### FINAL REPORT STUDY TITLE

ACUTE DERMAL IRRITATION STUDY IN

RABBITS STUDY No.: DATA REQUIREMENT U.S. EPA Health Effects Test Guidelines , OPPTS 870.2500 (1998) OECD Guidelines for the Testing of Chemicals, Te st No 404 (2002) JMAFF 12- Nousan-8147 (2000) Official Journal ofthe Europea n Commu nitie s, Methods for the Determination of Toxicity and Other Health Effec ts, Part B.4 (Skin Irritation), Council Regulation (EC) No. 

### 440/2 004

Copy No. 2/ 2 

### AUTHOR

STUDY COMPLETED ON 24 May 2011



### SPONSOR DOW EUROPE GMBH BACHTOBELSTRASSE 3 CH-8810 HORGEN

SWITZERLAND 

### TEST FACILITY DEPARTMENT OF SAFETY ASSESSMENT ADV I NUS THERAPEUTICS LIMITED POST BOX No. 58 13, PLOT Nos. 2 1 & 

### 22 PEENYA II PHASE , BANGALORE - 560 058 I ND IA
Page 1146

### C OM PLI ANCE WI T H GOOD L ABORA T ORY PRAC TI CE STAN D ARD S Co mp o und : ( S tu dy Ti tle: Ac u te D e rm a l Irritati o n Stud y in Ra bb i ts Exce pt a s no te d b e low, th e stud y de s c rib e d in thi s re po r t wa s co nducted in co mpl ia nce w ith the fo ll ow in g Good La borato ry Pract ice Sta nd ard s: O rgan isat io n fo r Econo mi c Co-o p e rat io n a nd D eve lopm ent (OEC D ) 

### EN V /

MCI CH E M (98) 1 7 

### Euro p e an Eco no mi c Co mmuni ty (EEC) Co mm is s io n D irec ti ve 2 004 11 

### O I EC Fe brua r y 20 , 20 04 J ap an ese Min is try ofAg ri c ul ture , Fo restr y, and F i she ri es (J MAFF) No us an No tifi cati o n No. 62 8 3 Ag ri c ul tura l Prod ucti o n Burea u I O c to b e r 1 99 9 Exce pti o n to GL P c om pli ance is a s li s ted be low : • Testing homoge nei ty, co n ce ntrat io n and stab ili ty of te s t s ub sta nce in the ve hicl e . • A rc hi v in g ofraw data at the test fac ili ty. • Exception to g uid e lin e 404 , fo r not testin g we ight of ev idence a na l ys is by th e te s t fac il ity. 

### :) A - 

## I""() 20 

### I \ 

### D ate Stud y Directo r

S KI N C op y No. 212 Pa ge 2/ 46

### QUALITY ASSURANCE STATEMENT The Study No.: ent itled " Acute Dermal Irr i tat ion Study in Rabb its" has been inspected in accordance the OECD Pr in c i p les of Good Laboratory Practice (a s revised in 1997) ENV/ M CIC HEM (98)17 , OECD Pari s, 1998, JMAFF GLP standa rd s: II -Nousan-No.6283, I October 1999, and EC Directive 200411 

### O /

EC, Officia l Journal ofthe European Union, 

### L50/ 44, Feb.20,2004 . This study was in spected and finding s reported to Management and to the Study Director on the date s s hown below: 

### INSPECTION REPORTING DATE PHASE DATE I I February 20 I I 23 February 20 II 23 March 20 II and 24 March 20 I I 23 May 201 1 Initiation Phase Review of s tud y p lan In-Life Phase Te st s ub s tance app lication Reporting Phase Review of draft report
Review of final re port I I February 20 I I 28 February 20 I I 24 March 20 I I

23 May 2011 In s pection s were performed according to the Standard Operat ing Pro ce dure s of the test faci lity' s Qua li ty Assurance Unit. The fina l report was in s pected against th e approved study p lan and pertinent raw data and accurate ly reflects the raw data . Date:**2~,** t()I\Y , )1)\\

Copy No. 2/2 

### Head, GLP Section Q ual ity Assurance Unit Advinus Therapeutic s Limited , Banga lore

Page 3 /4 6

### 1. 

### STUD Y PERSONNEL T h e following per s o nnel p artic ip ated in the conduct ofthe st ud y . 

### Na me , Responsibility , Sect ion / Department

Copy No. 2 /2 

### F unction Sig nature with date Overa ll in-charge for the co n duct ofthe s tudy and report preparation A ss is tance in conduct of study a nd re p ort \ preparation Veterinary s erv ic e s

A ss is tance in th e co ndu ct of study

Data e ntry and report compi lat ion

Page 4/46

### TABLE OF CONTENTS STUDY T ITLE . ...... . ...... .. . ... ... ... ... .... . . . .. ... . ... .. ... . ... ... .... . .............................................. . ..... . . 1 COMPLIANCE WITH GOOD LABORATORY PRACT ICE STANDARDS ........ . .... .. . .. 2 QUALITY ASSURANCE STATEMENT . .. .. .. ............. .. .... ..... .. .......... . .... .. . ..... . . . .. . ... . . . ... . . . 3 I. 

### 2. 3. 

### 4. 5 . 6 . 7 . 

### 8. 8. 1 8. 1 . 1 8.1.2 8.2 8.2. 1 8.2.1. 1 8 . 2 .1. 2 8.2. 1 .3 8.2.1.4 8 . 2 . 1. 5 

### 8.2. 1 .6 

### 8 . 3 8 .3. I 8 .3.2 8.3.3 8.3.4 STUDY PERSONNEL .................. . .. .. .. ............... .. ... ... ... ...... . .. ... . .... . .. .. . ............. 4 SUMMARY .......................................... . . .. . ..... .. .. ... ... ... .. . ..... .. .. ... ..... ................... 7 STUDY DETAILS ... . .................. . .. .. ............. .... .. ... ... .. ... .. .. ... ... ... .. . .......... .... . ..... . 8 OBJECT IVES .. . .. .... .. ... . ......... . ....... . .. ... . .. .. . . .. .................................................. ... . 9 J UST IF ICAT I ON FOR SELECT ION OF TEST SYSTEM ...... ... .......... .. .... .... . 9 J USTIF ICATION OF ROUTE OF ADMfN l STRAT ION ............. .... .. ...... ...... .. 9 TEST PROCEDURE GUIDELfNES ........ ... ............ ......... .......... . ....... .... .. .. .. .... . 9 MATER I ALS AND METHODS ........................... ........ .......... ............ .... . ........ I 0 Materia ls ............................................. .. ..... . ... . .. ..... ... .. . .. .. .. ...... ... . .............. .. ..... 1 0 Te s t s ub stan ce Information ...... .. .... .. . .... .... .... .. ... .......... ................ .................... . 10 Test System .............................. .. ...................... . .. ...... .. .. .. ... .. .. .. .. .. .... .. .. ............. I I Methods . . . .. . ... . ........ . ....................... . .. . ... .. ..... . ... . . ................ .. .................... .... . .. . . 12 Performan ce of th e Te s t ............ .............. ........ .......................... .. ...... .. .............. 12 Hu sba ndry . . ... . .. . ............... . ................... . .. ... . .. . .. .. .............. .. ....... . .......... .. ........... 1 2 Samp le prepa rat ion ....... .. ... . ............................... . ..... . ... ... ... . .. . .. .... . . .. . .. . ..... . ....... 13 Preparation of Test Anima ls .... .. .... ...................... ..... ................................... .... . 13 Testing Option .. .... ......................... . .. .. . .. . .. .. .. .. .......... ...... .......... .. ...................... 13 Te st s ub stance Applicatio n ...... .. ....... .............. .. .......................... . ...... .... .. ...... .. . 1 3 Expos ure ofAn ima ls ........................... .. ....... .. .. .. .......................... .. ................... 1 3 Ob se rvation s ..................................... . ............ . .. . . . .. ... .. . . .. ... . .. ....... .. ..... . .. .... . ...... I 3 Durat ion of Ob servat ion .......................... ........ ................................................. 13 Tox ic Signs and Pre-Term in al D ea ths ............ .. .. .. .. ...... ...... ...... .. .. ... .. ............... 14 Body Wei g ht s . . . .. . . .. ... . .. . ........ . .... . ..... . . .. .. . .... . ............. .. ...... .......... ... . .................. 14 Sk in Scor in g .............................................. .. .... . .. .... ........ . .. . ...... .. ....................... 14 Copy No. 212 

### Page 5/ 46

### 8.3.5 Grading of sk in reaction s ............................. . ...... .... .............. .. . . ..... . .. . . . ...... . ...... 14 9. RESULTS ........................................ . .. ... . ... .............................. . .. . .. . ... .... ........... 15 9. 1 Toxic signs and pre-terminal death s ................... .............. . . .. . . .... . ..... .. ............ . . 1 5 9.2 Body weights . . . ..... .... ... .. . .. . . .. .. . . ....................... . ..... ..... . ... ....... . ............... . ... ... .... 15 9.3 Skin reaction s .................... . ..................... . .. . . . . . .... . ........................ .. . .. . .. ... .. .. . ..... 15 10. CONCLUSION ................................ . ... .. . ... .... . .......... ... ........ . ........ . .. . .... ... ......... 15 II. ARCHIVING ................. . .... . . .. .. . . .. . . .......................... .... . ... . ............................... 1 5 12. REPORT DISTRIBUTION ............... . . . .. ... ... . ..... .. ................................ . . ......... . 16 13 . TABLES . ... ... ... .. .... . . . .. . ... .. . . .... . .. ............................. . . ... ... . . . . . ...... . .............. ........ 17 TABLE I. 

