLUME APPL IED, L CONSTANT DENSITY=1.0 3 CONSTANT RESID=0.0 !AMOUNT STICKING TO EXPOSURE SYSTEM, MG

CONSTANT BRUSH=0.0 ! SET TO 1.0 FOR BRU SH/LIQUID EXPOSURE; PMS 8 - 20 - 13 DDN = CONCL*VLIQ !IN VITRO HUMAN VAN DYK ET AL. AIHA J 56 : 651 - 660 !START WITH SMALL SA SO VSKE IS NON - ZERO (USED IN DENOMI NATOR OF CSK CALCULA TION) ! EXPOSURE CONDITION S BASED ON USER DEFI NED INITIAL AMOUNTS OF CHEMICAL (MG) IF (CONCPPM.EQ.0.0) THEN CONCMG=CONCMGM/1000. 0 !CONCERT MG/M3 TO MG/L ELSE CONCMG = CONCPPM*MW/ 24451. !CONVERT P PM TO MG/LITER! ENDIF !CONSTANT CONCMG=0 !HANNOVER STUDY UNIT MG/M3 SO CONCMG /100 0(L/M3) CONSTANT DOSEINTER VAL=24.0 !TIME BETWEEN DAILY DOSES ! SIMULATION CONTROL PA RAMETERS CONSTANT STARTDS = 0 .0 ! TIME F IRST DOSE IS GIVEN ( HRS) CONSTANT TSTOP = 6 480.0 ! RUN SI MULATION FOR ABOUT 9 MONTHS CONSTANT CINTC = 0 .1 CONSTANT GDSTART = 0.0 ! GESTATION DAY ON W HICH SIMULATION STAR TS; PMS 8 - 20 - 13 ! S CALED HUMAN PULMONAR Y VENTILATION RATE ( L/HR) QP = QPC * (BWINIT** 0.75) QALV = 0.67 * QP ! SCALED HUMAN BLOOD FLOWS (L/HR) QCINIT = QCC * (BWIN IT**0.75) QFATI = QFATC * QCIN IT QLIV = QLIVC * QCINI T QMAMI = QMAMC * QCIN IT

QPLAI = 58.5 * VPLAI ! VALUE FOR 'DAYS'=0 PER CALCULATION BELO W; PMS, 8 - 20 - 13 QRAP = QRAPC * QCINI T QSLW = (QSLWC * QCIN IT) - QPLAI ! - QSKCC ! QSKCC IS ALREADY S UBTRACTED IN SETTING QSLWC ABOVE; PMS 8 - 20 - 13 ! BUT INITIAL PLACEN TAL BLOOD FLOW I S NOT, SO NOW SUBTRA CTED HERE; PMS 8 - 20 - 13 ! QSLW5= (QSLWC5* Q CINIT) ! WILL CALCULATE BY SUBTRACTION IN THE D ERIVATIVE SECTION; P MS 8 - 1913

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Page 34 QUTRI = QUTRC * QCIN IT QSKL = QSKLC * QCINI T QSKV = QSKVC * QCINI T ! SCALED HUMAN TISSU E VOLUMES (L) VALV = VALVC * BWINI T !VFATI = VFATC * BWI NIT VFATI = BWINIT*(VFAT C+(0.09*EXP( - 12.90995862*EXP( - 0.000797*24.0*GDSTAR T)))) VFETI = 3.50 * (EXP( - 16.081*EXP( - 5.67E - 4*24.0*GDSTART))+ EX P( - 140.178*EXP( - 7.01E 4*24.0*GDSTART))) !VMA MI = VMAMC * BWINIT VMAMI = BWINIT*(VMAM C+(0.0065*EXP( - 7.444868477*EXP( - 0.000678*24.0*GDSTAR T))))

!VPLAI = 0.85*EXP( - 9.434) ! VALUE FOR 'DAYS'=0 PER CALCULATION BELO W; PMS 8 - 19 - 13 VPLAI = 0.85*EXP( - 9.434*EXP( - 5.23E - 4*24.0*GDSTART)) !VUTR I = VUTRC * BWINIT VUTRI = BWINIT*(VUTR C+(0.02*EXP( - 4.715669973*EXP( - 0.000376*24.0*GDSTAR T)))) VLIV = VLIVC * BWINI T VRAP = VRAPC * BWINI T VSKL = VSKLC * BWINI T VSKV = VSKVC * BWINI T VBL=VBLC * BWINIT VSLW = (VSLWC * BWIN IT) ! - VSKCC; PMS 8 - 20 - 13 ! VSLW5 = VSLWC5 *B WINIT ! NOW CALCULATED BY SUBTRACTION IN DERIV ATIVE SECTION; PMS 8 - 20 - 13 ! SCALED HUMAN METAB OLISM PARAMETERS VMAXE = VMAXEC*(BWIN IT**0.75) !URINE 5HNMP VMXNE=VMXNEC*(B WINIT**0.75) !URINE NMP VMAX = VMAXC * (BWIN IT**0.75) VMAX1 = VMAX2C * (BW INIT**0.75) ! INITIALIZE HUMAN N MP AMOUNTS IN TISSUE S IAART = ICART * VALV IAFAT = ICFAT * VFAT I IALIV = ICLIV * VLIV IAMAM = ICMAM * VMAM I IARAP = ICRAP * VRAP IASKL = ICSKN * VSKL ! VSKCC ! PMS 8 - 20 - 13 IASKV = ICSKN * VSKV IASLW = ICSLW * VSLW IAUTR = ICUTR * VUTR I INITTOT = IAART + IA FAT + IALIV + IAMAM + IARAP + IASKL + IA SKV + IASLW + IAUTR ! INITIALIZE STAR TING VALUES BW = BWINIT DRINK = (PDRINK * BW ) / 24.0 ! DRIN KING WATER DOSE (MG/ HR)

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Page 35 CINT = CINTC IV = 0.0 DAYEXP = 1.0 CINH = 0.0 CONSTANT FRACIN = 0 .97 !FRACTIONAL UPTAKE OF NMP BY INH AL,START AT 65% !OF ALVEOLAR - AS IN AKESSON ET AL 1997 CONSTANT FRACOR = 1 .0 !FRACTION AB SORBED ORALLY, INITA LLY 100% ! CONVERT ORAL DOSE FROM UG/KG TO UMOLES ! MODIFY DOSE TO ACC OUNT FOR FRACTIONAL ABSORPTION ODOSE1= PDOSE * BW * FRAC OR ! UMOLES ODOSE2= PDOSE2* BW * FRACOR ! UMOLES ODOSE3= PDOSE3* BW * FRACOR ! UMOLES CONSTANT TIME=0.0 CONSTANT TIME1 = 0.0 ! !'DAILY RAT EXPO ( HR)' CONSTANT TIME2 = 4.0 ! !'SECOND DAILY EXP OSURE (HR)' CONSTANT TIME3 = 4.0 ! !'THIRD DAI LY DOSE' CONSTANT REPTM=720.0 ! CHANGE TO 24 FOR D AILY DOSING SCHEDULE DOSE1 .AT. TIME1 DZONE = 1.0 ! START WITH EXPOSUR E ON SCHEDULE OFFD.AT.P2 SCHEDULE OND2.AT.24. 0 IF (ON3) SCHEDULE ON D3.AT.S3 END ! END OF INITIAL DYNAMIC ALGORITHM IALG = 2 ! GEAR STIFF METHOD DISCRETE DOSE1 ODOSE = ODOSE+ODOSE1 SCHEDULE DOSE2 .AT. (TIME+TIME2) END DISCRETE DOSE2 ODOSE = ODOSE+ODOSE2 SCHEDULE DOSE3 .AT. (TIME+TIME3) END DISCRETE DOSE3 ODOSE = ODOSE+ODOSE3 SCHEDUL E DOSE1 .AT. (TIME+R EPTM - TIME2 - TIME3) END

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Page 36 DISCRETE DOSEON ! START DOSING INTERVAL DOSEINT = 2 4.0 ! INTERV AL TO REPEAT DOSING SCHEDULE DOSEOFF .AT . T + TCHNG IF ((T.GE.STARTDS) . AND. (T.LT.TMAX)) TH EN

IF (T.LE.(STARTDS+TC HNG)) THEN I F (IVDOSE.GT.0.0) CI NT = MIN(CINTC, (TCH NG/10.0)) IV = (IVDOSE*BW) / T CHNG ! RATE OF IN TRAVENOUS DOSING (MG /HR)

