## FINAL REPORT

Sensitization Screen using the Direct Peptide Reactivity Assay (DPRA) Cyprotex Study Number: 9320- 101114



### Sponsor: International Flavors and Fragrances , Inc. 800 Rose Lane Union Beach , NJ 07735 Testing Facility:

Cyprotex, LLC . 4717 Campus Dr. Kalamazoo Ml 49008

### Study # : 

### 9320-101 11 4 

## Table of Contents Signatures ............................................................................................................................................... 3 Contributing Personnel .......................................................................................................................... 4 Study Dates ....................................................................................................................... . .... .. ...... .. .......4 Executive Summary................................................................................................................ . ...............5 1 . Sponsor............................................ . ....................................... . ........ ... ........ . .................. . .......6 2 . Testing Facility ....................................................................... . .................................................. ............................ 6 3. Materials & Methods.................................................................................... ............. . ........................................... 6 a. Test & Reference Articles .............................. .. ............................... ............................................................ 6 b . 

### Justification of Test System .. . ..... . ....... ... . ............................................. . ........ ............................................. 6 c. Preparation of Samples ................................................................................................................. ........... ....... 7 d . Evaluation of Test Articles in the Assay .... .. .. .............................................................. .. .. . ....................... 7 e. Test Validity an Acceptance Criteria ............... . ................................................ . ............................................ 7 4. Results & Discussion ......................... ... ................................. .. ....................................................... ..................... 8 

### 5. References .......... . ............................................................................................................... ................. .. .................... 9 6. Appendix A: Summary LC/MS/MS data for Lysine peptide ................... ......................................... .................. 9 7. Appendix B: Summary LC/MS/MS data for Cysteine peptide...................................... . ..... . ............................ 

### 12

Page 2 of 15 Confidential Document

### Prepared 

### by: Donald Keller, MS Study Director 

## Signatures

Page 3 of 15 

### Study#: 9320-101114

Confidential Document

### Study#: 9320-101114 

## Contributing Personnel The following scientists and supervisory personnel were involved in the conduct ofthis study : Donald Keller, MS , Study Director Briana Franz , BS , Director of Laboratory Operations Lisa Blakeman , BS , Associate Scientist Gregory Cavey, BS , Principle Investigators , Launch Ml Lab Francisca Wong , BS , Research Scientist, Launch Ml Lab 

## Study Dates Experimental Start Date : April 8, 2014 Experimental Termination Date : April 29 , 2014

Page 4 of 15 Confidential DocumentStudy#: 

### 9320-101114 

## Executive Summary The purpose of this study was to screen test articles for their potential to act as chemical sensitizers using Direct Peptide Reactivity Assay (DPRA}, a test used to assay reactivity of test articles with small peptides . A summary of the results for the 8 test articles are given below . Table 1 . Results of DPRA for 8 test articles with controls Compound Cvs Oep Lvs Deo Avf!.. Dep Classification Benzoic Acid -6.7 -1.1 -3.9 Minimal Reactivity p-Benzoquinone 98.3 97 .9 98.1 High Reactivity

TM05-0293 -10.4 2.6 -3.9 Minimal Reactivity TM08-0338 -7.6 20.7 6.6 Low Reactivity TM09-0035 -14.5 12.0 -1.3 Minimal Reactivity TM09-0536 22.9 1.8 12.4 Low Reactivity TM10-0210 70.7 5.7 38.2 Moderate Reactivity TMl0-0367 6.3 1.7 4.0 Minimal Reactivity TM11-0078 77.1 6.9 42.0 Moderate React ivity TM11 -0230 5.8 -4.5 0.6 Minimal Reactivity 

### For this test: low, moderate , and high reactivity were considered positive ; while minimal reactivity was considered negative . The data were based on the classification tree described by Gerberick , 2007 (Figure 1 below) . Figure 1: DPRA Classification Tree



## 0: **t:s.: ~** 

(29115/20/17) .