### Body Weight and Pre-term in a l Death s .................. ... .. . .. .. .. ... ....... 18 TABLE 2. Sk in Reaction Scores ...... . .. ... ... ... ... . .................... . ..... . ........ .... ...... 1 9 TABLE 3. Mea n Sk in Reaction Scores ........ . .................. . . ... . ... . .. . . . .............. .20 TABLE 4. Indi vidua l Toxic Signs . .. ... .. ... . .......................... . .. . . .. .. . . . ... . .......... 2 1 14 . APPEND ICES ... . ..... . ... .. . .. . . .... .... . .. ... . .............. ... ........... . ... . .. .. . . ..................... .. .22 APPENDIX I . Certificate of Analys is ............... ........ ........................... .. . .. ... . .23 APPENDIX 2. Study Plan ....... ... .................. . .. .. .... .. ............ . .. ..... .. ... . . .. .. . ........ 24 1 5. ANNEXURES ......................................... ................ .............. .. ..... . . . .. ... . . .......... 40 ANNEXURE I .A na l ysis Report - Anima l Diet Samp le ..... . ..... . .. . . ... ............. .41 ANNEXURE 2. Analy s is Report - Water Samp le .. .. .... . . ... . .. ..................... ...... .42 ANNEXURE 3 . GLP Certificate - Germa ny ............ . ... .. .. .. ......................... . .. . .43 ANNEXURE 4. GLP Ce r tificate - The Netherlands . .. ... . ......... .. ...... .. ... . . .. ...... .44 ANNEXURE 5 . GLP Certificate - In dia .................... ..... .... . . . . .. .. . . . ..... ... ......... .46

Co py No. 212 Page 6/46

### 2. SUMMARY The ac ute de rm a l irritat ion s tudy in Rabbits was conducted to eva lu ate the ski n irritation potential of Five hundred mg (O.5g) of the te st substance was made in to a paste with s ufficient volume of water and mixed with a glass rod and was aPflied to the do se si te and covered with a gauze pad of size approximately 6 cm (2 x 3 cm6ply) . The patche s were sec ured to the body of the animal by a non-irritating se mi-occlu s i ve adhes ive tape. After 4 hours contact period the bandage was removed and the dose s ite s were wiped with water. The degree of irritation wa s evaluated and sco red by Drai ze's evaluation method at I, 24 , 48 and 72 hours po s t removal of the test patch . The s kin reactions are presented in the table below. There were no toxic s ign s, pre-termina l deaths and no sk in reaction s observed. The mean skin irritation sco re s were as follows :

Copy No. 2 /2 Rabbit No. RB8764

RB8765

RB8766 Sex M

M

M Treatment Period (hours ) 4

4

4 E lapsed time Erythema (p os t rem o val of

the te st patch) score J h our 0 24 hours 0 48 hours 0 72 hours 0

I hour 0 24 hours 0 48 ho urs 0 72 hours 0

1 hour 0 24 ho urs 0 48 hours 0 72 hours 0 Edema Tota l Score 

### sco re

0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0

Page 7/46

### 3. 

### STUDY DETAILS Study Title Test Substance Study No. Sponsor

Monitor in g Scient ist

Test Fac ility

Study Initiation Date Experimental Start in g Date Acc limati zat ion

Treatment Ob se r vat ions Exper im ental Comp letion Date Draft Report Study Co mpletion Date

C opy No. 212 

### Acute Dermal Irritation study in Rabbit s (

Dow Europe GmbH Bachtobel stras se 3 CH-8810 Horgen Sw itze rl and Donna Anderson The Dow Chemical Company Toxicology & 

### Env ironm ental Re search & 

### Consu ltin g (TERC) Building 5 727 Norr istown Road, P.O. Box 904 Spring Hou se , PA 1 9477 -0 904 Ema il: DonnaAnders on @ dow.com Department of Safety Assessment Adv inu s Th e rapeutic s L imited Po st Box No. 5813, Plot Nos . 21 & 

### 22 Peen ya II Pha se, B a ngalor e 560 0 58 , INDIA 18 February 20 II 18 February 20 II Start: 18 February 20 II End : 22 February 2011 (single an im a l ) and 23 February 20 II (additional two animals) Start: 23 Februa r y 20 II (sing le an im al) 24 February 20 II (addit ional animals) Start: 23 February 20 II End: 27 February 20 II 27 February 20 II 30 March 2 0 II 24 May 20 11 Page 8/46

### 4 . 

### OBJECTIVES T he objective of thi s acute dermal irritation study was to provide inf ormat ion on the potential for s kin co rro s ivity / irri tat ion to arise from a s ingle topical exposure to the te st s ub stance. 

### 5. JUSTIFICATION FOR SELECTION OF TEST SYSTEM T he rabbit is th e sys tem of choice because, hi storically , it has been th e preferred and mo st commonly use d s pecie s for primary s kin irritation te s t s. 6. 

### JUSTIFICATION OF ROUTE OF ADMINISTRATION Topica l app li cation was use d becau se it is recommended in the ref ere nced guidelines, and becau se human exposure may occur via this route. 

### 7. 

### TEST PROCEDURE GUIDELINES The procedure s as de sc ribed in thi s study plan are ba se d o n the following te sting guidelines: • OECD Gu id eline for Testing of C hemical s, Sect ion 4 , Number 404. " Acute D erm a l Irritat ion / corrosion ," adopted: 24th Apri l 2002.



## »> Exception to g uideline 404, for not te stin g weight of ev idence analysis by th e te st facility. • U.S. EPA Hea lth Effects Test G uideline s , OPPTS 870.2500 , Acute Dermal Irri tat ion, August 1998 . • JMAFF 12-Nou sa n-8147 , Nove mber 2000. • Official Journal of th e European Commun iti es , Method s for th e Determination of Tox ic ity, Part B.4 (Skin Irritat ion), Directiv e 2004/73/EC, 29 April 2004.

Co py No. 212 Page 9 / 46

### 8. MATERIALS AN D METHODS 8 . 1 Materials 8.1.1 Test s ubstance Information (As furnished by the Sponsor) Test s ubstance / I te m Lot No . Manufactured by (Na me and Addre ss) S uppli e d by (Na me and Address) Date of manufacture Date ofexpi ry Purity as per Ce r tificate of A na lys is Physica l appearance Sto ra ge co ndition s (

The Dow Chem ic a l Com pany Midland , MI 48674 USA T he Dow C he mic a l Com pany Mid land, MI 48674 USA Not App li cab le 06 March 2012

Off-whit e so lid Ambient (+ 1 8 to +3 6 °C) The te st s ub stance , identified as was received o n 03 Febru ary 20 II and was f urther identified as 008- 26 by tes t facility, Reference Nu mb e r dated 07 February 20 I I. The test s ub stance is a so lid and is stored at a mbient co ndi tio n (+ 1 8 to + 36 ° C). Documentation ofthe method s of synth es is, fabrication, or derivation ofthe te st s ub sta nce is reta in e d by the Spo nso r. Determination of the stab ility, id e ntity, strength , purity and composit ion of the te st s ubsta nce is the respons ibi li ty of the s tudy Spo nso r. T he fo ll ow ing information re lated to the characterization of the test s ubsta nce was provided by the s po nso r.

Co py No. 2/2 Pa ge 10/ 46

### Informat ion as prov id e d by Sponsor are as fo ll ows : pH: 6.47 (A na lysed in- h ouse). Spec ifi c grav ity / den s it y: No t App licab le. Test s ubstance is a so li d 

### 8 . 1 .2 Test System An im als Source

N umber and sex Age at treatment Date of birth Body we ig ht ra nge at treatment Id entificatio n
Rabbit accession numbe r s Accl im at ization

Co py No. 2/ 2 

### New Z ealand White rabbit s Inh ou se Bre d (Outbred) New Zea land White rabbit s Toxicology D epartment of Safety Assessme nt A dv inu s T herape utics Limited Banga lo re 560 058 , I NDIA 3 Ma le rabb it s 6-7 mo nth s 30 Jul y 20 10 2 . 77 to 2.94 kg T he an im a ls were ind ividual ly ide ntifi e d by anim a l access ion number , cage labe l and turmeric co lou r body marking. RB8764 to RB8766 O n e rabbi t (RB8764) was acclimatized for five days whil e the othe r two (RB8765 and RB8766) rabbit s were accl im atized for s ix day s under lab orato ry co ndi t ions after ph ys ica l exa min at io n.

Page 1 1146

### 8.2 Methods 8.2.1 Performance of the Test 8.2.1.1 Husbandry Condit ions Anima ls were housed under standard laboratory conditions , air conditioned with adequate fresh a ir supp ly (12-15 a ir cha nges/ho ur). Environment: temperature 21 - 23°C, relative humidity 65 - 67%, w ith a 12 hour li ght and 12 hour dark cyc le. The maximum and minimum temperature and relative humidity in the experimenta l room were recorded once daily. The relative humidity in the experime nt al room was calcu lated from dry and wet bulb temperature recording s . Housing The rabbit s were hou se d in div idu a ll y in rabbit cages (approx. size: L 65 x B 65 x H 45 cm) with Nory l s ha ll ow cage body and facilities for pelleted food (Sta inle ss stee l feed hopper) and drinking water (750 mL markrolon bottle fitted with s ipp er tube). The litter collection tray (noryl waste tray) were washed daily with water (except on Su nd ays). Water was replenished daily. The water bottle s and feed hoppers were changed once a week. Diet: 

### ad libitum The animal s were offered rabbit feed manufactured by Pranav agro Indu strie s Ltd, Sangli. The diet ana lys is report i s enclosed as Annexure I. Specific contam in ants (heavy metals organochlorines and organophosphates) in the diet are ana l ysed periodically and the reports are included in the raw data file. Water: 

### ad libitum The animals were provided deep bore-well water passed through activated charcoal filter and exposed to UV rays in Aquaguard on-l in e water filter-cumpurifier manufactured by Eureka Forbes Ltd. , Mumba i - 400 00 I , Indi a. The water bottle s were replen is hed once dai Iy and the water bottle s changed once a week. The water analysis report i s enclosed as Annexure 2.

Copy No. 2/2 Page 12/ 46

## 8.2.1.2

8.2.1.3

8.2.1.4
8.2.1.5

8.2.1.6 Sample preparation A quantity of 0.5 g oftest sub stance as recei ved was made into paste by adding s ufficient vo lum e ofwater and mixed w ith a g la ss rod. Preparation of Test Animals Approximately 24 hours prior to treatment , the fur on the left si de of the dorsolateral trunk surfa ce [about 14 x 19 cm] was clipped with an electric clipper -Ae scu lap ® - Germany. Care was taken to avoid abrad ing the s kin. After clipping and prior to application, the animal ' s sk in (test s ite) was checked for any abnormalities according to the "P rimary Skin Irritation Scoring Syste m" , and the test s ite was found to be normal. Testing Option The st ud y was initiated in a stepwi se procedure ( I+ 2 Rabbits). Test substance Application Preparation of Dose Site Approximately 6 cm 2 

### intact test s ite was se lected on each animal. The ad jacent untre ated sk in of each animal served as the control s ite. Application of Test Substance A quantity of 0.5 g oftest su b stanc e as received was made into paste by adding s ufficient volume of water and mixed with a g la ss rod. The te st substance was applied directly to the sk in of the test s ite and covered with a gauze pad. The entire trunk of each animal was then wrapped w ith non-irritating se miocclusive adhesive tape to avoid dislocation ofthe patch. Exposure of Animals In a stepwi se manner (1 + 2 rabbit s) all the three rabbit s were exposed to the te st substa nce each with one test patch only for a four hour exposure period. The rabbits were restrained using E li zabetha n co llar for 72 hours post app lic at io n ofthe test patch. 