ENDIF ENDIF END ! DOSEON DISCRETE DOSEOFF CINH = 0.0 CINT = CINTC IV = 0.0 END DISCRETE OND2 DZONE=1.0 SCHEDULE OND2.AT.( T+24.0) SCHEDULE OFFD.AT.(T+ P2) END DISCRETE OND3 DZONE=1.0 SCHEDULE OND3.AT.(T+ 24.0) SCHEDULE OFFD.AT.(T+ P3) END !EXPOSURE CONTROL DISCRETE OFFD DZONE=0.0 !TURN OFF DERMAL END DERIVATIVE HOURS = T MINUTES = T * 60.0 DAYS = T / 24.0 + GD START ! PMS 8 - 20 - 13, ADDED GDSTART

GTIME = T + GDSTART* 24.0 ! PMS 8 - 20 - 13, REPLACES "T" IN TISSUE VOLUME CALCS BELOW ! VOLUME OF HUMAN FA T (L) VFAT = BWINIT*(VFATC +(0.09*EXP( - 12.90995862*EXP( - 0.000797*GTIME)))) ! VOLUME OF HUMAN FETUS (L) VFET = 3.50 * (EXP( - 16.081*EXP( - 5.67E - 4*GTIME))+ EXP( - 140.178*EXP( - 7.01E - 4*GTIME))) ! VOLUME OF HUMAN MA MMARY TISSUE (L) VMAM = BWINIT*(VMAMC +(0.0065*EXP( - 7.444868477*EXP( - 0.000678*GTIME))))

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Page 37 ! VOLUME OF HUMAN PL ACENTA (L) VPLA = 0.85*EXP( - 9.434*EXP( - 5.23E - 4*GTIME)) ! VOLUME OF HUMAN UT ERUS (L) VUTR = BWINIT*(VUTRC +(0.02*EXP( - 4.715669973*EXP( - 0.000376*GTIME)))) ! INCREASE IN HUMAN BODY WEIGHT (KG) BW = BWINIT + (VFAT - VFATI) + VFET + (VMA M - VMAMI) + VP LA + (VUTR - VUTRI) ! SCALED HUMAN ALVEO LAR VENTILATION (L/H R) QP = QPC * (BW**0.75 ) QALV = 0.67 * QP ! INCREASE IN HUMAN BLOOD FLOWS (L/HR) QFAT = QFATI * (VFAT / VFATI) QMAM = QMAMI * (VMAM / VMAMI) QUTR = QUTRI * (VUTR / VUTRI) ! HUMAN BLOOD FLOW T O PLACENTA (L/HR) QPLA = 58.5 * VPLA ! INCREASED HUMAN CA RDIAC OUTPUT (L/HR) ! QC = QCINIT + (QFA T - QFATI) + (QMAM - QMAMI) + (QPLA) + (Q UTR - QUTRI) QC = QCINIT + (QFAT - QF ATI) + (QMAM - QMAMI) + (QPLA - QPLAI) + (QUTR - QUTRI) ! NOW SUBTRACTING QP LAI ABOVE; PMS 8 - 20 - 13 QSLW5 = QC - (QFAT + QLIV + QRAP) ! PMS, 8 - 20 - 13 VSLW5 = BW - (VFAT + VLIV + VRAP) ! PMS, 8 - 20 - 13 ! SCALED PERMEABILIT Y - AREA PRODUCT PAF = PAFC * (VFET**0.75 ) ! ------------------ HUMAN NMP MODEL -------------------- ----- ! AMOUNT EXHALED (MG ) RAEXH = QALV * CALV AEXH = INTEG(RAEXH, 0.0) CI = CONCMG*CZONE + RESLVL(T) ! FOR A 5 DAY/WK EXP OSURE, CHANGE FIRST PULSE TO PULSE(0,7* 24,5*24) ! FOR DAILY, PULSE(0 ,1E6,24)

TORAL= ODOSE1 - AO !AMT ABSORBED ORALLY , MG! RSTOM = - KAS*AO RAO = KAS*AO ! CH ANGE IN STOMACH (UMO LE/HR) AO=ODOSE1+INTEG(RSTO M,0.0) ! AMT IN S TOMACH (UMOLE)

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Page 38 ! AMOUNT IN FAT (MG) RAFAT = QFAT * (CART - CVFAT) AFAT = INTEG(RAFAT, IAFAT) CFAT = AFAT / VFAT CVFAT = CFAT / PFAT ! AMOUNT IN FETUS (M G) RAFET = PAF * (CPLA - CFET) AFET = INTEG(RAFET, 0.0) CFET = AFET / VFET AUCCFET = INTEG(CFET , 0.0) ! AMOUNT IN LIVER (M G) RALIV = (QLIV * (CAR T - CVLIV)) + RAO + DRIN K - RAMET1 ALIV = INTEG(RALIV, IALIV) CLIV = ALIV / VLIV CVLIV = CLIV / PLIV ! AMOUNT METABOLISED IN LIVER -- SATURABLE (MG) RAMET1 = (VMAX * CVL IV) / (K M + CVLIV) AMET1 = INTEG(RAMET1 , 0.0) ! AMOUNT IN MAMMARY TISSUE (MG) RAMAM = QMAM * (CART - CVMAM) AMAM = INTEG(RAMAM, IAMAM) CMAM = AMAM / VMAM CVMAM = CMAM / PMAM ! AMOUNT IN PLACENTA (MG) RAPLA = (QPLA * (CAR T - CVPLA)) + (PAF * (CF ET - CPLA)) APLA = INTEG(RAPLA, 0.0) CPLA = APLA / VPLA CVPLA = CPLA / PPLA ! AMOUNT IN RAPIDLY PERFUSED TISSUE (MG) RARAP = QRAP * (CART - CVRAP) ARAP = INTEG(RARAP, IARAP) CRAP = ARAP / VRAP CVRAP = CRAP / PRAP !ASKL = AMOUNT NMP I N LIQUID - EXPOSED SKIN TISSUES (MG) AND DERMAL DOSI NG (FROM VAPOR) ! EQUATIONS BELOW SE T FOR LIQUID - EXPOSED SKIN, PMS 8 - 21 - 13 RASKL = QSKL*(CART - CVSKL) + RADVL+RASL ASKL = INTEG(RASKL,0.0) ! CVSKL = ASKL/VSKL !(VSKCC) ! PMS 8 - 20 - 13 ! CSKL = CVSKL/PSKL !'NMP IN SKIN, MG/L' CSKL = ASKL/VSKL !(VSKCC) ! CALCULATI ON OF VENOUS BLOOD A ND TISSUE CONCN'S WA S REVERSED; PMS 8 - 21 - 13 CVSKL = CSKL/PSKB !'NMP IN SKIN, MG/L'

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Page 39 !CVSK3 = CVSK*1000/M WNMP !'NMP IN CV SK, MICROMOL/L' CZONE = PULSE(0.0,FU LLWEEK,HRSWEEK)*DZON E ! PMS 8 - 20 - 13 ! FOR A 5 DAY/WK EXP OSURE, USE FULLWEEK= 7*24, HRSWEEK=5*24 ( DAYSWK=5) ! FOR A SINGLE DAY, FULLWEEK=1E16, HRSWEEK=24 (DAYSWK=1 ) SDELIV=SRATE*CZONE ! CONSTANT - RATE SPRAY DELIVERY; PMS 8 - 20 - 13 ! SPRAY - DERMAL EXPOSURES, AS SUMED SIMULTANEOUS W ITH INHALATION RADVL = (PV*SAL/1000 .0)*(CI - (CSKL/PSKA))*(1.0 - CZONE)*(SDELIV.EQ.0. 0) + SDELIV ! RADV ALLOWS ABSORPTION/DESORPTIO N FROM AIR WHEN THER E IS NOT SPRAY OR ! BRUSHING DERMAL EX POSURE, WHEN BOTH SD ELIV AND DZONE ARE ZERO; PMS 8 - 20 - 13 ADVL = INTEG(RADVL,0 .0) !'AMT NMP ABSORBED D ERMAL,MG' CONCL2=CONCL*FAD CSURF=CONCL2 - (ADSL/VLIQ) ! FOR APPLI CATIONS WIH NEAR - CONSTANT CSURF, SET VLIQ=1E9 OR HIGHER; PMS 8 - 2 - 13 RASL=(PVL*SAL/1000.0 )*(CSURF - (CSKL/PSKL))*CZONE*B RUSH !RASL=((PVL*SA/1000) *CSURF) - (CVSK/PSKL) ADSL=INTEG(RASL,0.0) !ASKV = AMOUNT NMP I N VAPOR - EXPOSED SKIN TISSUES (MG) AND DERMAL DOSI N G (FROM VAPOR); PMS 8 - 21 - 13 RASKV = QSKV*(CART - CVSKV) + RADVV ASKV = INTEG(RASKV,0 .0) ! CVSKV = ASKV/VSK V !(VSKCC) ! PMS 8 - 20 - 13 ! CSKV = CVSKL/PS KV !'NMP IN SKIN, MG/L' CSKV = ASKV/VSKV !(VSKCC) ! PMS 8 - 20 - 13 CVSKV = CSKV/PSKB !'NMP IN SKIN, MG/L' !CONCDERM=CONCMG* PU LSE(0,1E6,24)*(PULSE (S2,24,P2)+ PULSE(S3 ,24,P3)) ! RADVV = (PV*SA /1000.0)*(CONCDERM - (CVSKV/PSKA))!*DZONE RADVV = (PV*SAV/1000 .0)*(CI - (CSKV/PSKA)) ADVV = INTEG(RADVV, 0.0) !'AMT NMP ABSORBED D ERMAL,MG' ! AMOUNT IN SLOWLY P ERFUSED TISSUE (MG) RASLW = QSLW * (CART - CVSLW) ASLW = INTEG(RASLW, IASLW) CSLW = ASLW / VSLW CVSLW = CSLW / PSLW ! AMOUNT IN UTERUS ( MG) RAUTR = QUTR * (CART - CVUTR) AUTR = INTEG(RAUTR, IAUTR) CUTR = AUTR / VUTR CVUTR = CUTR / PUTR ! BLOOD VENOUS ARTER IAL (C) CVEN=(QFAT*CVFAT + Q LIV*CVLIV + QMAM*CVM AM + QPLA*CVPLA + QR AP*CVRAP + QSLW*CVSL W & + QUTR*CVUTR + QSKV* CVSKV + QSKL*CVSKL + IV) / Q C