### >-- **~SIW~** Avg Score< 22



### 62 **~** - 

### ~ Avg Score > 22.62 % 

# / ""'-.. 

# -

--- > ----..__ / Tes t ' '-- / Tell \ Avg Score< 6.376% **(29/11/~/0)**

**(0 /1~**  Avg Score > 6. 376°k -

**~**



### 1. Sponsor Minimal Reactivity (2615/1/0) Avg Score < 42 .47%

**vg** Score > 42.47°k

**~--~----~** I I

Low Reactivity

(3 1 6 1 2 10) Moderate Reacttvity (0 / 1 / 6 / 3}

DPRA classification tree from Gerberick et al. , 2007 . Page 5 of 15 High Reactivity (0 /3/11/1 4}

Confidential Document

### International Flavor and Fragrances, Inc. 

### 800 Rose Lane Union Beach , NJ 07735 

### 2. Testing Facility Cyprotex US , LLC 4717 Campus Drive Kalamazoo , Ml 

### 49008 Performing Laboratory 

### Launch Ml Lab 4717 Campus Drive , Kalamazoo Ml 49008 Study#: 

### 9320-101114

Phase Performed : LC/MS/MS analysis of peptide/compound reactions 

### 3. Materials & 

### Methods a. Test & 

### Reference Articles

**Com~ound** 

### Name Lot Storage Condition Molecular Weight

**Notes/Purit~** 

### Number TM 08-0338 RDJL2759 Rm . Temp in dark 194 .31 soluble in DMS0/100% TM 11 -0078 RDNG22329 Refrig . In dark 182 . 13 soluble in DMS0/1 00% 1 

### TM 1 0-0210 RDR07895 Refrig . In dark 194 . 17 soluble in DMS0/ 100% TM 10-0367 RDNG22339 2- 10 C, in dark 184 . 18 soluble in DMS0/ 100 % TM 09-0536 RDIA5595 Rm . Temp in dark 192 .3 soluble in DMS0/ 100% TM 11-0230 RDBB16179 refrigerated and 148 soluble in DMS0/ 100% 1 

### protected from light TM 05-0293 RDRW23746 Rm . Temp in dark 156.2 soluble in DMS0/100 % TM 09-0035 RDRW23748 Rm . Temp in dark 200 .2 soluble in DMS0/1 00 % 1 

### p-Benzoquinone MKBG6486V 2-10 C , in dark 108 .09 so luble in DMS0/98%

Benzoic acid MKBG6929V Rm . Temp 122 12 soluble in DMS0/99 .5% MKBG9391V 1

### Purity not

**~rovided** 

### by Sponsor therefore assumed 100% 

### b. Justification of Test System Direct Peptide Reactivity Assay: DPRA was developed by Frank Gerberick and colleagues (2004) and was further refined in 2007 (Gerberick et al. , 2007). In this assay , the test articles were incubated concurrently in two separate buffers , one with cysteine (Ac-RFAACAA-COOH ) and one with lysine ( Ac-RFAAKAA-COOH ). Reactive chem icals bind one or both of the peptides thereby reducing their free concentration levels . The disappearance of each peptide was measured by LC/MS/MS . This method did not require any biological material such as enzymes in order for this reaction to take place . It is important to note that the cysteine peptide captures soft electrophiles , while the lysine peptide captures hard electrophiles . It is also important to note that the standard glutathione reactivity assay commonly used to screen for skin sensitizers captures only soft electrophiles , as glutathione is a soft nucleophile . This makes the DPRA assay a good choice to screen for reactive chemica ls which is associated with allergic contact dermatitis . Page 6 of 15 Confidential Document

## 6- cyprot ex Study#: 9320-101114



### c. Preparation of Samples Test Article Stocks : Test articles were received at Cyprotex and stored according to section 3.a. A stock solution of each test article was prepared by adding an appropriate amount of 1 : 1 OMSO:acetonitrile to yield a final concentration of 100 mM . Reference materials : Control stocks were prepared in 1 : 1 DMSO :acetonitrile to yield a final concentration of 100 mM . Peptides : A stock solution of the lysine peptide (125 mM) was prepared by diluting the peptide with Peptide Reaction/Storage buffer, and a stock solution of cysteine peptide (125 mM) was prepared by diluting the peptide with dimethylformamide