### 8.3 Observations 

### 8.3.1 Duration of Observation The rabbits were observed up to 72 hour s post re moval ofthe test patch. Copy No . 212 Page 13/ 46

### 8.3.2 Toxic Signs and Pre-Terminal Deaths Rabbits were observed for to x ic s ign s and pre-terminal death s for the fir st four hour s (at hourl y intervals) on the day of test s ub sta nce application and once daily thereafter ti ll the end ofthe observation period. 

### 8.3 .3 Body Weights Individual body weights of the rabbit s were recorded at the start of acc lim at ization, day I of treatment Gust before te st s ub stance app lication) and at the termination of observation. 

### 8.3.4 Skin Scoring Following the exposure period, test patche s were removed and the application sites were washed with water and clean towel s to remove any re s idual te st substance. The 4 hour dose s ite s were examined for s ign s of erythema and edema within 60 minute s and at interval s of approximate ly 24 , 48 and 72 hour s after te st patch removal accord in g to the "Primary Skin Irritation Scoring System" deve lop ed by Draize . Individual s kin scores were recorded for each rabbit. 

### 8 .3.5 Grading of skin reactions The s kin reaction was assessed according to the numerical sco ring syste m of Draize et.a l (1944). 

### 1. ERYTHEMA AND ESCHAR FORMATION No erythema.................... . ..................................... ...... 0 Very s light eryth ema (barely perceptible)............. .. .. .. ......... 1 We ll-defined eryth ema.................................. ................ 2 Moderate to severe erythem a.......... .................................. 3 Severe erythema (beet redness) to sl ight esc har format ion (injuries in depth) ......................................................................... 4 

### MAXIMUM POSSIBLE SCORE - 4 2. EDEMA FORMATION No edema 0 Very sl ight edema (bare ly perceptible) .......................................... 1 S light edema (edges ofarea we ll defined by definite rai s in g) ......... 2 Moderate edema (raised approx imate ly 1 millim etre).... ................. 3 Severe edema (raised more th an 1 mill imetre and extending beyond area ofexpos ure)............................................................... 4 

### MAXIMUM POSSIBLE SCORE - 4 Copy No. 2/2 Page 14 /46

### 9. RESULTS The toxic s igns, body weight and pre-terminal death s are prese n ted in Tab les I a nd 4. The sk in reaction sco re s are s hown in Table 2 and mean s kin reactions are presented in Table 3. 9.1 Toxic sig ns and pre-terminal deaths Refer to Table I and Table 4 There were no toxic signs and pre-terminal death s during the co urse of the experiment. 9.2 Body weights Refer to Table I The body we ight s ofa ll the rabbits in creased through the observat io n period. 9.3 Skin reactions Refer to Table 2 and Table 3 There were no sk in reaction s observed III 

### any of the rabbit s throu gh the observat ion period. 

### 10. 

### CONCLUSION Under the te st in g cond iti ons of thi s study, the test su b sta nce did not s how any ev idence ofdermal irritat ion. 11. 

### ARCHIVING The original signed final report wi ll be se nt to the Sponsor and one s igned final report wi ll be retained by Advinus. The original raw data , documentation, record s, the orig in al s tudy plan , and final report generated as a result of thi s st udy w ill be se nt to the Sponsor for retention fo ll ow in g s ignin g of the final report. Copies of the same (authorized by the Study Director) wi ll be retained by Advinus. Adv inu s wi ll maintain these record s for a period of at least five yea rs. After thi s time, the Sponsor of the s tudy will be offered the opportunity to take po ssessio n of the record s or w ill be charged an arch i ving fee for continued archiving by Adv inus or to dispose of the raw dat a in consu ltation w ith the Sponsor. A repre se ntativ e sa mple of approx im ately one gram of the te st s ub stance was se nt from the test s ub sta nce s tore s to the archives in the te s t fac ility before the fir s t di spen s in g of test substance to studie s . Thi s sa mple Copy No. 212 Page 15 / 46

### s hall be stored for a period of 2 years from the date of this final report or ti ll next GLP in s pection , whichever is later , howev er not beyond 5 years. In 

### the event of any in spect ion by regul atory authorities , seek in g origina l raw data for verification, the s pon so r would be re spon s ible either to se nd the original raw data to Advinus Therapeutics Limited or to the regulatory agenc ies for verification. 

### 12. REPORT DISTRIBUTION

Copy No. 212 

### The final report (original copies) wi ll be di s tributed as follows: Test Facility Archives: On e s ig ned final report in original (Copy No. 1/2). Sponsor: One s ig ned final report in origina l (Copy No.2/2) and one Soft copy ofthe report in PDF format.

Page 16 /4 6Copy No. 212 

### 13. TABLES

Page 17 / 46

### TABLE 1. Body Weight and Pre-terminal Deaths Body we ight 

### (kg) Rabbit At Start of At treatment At

No. Sex Acc li matization (Day I) Termination 

### RB8764 M 

### 2 . 54 2.77 2 . 9 1 RB8765 M 

### 2.71 2 . 81 2.95 RB8766 M 

### 2 . 89 2.94 3 .14 M: Male , Note: T he re we re no pre -terminal deaths.

SKJN Page 18 /46 Co p y No. 212

### TABLE 2. Skin Reaction Score s Ra bbit Treatm e nt Sex peri o d N o . (hours) RB8 7 64 M 4

RB8765 M 4

RB8766 M 4 M:Ma le; 0: N o E ryth e maIN o Edem a

C opy No. 2/ 2 

### Ob se rvation time (po st remova l of

t he te s t patch) I hour 24 hours 48 hour s 72 h o ur s

I hour 24 hour s 48 hours 72 hours

I hour 2 4 hours 48 h ours 72 h o ur s Er ythema Ede ma Tota l score Score s co re

0 0 0 0 0 0 0 0 0 

### 0 0 0 0 0 0 0 0 0 0 0 0 0 0 

### 0 0 0 0 0 

### 0 0 

### 0 0 0 0 0 0

Page 19 / 46

### TABLE 3. Mean Skin Reaction Scores Ob se rvation (post remova l of Erythema Score Edema Score Tota l Mean Score

the te st patch) I hour 0 0 0 24 hour s 0 0 0 48 hour s 0 0 0 72 hOllr s 0 0 0

Page 20 / 46 C opy No. 212

### TABLE 4. Individual 

### Toxic S ign s Ra bbit Day of Ob s e rvation

No. Sex Day I 2 3 I hour 2 h o urs 3 hou rs 4 hours 24 hours RB8764 M N N N N N N N RB8765 M N N N N 

### N N N RB8766 M N N N N N N N M: Male; N: Norm a l

Page 2 1/46 C op y No. 2/2·SKlN C opy No. 2/ 2 

### 14. APPENDICES

Page 22/ 46

### APPENDIX 

### 1. Cert ific ate of Ana lys is Page 3 of 19

2oft8 CERTIF l CATE OF ANALXSlS FOR TESTIREFERENCElCQNTROL SUBSTANCES Tl TLE/OBJ£CT IVE: TF.ST/R[FERENCEICONTROL SUBS TANCE: DESCRIPTION :

CAS No., "'"' STRUCTURE: MOLECULAR WEIGITT: STUDYTN TTIATION DATE: 15June2010 METHODS USeD: PURITY: Gas chrontltography with name ion iutiOIl dettclion {(;C.FID) IUld Karl Fischer li lr.llion. IDENTIFICATION; Fourier Transfonn- Inframl (FT.IR) spectroscopy IJId gas c hromatography.mass**s~ctromctry** (G C-MS) R£SULTS AND CONCLUSIONS: Structural confirmation ofLhc**t~ 1**  malerioJ was performed byFT .I R and GC·MS. x PURITY DETERMINATION Result: oonfidcooc l e vel ) after correcTing f or the Karl Fischer witer**esurL~.** OTHER (S pecify) ; 655 ppm water by K arl Fischer titration. No impurities were detected lit**~** O. J % by GC-FID analys is . CA LCULATIONS: Arc. Percent: x (GC-FID) Internal S landMd : N/A External StandMd; N / A Odler (e.'plain): Karl Fischer "trn llon AJI ori ginall1lw data assoc iated with th i, study were archived in the Sponsor fa ci l ity arc hlv!:. Only desCliptive statistics were used unles s otherwise noted in tile re s ults. This study wu cunducted in acco r dAnce wilh the Good Laboratory Practice Standud, 40 CFR Part 792 unless ollierwist' nuted. Due to the shurt letm nature ofthc: study, the stnbilily ofthe les t s ubstance under storAge conditions pcr 40 CFR Pnrt 792.1 05(e) lit Ihe lest site was 1I0t verified. Comp letion Date: 

### 7j"",ba ro



### _____ u.<kl. ;Lo.JQ_' __ _jl",rSTUDY DIRECTOR AND TEST ING J ; ACILTTY ADDRESS: Impact Analyti cal, 1910 W. 51. Andrews Rd. Midland, Mr 4&640 

### THI S IS A TRUE COpy OF TH E**ORrG1NA~ D,~**  

### .. 

### :·:.!\ 

## CAe 12-2.3 -- 10

SK I N Copy No, 2/ 2 Pa ge 23/46

### APPENDIX 2. Study Plan STUDY PLAN
STU DY PLAN No. : SPTEST IT EM CODE I3Y TEST fAC I LITY : 1)08 - 2 6 STUDY CODE : SK IN 