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Page 40 !(QFAT + QLIV + QMAM + QPLA + QRAP + QSLW + QUTR + QSKV + QSKL ) / QC

! TOTAL VENOUS BLOOD !RABL= QC * (CVEN - CART) ! RATE OF CHANGE IN MIXED B LOOD !ABL= INTEG(RABL,0.0 ) ! AMOUNT IN MIXED BLOOD ! ABOVE NOT USED; PMS 8 - 21 - 13 ! AMOUNT IN ARTERIAL BLOOD (MG) RABLD = QALV*(CI*FRA CIN - CALV) + QC*(CVEN - CART) - RAUNP ABLD = INTEG(RABLD, IAART) CART = ABLD / VBL CALV = CART / PB CALVPPM = CALV * 244 50.0 / MW AUCCBLD = INTEG(CART , 0.0) ! AMOUNT IN URINE (MG) !RAUNP = KLN*CART !FIRST ORDER RATE OF LOSS (URINE RAUNP = VMXNE*CART/( KMNE+CART) !SATURABL E ELIMINATION AUNP = INTEG(RAUNP,0 .0) ! -------------------- HUMAN 5HNMP MODEL -------------------- ------ ! AMOUNT EXHALED (MG ) ! RAEXH1 = QALV * CALV 1 ! AEXH1 = INTEG( RAEXH1, 0.0) ! CALVPPM1 = CALV1 * (24450.0 / MW1) ! AMOUNT IN FAT (MG) RAFAT1 = QFAT * (CAR T1 - CVFAT1) AFAT1 = INTEG(RAFAT1 , 0.0) CFAT1 = AFAT1 / VFAT CVFAT1 = CFAT1 / PFA T1 ! AMOUNT IN LIVE R (MG) RALIV1 = ((QLIV * (C ART1 - CVLIV1)) + (RAMET1*S TOCH)) - RAMETM1 ALIV1 = INTEG(RALIV1 , 0.0) CLIV1 = ALIV1 / VLIV CVLIV1 = CLIV1 / PLI V1 ! AMOUNT METABOLISED IN LIVER -- SATURABLE (MG) RAMETM1 = (VMAX1 * C VLIV1) / (KM2 + CVLI V1) AMETM1 = INTEG(RAMET M1, 0.0) ! AMOUNT IN RAPIDLY PERFUSED TISSUE (MG) RARAP1 = QRAP * (CAR T1 - CVRAP1) ARAP1 = INTEG(RARAP1 , 0.0) CRAP1 = ARAP1 / VRAP CVRAP1 = CRAP1 / PRA P1 ! AMOUNT IN SLOWLY P ERFUSED TISSUE (MG)

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Page 41 RASLW1 = (QSLW5) * ( CART1 - CVSLW1) ASLW1 = INTEG(RASLW1 ,0.0) CSLW1 = ASLW1 / VSLW 5 CVSLW1 = CSLW1 / PSL W1 ! CONCENTRATION IN M IXED VENOUS BLOOD (M G/L) CVEN1 = (QFAT*CVFAT1 + QLIV*CVLIV1 + QRAP *CVRAP1 +QSLW5*CVSLW 1)/QC RART1 = QC*(CVEN1 - CART1) - RAUHP ABLD1=INTEG(RART1,0. 0) CART1 = ABLD1/VBL ! AMOUNT IN ARTERIAL BLOOD (MG) !CALV1 = CART1 / PB1 AUCCBLD1 = INTEG(CAR T1, 0.0) ! AMOUNT IN URINE (M G) RAUHP = VMAXE*CART1/ (KME+CART1) !SATURAB LE ELIMINATION !RAUHP =KLC*CART1 AUHP = INTEG(RAUHP,0 .0) INHALTOT=INTEG((QALV *(CI*FRACIN - CALV)), 0.0) IVTOT=INTEG(IV, 0.0) ! ----------------- CHECK MASS BALANCE -------------------- ---------- INTOT=INTEG((QALV*CI *FRACIN), 0.0) ! NEW SKIN TERMS ADD ED BELOW; PMS 8 - 21 - 13 TDOSE = INTOT + AO + INITTOT+TORAL+ADSL +ADVL+ADVV !+ INTEG( IV, 0.0) NMPTOT = ABLD + AFAT + AFET + ALIV + AMAM + APLA + ARAP + ASKL + ASKV + ASLW + AUTR + AEXH + AUNP + AMET1 MASSBAL = TDOSE/(NMP TOT+0.000000000001) TERMT(T.GT.TSTOP, 'S IMULAT ION FINISHED') END ! END OF DERIVATIVE TERMINAL DAUCCBLD = (AUCCBLD / TSTOP) * 24.0 DAUCCBLD1 = (AUCCBLD 1 / TSTOP) * 24.0 DAUCTOT = DAUCCBLD + DAUCCBLD1 DAUCCFET = (AUCCFET / TSTOP) * 24.0 DAUCTFET = DAUCCFET END END ! END OF DYNAMIC END ! END OF PROGRAM

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Page 42 **RATPARAMS.M** WESITG=0; WEDITG=0; VCHC=1e9, KLOSS=0.0, DOSE=0,TINF=0.01,PDOSE=0,DOSE2=0, CONCCHPPM0 = 0 CONCL=0, IVDOSE=0, TCHNG=999.0,TSTOP=120,CONCPPM=0,CONCMGS=0,DSK=0 %FAD=0.76 % Value from Payanderm.m; should only effect dermal exposure; PS 5 - 1 - 13 FAD=1 % From Poet 5 - 16 - 13 Payanderm.m file; PS 5 - 17 - 13 GDDAYS=0, SA=0.00001,DOSEINTERVAL=720,CINT=1, VLIQ=1e - 99, FRACIN=1 %1E - 55 % Changed to 1 to match ghantinahladata.m value; should not change w/ exposure route; PS 5 - 1 - 13 NUMFET=0.01 % Added to minimize impact on other volumes; Paul Schlosser (PS), U.S. EPA, 05 - 01 - 2103 KAS=1.36,FRACOR=0.68 % KPL=0.0000016 %KPL=4.3e - 3 % Value from Payanderm.m; should only effect derm al exposure; PS 5 - 1 - 13 KPL=4.6e - 3 % From Poet 5 - 16 - 13 Payanderm.m file; PS 5 - 17 - 13 VLIVC=0.0366 VLUC=0.005 VFATC=0.09 VRAPC=0.071 QLIVC=0.183 QPC=16.0 QCC=16.0 QFATC=0.07 QSKNC=0.058 QMAMC=1e - 5 QUTRC=1e - 5 KM=234 VMAXC =21.8 KM2=48 VMAX2C=2.4 QSC=0.14 BWINIT=0.23 GDDAYS=0 GDMONTHS=0 KLC=3.9 KLNC=0.0019 PAFC=0 MAXT=1e - 2 MINT=1E - 9 QFATC = 0.072 QLIVC = 0.183 QMAMC = 0.001 QSKNC = 0.058 QUTRC = 0.001 QRAPC = 0.512 VLUC = 0.007