. Peptides were stored at approximately 

# -aoo c desiccated . Peptides were from LifeTein LLC (South Plainfield , NJ) . 

### d. Evaluation of Test Articles in the Assay DPRA: DPRA was run according to Cyprotex SOP-2078. Test articles and reference articles were prepared at 100 mM in 1 : 1 DMSO :acetonitrile as stated above. The cysteine peptide was prepared at 125 mM in DMF (dimethylformamide) and the lysine peptide was prepared at 125 mM in lysine Peptide Reaction/Storage buffer. The reaction mix for cysteine peptide had a 1 : 10 test peptide to test article ratio (0 .5 mM cysteine to 5 mM test article) . The reaction mix for lysine peptide had a 1 :50 peptide to test article ratio (0.5 mM lysine to 25 mM test article) . Reactions for each test article were performed in triplicate and LC/MS/MS analysis was performed using three injections for each reaction. A vehicle control was run in parallel with sample reactions to determine percent depletion relative to vehicle controls (N=3) . Positive and negative controls were included (N=3) . In addition to making up test and reference article reactions , peptides were serially diluted in buffer to produce standard curves . Test plates were sealed and reactions were run for 24 hr at room temperature in the dark. Samples were assessed via LC/MS/MS using a Waters Alliance 2795 HPLC equipped with a 2996 Photodiode Array detector and a Micromass Quattro Premier mass spectrometer. Each sample was injected in triplicate according to Cyprotex SOP . After determination of peptide remaining in the analysis, percent depletion relative to vehicle controls was calculated relative to time zero or no test article samples . Peptide reactivity was reported as percent depletion and was calculated using the following formula : % Dep Peptide = (1-(test compound area/ vehicle control area) x 100. 

### e. Test Validity an Acceptance Criteria For data generated at Cyprotex, basic statistical analysis was performed on the data , which included means of replicates , standard deviations , and CV% . Values within a dose group that varied from the mean by more than .!,2 standard deviations were omitted from the final mean calculation . The results of each assay was evaluated and compared to reference controls . DPRA results were expressed as percent of control. All data were placed in a final datasheet and used to determine reactivity classification . Reference controls were within Cyprotex criteria for all acceptable runs . Page 7 of 15 Confidential Document

### Study#: 9320-101114 

### 4. Results & 

### Discussion

DPRA was performed to analyze for sensitization potential. The results for the test articles are shown below: Compound Cvs Dep Lvs Dep Avf!. Dep Classification Benzoic Acid -6 .7 - 1 . 1 -3 .9 Minimal Reactivity pBenzoquinone 98 . 3 97 .9 98 . 1 High Reactivity

TM05-0293 -10.4 2 .6 -3.9 Minimal Reactivity TM08-0338 -7.6 20.7 6 .6 Low Reactivity TM09-0035 -14.5 12 .0 - 1.3 Minimal Reactivity TM09-0536 22 .9 1.8 12.4 Low Reactivity TM10-0210 70.7 5 .7 38 .2 Moderate Reactivity TM10-0367 6.3 1.7 4 .0 Minimal Reactivity TM11-0078 77 . 1 6.9 42.0 Moderate Reactivity TM11-0230 5.8 -4.5 0 .6 Minimal Reactivity 

### Benzoic acid was minimally reactive while p-Benzoquinone was highly reactive with both peptides as expected . Test articles TM10-0210 and TM11-0078 were reactive with the cysteine peptide and as a result were ranked as moderately reactive overall. It should be noted that the cutoff for highly reactivity is 42 .47% so TM 

### 11-0078 is just below this cutoff. The remaining test articles showed low to minimal reactivity overall and varied in terms of which peptide was reacted with more strongly . For this test, low, moderate , and high reactivity were considered positive , while minimal reactivity was considered negative .

Table 1 : Cysteine data summarized Avg 

# I Cysteine Peptide Area SO area %CV % Dep BenzoicAcid 57460 .6 3099.7 5 .4 -6 .7 Para benzoquinone 903 .4 93 .3 10.3 98.3 TM05-0293 59442 .6 4187 .9 7 .0 -1 0 .4 TM08-0338 57936 .7 7683 .7 13 .3 -7 .6 TM09-0035 61698.5 5053.7 8.2 -14.5 TM09-0536 41544 .3 4207.1 10.1 22 .9 TM10-0210 15769.9 2929 .6 18.6 70 .7 TM10-0367 50449 .4 6758.5 13.4 6 .3 TM11-0078 12340.7 1351.0 10.9 77 . 1 TM11 -0230 50752 .0 2983 .6 5.9 5 .8 Vehicle-ACN-DMSO 53861.9 5381.3 10.0 0 .0