### ACUTE DEHMAL IRRI TATION STUDY I RABmTS

C op)' No . **I I**  **I** SKJN Co p y No. 2/ 2 

### TEST ITEM: STUDY No . : SPONSOR Dow E u rope GmbH Bach t obelstra sse 3 e lI- 88t 0 Horgen Sw itzerla nd

TEST FACILITY DEI'A ETM E N T OF SAFETY ASSESSMENT ADVINUS THERAP EUTICS LIMn- ED POST BOX No. 5813 . PLO T Nos . 2 1 & 

### 22 

### P EENY A II P H.ASE, BANGALORE - 560 058 I NDIA

Pa ge 1/16 Page 24/ 46

### APPENDIX 2 contd. Study p lan CONTE TS I. ST U D Y D E TAI LS ... . .... " " . .... "". ". ".". " ... ,, " .,.".

. . .• " .... " ...• " . ,, " . "",4 

### 2. 

### QU ALI TY ASS U RANCE " .. . " . "." "". "" " ."" ....... " " . . . .. .. " " . . . . . . .... " ",,5 J . 

### GJ.P C OMPLTANCE " .. . "" . ... ". """""" "" " ". " .. . . . .. " . ... .. " ".,,"" . . . . ". 

### " ,,5 4 . TES T PRO CE D U RE G U ID E LI NE S """.""""" . . . •,, . " " . . ""." " " .. "" ",,0 

### 5. AM EN D 

### l EN T PRO CE DUR E S."."" . "" ... . " ." " " .... "" .. ,, .• "".,,""" " " 

### ,,0 (, . S A r:ETY PRE C A U T I O NS .". "" ." " " " ". " . " . . . . ••"" ... . .•• ". " . . . .. . "",, ... 

### "".6 7. OB J EC TI V E ".""". " """ .. ,, . ,, . "" . . ""."" .. """."."""."",, .. ,, . ,,"" " " " """ 7 8. J U STIFI CA TION FOR S E LE CT ION O F TE S T SY STE M " " " .... ".".7 

### 9. JUST ' I F I C ATIO N FOR R O U T E OF ADMIN I S TRA TI ON" " . " . . .. 

### ". " .7 10 . MA T E RTAT.S A N D M E THOD S. """ " """" " " " " . . " .. . " "". " ". " "" .. " .. ,,7 1 0 . 1 Mater i a l s.". " . .. " ".""" .. .. . "",, . " .. "" .. ,," " ". " .. . . .. """ . . . ... .. " ...... " . . "" ,, . " .. 7 10 . 1.1 1 0.1. 2 10 .2 1 0 . 2. 1 10 .2.2 

### 10.2 .2. I 1 0 . 2 .2.2 1 0 .2.2.3 1 0. 2 . 2.4 1 0. 2.2.5 

### 10 .3 1 0 .3. 1 1 0 . 3 .2 1 0 .3.3 10 .3 .4 I I. 1 1. I 

### 12. T es t**~(cl1l** 

### ". " . "" . . """ ...... " "" " . " .. " .. ,, " . . . "" " " """ .. .. . "" " .. "" .". 7 Tes t S u bstance Inf o rm a t io n ... . .. . .. . ... . .... .. . ... ... . .. .. ......... . . , . , .... . ........... . .. .. 8 Me t h ods ... . . .. " .. . ... . . ... .. . ..... . .. . . .... . .. . •. . . .... " . . . .. " . . . .. . .. . .... ... ... .. ... .. ..... . . .. .. ... 9 Husbandry .... " . " . . " ..... " " .... .. .. . .. .. " ." "" " . " .... " " " .. " "" .. . ... " ".". ".9 l") e r f o rtn a n ce o f te s t ... .. ... _ . . . ... .. . ..... . . ..... . . ... ... ... . ... , . . . . .. . .. . .. • ... . .. . .. .. . . . . ... 10 

### Sampl e Pre p a rati o n " """ " .",," .... " .... . " " "" " ... " " .. . ". "." .... . ",," 1

# ° Prep£trati o l1 o f t es t an i mal s ... . . . ......... . .. . ... . . . .. . . . . .. .... . . . ..... .. ...... . .......... . .. 10 T es t in g o pt io n ................ . .. . .. .......... .. . ..... . . ..... . . . . .. .. . . .. 1 0 

### Te s l s ub s tance app l icati o n " ...... " ... " .... " .... ... " . . . .. .... " . " " " .. "" ... " " .. . .. 

### 10 Ex posu re 

# or anima ls ... .. , . . . ..... " ... . ... . . . . .. ... .. . .. .. .. ... .. ..... . .. .. . . . . ... . .... 1 ] O bse r v a ti o n s " ".""" ".".",, ... .. " " " ....... ". "."" "." .... .. " ... " ,, " ,, . "." . ,, " ,, " I 

### J C lini c a l Oh se r v at i on s .. . .. . .. . ..... . .. .. . .. .. . ••....•. . . ... . .. . .. . .... . .... . ... . ..•• . .. . ..... .. . 1 ] 

### B o dy w e ig ht s . " . . " . " .. . "" ... .... .. .. "."". " ".""." "" ..... .... .. ... " .. " .... ,, ." 

### I I Skill s co rin g .. ". ". ""." . " . .. . " "" .. " " . .. " .. ... " " . " ..... "" " .. " .. " .. .. " ... " I I 

### Gradin g 

## or s k i n re a c ti o n s . .. .. ... ... .. ................. . . .... .. . . . . . ..... . . . ......... .. .... . . 1 2 R ESULTS " ... ".". " .. """ " .. "" .. .. .... . " " " " ". ,,"" ' "'' ' ' . " .. " " .... .. ". " " .. " " . 1 2 /);\ '1'1 \ C OMPTl .l \ T I O N . . " ...... " ... " ... .. .. .. " .. ". " . " .. ". "" .. " .. .. " . . " .. " ... 1 2 REPORTI NG ... " .. "" .... . " ... ,," .. . " . . ".". " .. ..... .. " ". " . " . . " . ,, " " ... " """. "" 1 3 SP -G7 693

_ SI<IN Copy No. J II Pagl' 21 16

Co py No. 2 /2 Page 25 /46

### APPENDIX 

### 2 eoutd . St udy piau 13. ARCH I V I N G ... .... ...... . . . ... .. .. . . . ... . . . . . .. ..... . . . . . ....... . ... .. 14 14. ST U D Y PLAN D l s TR I Blr nON .. ........ ..... .. ........ . .. ...... .. .. ....... .. ....... 14 1 5. R E P O RT DI ST RIB UT I ON .... . . . .............. .......... . . . .. .. .. . .. . . .............. 15 16. R EFERENCES .. . . .. ......... .. ..... . .. ....... .... ..... .... . ... . ........... ..................... . 15 1 7. AG R EE ME N T ........ .......... ........ . ........ . .... .. ... . ............. . .... ........ . . .. .. . . . .. . 16

S PC Oll Y N o . I II
C opy No. 2/ 2 Pag e 3 / 1(;

Pa g e 26/46

### APPENDIX 

### 2 contd . Study plan I. STUDY DETAILS Study T itle 

### Test subs tance Study - Number Test F a c ilit y

Sponsor

l\1oni (oring Scient is t

Study Pers onne l Study DirccLO r Te c hnical Co-o rdin ato r Cli ni cal Vet e rin ari a n S Iuely Sc h ed ul e S tud y initiati o n date Expe ri menta l start in g du t e

SP· SKtN Co py No. III ·SKIN C opy No. 2/ 2 Ac u te Dennn i I rr i tat i on st ud y in Rabbits ( Department o f Safety J\ s sessment Advin ll s T' herapeulics Limit ed PasI Box 1 o. 58 1 3. Pl o t Nos . 21 & 22 Pcenyn 1I**Phas ~**  Banga l orc 560 058, IND IA Dow Europe GmbH Bacht ob clstra ssc 3 Cl 1-88 10 B orgen Switze rl c ll1 d Donna Anderson The D ow Chemica l Co mpany Toxicology & E n vi ron m enta l Researc h 

### & Consu ltin g (TERC) [3ui ld ing 5 727 orri stown Road. 1'.0 . B o x 904 Spring House, PA 1 9477-090 4 Ema il :**DOl1r}(lAnder~on dow** **coll'l** 1' . J. Prakash, M.Se. S. B. Mo h an Kumar. ! " I. Sc. S. Rlllll es h , B.V.Se. & A.H. J 8 February 2011 18 February 201 J

PlI gl' **4 /**  **1 (i**  Page 27/46

### APPEND IX 2 contd. Study plan Accl im at ization


### Treat ment Observat i o n s Expe rimental cOl llpl ction date Draft rep o rt S tud y completion datc Start: 18 February 20 II End : 22 February 20 11 (single an imal) and 23 February 2011 (add iti onal two 

### an imalJs) 

## * St art: 23 February 20 11 (si ng le animal) 24 February 2011 (additional anima]!s)" S tart: 23 February 20 I I Lat es t 

### by 1 5 March 

### 20 II La test by 31 Marc h 20 I I La tes t by 

### JUlle 20 I I

• . \Vill be incl uded i fl h c test sub stflnce prove s to be non ·corros i ve and i or n o t a severe irri tan t depending on the si n gle anima l te st obscrv aii o l1 s . Th e confi r matory**t~ l**  Illay be conducted in a seq l1cntial man ner us in g o n e an imal p l.! 1' step or u sing l\.v(l a dditional animal s. The de ta ils 

## or confi rm ato ry t es t wiJl b e included in the report. 

### 2. QUALITY ASSUUANCF. Tile Qua lit y I\!=isurance U ni t o f Advinlls Ther a p e llti cs Li m ited. Dangalore - 56 0 058 , Ind ia, w ill inspect the s tudy , the**r~l\:v** dnta. the draft "nd fina l rep o rt. F indin gs of 

### a ll in s p ec ti ons wi ll 

### be re p orted to the**~1ana gc** **l11enl** and to the Study Direct o r. rn spec ti ol1 dat es an d reporting d a te s wi ll be entered in the study re port. Th e Quality Assurance Unit has reviewed th e final stu dy p l an an d will rec eive a copy thereor. 

### 3. GLP COMPLIANCE The s tudy w ill b e pe rfo r med in accordance with the J ollow in g GLP rcg u iatie)Jls: • OEe!) Pri n c ipl es ofGL P (as rev ised in 1 997), ENV I MC I CHEM (98) 1 7, OEeD, Pmi s, 1998. • JMAFF GL P Sta nd ards fo r A g ri cu ltura l C hemi ca l s: Il-No ll s anNo. 6283, I O cto ber. 1999 . 