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Page 43 VFATC = 0.10 VLIVC = 0.034 VMAMC = 0.01 VRAPC = 0.071 VUTRC = 0.002 VBLC = 0.067 PB=450.0 PF=0.62 PL=1.02 PR=1.02 PS=0.74 PLU=0.10 %PSKA= 450.0 %Air - skin transport equations, where PSKA appears, are commented % out in Poet 5 - 15 - 13 NMPpreg_rat.m; PS 5 - 17 - 13 %PSK=150 PSKL = 0.42 % MEASURED % 450 % Value for Poet 5 - 16 - 13 Payanderm.m file; PS 5 - 17 - 13 PSKB = 0.12 % SKIN:SALINE/BLOOD:SALINE PSKA = 55 % SKIN:SALINE*BLOOD:AIR/BLOOD:SALINE PM=1.0 PPLA=0.309 PUTR=0.34 PLHNP=3.0 PBHNP=0.73 PFHNP=0.40 PPLHNP=01. 07

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Page 44 **PREG_RAT_PARAMS.M** % To assure parameter consistency, calling ratparam first below and % commenting out redundant setting of parameters here. % Paul Schlosser, U.S. EPA , 05 - 01 - 2013 ratparam % VCHC=1.0E+9, KLOSS=0.0, DOSE=0,TINF=0.01,PDOSE=0 % set in ratparam % CONCL=0, IVDOSE=0, TCHNG=999.0,TSTOP=120,CONCPPM=0,CONCMGM=0 % GDDAYS=6, SA=0.00001,DOSEINTERVAL=720 QUTRC=0.005, %QRAPC=0.512 VLIVC=0.0366,VLUC=0.005,VFATC=0.09, %VRAPC=0.071, QLIVC= 0.183,

QPC=15,QCC=15, % These are both 16 in ratparam; PS 5 - 1 - 13 %QFATC=0.07,QSKNC=0.058 % set in ratparam % KM=234,VMAXC=21.8, KM2=48, VMAX2C=2.1 % set in ratparam BWINIT=0.235,GDDAYS=6, %GDMONTHS=0 % KLC=3.9,KLNC=0.002, % set in ratparam

PAFC=0.1,NUMFET=7 NUMFET=14,PUPBW=5670 % Taken f rom pregparamsoutput.m %MAXT=1.0e - 4 %MINT=1E - 9,VUTRC=0.002,VMAMC = 0.01 % set in ratparam %PAFC OF 0.1 IS NEAR MAX TRANSFER SEE GRAPHPAD PAF EFFECT 11 08

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Page 45 **FIG_1_WELLS_1988_IV_PLASMA.M** %PROCED WELLS - IV %WELLS AND DIGENIS 1988 prepare @all @clear ra tparam DOSE=0,PDOSE=0,TCHNG=0.0083,TINF=0.0083,CINT=0.01 BWINIT=0.35, IVDOSE=45, TSTOP=24,GDDAYS=0 !!start/nc MASBAL % DATA WELLS (T,CV,Poet 2013 CV) DWELLS = [0.08 90 65.59071 0.17 70 65.59071 0.25 60 64.07336 0.33 58 62.9852 0.50 56 60.90279 0.75 58 58.0206 1.00 52 55.2812 1.50 52 50.15439 2.0 50 45.45177 4.0 40 30.32493 6.0 35 19.94611 ]; plot(_t, _cv, DWELLS(:,1), DWELLS(:,2), DWELLS(:,1), DWELLS(:,3),'Fig 2 Wells 1988 IV plasma.aps')

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Page 46 **FIG_2_PAYAN_2002_IV_PLASMA.M** %PROCED WELLS - IV %WELLS AND DIG ENIS 1988 prepare @all @clear ratparam DOSE=0,PDOSE=0,TCHNG=0.0083,TINF=0.0083,CINT=0.01 BWINIT=0.35, IVDOSE=0.1, TSTOP=24,GDDAYS=1 !!start/nc MASBAL % DATA PAYAN (T,CV,Poet 2013 CV) DPAYAN = [0.02 0.155 0.2573098 0.08 0.131 0.1561921 0.17 0.118 0.1433084 0.5 0.115 0.131193 1 0.112 0.1162329 1.5 0.109 0.1030575 2 0.103 0.09138391 3 0.093 0.07185712 4 0.06 0.05650498 ]; plot(_t, _cv, DPAYAN(:,1), DPAYAN(:,2), DPAYAN(:,1), DPAYAN(:,3),'Fig 2 Payan 2002 IV plasma.aps')

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Page 47 **FIG_3AB_PAYAN_2002_IV_5HNMP_ PLASMA_URINE.M**  prepare @all @clear ratparam % Commenting out items below set identicaly in ratparam; Paul Schlosser, U.S. EPA, 05 - 01 - 2013 %VCHC=1.0E+9, KLOSS=0.0, DOSE=0,TINF=0.01 % CONCL=0, IVDOSE=0, TCHNG=0.01,TSTOP=78 % GDDAYS=0, SA=0.00001 ,CONCPPM=0,CONCMGM=0 BWINIT=0.25,CINT=0.1 IVDOSE=0.1 !!START /nc holdcvhp=[_t _cvhp]; holdauhp=[_t _auhp]; IVDOSE=1 !!START /nc holdcvhp=[holdcvhp _cvhp]; holdauhp=[holdauhp _auhp]; IVDOSE=10 !!START /nc holdcvhp=[holdcvhp _cvhp]; holdauhp=[holdauhp _auhp]; IVDOSE=100 !!START /nc holdcvhp=[holdcvhp _cvhp]; holdauhp=[holdauhp _auhp]; IVDOSE=500,BWINIT=0.275 !!START /nc holdcvhp=[holdcvhp _cvhp]; holdauhp=[holdauhp _auhp]; % DATA p5HNMP (T,CVHP,Poet 2013 CVHP) p5HNMP = [0.01 0.000182 0.001615 0.015095 0.099633 0.207601 5 0.042203 0.422267 4.237931 39.48625 109.9071 10 0.02516 0.252532 2.613575 31.12196 133.5288 20 0.004531 0.045548 0.478971 7.101832 69.10229 30 0.000617 0.006203 0.065172 0.993501 15.54205 40 0.0000752 0. 000756 0.007927 0.119737 2.215258 50 0.00000867 0.000087 0.000911 0.013623 0.27038

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Page 48 60 0.000000966 0.00000969 0.000101 0.001503 0.031528 70 0.000000105 0.00000106 0.000011 0.000163 0.0036 ]; % DATA u5HNMP (T,AUHP,Poet 2013 AUHP) u5HNMP = [0.01 1.19E - 08 0.0 0000009 0.00000084 0.00000606 0.0000154 5 0.003922 0.039152 0.384723 3.146931 8.153724 10 0.008028 0.08031 0.804688 7.576738 24.42693 20 0.011128 0.111449 1.130311 11.91568 52.64661 30 0.011648 0.116677 1.185414 12.75838 63.2357 40 0.011719 0.117399 1.1930 1 12.87606 65.35392 50 0.011729 0.11749 1.193972 12.89082 65.65677 60 0.01173 0.117501 1.194088 12.89259 65.6955 70 0.01173 0.117503 1.194102 12.8928 65.70028 ]; % DATA payanPlas (T,CVHP,Payan 2002 CVHP) payanplas = [1 0.00061 NaN NaN NaN NaN 1.5 0.00055 NaN NaN NaN NaN 2 0.00161 NaN NaN NaN NaN 3 0.00398 NaN NaN NaN NaN 4 0.0251 0.376 3.28 NaN NaN 6 0.0341 NaN NaN NaN NaN 8 0.0187 NaN NaN 23.5 NaN 10 0.0095 NaN NaN NaN NaN 24 0.00007 NaN NaN NaN 46.9 ]; % DATA payanUrin (T,AUHP,Payan 2002 AUHP) payanurin = [4 0.0009 0.0153 0.164 0.725 4.83 8 0.005 0.0507 0.591 2.473 10.29 24 0.0123 0.1213 1.27 13.62 54.77 48 0.0127 0.12608 1.29 12.22 63.94 72 0.0128 0.12742 1.298 12.35 64.38 ]; plot(holdcvhp(:,1),holdcvhp(:,2:6),p5HNMP(:,1), p5HNMP (:,2:6),payanplas(:,1) , payanplas (:,2:6), 'Fig 2 Payan 2002 IV plasma 5HNMP.aps') plot(holdauhp(:,1),holdauhp(:,2:6),u5HNMP(:,1), u5HNMP (:,2:6),payanurin(:,1), payanurin (:,2:6), 'Fig 2 Payan 2002 IV urine 5HNMP.aps')