### Table 2 : Lysine data summarized Page 8 of 15 Confidential DocumentStudy#: 

### 9320-101114 Lysine peptide Avg Area SD area %CV % Dep

BenzoicAcid 270521.6 26814.7 9.9 -1.1 Para benzoquinone 5606.8 1786.9 31.9 97.9 TM05-0293 260610.9 32836.5 12.6 2.6 TM08-0338 212111.2 14263.6 6.7 20.7 TM09-0035 235415.2 17730.1 7.5 12.0 TM09-0536 262604.3 66508.3 25.3 1.8 TM10-0210 252160.6 27173.0 10.8 5.7 TM10-0367 263028.2 34965.3 13.3 1.7 TMll-0078 249149.0 15785.0 6.3 6.9 TMll -0230 279556.6 29572.9 10.6 -4.5 Vehicle-ACN-DMSO 267534.7 36371.2 13.6 0.0



### 5. References Gerberick GF , Vassallo JD , Bailey RE , Chaney JG , Morall SW, Lepoittevin JP (2004) . Development of a Peptide Reactivity Assay for Screening Contact Allergens . Toxicological Sciences 

### 81 , 332-343 . Gerberick GF, Vassallo JD , Foertsch LM , Price 88 , Lepoittevin JP (2007). Quantificaton of Chemical Peptide Reactivity for Screening Contact Allergens : A Classification Tree Model Approach. Toxicological Sciences 

### 97 (2), 417-427 . 

### 6. Appendix A: Summary LC/MS/MS data for Lysine peptide lnj . Name RT Response Type Vol uM BenzoicAcid 040914 Lys 1A 2.22 266208.5 Analyte 3 524.9781 BenzoicAcid 040914 Lys 1B 2.23 306049.6 Analyte 3 605.8758 BenzoicAcid 040914 Lys 1C 2.23 235803 .9 Analyte 3 463.6611 BenzoicAcid 040914 Lys 2A 2.22 272406.8 Analyte 3 537.5226 BenzoicAcid 040914 Lys 2B 2.23 305442.9 Analyte 3 604.6393 BenzoicAcid 040914 Lys 2C 2.23 261621.6 Analyte 3 515.7045 BenzoicAcid 040914 Lys 3A 2.22 257355 .7 Analyte 3 507.0875 BenzoicAcid 040914 Lys 3B 2.22 294290.8 Analyte 3 581.9339 BenzoicAcid 040914 Lys 3C 2.22 235514.8 Analyte 3 463.0796 Parabenzoquinone 040914 Lys 1A 2 .23 3469.02 Analyte 3 6.4472 Parabenzoquinone 040914 Lys 1B 2.23 5185.1 Analyte 3 9.7542 Parabenzoquinone 040914 Lys 1C 2.23 6907.44 Analyte 3 13.0743 Parabenzoquinone 040914 Lys 2A 2.22 3520.45 Analyte 3 6.5463 Page 9 of 1 5 Confidential DocumentStudy#: 

### 9320-101114 Parabenzoquinone 040914 Lys 2B 2.23 7513.36 Analyte 3 14.2426 Parabenzoquinone 040914 Lys 2C 2.23 6296.61 Analyte 3 11 .8967 Parabenzoquinone 040914 Lys 3A 2.23 5575 .09 Analyte 3 10.5059 Parabenzoquinone 040914 Lys 3B 2.22 8270 . 1 Analyte 3 15 .7018 Parabenzoquinone 040914 Lys 3C 2.23 3723 .92 Analyte 3 6.9383 TM05-0293 040914 Lys 1A 2 .22 263283.5 Analyte 3 519 .0636 TM05-0293 040914 Lys 1B 2.22 259127.8 Analyte 3 510.6662 TM05-0293 040914 Lys 1C 2.23 240411.2 Analyte 3 472.9295 TM05-0293 040914 Lys 2A 2.22 242184.9 Analyte 3 476.4999 TM05-0293 040914 Lys 2B 2.22 312666.1 Analyte 3 619 .372 TM05-0293 040914 Lys 2C 2.24 241424.8 Analyte 3 474 .9697 TM05-0293 040914 Lys 3A 2 .22 292759.1 Analyte 3 578.8191 TM05-0293 040914 Lys 3B 2.24 287913.6 Analyte 3 568 .9724 TM05-0293 040914 Lys 3C 2.24 205727.3 Analyte 3 403 .3561 TM08-0338 040914 Lys 1A 2.23 238291.7 Analyte 3 468 .6647 TM08-0338 040914 Lys 1B 2.22 224764.3 Analyte 3 441.486 TM08-0338 040914 Lys 1C 2 .24 192956.6 Analyte 3 377 .8543 TM08-0338 040914 Lys 2A 2 .22 215796 .2 Analyte 3 423.5062 TM08-0338 040914 Lys 2B 2.23 210200 .8 Analyte 3 412.3038 TM08-0338 040914 Lys 2C 2 .23 197324.9 Analyte 3 386.5704 TM08-0338 040914 Lys 3A 2.23 218452 .6 Analyte 3 428 .8286 TM08-0338 040914 Lys 3B 2.22 210826 Analyte 3 413.5549 TM08-0338 040914 Lys 3C 2 .24 200387.6 Analyte 3 392.6857 TM09-0035 040914 Lys 1A 2 .22 238628.2 Analyte 3 469.3416 TM09-0035 040914 Lys 1B 2.23 257224.5 Analyte 3 506.8224 TM09-0035 040914 Lys 1C 2 .23 241609 Analyte 3 475.3405 TM09-0035 040914 Lys 2A 2 .22 253406.1 Analyte 3 499.1156 TM09-0035 040914 Lys 2B 2 .23 248676.2 Analyte 