### • Ee D i rec ti ve 2004 1 10 1E C , 

### Official J o urna l o f the Eu ro pe a n U nion , LSOI 44, Feb , 

### 20. 2004. 

### • This study will also b e c o ndu c ted as per th e Illutually " g reed study plan and th e Standard Opera tin g Pr ocedu r es.

S PCopy Nu. 1/ 1 Pa,-!c 511"

C opy No. 2/ 2 Page 28/46

### APPEN DI X 2 c ou t d . S tud y plan EXt..:Cp l io ll S (0 th e G L P complia n ce a r c Ii s tt:!d b elow: • Test ing h o m oge n eity. co n cc n tr a t io n and s labi Iit y of les t s u bs t a n ce i n th e veh icl e. • Arc hi vi n g of raw d ata at th e t es t f ac i l ity . • Exc epti o n to g u id e lin e 404, f or n.ot tes ti ng we ig ht of cvidc m.: c a n a l ys i s by the test fac il i ty. 4. TE S T PRO C E D U R E GUI!) E LINES T h e p roce du res as d esc rib ed in thi s s tu dy plan a rc b ase d o n th e io ll ow ing tes tin g gu i de lin es: • DEC O G ui de li n e rar Testi n g o f C h e m ic al s, Sect io n 4 , N um ber 404. '"A.cute D e rm a l Irri ta ti o n 

### I co rrof; i on," a d op ted: 241h Apri l 2002. • U.S. E P A H e a l th Ef f ects Test Gu i de li nes, O P P TS g70.2500. AC LIt e D eJ' m a ll rritation, A u g u st 1 998. • J M AI'!' 1 2- o ll sa n - S 1 47 , Nove mb er 2000. 

### • O ffic ia l J o urnal of th e Euro p ean Co n 1 1l1uniti cs Me thods fo r 1h<..' D cte rminat ion of Tux i c it y, P a r t 

### 13.4 (S k in I rritatio n ) . Di r ec ti ve 

### 20 0 4173!EC. 29 Apr i l 

### 2 0 04. 5 . A MEN D MENT PRO CE DURES A ll**am~ ndll1** **ls** to 

### un cl l or**cvifl ti** **~** fr o m th i s s t udy 

### plan and th e reasons th e r efore sha ll be doc u mented, dated . s i g n cd by t h e S t ud y D irec to r , a p p rove d 

### by manage m ent (a s may be re qu ired) a n d 

### m ai n tai n e d ,",vitb th e s lud y p la n . I f lmm e di a te ac t ion is ncccssnry, ve rba l ag r ee m e nt \,,' i th 

### lh e sponso r w il l b e co n firmed ;:1$ soo n a s p oss ibl e 

### by s tu dy plan amend m e n t. An y H lll enci lll cn t s to a n d /o r d ev ia ti o n s 

### fro l n thi s stu d y plan w ill be r eco rd ed i n t h e raw d ata an d doc um e n ted in t he fina l r epo r t. 6. S AFETY J>HE C A UT I O NS Glov e s, cap. n I Ce InHsk a nd gogg les ( i f re qui re d ) w ill b e use d in 

### ad d itio n to pro tec tiv e bo d y gn nn c nt s a nd s h oes to e n s ure adeq u ate p e r so na l h e a lt h and s a fe t y 

### a nd 1.0 

### av o id i n h a la ti o n a lld sk ill co n t ac t 'wi th th c tes t s u bsta n ce. In case of ey e contn e l , t h e l..'yc wi ll he \vas h ed 

### tho r o u g hl y , vi t h \va t e r 

### an d m e d ica l trc a tnH!llt \ ' 

### i ll be soug h t. 111 

### case o f ski n c ont ac t , it 

### , :v i I] b e \:vas h e d \v i th soap and 

### w a tcr w i th s u bsequc nt 

### I ncdical a id. S P C op )' No, I I I P a g e 6/ 1(I

Co p y No . 2/ 2 P age 2 9 / 46

### APPENDIX 2 contd. Study plan 7. OB.JECTIVE Th e o b jec t.i ve of thi s acute de rm al irri t ation s tud y i s to provide i nfo r ma t ion on th e potent i a l for sk i n corrosiv i ty **I** i r ritati o n a ri s in g 

### frol11 a si n g le topi ca l exposure to th e tcs t substa n ce. 8. .JUSTIFI CAT IO N FOR SELEC TION OF TEST SYSTEM Th e r abbit is the syS fcm 

### of ch o ic e**because ~**  

### h isto ri ca ll y , 

### i t h a s been the preferred and lno s t conllnon ly lIsed spec i e s for primary**~ki n**  irrit a t io n tests. 

### 9. JUSTIFICATION FOR RO UTE OF ADMINISTRATION



### to. 10.1 11l.l.! 

### Topical a ppli cat i on w ill be u se d because it i s re co mmend ed it< th e refere n ce d g uid e li nes , and bec a u se h t l111 a n e xp os u re 111ay occ ur via t hi s r o ute . 

### MATERIALS AND METHOU S 1\1atcr ials

' l ' cst SYS ( CIn 

### Ani n 1als 

### Sou rce

No. of 

### rabb it s B o d y \",e i g ht range al treat ln ent A ge at tn!a tmenl 

### ld ent i tication New Ze aland White R abb i ts Inh o use Bred (Outb red) N e w 

### Ze aland White R abb its Tox ic o l ogy Department of Safe ty As sc s s Il1 l.! nl 

### AdvillUS T h erap eu tic s Limited B a n ga lo re 

### 560 058, IND IA U p 

### to thr ee m ak 

### 2.2 to 3 . 2 kg Y o un g a dult (the exac t a ge w i ll be m en ti o n ed in thc repo rt) Uy 

### rabbit access ion 

### number. Id cnt ifi<.:ali oll o r 

### indi v idual n n i nutl is b y c a ge label. turm e r ic co l o llr body 111m " kin g.

S I' · S I(J N C opy N o . **t I**  **l** Pa g e 71 16 C opy No. 212 Page 30 / 46

### APP EN DI X 2 contd . S tudy plan

1 0. 1. 2 

### Rab bi t acc e ssio n numb e r s A ce l i mal i;(.a t ion 

### RB8 764 to R J3 87 6 6 A fter ph y s ic a l exmn i n a ti on fo r goo d h e alth a nd s u itabili ty f or ex p e rim e ll( , 

### the ra bbit s w ill b e acc l im a ti zed [or a t l eas t fi v e d ays b ef o re trea tm en t. T e s t S ub sta n ce I nf orJll n tiuli 

### (As fUl11i s h e d b y rh e Spo n so r)

T es t s u bs tan ce / J 

### (e m 

### L o t No. M a n u f a c t.ur cd b y (Na me a n d A ddress) S up p lied by (Nam e a n d Ad d ress) D a te of 

### Jll a nu fac lu re Dat e of ex p iry Pu ri ty as per Ce r t i f icate 

### of A n a l ys i s 

### Ph y s ic al app ea ran ce S to rage co ndi t io ns 

### Th e D ow C h e m ic a l Co mpan y Mid land . M I 4 86 7 4 

### U SA The D o '\ v C h e luic a i Co m p u n y 

### M i dland , M I 4 86 74 

### U S A N o t A ppl ica b le 06 M a rch 20 1 2

Of f - wh i te so lid 

### A m b i e nt ( +18 ( 0 

### + 3 6 " C ) T h e tes t s ubs( an c c . id c n t i ri ed a s B e n z o y l a (e d C a tec h o L 

### was re ce ive d o n 03 F e b r u a ry 2 0 1 I a nd wa s furt h e r iden t i f i e d as 0 08 - 26 b y te s t f a c i l i ty . R cferc n ce N umb e r d a ted 07 Fe hru ary 20 1 1 . T he tes t s u bs ta n ce is a soli d and is sto re d a t al11 bie nt con d i ti o n ( + 

### I 8 to 

### +36 ° C). Doc um e ntali o n of the me th o d s of sy n t h es is. fabr i ca ti o n . o r de r i v ati o n o f t he tes t s u bst anc e i s rcta i nc d by t h e 

### S p onsor. D Cl e r m inaU o n o f t h e sta b ility, icie n ti ty , s t r eng th . pu r i ty and co m pos i t i o n o f th e le st su bs t ance is th e res p ons i b ilit y of t h e stu d y Spo n ::;or.**~** r ol l o\ov in g i nformat i on re l ate d to t h e cha l 'a clcri;:,n ti on 

### o r th e tes t s ub s tance "vas p r ovi d e d 

### by th e sp ons o r . S P Co p y N o. II I C op y No. 2/ 2 Pa ge 31 / 46

### APPENDIX 2 contd. Stud y pl a n

10. 2 10.2.1 

### In f o rmmi on a s p rovided by 

### Spon so r a rc as f o l lows: pH : 6.47 (Ana l ysed ill -hou se). Specific grav ity **I** 

### density: No t App li cab le . Test substance is a so lid , Met hod s Husbandry 

### Co ndi t io n s A nit nals \ · vill be h O ll sed u nde r stan dard lab ora to ry co nditi o n s, ai r 

### co nditi o n ed v.dth adequate f resh a ir sup ply ( 1 2-15 air**chang~s oll** **.** 

### Environment: tempe r atu re 1 7-23 °C, re lative humi dity 30-70%. w i th 

### a J 

### 2 h o u r lig ht and 12 hour da r k 

### cyck. T h e Inaximulll 

### a n d minil111 1111 t e l l1p e r a tur c 

### a n d r e l a tive Inlln idit y in 

### the ex p c rilnou ta l f \.)om 

### wi ll b e reco rd ed o n ce dai l y. The relati ve hU111id i ty i n 

### the exper i me n ta l room \Ni l! be ca lcul ate d fro m d r y and wel bu lb temperat u re reco rdin gs. H o u s in g 

### l-lo ll sed indi vidu all y in rabb it cages (a pp rox. s ize : 

### L 65 x 

### B 65 x 

## r r 45 e m ) wi t h naryl s h allow cage 

### b o dy and faci l itie s [o r pcllctct! food (S tai n kss s t eel f eed h o pper) a nd drin k in g wate r (750 1111 markrol on bO ltle fitt ed 