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Page 49 **FIG_4_PAYAN_2003_DERMAL_PLASMA.M** prepare @all @clear % ratparams ratparam % Added by Paul Schlosser (PS), U.S. EPA, to assure parameter consistency; 05 - 01 - 2013 %preg_rat_params %payan dermal exposures: Payan et al. DMD 03 % DOSE=0,PDOSE=0, % Commented out, PS 5 - 1 - 13 TCHNG=72,TSTOP=54, SA=10,VLIQ=200e - 6 BWinit=0.250 % BWinit was 0.275; reset from Poet 5 - 16 - 13 Payenderm.m; PS 5 - 17 - 13 % CONCL=1030, FAD=0.76,PSK=150 %FAD - urine+carcas+tissues CONCL=1050000, CINT=0.5 % from Poet 5 - 16 - 13 Payenderm.m; PS 5 - 17 - 13 % PSK and FAD (now) set in ratparam to assure c osnsitency; PS 5 - 1 - 13 %KPL=4.3e - 3 % Moved to ratparam file, PS 5 - 1 - 13 !!START /nc holdauhp=[_t _auhp]; holdaunp=[_t _aunp]; holdca=[_t _cv]; holdch=[_t _cvhp]; holdcsurf=[_t _csurf]; % Commenting out of following lines based on Poet 5 - 16 - 13 Payende rm.m; PS 5 - 17 - 13 %BWinit=0.275,CONCL=1030,VLIQ=0.000400 % !!START /nc % holdauhp=[holdauhp _auhp]; %holdaunp=[holdaunp _aunp]; %holdca=[holdca _cv]; %holdch=[holdch _cvhp]; %holdcsurf=[holdcsurf _csurf]; MASBAL % DATA pNMP (T,Payan 2013 CV) pNMP = [0.5 12 8.652 2.5 424.496 5 532.623 7.5 508.955 10 434.405 12.5 346.867 15 263.728 17.5 192.406 20 179.829 22.5 99.759 25 63.993 27.5 34.099 30 17.645 32.5 8.97 35 4.516

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Page 50 37.5 2.262 40 1.13 42.5 0.564 45 0.282 47.5 0.141 50 0.0701 50.5 0.061 51 0.0531 51.5 0.0462 52 0.0402 52.5 0.035 55 0.0175 57.5 0.00874 60 0.00437 ]; % DATA PAYAN (T,Payan 2003 CVHP) PAYAN = [0.51 160 0.87 260 1.6 330 1.84 410 2.57 440 2.81 490 3.18 510 3.78 550 4.63 540 5.85 540 7.8 530 9.74 490 23.7 100 25.7 110 29.9 60 47.9 0 54.2 0 ]; % plot(holdcsurf(:,1),holdcsurf(:,2), 'figcsurf.aps') %plot(holdauhp(:,1),holdauhp(:,2), 'figDERMALAUHP.aps') %plot(holdaunp(:,1),holdaunp(:,2), 'figDERMALAUnP.aps') plot(holdca(:,1),holdca(:,2), pNMP(:,1), pNMP (:,2),PAYAN (:,1), PAYAN (:,2), 'Fig 7 Payan 2 003 Dermal plasma.aps') %plot(holdch(:,1),holdch(:,2), 'figDERMALplasmahp.aps')

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Page 51 **HUMAN_PARAMS.M** WESITG=0; WEDITG=0; SRATE=0; RESLVL=[zeros(1,1441) (0:1440)]'; QPC = 15; QLIVC = 0.25; QSKC = 0.058; BWINIT = 58; VFATC = 0.23; VRAPC = 0.042; P = 0.0036; HT = 180; KAS = 1.36; ICFAT = 0; ICSKN = 0; CONCMGM = 0; PDOSE2 = 0; TCHNG = 8; S2 = 0; P2 = 8; S3 = 6720; P3 = 6720; ON3=0; DENSITY = 1.03; VLIQ = 1.00e - 99; BRUSH=0; STARTDS = 0; FRACIN = 1; TIME1 = 8; REPTM = 24; NSTP = 10; QCC = 15; QMAMC = 0.027; QUTRC = 0 .005; VALVC = 0.0079; VLIVC = 0.031; VUTRC = 0.0014; PV = 32; MW = 99.13; KM2 = 50.5; VMAX2C = 5.9; VMAXC = 125; KM = 151; KME = 80.8; VMXNEC = 0.011; KMNE = 2.46; VMAXEC = 7.3; ICLIV = 0; ICSLW = 0; IVDOSE = 0; PDOSE3 = 0; DAYSWK = 1; % Days per week of exposure, eg 5 for workplace; PMS 8 - 28 - 13 CONCL = 0;

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Page 52 RESID = 0; TSTOP = 24; FRACOR = 0.68; TIME2 = 6720; CINT = 0.1; MAXT = 0.001; QFATC = 0.05; QRAPC = 0.48; PAFC = 0.1; VBLC = 0.06; VMAMC = 0.0062; VSKC = 0.051; SAL = 0.0001; SAV = 6700; MW1 = 116.14; ICRAP = 0; CONCPPM = 0; PDOSE = 0; PDRINK = 0; TMAX = 24; PVL=2.7e - 3; % Added per Poet 5 - 16 - 13 human_params.m; Paul Schlosser, U.S. EPA (PMS), 5 - 17 - 13 % DOSEINTERVAL = 24; % Not used, PMS 8 - 28 - 13 DOSEINT=999; CINTC = 0.1; TIME = 0; TI ME3 = 6720; IALG = 2; MINT = 1.00e - 09; PB = 450; PMAM = 1; PSLW = 0.77; PSKL = 0.42 % Rat skin:saline, PMS 8 - 28 - 13 PSKB = 0.099 % (Rat skin:saline)/(human blood:saline), PMS 8 - 28 - 13 PSKA = 44.5 %use (blood/air)*(rat skin:liquid)/(human blood:liquid), PMS 8 - 28 - 13 % PSKA = 450 %750; Changed per Poet 5 - 16 - 13 human_params.m; PMS 5 - 17 - 13 PBHNP = 0; PLIV = 0.82; PRAP = 0.94; PLIV1 = 2.5; PRAP1 = 6.5; ICART = 0; PSLW1 = 0.08; PFAT = 0.49; PPLA = 0.31; PUTR = 0.1; PLU = 0.1; PB1 = 1; PFAT1 = 0.23;

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Page 53 %FAD=0.000001 FAD = 1 % Value used in Poet 5 - 16 - 13 BADER_DRM.m and AkkesDerm.m; PMS 5 - 17 - 13 %DERM=0 % Not used in Poet 5 - 16 - 13 'HumPregRetreive Restored 1.csl'; PMS 5 - 17 - 13 VCHC=1.0e+9; KLOSS=0.0; % From human simulation scripts; use as default for human; PMS 8 - 28 - 13 st art @nocallback

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Page 54 **POET_2013_FIG_5_AND_6.M** human_params P2=3; S3=3.169; P3=3; ON3=1; DAYSWK=1; BWINIT=79; HT=180; TSTOP=48; % Poet 2013 Inhalation plasma NMP (T, 80mg CVEN, 39mg CVEN, 9.7 mg CVEN) PLAS_NMP = [1 0.683103 0.332836 0.082749 2 1.024672 0.49900 1 0.12401 4 1.378491 0.670665 0.166542 6 1.661011 0.807381 0.200346 8 0.870433 0.422351 0.104658 10 0.476452 0.230971 0.057195 12 0.260598 0.126264 0.031254 14 0.14247 0.069009 0.017078 16 0.077869 0.037711 0.009332 18 0.045205 0.02189 0.005416 20 0.024702 0.011961 0.002959 ]; % Poet 2013 Inhalation plasma NMP (T, 80mg CVEN1, 39mg CVEN1, 9.7 mg CVEN1) PLAS_5HNMP = [1 0.24528 0.119668 0.02978 2 0.654421 0.319214 0.079424 4 1.63541 0.796202 0.197813 6 2.698992 1.309727 0.324586 8 3.13353 1.511975 0.373107 1 0 2.989524 1.433702 0.352195 12 2.622757 1.250767 0.306007 14 2.196787 1.042511 0.25417 16 1.78852 0.845258 0.205485 18 1.42952 0.673285 0.163293 20 1.128456 0.530008 0.128301 30 0.316655 0.147623 0.035559 40 0.084532 0.039321 0.009458 ]; % Poet 2013 Inha lation plasma NMP (T, 80mg AUNP, 39mg AUNP, 9.7 mg AUNP) URIN_NMP = [1 0.062401 0.038817 0.012091 2 0.152052 0.100311 0.033677 4 0.322807 0.223295 0.080098 6 0.538127 0.383801 0.144246 8 0.70041 0.501467 0.189331 10 0.83527 0.588113 0.217245 12 0.923142 0.638799 0.231732 14 0.97874 0.668416 0.239602 16 1.006836 0.682649 0.243234 18 1.019841 0.68907 0.244841 20 1.026145 0.692145 0.245604 30 1.031765 0.694865 0.246275