### 3 489.5767 TM09-0035 040914 Lys 2C 2.22 237212.6 Analyte 3 466.494 TM09-0035 040914 Lys 3A 2 .23 205849.6 Analyte 3 403.6007 TM09-0035 040914 Lys 38 2.23 220471.4 Analyte 3 432.8755 TM09-0035 040914 Lys 3C 2.23 215658.7 Analyte 3 423.2309 TM09-0536 040914 Lys 1A 2.23 310296.6 Analyte 3 614.5367 TM09-0536 040914 Lys 1B 2.23 312523.1 Analyte 3 619.0802 TM09-0536 040914 Lys 1C 2 .24 178842.7 Analyte 3 349.7418 TM09-0536 040914 Lys 2A 2.22 291006.7 Analyte 3 575 .257 TM09-0536 040914 Lys 2B 2 .22 310953.7 Analyte 3 615.8775 TM09-0536 040914 Lys 2C 2.23 167661 Analyte 3 327 .5224 TM09-0536 040914 Lys 3A 2.23 304474.6 Analyte 3 602 . 6657 TM09-0536 040914 Lys 3B 2.24 310879.4 Analyte 3 615.7258 Page 10 of 1 5 Confidential Document

### Study # : 

### 9320-101114 TM09-0536 040914 Lys 3C 2.23 176801 Analyte 3 345.6811 

# I TM10-0210 040914 Lys 1A 2.23 243666.5 Analyte 3 479.4831 

## ! TM10-0210 040914 Lys 1B 2.23 284724.3 Analyte 3 562 .4962 TMl0-0210 040914 Lys 1C 2.23 260436.5 Analyte 3 513.31 TM10-0210 040914 Lys 2A 2.22 228315.1 Analyte 3 448.6132 TM10-0210 040914 Lys 2B 2.23 271798.3 Analyte 3 536 .2904 TM10-0210 040914 Lys 2C 2.22 252806.3 Analyte 3 497 .9054 TM10-0210 040914 Lys 3A 2.22 195044.3 Analyte 3 382.0191 TMl0-0210 040914 Lys 3B 2 .23 272946.7 Analyte 3 538.6159 TM10-0210 040914 Lys 3C 2.23 259707 Analyte 3 511.8362 TM10-0367 040914 Lys 1A 2.23 216953.2 Analyte 3 425 .824 TM10-0367 040914 Lys 1B 2.22 284468.7 Analyte 3 561.9773 TM10-0367 040914 Lys 1C 2.23 295581.8 Analyte 3 584 .5596 TMl0-0367 040914 Lys 2A 2 .24 204033.5 Analyte 3 399.9702 TM10-0367 040914 Lys 2B 2.23 284704.9 Analyte 3 562.4568 TM10-0367 040914 Lys 2C 2.23 294904.5 Analyte 3 583 . 1819 TMl0-0367 040914 Lys 3A 2.23 239301.4 Analyte 3 470 .6961 TM10-0367 040914 Lys 3B 2 .23 259812 Analyte 3 512.0483 TM10-0367 040914 Lys 3C 2.24 287494.4 Analyte 3 568 .1 209 TM11-0078 040914 Lys 1A 2.22 27142 5.9 Analyte 