### w i l 'h sippe r lube) . The liltcr collec ti on t r ay (noryl \ vas Le 

### tray) w ill be cha n ge d daily (except o n Sunday s), Diet: **ad libifum**  R,

abb it Ieed In(;tnufa<.:lurcd by Pranav agro I ndustries L td , Sangli, 

### Maha ra s h l l"a , India , wi l1 be provided ad libilur n 

### to the rabb its. T h e pr oc u red 

### feed w ill b e su bjected to ana lysi s of compos i tio n and th e an a l ysis report i n c lu de d in the re p o rt. Spec i fic con tami n ants (heavy m e ta ls o rga n oc h lor ill cs and o rgano ph osphH tes) i n the diet a r c a nal ysed periodically and t h e re port \ vi lJ be i ncl u ded in th e s tu dy ti le. \Valer: ad libitum 

### D ecp b o re-wel l wate r passed Uu ough ac tivated charcoa l t i lter and exposed to UV ra ys ill Aquaguard in-Jine \vuter fi h cr-{,; unl - purificr 

### m a nu fa ctured by E u reka rorb es Ltd .. MUlll 

### b a i - 4 0 0 00 I , IND I A , w il l b e prov i ded. The \vater bo ul e \vilJ be rep l e n is h e d O JH':C daily <- lIl ei**J~** Co p y ,,' 0. I I I P ngc 9/ 1(,

Co py No. 212 Page 32/46

### APPENDIX 2 contd . Study plan the \vate r bo ttl es changed o n ce a vl cck. Th e \ · va ter analy s i s**csu lt** **~** 

### w ill be 

### furni s hed in 

### t he re p ort. 10.2.2 PCI"formancc of te s t 

### J 0.2.2.1 Salnp lc l)rcparation A 

### qu an t ity o f 0.5 

### g of t es t it c I11 

### as r ece i ved w ill be mad e i nto pa st e by 

### adding s u ff i c ie nt voll1Jllc of "vater nnd m ixed w i th 

### a g lass r o d . 10.2.2.2**PI ~c** **plll'ntion** 

### of test aninlals Ap proxim at e ly 24 h o ur s bcfol'e trcnllnent, th e illr o n th e l e n side of 

### th e do r sola ter a l trun k s urf n ee 

### I ab ou t 1 2-20 x 1 8 - 20 e m 

### 1 w i 

### II be cl i pp e d v vilh a ll e lec tri c clipp e r**c~ cu** **la ®**  

### GC flnrln y. Ca r e 

### w ill be take n to avo id a bra din g the sk i n. A f ter clippin g and prior to app li ca ti on. th e anhna l's skin \-v ill b e c h eck ed for an y abno nll a li tics 

### acco r d in g to { h e " Primary S kin Irri tat io n Scori n g Sys te ln ". If 

### any si t e sco r es a r c greate r t h an ze r o, that aninHl1 \vill be re m o ved fr o m tcst a n d re p laced and ihis \'I.:i ll b e r ecorded in rn\.v da t. a a nd 

### \vill be reported. 10.2.2.3 Testing option 

### Th e s tudy will b e initi u te d with a ::;te pwisc p r oce dur e ( l + 2 R a bbi ts ) . 10.2.2.4 Test 

### s ubstance app lication P"cpnrntion of test S it e 

### App ro:< in 1a te ly () e m 2 

### i n tac t test s it e \ v ill be se lect e d on each an iJn al. The a dja <.:e ll( 

### u ntr ea te d sk in of eac h anima l \"i ll serve a s t h e co ntr o l site. Applicatiun of Test S lIb stllllCC /\ quant i ty of 0.5 g of te s t itC Jll 

### as received w ill be made in to pa s te 

### by addin g suffic ient volume of \ :va t e r and mixed 

### with a g J ass rod. Ge nera ll y, the t cs t. su b sta nce wi ll be 

### a pplied directl y to 

### tbe s kin of th e t es t si te, h owe ver. in so m e cases it may be n ecessary to apply t h e tes t s ub s t a ll ce 

### t o th e ga u ze p ad pri o r to a p p lic a t io n to e n su r e p ru p e r pl acc ll 1cIl l 

### <; tnd distribution. The e ntire trunk of each an im a l \v ill then be \vrapped wit h n OIl - ir rit a t.in g se mi -occ lu s i ve ad h es i ve tap e to avoid dislocation of th e patch.

_ Aninl nls 

### will b e expose d to th e t es t' 

### s ub s tan ce for a p e ri o d 

### of 

### 4 h o ur s. El iza b et han co lla r s v.' HI b e pla ced o n cach rabbit fo r 

### th e de s i g n ated expos ure perio d . S P Co p y No. I I I C opy No. 2/ 2 Page 33 /46

### APPENDIX 2 contd. Study plan 10.2.2.5 EX(losli rc of anirnal s

10.3 10.3.1

10.3.2

10.3.3 I n a s t ep,"v isc m a nn e r ( I ·t 2 R a b bit s) a ll th e t hree r a b bit s wi ll b e e xp ose d to the t(.; :<; t.**sub lan** **c** 

### c[lch \ , v ith 

### o ll e t es t pat c h 

### o nly f o r a 

### t'0 1.lr h O ll!" ex p o!-i ur c pe ri o d . Obscn ' ations Cl inical ObSCI"VH(ions H. a b bit s \vi ll b e o b se r ve d fo r rox ie s ig n s and pre-t e r mi nal d e ath s fo r th e fir st fo ur ho ur s ( at hourl y int e rv a ls) o n the day of te s t s ubstan ce appl i cati o n and o nc e dail y the r e a fter t ill the end o f the o b se r v ati o n . O b serv ati o n will i n c lu de gross e v aluati o n o f s kin a nd fur . eyes a nd JllUC () lI S ln e mbra n es. r esp ira tory , 

### c irc u lat o r y, a ut o n O lll<:lti c 

### a nd central n e rv o u s SYS t C 1l1 S . SO JlH : l lo m o t o r 

### activ i ty a nd b e ha v i o r p att e r n . Particula r a tte nti o n , · vi1l be d i rec ted t o obse rv ati on 

### o f t r en1 0 r s, c onv u ls ion , s aJi v a1ion , di a rrh e a and c om a. Jlod)' , veights Ind iv idual b o d y , -ve ig h( s o f the a nill1al s w ill b e r e c o rde d a t th e sta rt of ac clitl1 ati za t io n , da y I o f tre atll1ent Gu s t b efo r e tt: s l**ub J1c** **c** appJi cal i o n ) and a t termin a ti o n o f o b s ervati o n ! death . Skin scoring Fo ll o ,vin g th e e xp os ure p e ri o d. the p a tches v w'ill be J"en H)vc d ,mel th e app)j c at.i o n s it e wiU b e v :as h e d w ith w' at e r o r appro pri at e so l ve nt s u s in g cle an t o\ve l s t o r C I1l 0Ve a n y r es idual t es t su b sta n ce . Th e 4 h ou r appli cat i o n s it es wi ll b e c x alnin e d fo r s ign s o f e r y thc nu t u nd edema \-vi thi n 3 0 - 60 luinll t e s a nd a t inte r va l s of appro x in1ut c l y 2 4 . 4 8 an d 72 h o urs u n cr p a t c h re m o v a l a c co rdin g t o the.; "Pri r n il r y S kin Irr it a t io n Sco rin g S ys t e m" de v el o p e d by Dnd £:c . If th e r e i s n o e vid e n ce o f d e rm al i rrita ti o n in an y les t rabb it at 72 h o urs . th e stud y**,~ ll**  b e t e rminated . I f irrjtati o n pe r s i s t s in an y r a bb i t a t 72 h o u r s . sco rin g , . v ill co ntinue for all rabbit s al 7 . 10 an.d 14 d ay s a fter patch r Clll ov al or until a ll s i g n s o f i rrit a ti o n a rc c o mpletely r e versed (n s c o r e o f :t.. cro) in all n lbhi ts . \vhi c h cve r oc curs fir s t. In d i v i d ual sco re s wi ll b e rec ord e d f o r e aeh rabb i t. A n a rr a ti ve d escri p t i o J1 

# or per tinent s k in o b se rv a ti o n s Ul1d un y s i gns of g r o ss l ox i c i ty \-v ill b e re co rd e d . In a d diti o n. ev aluati o n o f th e r eve r s i b ili ty o r irr evers ih i l i ty o Ct h e o bserv ed effec t s \ · \l ill b e n o t e d . S P**co p~** **'** r\· o. I I I Pn gc 11 116 ·SKlN Co py No. 2 / 2 Page 34/ 46

### APPEN DI X 2 co nt d . Study pl a n J f at nny time durin g th e s tu dy. corrosion i s noted . (h e St udy Di recto r w i ll notify the S p onsor that the study !-iho u ld be terminated . 

### fr dama ge is extensive find the Spo n sor i s 1I 11a va i tab le to aut h ori ze tenninalion 

## or the stu dy, the S tu dy J)i rec tor m ay unilaterally decide to h ave th e a nima ls cU lh anizcd imm ed iat ely 

### for hUl1UII1C reaso n s 

### and the Sponsor 

### will be n otified 

### as suon 

### as poss i ble. 10.3.4 Grad i ng of sk i n l -cOlctions The skin reaction i s assesse d acco rd ing to th e numerica l s coring sys tem of Oraizc cut! (1944) .

1. ERYTHEMA AND ESCHAR FORMATION

No erythema ... . .. . .... . 

## o Very sl i g ht e rythema (bal'cl y perceptible)... ........... I Well - d e fined erythema ............................ . .. ........ . . ·· .. ·· .. · 2 Moderate 1.0 severe eryt hema ....... ....... ...... .... ... . .......... 3 Severe erythema (beet redness) to slight esc har for m ation (injur ies in depth) ........ ..................... . . . . . ........... 4 MAXIMUM l'OSSlULE SCORE - 

### 4 

### 2. EDEMA FORMATION

No eden l a . . ........ .......... . . .......... ....... ........ _. . .... ..... 

### 0 Very slight cdcl11u (barely perceptible) ................... 1 S li gh t edema (edges of area we ll defined by definit e raising) . .. 2 rV

l odcratc 

### cdenla (rai sed approximately I rni l lillll::lr c)... 3 Severe CdCJl1 .fl (raised m orc than I millimetre a nd exte nd i n g beyond area of exposlIre)............... 4 MAXIMUM T ' OSSrIlT,E SCORE - 

### 4 I I. RESULTS 11.1 Dat" compilation Tile following data wi ll b e recorded on datu sheets and transcribed fo r compi lati o n and a n a lysis : irrita tion scores. des c ript i on of" th e deg re e and nature of irritation. th e presence of dermal lesions. und allY erfeets other than cle nn " i noted ciuring clinical observat i ons and hody wei g ht s.