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Page 55 40 1.031889 0.694925 0.24629 ]; % Poet 2013 Inhalation urine 5HNMP (T, 80mg AUHP, 39mg AU HP, 9.7 mg AUHP) URIN_5HNMP = [1 0.275716 0.134652 0.033533 2 1.463359 0.715887 0.178497 4 6.268797 3.0758 0.768508 6 16.61853 8.177778 2.047459 8 16.61853 8.177778 2.047459 10 41.92996 20.65742 5.175538 12 54.71574 26.91465 6.735197 14 66.35912 32.57506 8 .13928 16 76.81064 37.62227 9.385295 18 84.24161 41.1902 10.26256 20 90.03312 43.95864 10.94115 30 103.9081 50.54583 12.54824 40 107.083 52.04393 12.91223 ]; % Hannover Inhalation plasma NMP (T, 80mg CVEN, 39mg CVEN, 9.7 mg CVEN) H_PLAS_NMP = [3.096 0.954 3.292 0.458 3.29 0.17 6.241 1.517 6.153 0.649 6.29 0.29 7.358 0.938 7.337 0.417 7.29 0.18 8.251 0.719 8.38 0.361 8.29 0.14 10.11 0.505 10.14 0.258 10.29 0.13 24.358 0.088 24.551 0.027 24.81 0.04 48.641 0.005 47.273 0.017 NaN NaN ]; % Hannover Inhalation plasma NMP (T, 80mg CVEN1, 39mg CVEN1, 9.7 mg CVEN1) H_PLAS_5HNMP = [3.096 1.44 3.292 0.688 3.29 0.21 6.241 2.94 6.153 1.425 6.29 0.39 7.358 3.19 7.337 1.488 7.29 0.39 8.251 3.14 8.38 1.463 8.29 0.36 10.11 2.91 10.14 1.35 10.29 0.36 24.358 0.61 24.551 0.2 38 NaN NaN ]; % Hannover Inhalation plasma NMP (T, 80mg AUNP, 39mg AUNP, 9.7 mg AUNP) H_URIN_NMP = [3.096 0.23 3.292 0.132 3.29 0.08 7.358 0.67 7.337 0.339 7.29 0.16 10.11 0.86 10.14 0.512 10.29 0.2 24.358 1.03 24.551 0.565 24.81 0.26 48.641 1.07 47.273 0 .599 48.37 0.26 ]; % Hannover Inhalation urine 5HNMP (T, 80mg AUHP, 39mg AUHP, 9.7 mg AUHP) H_URIN_5HNMP = [3.096 5.74 3.292 3.72 3.29 2.51 7.358 22.84 7.337 10.81 7.29 5.73

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Page 56 10.11 50.47 10.14 22.22 10.29 8.75 24.358 89.36 24.551 45.11 24.81 18.36 48.641 99.25 47.273 48.87 48.37 20.51 ]; prepare @clear T CVEN CVEN1 AUNP AUHP CONCMGM=80, start @nocallback holdcv=[_t _cven]; holdcvhp=[_t _cven1]; holdaunp=[_t _aunp]; holdauhp=[_t _auhp]; for CONCMGM=[39 9.7] start @nocallback holdcv=[holdcv _cven ]; holdcvhp=[holdcvhp _cven1]; holdaunp=[holdaunp _aunp]; holdauhp=[holdauhp _auhp]; end plot(holdcv(:,1),holdcv(:,2:4), PLAS_NMP(:,1), PLAS_NMP(:,2:4),H_PLAS_NMP(:,1), H_PLAS_NMP(:,2),H_PLAS_NMP(:,3), H_PLAS_NMP(:,4),H_PLAS_NMP(:,5), H_PLAS_NMP(:,6 ),'Poet 2013 Fig 4 Hannover plasma NMP.APS') plot(holdcvhp(:,1),holdcvhp(:,2:4),PLAS_5HNMP(:,1), PLAS_5HNMP(:,2:4),H_PLAS_5HNMP(:,1),H_PLAS_5HNMP(:,2),H_PLAS_NMP(:,3), H_PLAS_5HNMP(:,4),H_PLAS_5HNMP(:,5), H_PLAS_5HNMP(:,6),'Poet 2013 Fig 4 Hannover plasma 5HNMP.APS') plot(holdaunp(:,1),holdaunp(:,2:4),URIN_NMP(:,1), URIN_NMP(:,2:4),H_URIN_NMP(:,1), H_URIN_NMP(:,2),H_URIN_NMP(:,3), H_URIN_NMP(:,4),H_URIN_NMP(:,5), H_URIN_NMP(:,6),'Poet 2013 Fig 4 Hannover urine NMP.APS') plot(holdauhp(:,1),holdauhp(:,2:4),UR IN_5HNMP(:,1), URIN_5HNMP(:,2:4),H_URIN_5HNMP(:,1), H_URIN_5HNMP(:,2),H_URIN_5HNMP(:,3), H_URIN_5HNMP(:,4),H_URIN_5HNMP(:,5), H_URIN_5HNMP(:,6),'Poet 2013 Fig 4 Hannover urine 5HNMP.APS')

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Page 57 **POET_2013_FIG_7_PLASMA.M** human_params P2=8; SA=7500; BWINIT=75; HT =178.5; TSTOP=72 QPC=40,QCC=23,QSKC=0.18 %Andersen et al '87 as work, CORLEY ET AL % Poet 2013 Inhalation plasma NMP (T, 53mg CVEN, 24mg CVEN, 10mg CVEN) PLAS_NMP = [1 0.164826 0.395742 0.874626 2 0.246282 0.591566 1.30846 4 0.344082 0.827175 1.832502 6 0.392776 0.944901 2.096089 8 0.416782 1.003176 2.228192 10 0.182521 0.439988 0.979863 12 0.090665 0.218696 0.487648 14 0.045029 0.10865 0.242425 16 0.022361 0.053964 0.120446 18 0.011104 0.026799 0.059824 20 0.005514 0.013307 0.029709 22 0.002738 0.006608 0.014753 24 0.001359 0.003281 0.007326 ]; % Akesson adn Paulsson Inhalation plasma NMP (T, 80mg CVEN, 39mg CVEN, 9.7 mg CVEN) AP_PLAS_NMP = [4 0.3 0.99 1.6 8 0.49 0.82 2.6 9 0.3 0.72 2 10 0.22 0.51 1.28 12 0.12 0.3 0.75 16 0.08 0.2 0.3 24 0.03 0.06 0.08 3 2 0.01 0.02 0.03 48 0.01 0.01 0.02 ]; prepare @clear T CVEN CVEN1 AUNP AUHP CONCMGM=53; start @nocallback holdcv=[_t _cven]; holdcvhp=[_t _cven1]; holdaunp=[_t _aunp]; holdauhp=[_t _auhp]; for CONCMGM=[24 10] start @nocallback holdcv=[holdcv _ cven]; holdcvhp=[holdcvhp _cven1]; holdaunp=[holdaunp _aunp]; holdauhp=[holdauhp _auhp]; end

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Page 58 plot(holdcv(:,1),holdcv(:,2:4),PLAS_NMP(:,1),PLAS_NMP(:,[4 3 2]),AP_PLAS_NMP(:,1), AP_PLAS_NMP(:,[4 3 2]), 'Poet 2013 Fig 5 Akesson and Paulsson plasma') %plot (holdcvhp(:,1),holdcvhp(:,2:4),'FIGAKinhalcvhp.APS') %plot(holdauhp(:,1),holdauhp(:,2:4), 'FIGAKinhalaunp.APS') %plot(holdaunp(:,1),holdaunp(:,2:4),'FIGAKinhalauhp.APS')

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Page 59 **POET_2013_FIG 8AB_PLASMA_&_URINE.M** human_params % Uncommented to assure consistent p arameters; Paul Schlosser, U.S. EPA (PS), 5 - 17 - 2013 SAL=5; SAV=1e - 4; BWINIT=67.5; HT=160.0; %Wikipedia - German men weight 82.4 kg, women weigh 67.5kg) CONCL=1045000; VLIQ=0.0003; BRUSH=1; TSTOP=48; P2=6; WKDAYS=1; CINTC=0.1; %FAD=1 %most was recovered on pad - 18.6 is "lost" to system. % FAD set in human_params.m, PS 5 - 17 - 13 %PV=0 % Intrinsic property for skin - air transport should not change from that set in human_params.m ...