### 3 535.5362 TM11-0078 040914 Lys 1B 2.23 253797 Analyte 

### 3 499.9042 TM11-0078 040914 Lys 1C 2.23 251718.2 Analyte 3 495.7106 TM11-0078 040914 Lys 2A 2.23 247741.4 Analyte 3 487 .6926 TM11 -0078 040914 Lys 2B 2 . 22 260233.6 Analyte 3 512.9 TM11-0078 040914 Lys 2C 2.23 237834.8 Analyte 3 467.7456 TM11 -0078_040914 Lys 3A 2 . 23 214656.2 Analyte 3 421.2228 TM11 -0078 040914 Lys 3B 2.22 251011.2 Analyte 3 494 .2847 TM11-0078 040914 Lys 3C 2.24 253922 .3 Analyte 3 500.1571 TM11 -0230 040914 Lys 1A 2 . 24 264924.1 Analyte 3 522 .3805 TM11-0230 040914 Lys 1B 2 .23 327290.4 Ana lyte 

### 3 649 .2652 TMll -0230 040914 Lys 1C 2.22 250085.5 Analyte 3 492.418 TMll-0230 040914 Lys 2A 2.23 271451.5 Analyte 3 535.5882 TM11-0230 040914 Lys 2B 2.23 307518.3 Analyte 3 608.8702 TM11 -0230 040914 Lys 2C 2 . 23 251278.4 Analyte 3 494.8235 TMll-0230 040914 Lys 3A 2.23 280230.3 Analyte 3 553.3776 TM11 -0230 040914 Lys 3B 2.23 313072.9 Analyte 3 620.2024 TM11 -0230 040914 Lys 3C 2.24 250157 .6 Analyte 3 492.5634 Vehicle-ACN-DMSO 040914 Lys 1A 2 .22 266190 .7 Analyte 3 524 .9419 Vehicle-ACN-DMSO 040914 Lys 1B 2 .24 313505.9 Analyte 3 621.0863 Vehicle-ACN-DMSO 040914 Lys 1C 2.23 242638 Analyte 3 477.4121 Page 11 of 15 Confidential DocumentStudy#: 

### 9320-101114 Vehicle-ACN-DMSO 040914 Lys 2A 2.22 241690.8 Analyte 3 475.5051 Vehicle-ACN-DMSO 040914 Lys 2B 2.23 300830.4 Analyte 3 595.2422 Vehicle-ACN-DMSO 040914 Lys 2C 2.22 234929.1 Analyte 3 461 .9022 Vehicle-ACN-DMSO 040914 Lys 3A 2.23 254614.9 Analyte 3 501.5548 Vehicle-ACN-DMSO 040914 Lys 3B 2.23 325044.3 Analyte 3 644.6683 Vehicle-ACN-DMSO 040914 Lys 3C 2.23 228368.3 Analyte 3 448.72 