S PC op y No. I J I
Co p y No . 212 I' a ge' 1 2 / 1(i Page 35/46

### APPENDIX 2 contd. Study plan All finding s will be recor d e d in th e st and a rd rep o rl i n g f ormu ls and prese n ted in th e rep o rt. l2. 

### REPORTING Th e final r e p o rt w ill in cl ud e t he r o ll owi n g infonnnri o n : 

### y The nam e a nd a d d ress of th e s p o n so r a n d th e les t f aci l ity a lo n g w i th the s tu d y sc hedule . 

## >- Th e 

### nrul1c s and signat ure s of a ll pers o nn eJ invo l ved i n the s tu ciy . in cludi n g t h e St udy D irec t o r and other sc i e n t i s ts .**~** Tes t s ub s t a n ce: 

### • T es t s ub s tan ce 

### i nr o nn at i o n a s pro v ided 

### b y th e spo n so r . 

## >- D a t a derived a t e a c h s ta g e of t es ting strat egy, ;;.. Descr ip t i on 

## or r<::l evan t dat a ava ilabl e fro m prior t es tin g . J;.. T est anim a l s: 

### • species/s t rai n u sed; • l1L1111 ber ofcUlimal s o f eac h sex; • indi v idu a l a n inutl \ · \lc i g ht s a t s t a rt a n d concl u s io n o f t es t ; • age a t**eat l11** **t~** • so urce o f a ni nta l s . h o u s in g co ndit ions _ d j et. e t.c. r 

### Te st co n dit ions: • lec h niq u e 

### of patch si t e**prcpara n~**  • d e ta i l s of

### patch rn a te ri a l s lIs e d and patchin g tec h niq u e: 

### • detai l s of t est s ub s ta nce 

### p reparaUon, applicati o n and re ll1 o va l ; 

## >- Re su lt s: 

### • tabulat i o n o f irri t at i on/ co n -os i , o n 

### res p o n se**~co cs**  

### f or e ach a n i n u li at 

### t h e rinl e 

### p o int s nlca s urcd ; • d esc ripti o n 

# or a ll l esio n s observe d;

,.. A d esc ri pti o n of a ll r cs ui( s. 

## r /\ . 11 st ud y p l a n deviat io n s, 

### i f nn)' . .I"'" l n di vi duHll o xi<.- s i gns and necrop sy find ings ir a n y.**~** A d esc ript ion o f a ll c irclIIll s 1anccs if any that ma y 11:1\,(.' a lTc c k:d t h e q uali ty o r int eg r ity Ofl h c study . SI' - C opy No. 111 Co py No. 2/ 2 Page 36/46

### APPENDIX 2 contd. Study plan )..- The Qu a l ity As s urance S tatclnenL s i g n e d 

### by the Quality Ass Ufi : 1l

1CC U n i l. :;;... The GLP Co mpliance Stateme nt , s igned by the Study Dire c tor. 

### ? The s torage l ocati o n s of aU**ra v~'**  data . th e rep or t, a sampl e o r th e 

### te s t suh s tance and the arch i ving p e ri od. 

# » GLP c ertifi ca t es. 13. A R CH IVING The orig in al s igned final repo rt "..,ill be sen t to th e Spo n s or and o n e s ign ed final rep o rt wi l1 be r e ta ined 

### by Advi n us. Th e o ri g ina l raw data. dOClIll1Cn t al i on, re co rds. the or igina l st u dy plan , and fin a l report genera ted as a result of th js s tud y wi ll be se nt to t he Sponso r fo r re tentio n follo\.ving s igning of t h e f : inn l re p o rt. Co pie s of ( 'h e 

### sa me (a uthor ize d b y the St udy Director) will be retained b y Adv inu s . Advinlls 

### \. v ill maintain the se records f OI" u pe riod o f a l lea s t 

### fi ve years. After t h i s t i me. the S ponsor o f tb e st ud y will be of f ered the o pportunity to take p ossess ion of the re c o rd s o r ' ,"v iII be c har ged an a rc hivin g fee for contin u ed a r chiv in g by Advi nlls or to di s p ose of t h e 

### ra v l d a ta in co nsulta tio n w ith the Sp o n so r, **1\** repre se ntati ve s<i l npi e or approxi m ately o ne ,g ram o f the tes t 

### i te nl \,,-'ill be: s ent from th e test i te n1 s to re s t o th e archive s in th e te st 

### fa c ililY befo re; the fir s ! di s pensin g o f test it em t o st u d ie s. Th i s satnple sha ll be s to n:,' cI for 

### a p e riod o f 2 yea r s fr o l11 the date o f t bi s final r epo rt 01' 

### ti ll n ext GLP in sp e c ti o ll ;> \"vh ich cve r is laler, ho wever n o t be yo nd 5 years. ]n the e v e n t of an y in s pecti o n by regu l a t o ry**aut tie** **s~** see k ing o riginal nnv data for verification , the s p o n sor \.vQ u ld be**e~po iblc**  either to se n d the o ri gi n a l raw d ala to Ad v in us Thera p e ulics Limi ted o r to th e r egu l ato r y agcncic!) fo r vc riJjc at ion. L4. STUOY 

### l'LAN DISTRJBOTION Th e fill a l s tu dy plnn (o ri g inal cop ies) wi ll b e di stri buted as ( o ll ows: Spons or: S oft co p y of the sig ned S tud y p l a n i n PDF f o n llal an d one s i g n e d study p l a n in o ri g inal (Copy l'hL **1 /1**  **).** 

### St u dy D i r ector: On e s i gne d s tudy p lan i ll 

### o ri g in al (Copy No. I II).

S P C O P ) ' No. 1 / 1 Pag e 1 411 ( )

Co py No. 212 Page 37 / 46

### APPEN D IX 2 con t d. S tudy pl a n 15. REPORT DISTIUB U TlON The final report (or ig inal copies) will be d i stributed !I S follow s : Test Fac i lit y Archives: One s i g n ed t i nal report in o ri g inal (COpy No.1 /2). Sponso r : One signed fina l report i n original (Co p y 'l"'os.2/2) and One 

### Soft copy of th e r c p nrt in 

### PDF for m a t . 

### 1 6 . HEFERENCES I. LJ raizc, .1.11. , W oodward, G and Cnlvc ry , H.O (1944) . .I .Pharm aeo l. Exp.Th e r .83: 384. 2. Dra ize . .l..I 1 (1959) : Dermal Toxici ty In : Appraisal o [tl", snrcty o f chemicals in**Foods~** Drugs and COSll1 c ti cS . Association o f Foo d a nd Drug Officia l s o f the United S tates, Aus t in , Texns. 

### p.47. 3. OECD (2000) Guidance D oc u ment on t he R ecogniti on. 

### Assess r nent and Usc of C li ni ca l Signs as I-lunl a nc 

### Endpoints for 

### Experi m e ntal A nimals**U~c d**  

### in S afe ly Evalua tion Env iro n me ll ta l Health an d Safety**~I]onog 'a** **ph** S er i es on Tes tin g and Assessment No 1 9 . (ENVI.I M /MONO(2000)7 .

S I' - S KIN C(' " y No. 

## Til P lI J!. 4. ' 1511 6

Co py No . 2/ 2 I 'age 38/ 4 6

### APPENDIX 2 contd. Study plan 1 7 . AGREEMENT T hi s S tu d y I'lal1 f o r Study No.: : A c u te derma l irrit ati o ll / co rros ion s tudy in Rah bi ts " h as b ee n mutuall y agn.!(! d and s ig n ed. 

### S ponsor Sludy plan AIlp/'ovIII: T he fin n l ve l' s io n or th e s tudy plan was a ppr ove d b y e m ail fi ' om the stu dy m o ni to!' o n 1 7 Feb ru a ry 201 1 fo r Study Direct o r 's Si g nature. 

### for TEST FACILITY

STll D Y DIREC T O J{ Date: III**~"** 

### r eb ?o 

### II

Q U ALITY ASSU J{i\ NCF. UN IT O a tc : 

### I 

### r, t " (-eb ru..""1 2 01 1

S P Co p)' No. I / J Page ' M i ll ·SKIN C opy No. 212 Page 39/ 46Copy No. 212 

### 15. 

## ANNEXURES

Page 40 / 46

### ANNEXURE 1. 

### Ana lysis Report - Animal Diet Samp le ADVINUS THERAPEUTICS LIMITED 21 & 

### 22 , PEENYA INDUSTRIAL AREA, II PHASE BANGALORE • 560 058 ANALYSIS REPORT· ANIMAL DIET SAMPLE From: Analytica l R &D Department Advinus, B an ga lo re·560 058 To: D epartm ent of Safety Assessment Advinus, Bangal ore-560 058 Our Ref. No.: WCrr FS/216 1 Date: 27 . 12.2010 Samp le Detail s: Name : Rabbit Feed Sampling D ate: 03.12.2010 Batch No. : 60602 Supp li e r : Pranav Agro Indu strie s Ltd., Bang alore Manufacturer : Pranav Agro Indu strie s Ltd ., Bangalore

SI. No. Parameter I. 

### Moisture 2. Crude protein (N x 6.25) 3. Crud e fat (Ether extract) 

### 4. Crude fibre 

### 6. Acid in so luble ash 7. N itroge n free ex trac t 8. Ca l ci um (Ca) 9. P h osph oru s (P )

Co py No . 2/2 

### ANALYSIS RESULTS (Ana lysis On 

### "as is basis") (%) 12.59 22.51 3.88 1.97 3.62 48.93 0.56 0.10



### Analytical R&D Departm ent Page 41/46

### ANNEXURE 2. A nal ys is Report - Wate r Sa mp le ADVINUS THERAPEUTICS LIMITED 21 & 22, PEENYA INDUSTRIAL AREA, II PHASE BANGALORE 560 058 

### ANALYSIS REPORT - WATER SAMPLE Fr0m: Annlyti(,f'll R & n**l) pr~** **rtm f"** **nt** Advinus, Bangalore -560 058 To' np;pMlmf':n l of**S~\fp.,y A~Sf'** **"Smf'.nl** Advinus, Bangalore-560 058 Our Ref. No: 

### wcrrWS/256 Dat e: 24/01120 I I Sample Details: SOllIce of Collection: Outlet of the Aquaguard (At use point) Date of Collection: 10101120 II ANALYSIS RESULTS

S I. Parame te r No.