% Since air concentration(s) are set to zero, this should not need to be zeroed here; PS 5 - 17 - 13

% Allowing PV=32 (default value) reduces predicted NMP and 5 - HNMP by ~ 6% vs. PV = 0; PS 5 - 17 - 13 % PVL= 2.9e - 003 % If PV=32, this value of PVL gives nearly the same 'cvhp' and 'auhp' simulations; PS 5 - 17 - 13 % Poet 2013 Dermal sims plasma NMP: 0.3 ml NMP applied) PLAS_NMP = [2 0.2704 0.2170 4 0.6709 0.5418 6 1.050 0.8547 8 1.1445 0.9437 10 1.0497 0.8795 12 0.8898 0.7581 14 0.7220 0.6256 16 0.5704 0.5026 18 0.5635 0.4 968 20 0.3401 0.3095 22 0.2590 0.2395 24 0.1962 0.1843 30 0.0837 0.0822 40 0.0197 0.0208 ]; % Poet 2013 Dermal sims urine NMP: 0.3 ml NMP applied) URIN_NMP = [2 0.4701 0.4381 4 2.4293 2.2716 6 6.0414 5.6806 8 10.7190 10.1404 10 15.3381 14.6079 12 19.4052 18.6049 14 22.7817 21.9778 16 NaN 24.98211 18 27.6136 26.9195 20 29.2560 28.6418 22 30.5132 29.9812 24 31.4690 31.0154 30 33.1474 32.8825 40 34.0853 33.9834

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Page 60 ]; % Akesson 2004 Dermal plasma NMP: 0.3 ml NMP applied) A_PLAS_NMP = [1.01 0.22 0.07 1.94 0.66 0.49 4.06 1.15 0.85 5.83 1.01 1.03 7.95 1.01 0.97 12.1 0.58 0.73 24 0.18 0.14 30.1 0.07 0.04 47.9 0.02 0.01 ]; % Akesson 2004 Dermal urine NMP: 0.3 ml NMP applied) A_URIN_NMP = [1 0.610509 0.451446 3 5.998437 4.368267 5 13.64819 9.921695 7 21.16922 16.615 23 9 26.72265 21.70894 11 30.84175 24.85343 14 36.38598 30.03908 20 41.33442 34.87718 27 42.67313 36.24163 39 42.87835 36.44023 ]; prepare @clear T CVEN1 AUHP % women start @nocallback holdcvhp=[_t _cven1]; holdauhp=[_t _auhp]; BWINIT=82.4; % men start @nocallback holdcvhp=[holdcvhp _cven1]; holdauhp=[holdauhp _auhp]; plot(holdcvhp(:,1),holdcvhp(:,2:3),PLAS_NMP(:,1), PLAS_NMP(:,2:3),A_PLAS_NMP(:,1),A_PLAS_NMP(:,2:3), 'Poet 2013 Fig 8 plasma.APS') plot(holdauhp(:,1),holdauhp(:,2:3),URIN_NMP(: ,1), URIN_NMP(:,2:3),A_URIN_NMP(:,1),A_URIN_NMP(:,2:3), 'Poet 2013 Fig 8 urine.APS') %ADVL %AUNP

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Page 61 **POET_2013_FIG_9_PLASMA.M** human_params % Uncommented to assure consistent parameters; Paul Schlosser, U.S. EPA (PS), 5 - 17 - 2013 DOSE=0,PDOSE =0,TCHNG=4,DOSINTERVAL=2.93,IVDOSE=0 CONCMGM=0,SAL=5, SAV=1e - 4 CONCL=1045000,VLIQ=0.0003 BWINIT=79, HT=160, TSTOP=48,TCHNG=6, BRUSH=1, P2=6, ON3=0 %FAD=1 %most was recovered on pad - 18.6 is "lost" to system. % FAD set in human_params.m, PS 5 - 17 - 13 PV=0 % Intrinsic property for skin - air transport should not change from that set in human_params.m ...

% Since air concentration(s) are set to zero, this should not need to be zeroed here; PS 5 - 17 - 13

% Allowing PV=32 (default value) reduces predicted NMP and 5 - HNMP by ~ 6% vs. PV = 0; PS 5 - 17 - 13 % PVL= 2.9e - 003 % If PV=32, this value of PVL gives nearly the same 'cvhp' and 'auhp' simulations; PS 5 - 17 - 13 % Poet 2013 Dermal sims plasma NMP: 0.3 ml NMP applied) PLAS_NMP = [2 0.2527079 4 0.4365436 6 0.51 2324 8 0.338109 10 0.1865714 12 0.1029197 14 0.05676336 16 0.03130336 18 0.01726188 20 0.009518544 22 0.00524862 24 0.002894112 30 0.000485194 40 0.000024731 ]; % Akesson and Paulsson 1997 inhalation data AP_PLAS_NMP = [4 0.3 8 0.49 9 0.3 10 0.22 12 0.12 16 0.08 24 0.03 32 0.01 48 0.01 ];

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Page 62 CINTC=0.1; prepare @clear T CVEN !!START /NC holdcvnp=[_t _cven]; plot(holdcvnp(:,1),holdcvnp(:,2),PLAS_NMP(:,1),PLAS_NMP(:,2),AP_PLAS_NMP(:,1),AP_PLAS_NMP(:,2), 'Poet 2013 Fig 9 plasma.APS')

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Page 63 **A PPENDIX**  **B. Correct**  **ions and changes in the PBPK models for N**  **- Methylpyrrolidone as**  **described by Poet (2013) (revised by T. Poet from that described in Poet et al., 2010) Rat PBPK Model**  Oral Dosing While oral exposure is not a route of con Exposure control Because both Becci et al. (1982) and Saillenfait et al. (2002) explicitly stated that the animal BWs were measured every 3 rd day of gestation, and the dermal/oral doses were adjusted accordingly on those days (as BW increases during pregnancy), corresponding conditional (if /then) statements were added to the ‘GAVD’ and ‘REAPPLY’ discrete blocks, to re - calculate the doses on those days. The code for the dermal discrete blocks follows. ASK0 is the absolute amount applied on each day; DSK is the dose/kg BW. Because Becci et a l. (1982) rubbed the material into the skin, it is assumed to be added directly into the skin compartment (ASK), rather than as a liquid on top. Hence the dose is given as an addition of ASK0 (mg/day applied) to ASK. DI SCRETE SKWASH ! PMS, 8 - 14 - 13 ASK = 0.0 ! Assume skin washing in Becci et al. (1982) removes all NMP from skin if (DAYS.LT.15.0) SCHEDULE REAPPLY.AT.(T+DOSEINTERVAL - TWASH) END DI SCRETE REAPPLY ! PMS, 8 - 14 - 13 IF (ROUND(DAYS).EQ.9.0) ASKO=DSK*BW IF (ROUND(DAYS).EQ.12.0) ASKO=DSK*BW IF (ROU ND(DAYS).EQ.15.0) ASKO=DSK*BW ASK = ASK + ASKO SCHEDULE SKWASH.AT.(T+TWASH) END Also, because Becci et al. (1982) washed the skin area exposed to dermal application at the end of a set time interval, a “SKWASH” discrete block was introduced at which tim e the amount in that patch of skin was assumed to be momentarily reduced to zero. During periods of dermal application, transport from the liquid to the skin was turned on using the pulse function, DZONE. After removal of the liquid it was assumed that N MP in the skin patch could volatilize into the otherwise clean air, with the rate defined by the same permeability constants, but using the skin:air partition coefficient. The rate of transfer to/from the skin area is then defined by: RADL=(KPL*SA/1000.0)* ((CSURF - (CSK/PSKL))*DZONE - (1.0 - DZONE)*(CSK/PSKA)) ! 2ND term, (1.0 - DZONE)*(CSK/PSKA), allows for evaporative loss when DZONE=0 Finally, a constant, CONCMGS, was introduced so that the air concentration could be set directly in mg/ m 3 . This is converted to the concentration in mg/L (CONCMG) in the code and added to the