### 7. Appendix 8: Summary LC/MS/MS data for Cysteine peptide lnj. Name RT Response Type Vol uM BenzoicAcid 042914 Cys 1A 2.38 54564.48 Analyte 3 314.45 BenzoicAcid 042914 Cys 1B 2.4 56505.727 Analyte 3 320.89 BenzoicAcid 042914 Cys 1C 2.42 57540.203 Analyte 3 317.43 BenzoicAcid 042914 Cys 2A 2.41 61364.672 Analyte 3 361.21 BenzoicAcid 042914 Cys 2B 2.4 55079.891 Analyte 3 310.92 BenzoicAcid 042914 Cys 2C 2.41 57490.797 Analyte 3 307.19 BenzoicAcid 042914 Cys 3A 2.4 62591.41 Analyte 3 371.11 BenzoicAcid 042914 Cys 3B 2.41 53168.629 Analyte 3 317.17 BenzoicAcid 042914 Cys 3C 2.41 58839.176 Analyte 3 324.87 Parabenzoquinone 042914 Cys 1A 2.4 928.169 Analyte 3 11.34 Parabenzoquinone 042914 Cys 1B 2.41 969 .609 Analyte 3 11.03 Parabenzoquinone 042914 Cys 1C 2.42 876.435 Analyte 3 10.17 Parabenzoquinone 042914 Cys 2A 2.41 780 .325 Analyte 3 9.98 Parabenzoquinone 042914 Cys 2B 2.43 1094.463 Analyte 3 11.67 Parabenzoquinone 042914 Cys 2C 2.42 854.748 Analyte 3 10.04 Parabenzoquinone 042914 Cys 3A 2.39 823.232 Analyte 3 10. 35 Parabenzoquinone 042914 Cys 3B 2.42 860.172 Analyte 3 11.39 Parabenzoquinone 042914 Cys 3C 2.41 943.894 Analyte 3 10.49 TM05-0293 042914 Cys 1A 2.41 63791.508 Analyte 3 374.02 TM05-0293 042914 Cys 1B 2.41 55743.16 Analyte 3 329.26 TM05-0293 042914 Cys 1C 2.41 52999.602 Analyte 3 299 .84 TM05-0293 042914 Cys 2A 2.41 65470.41 Analyte 3 352.89 TM05-0293 042914 Cys 2B 2.41 57368.285 Analyte 3 344.58 TM05-0293 042914 Cys 2C 2.42 56805.051 Analyte 3 312.82 TM05-0293 042914 Cys 3A 2.41 63675.801 Analyte 3 364.27 TM05-0293 042914 Cys 3B 2.41 58993.984 Analyte 3 348.98 TM05-0293 042914 Cys 3C 2.41 60136.031 Analyte 3 327.75 TM08-0338 042914 Cys 1A 2 .4 65931.852 Analyte 3 331.51 TM08-0338 042914 Cys 1B 2.4 59976.742 Analyte 3 316.43 Page 12 of 15 Confidential Document