I. Colour 2. Odour 3. Turbidity 4. PH 5. E lectrical Cond uctivity, dSm " 6. Tota l solids, (ppm) 7. Suspended solids, (ppm) 8. Dissolved so lids , (ppm) 9. D isso lved oxygen (ppm) 10. Bi ochemical Oxygen D eman d 5 days at 20 °C,



### - (ppm)

II. Chemical Oxygen D ema nd (ppm)

SKJN Copy No. 212 Conte nt Colou rl ess Odour less

Clear 6.61 1.373 797

1 8 779 4.1 2.4 12.1 S I. Parame ter Co ntent No. (ppm) 12 . Total hardne ss as 495 CaCO , 13 . Calcium as Ca H 105 14. Mag nes i um as Mg l+ 57 1 5. Chlorides as 

### cr 334 16 . Sulphates as **S04 .L-**  58 17. Carbonates as C0 3 -- - 18. B icarbonates as HeO]- 370 19 . Sodium as Na 79.86 20 . Pota ss ium as K 6.39

6cpattmcnt
Page 42/ 46

### ANNEXU RE 3 . G LP Ce rtific a t e - Ge rman y d 

# I:

/. 

# Ii ;



# I

# I

S KI N Co p y No. 2/ 2 Bundesinstitul fLl r Risikobewert un g I

Federal In st it ute for Hi s k Assessment 

# F'Jt 

# BfR

fti..",." ••lC"''''' _G ...... . ... ' .., I ."h !il«o 

### GUTE LABORPRAXIS / GOOD LABORATORY PRACTICE (gernaB I accord in g to § 1 9b Abs . 2 N r . 3 Chemi k alie n gesclz J Germa n C h emicals Act) Eine 3LP - !ns p e klion wurde uurc l .gefOhrt in I A GlP inspectio ,l was carried ou t;;at Prlifclnri c htung I Test Facifity A.d vinus ThetdpP'JtiCs Limitc<t (f

o rme r n a m e u ntil October 20 1 0: A d vi nu s T herap e ut ics Private Lim i te d ) 2 1 & 22 P h ase II , Pcc n ya Industri a l A r ea Banga l oro - 560 0 5 8, INDIA Prl.lfk atogo ri cn I Area of Expertise Pro fu n gen z ur Bestirnrnung der ph ysikal i sc h - chem i schen Eigenschaften und Geha ft sbes tir mn ungcn , Physical -c hemical t esting PrOfungen z ur Bes timmu ng der tox i ko togisc h e n E igenschafte n I Toxici ty s tud ies PrO fu ngen z u r B es timmun g**erbgutver~ndernden** Eigenschaft e n (ill vitro, ill vivo) I Mvta genlci ty s tud ies Okc:oxikOlogisct,e PrO fun gen ? ur B es ti m mung der Auswirkl m g en au f aqua li sc h e u nd terrestrische Orga n is m en I E n vi r on mental to xi c ity st ud ies on aqua ti c and ter res tr ialorganisniG Prilfu n gen zum Ver ho l tc n i m B odon. im Waccnr und i n dcr L u ft : Bionkkwnuln t io n I Stu d ic:;; I)r l b e h avio ur in soil, water aod a i r : bioaccumulation P rOfu ngen zur Best irnm u ng v on ROckstanden I Re si due s tud ies Analytische PrO fun gen a n biologisChen Malerialien I Analylicat and dinical chemis t ry testing Sons l ige P r Ofungen - Biona n aly lik Pharmakokinetlk, Sicherheilspharmakologie I o t h er sludies - bioanalytics , pharmacokinetics and safe ty pharmacology Datum der In spektio n I Date of Inspect i on July 07 - 10 ,2 009 Auf dcr Grund10ge des In s p e kt io nsb erichtes und dcr Besprechung Obcr zu crfo l gendc Mal1nahmen wi rd hiermil**bcst~tigt.** do ss i n dieser PrOfeinrich t ung die obe n gensnnlen P rOfungel' unter Ei nhaltung d er GL P - G rund sl:itze durchgefOhrt werd e n k On ner'! . { B as ed o n the in spection re p ort tlnd th e d isc ussi o n of follow up a ctivi t ies it ca n b e confirmed , t hai th e te s t facility i s able to conduct I he afo re m en ti o ned s tudi es in comp l iance wi th th e Prir,ciples o f GLP . Eine OberprO fung dieser GL P ·Best l.t l i g u ng isl**sp~ te** **tens** dre i Jahre nach d er o. g . I nspektion zu b ean t rage n , O hne d iesen Antrag wird nach Ablauf der F r ist die PrOfeinrichlung 8US dam d e utsc h e n G LP ·Obe rwachur,g spro gramm gen ommen u n d d iese GLP-Bes tatigung verliert ihre G Oltigk ei t. I Veri ficati on of th is GLP Certificate ha s t o be applie d three years afler th e abo v e m e ntion e d in spection at the l a tes \. E l apsing this te rm. I he test fa cility will b e taken ou l o f the German GLP Monitoring Programme and th is GLP Certifi cate becomes invalid . N ovember 26, 20 1 0 

### /'! ;-".... 

# ';-:

. ) 

## .: ..J. / > auUdft$ ; n$t,tvt fur**~-o'lvng** t,:6clftta11r6i1i\u 1e for Risk A!;Ii6 Sllrnen l

. , . Th,elaUee 86·92 " 1410 S 0on i n .. GERMANY C' 

### '1 

# I! 

# 'I I I I 

# ,I ! 

# I 

# I I 

# I II , I .1 

# , i il 

# il !I !I -, I

Pa g e 43/ 46

### ANNEXURE 4. GLP Certificate - The Netherlands

vOedfIJl e n w a ren autorit e it 

## ENDORSEMENT OF COMPLIANCE WITH THE OECD PRINCIPLES OF GOOD LABORATORY PRACTICE

Pursua nt t o the Netherl ands GLP Co mp lia n ce Monitoring Programme and accord ing to Directive 2004191EC the conformity wit h the OEeD Pr i nciples of GLP was assessed on 4· - 7 May 2009 at

Adv inu s Therapeutics Private Li mited 21 & 22 Phase II , Peenya In dustrial Area Bangalore - 560 058 IND IA

It is herewit h confirmed ttlat t he afo r e - men t ioned t est fac ility i s cur re ntly opera tin g in comp l iance w i th the OECD Principles of Good I. ab o ra tory Practice in th e following areas of expertise: ph ys i cal-c h emical testing, toxic i ty st ud i es, mutagenicity stu di es , e nvironm en tal studies on aquatic and terrestrial a nimal s , and analytical Dnd clin ica l che mi s try .

C opy No. 2 12 F o o d .) n d C onsu me r P rod uct Sa fe ly Auth ori ty 0/'NA) Prtn ses B eafri xl a an 2. 2595 A L D en H aag Pos lbu s 1 9 5 00,25 00 

### eM De n H na g , Th e N ethe rl a n d s Page 44 1 46

### ANNEXURE 4 contd. GLP Ce rtificate - The Netherlands

Food and Con sume r Produ ct Safety Authority h1inisIIY ot Agricullllre, Nawre and Food Qualiry

,. PO Box 19 506**~soo** C.N [)en ll all4} T he Netnerl , lIw:ls Advinus Thempeutics Limited for the attention of Dr. S. Natesan Vice President 21 & 22, Phas e II, Peenya Industrial Area Bangalore - 560 058 INDIA

Date 18 November 2010 Re. Change of name
Dear Dr. Nate san, I have received your letter of 26 October 2010 in good order. In yOllr Ictt e r you explained that Advinus Therapeutics Private Limited has changed its name into Advinus Therapeutics Limited. Further, you stated that the change of name has n o consequences for Hie ow n ership and t hat th e test facility wifl continue to function as earl ier. Th e G LP Comp li ance Monitor i ng Aut h o rity of The Netherlands has periodically in spected Advinu s Therapeutics Pr ivate limited. The m ost recent i nspect i on was Ctl rri ed out on 4 - 7 May 2009. Subsequently, the inspecto rate issued an En dorsement of GLP Compliance o n 27 August 2009. Th is endorsement refle cts the name of the test facility at t h e time of the inspection and will not be renewed unti l a new inspection has been conducted. Yours sincerely,

Manager GLP Compliance Monitodng Program

C opy No. 2/2**n~cs** Bca l r;xlllMt ] 2!.i9!lIlL Den**ia~9** PO 001( 19 506 25 -:: 0 e M Dcn Haag I he Nlltherlan os**wW .V""".1I1**  Con ta c t Dr. R.M.II. J,l spe'$ T ... 31 (0) 70 '14 84]69 M " )10 f ·, ) 1 (0)](14'1847'17**ob lilSPtlrs~** **vwa nl**  Ou r ref . Tfl. CVVYN20 I 01':933 J

Pa g e 45 /46

### ANNEXURE 5. GLP Certificate - India



## NATIOl'tAL GLP COMPLIANCE MONITORING **AUTHORITy** GOOD LABORATORY PRACTICE 

### GLP CERTIFICATE GLP Inspection was carried out at Advinus Therapeutics Private Limited, Plot Nos. 21 & 22, Phase-il, Post Box No. 5813 , Peenya Industrial Area, Bangalore-560 058, India in the following 

# areas ofexpertise: . • physical-cbentical testing • toxicity studies • mutagenicity studies . • environmental toxicity studies on aquatic & terrestrial organisms • studies on behaviour in water, Boil and air, bioaccumulation • residue studies • UJJlllYUQlI**~u** CUD.lCUI cnemJstry lesnng Based on the InspectWn 

### &e,>ort <Uld the fullow-up actWns taken by the te s t facilil)', it is confumed that the test facility is capable of conducting the above-mentioned tests/studies in compliance with OEm Principles of Good Laboratory Practice (GLP) and Norms, as adopted by th e National GLP Compliance Monitoring Authority. Ths GLP Certificate is valid for a period ofthree yeprs from November 7, 2008 subject to the condition thaI the test facility complies with the Term. & Conditions of the National GLP Compliance Monitoring Authority'. Document Number GLP-I0l.

Certificate No.: GLP/C-019 J.ssue Date:

SKlN Co py No. 2/ 2 24-12-2008 Helld National GLP Compliance MonJtoring Authority Depltrtmcnt of S,cience & Technology Technology Bbav811 New Delhi-110016



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