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Page 64 inhalation exposure, turned on and off using the switch, CIZONE, which is turned on and off using SCHEDULE/DISCRETE statements: CI = CCH*PULSE(0., DOSEINTERVAL,TCHNG) + CIZONE*CONCMG ! M G/L ! Added CIZONE*CONCMG, PMS, 8 - 13 - 13 Skin compartment Corrections to the mass balance equations for the rat skin are as indicated in the commented code copied below. It includes the initial condition, ASK0, for the initial dermal application, but is o therwise now the standard format for PBPK models. As received the code had multiplied CSK rather than CSKV (skin venous blood concentration) by the blood flow (QSKN) for the rate of efflux in blood, and had not separately calculated CSKV. RASK = QSKN*(CA - CSKV) + RADL ! NOW MINUS CSKV, NOT CSK; PMS 8 - 21 - 13 ASK = INTEG(RASK,ASKO) ! Initial value, ASKO, added for Becci et al. (1982) exposures; pms 8 - 14 - 13 CSK = ASK/VSK !'NMP IN SKIN, MG/L' CSKV = CSK/PSKB ! NMP IN VENOUS BLOOD, PMS 8 - 22 - 13 The cor responding flow term for transfer from the skin to the mixed venous blood compartment was also corrected (ie, to use CVSK instead of CSK). While these changes to the skin compartment equations initially degraded the fits to the dermal exposure considerably , it also appeared that the associated partition coefficients were not consistent with the measured values reported by Poet et al. (2010), Table 5. They were recalculated as follows: Skin:liquid, PSKL = 0.42: value as measured for skin:saline, vs. 450 S kin:blood, PSKB = 0.12: (skin:saline)/(blood:saline) Skin:air, PSKA = 55: (skin:saline) *(blood:air) /(blood:saline) = (skin:blood)*(blood:air) Blood flows Since the placenta is a separate compartment for the 5HNMP compartment, its blood - flow and volume wer e removed from the sums used for the ‘rest of body’ for 5HNMP. Also, the term for blood flow from the placenta was added to the mixed - venous blood mass balance for 5HNMP. To assure flow mass balance, instead of calculating cardiac output (QC) as an initia l amount plus the change from initial for each compartment, it was just calculated as the sum over all the compartments: ! QC = QCINIT + (QFAT - QFATI) + (QMAM - QMAMI) + QPLA+ (QUTR - QUTRI) QC = QFAT+QLIV+QSLW+QRAP+QSKN+QMAM+QPLA+QUTR ! pms, 8 - 13 - 13 Para meter Consolidation In the provided files, some physiological and chemical - specific parameter were set in separate scripts; e.g., skin transport parameters in the dermal exposure scripts. This approach creates the potential for inconsistent parameters bet ween different exposure simulations. Therefore all parameters are now set in the ratparam.m script except those which are experimental control variables (eg., air concentration,

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Page 65 duration of exposure). The final set of parameters used and any inconsistenc ies with previous values in ratparam.m that may have differed are noted in that script. **Human PBPK Model** Exposure and Timing Control A table function, RESLVL, was added as a place - holder for reading in defined (residential) inhalation exposure time - course s; specifically from U.S. EPA exposure assessment modeling. A constant, GDstart, the day of gestation on which the simulation starts, and a variable Gtime, the hours into gestation, were added to facilitate separating exposure control from gestation timing . A second set of DISCRETE/SCHEDULE blocks were added to allow for split exposure scenarios (morning/afternoon worker exposure; dual - episode residential exposures). DZONE, set in the DISCRETE/SCHEDULE blocks, controls the time within a day when discontinuous exposure occurs. Czone is the product of DZONE and a pulse function used to control for days/week exposure in workplace scenarios: Czone = pulse(0.0,fullweek,hrs week)*DZONE ! pms 8 - 20 - 13 ! for a 5 day/wk exposure, use fullweek=7*24, hrsweek=5*24 (Dayswk=5) ! for a single day, fullweek=1e16, hrsweek=24 (Dayswk=1) A binary constant, BRUSH, was added to set when dermal contact with liquid occurs. The rate for delive ry from a liquid film to the ‘SKL’ skin compartment (also see further below) is then defined by: RASL=(PVL*SAL/1000.0)*(CSURF - (CSK L /PSKL))*Czone*BRUSH A constant SRATE was added for the net rate of delivery by liquid droplets to the skin for workplace spra y applications. This is a net rate delivered into the skin compartment, rather than a liquid layer on the surface, assuming that the exposure modeling already accounts for material that may be temporarily deposited on the surface but not absorbed. (Absor ption from a liquid layer of a defined (possibly changing) concentration was retained for other exposure scenarios, including residential.) When spray delivery SRATE is non - zero, concentration - driven transport from liquid or vapor is turned off for the sp ray/liquid exposed skin. The equations for transfer of vapor (air concentration = CI) to the SKL compartment, which occurs during periods with no liquid/spray contact, **and/or** spray absorption for the SKL compartment are then: Sdeliv = SRATE * C zone ! Consta nt - rate spray delivery; pms 8 - 20 - 13 ! Spray - dermal exposures, assumed simultaneous with inhalation (unless FRACIN = 0) RADVL = (PV*SAL/1000.0)*(CI - (CSKL/PSKA))*(1.0 - Czone*BRUSH)*( S deliv.eq.0.0) + S deliv ! RADVL allows absorption/desorption from air whe n there is NOT spray or ! brushing dermal exposure, when both sdeliv and czone are zero; pms 8 - 20 - 13

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- METHYL PYRROLIDONE PBPK Models EP - C - 09 - 006 WA 4 - 01 September 11, 2013

Page 66 Skin compartment As for the rat, and noted in the main report, corrections were made to the human skin transport and PK (equations not shown here, but sam e as for rat). The partition coefficients were also recalculated as was done for the rat, with rat parameters for skin:saline and blood:air, but human blood:saline. The original skin compartment which is coded to include uptake from liquid - dermal contact was renamed by adding “L” to the end, SK  SKL, and second skin compartment to account for concurrent vapor - skin uptake, SKV, was added. This was done because when t he human model was calibrated for inhalation exposure, an exposed skin surface area of 6700 cm 2 was used. When this surface are is reduced to ~ 0, predicted blood levels of NMP shown in the upper panel of Figure 4 in the QA report are reduced ~ 45%. Thus vapor uptake through the skin is a significant component of inhalation exposure and there is no reason to assume, a priori , that this uptake does not occur through a similar area of exposed skin during workplace and residential exposures, except for any a rea that would have liquid contact or otherwise be occluded (e.g., by wearing rubber gloves). So the SKV compartment allows for simultaneous absorption of vapor through skin that does not have liquid contact, and from areas of skin with liquid contact. T he surface area of SKV and SKL are SAV and SAL, respectively, and can be set for different exposure scenarios. For EPA simulations, SAV was reduced from 6700 cm 2 by the area assumed to have liquid contact or covered by gloves for those scenarios. To eval uate the impact of this assumption for workplace exposure simulations were also conducted with SAV set to 0.01 cm 2 for a low rate of dermal delivery (600 mg/day). Tissue and blood - flow mass balances The model had been previously coded with an alveolar bloo d compartment (ALV), but this was commented out by the author in the DYNAMIC section. Therefore this volume fraction should not be subtracted when calculating the slowly - perfused volume. The fraction of blood - flow to slowly perfused tissue was updated to also account for the SKV compartment; on the other hand a separate skin compartment is not used for 5HNMP, so the skin blood flow is NOT subtracted for the metabolite - slowly perfused compartment (SLW5). These have all been corrected. QSKCC (original frac tional flow to the skin) had been subtracted twice, both in calculating QSLWC and then in the calculation of QSLW. The 2 nd subtracted created a mass balance error and hence was removed. On the other hand, placental blood flow is now subtracted, so the to tal flow to slowly - perfused continues to total cardiac output minus all other tissue/group flows. For tissues that change with gestation day, the initial values were corrected to match the calculation in the DYNAMIC section, which would apply at the first time - step. In the dynamic section, the calculation of QC was corrected to include the *increase* in placental flow (QPLA

– QPLAI) rather than the total placental flow (QPLA), since QCINIT includes QPLAI. QSLW5 and VSLW5 (5HNMP slow compartment flow and vo lume) are now calculated in the DYNAMIC section by subtraction. Oral absorption parameters and equations The oral absorption rate as a function of the amount in the stomach lumen compartment, AO, had been erroneously written as, RAO = KAS *FRACOR *AO, with t he initial amount in the compartment set to be

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- METHYL PYRROLIDONE PBPK Models EP - C - 09 - 006 WA 4 - 01 September 11, 2013

Page 67 the total administered dose, ODOSE. Since there is no other route of clearance from the stomach lumen compartment, this approach only reduces the effective absorption rate constant from KAS to KAS*FRACOR with out reducing the total amount absorbed. Using the code as provided and the parameters for absorption listed in Poet et al. (2010) gives a significant over - prediction of the plasma NMP levels, not consistent with the simulations shown in Fig. 5 of Poet et al. (2010), which appear to fit those data well. Therefore the code was corrected to make ODOSE = FRACOR*DOSE*BWINIT (instead of DOSE*BWINIT) and RAO = KAS * AO . When this was done the AUC for plasma NMP appeared to be approximately correct, but the initial rise vs. time was faster and the peak occurred earlier than shown in Fig. 5 of Poet et al. (2010). When KAS was then reduced by FRACOR (68%), the model simulat ions shown in the preface for this report were obtained. The simulations for plasma NMP are quite close to those shown in Figure 5 of Poet et al. (2010) and fit the data fairly well. Therefore it is assumed that the results of Poet et al. (2010) included the multiplication by FRACOR in computing RAO, but also reduced the oral dose by FRACOR. The U.S. EA version uses the corrected equations shown just above, to deconvolute the two parameters (FRACOR and KAS) and allow DOSE to simply be set to the applied dose. Parameter Consolidation As for the rat model, the human model physiological and biochemical parameters are now all set in a single script, human_params.m. Only constants which define specific exposure scenarios (include skin areas exposed) are defin ed in the specific simulation scripts.