### Study#: 9320-101114 TM08-0338 042914 Cys 1C 2.41 50066.715 Analyte 3 269.94 TM08-0338 042914 Cys 2A 2.39 67661.688 Analyte 3 327.49 TM08-0338 042914 Cys 2B 2.39 58192.637 Analyte 3 319.54 TM08-0338 042914 Cys 2C 2.41 45776.211 Analyte 3 253.21 TM08-0338 042914 Cys 3A 2.41 64809.23 Analyte 3 492.02 TM08-0338 042914 Cys 3B 2.41 58317.852 Analyte 3 301.63 TM08-0338 042914 Cys 3C 2 .42 50697.648 Analyte 3 266.76 TM09-0035 042914 Cys 1A 2.39 66370.43 Analyte 3 391.49 TM09-0035 042914 Cys 1B 2.4 60817.523 Analyte 3 363.2 TM09-0035 042914 Cys 1C 2 .41 55916 .969 Analyte 3 322.48 TM09-0035 042914 Cys 2A 2.39 69678.031 Analyte 3 392 .73 TM09-0035 042914 Cys 2B 2.41 59218.453 Analyte 3 343.59 TM09-0035 042914 Cys 2C 2 .41 57344 .992 Analyte 3 313.09 TM09-0035 042914 Cys 3A 2.4 68066.984 Analyte 3 388.3 TM09-0035 042914 Cys 3B 2.39 57576.77 Analyte 3 330.05 TM09-0035 042914 Cys 3C 2.42 60295 .922 Analyte 3 326.43 TM09-0536 042914 Cys 1A 2 .4 45463 .344 Analyte 3 260.16 TM09-0536 042914 Cys 1B 2 .4 41606.348 Analyte 3 247.15 TM09-0536 042914 Cys 1C 2 .41 35923.719 Analyte 3 204.54 TM09-0536 042914 Cys 2A 2.4 46152.043 Analyte 3 265.79 TM09-0536 042914 Cys 2B 2.42 43359 .809 Analyte 3 256 . 1 TM09-0536 042914 Cys 2C 2.41 35493.949 Analyte 3 196 .62 TM09-0536 042914 Cys 3A 2 .4 45496 .813 Analyte 3 267 .34 TM09-0536 042914 Cys 3B 2.42 4287 3 .539 Analyte 3 252.14 TM09-053 6 042914 Cys 3C 2 .41 37529.488 Analyte 3 206 . 18 TM10-0210 042914 Cys 1A 2.4 19793.67 Analyte 3 122 .95 TM10-0210 042914 Cys 1B 2 .41 15582 . 106 Analyte 3 146.32 TM10-0210 042914 Cys 1C 2 .41 13485 .937 Analyte 3 82 .26 TMl0-0210 042914 Cys 2A 2.41 19420.537 Analyte 3 119 .64 TM10-0210 042914 Cys 2B 2 .4 13957.505 Analyte 3 84 .88 TM10-0210 042914 Cys 2C 2.41 13073 .902 Analyte 3 79 .47 TM10-0210 042914 Cys 3A 2 .41 19447.652 Analyte 3 114.93 TMl0-0210 042914 Cys 3B 2 .41 13939 .77 Analyte 3 84 .49 TM10-0210 042914 Cys 3C 2 .43 13227.693 Analyte 3 77 .3 TM10-0367 042914 Cys 1A 2.39 53708.742 Analyte 3 318.78 TM10-0367 042914 Cys 1B 2 .41 52859 .918 Analyte 3 308.07 TM10-0367 042914 Cys 1C 2 .42 42359 .691 Analyte 3 231.43 TM10-0367 042914 Cys 2A 2 . 39 58097.18 Analyte 3 332 .63 TM10-0367 042914 Cys 2B 2.41 53929.074 Analyte 3 313.49 TM10-0367 042914 Cys 2C 2.41 41068.949 Analyte 3 232.12 Page 13 of 15 Confidential DocumentStudy#: 9320-101114 TM10-0367 042914 Cys 3A 2.4 57663.582 Analyte 3 591.12 TM 10-0367 042914 Cys 3B 2.4 52254 .34 Analyte 3 305.33 TM10-0367 042914 Cys 3C 2.41 42103.457 Analyte 3 226.74 TM11-0078 042914 Cys 1A 2.4 14194.23 Analyte 3 87.89 TM11 -0078 042914 Cys 1B 2.42 12062.03 Analyte 3 75.12 TM11 -0078 042914 Cys 1C 2.41 10940.657 Analyte 3 65.11 TM11-0078 042914 Cys 2A 2.39 13846.869 Analyte 3 83.21 TM11-0078 042914 Cys 2B 2.4 12626.575 Analyte 3 77.3 TM11-0078 042914 Cys 2C 2.41 10731.423 Analyte 3 128.23 TM11-0078 042914 Cys 3A 2.4 13840.578 Analyte 3 80.69 TM11-0078 042914 Cys 3B 2.41 11738.11 Analyte 3 73.26 TM11-0078 042914 Cys 3C 2.41 11085.54 Analyte 3 66.57 TM11-0230 042914 Cys 1A 2.39 53818.813 Analyte 3 318.54 TM11-0230 042914 Cys 1B 2.4 50481.371 Analyte 3 287.96 TM11-0230 042914 Cys 1C 2.4 50874.363 Analyte 3 273.04 TM11-0230 042914 Cys 2A 2.39 54379.434 Analyte 3 328.81 TM11-0230 042914 Cys 2B 2.4 48010.168 Analyte 3 273.56 TM11-0230 042914 Cys 2C 2.4 49198.027 Analyte 3 274.68 TM11 -0230 042914 Cys 3A 2.42 51539.563 Analyte 3 313.54 TM11 -0230 042914 Cys 3B 2.4 45146.973 Analyte 3 266 .76 TM11 -0230 042914 Cys 3C 2.41 53319.477 Analyte 3 278.94 Vehicle -ACN - DMSO 042914 Cys 1A 2.43 45209.895 Analyte 3 240.2 Vehicle-ACN - DMSO 042914 Cys 1B 2.41 62032.066 Analyte 3 349.25 Vehicle-ACN-DMSO 042914 Cys 1C 2.4 52292.09 Analyte 3 275.11 Vehicle-ACN-DMSO 042914 Cys 2A 2.4 49670 .344 Analyte 3 296.23 Vehicle-ACN-DMSO 042914 Cys 2B 2 .4 59084 .539 Analyte 3 326.38 Vehicle-ACN - DMSO 042914 Cys 2C 2 .41 52632.48 Analyte 3 283.59 Vehicle-ACN-DMSO 042914 Cys 3A 2.4 50711.883 Analyte 3 304.82 1- Vehicle -ACN-DMSO 042914 Cys 3B 2.41 59454.906 Analyte 3 325.49 Vehicle-ACN-DMSO 042914 Cys 3C 2.41 53668.621 Analyte 3 277 .83

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### Study#: 9320-101114

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