Document 3JBNemM3BVYKnvVo3Jy8bE60E

'Va*" 'W* AR226-2992 RECHERCHES B iO lO G lQ U E S Baugy, June 17, 1993 STUDY NO. 920083 E PRIMARY CUTANEOUS IRRITATION VMiT'/'ci l.-'r ;; Sponsor : ELF ATOCHEM SA La Dfense 10 Cedex 42 92091 PARIS LA DEFENSE FRANCE S^'!(i ' - T:-._ cH- 1;-' Ji .Company Sanitized. Does not contain TSCA 5 - Cl : 7S2'B3 F - TLCOPIE CO sF CFc FO . C U--i-; - RT "'2 C- <53*X7:3 - -\P. TRIAL COMPOUND : Cutaneous primary irritation index. SPONSOR SPONSOR CONTACT ADDRESS SITE OF TRIAL ELF ATOCHEM SA. : Mr REGNIER : La Dfense 10 Cedex 42 92091 PARIS LA DEFENSE - FRANCE : CENTRE DE RECHERCHES BIOLOGIQUES Chemin de Montifault 18800 BAUGY - FRANCE RESPONSIBLE STAFF FOR CERB : Scientific and Technical Director : S. RICHARD Pharmacien Docteur de 3me Cycle Matre en Pharmacologie Date Signature Head of Toxicology Department : C. AUDEVAL-GERARD Docteur Vtrinaire CES d'Ophtalmologie Study Director : C. BESSON DUT de Biologie Applique Date Signature Quality Assurance : C. VIGIER Y>[osJ 3 3 Date hCLS: Ar m a r Signature '<3 The present report is based upon the authentic experimental results obtained. Company'Sanitized. Do> contain w I w u / I I M U. C /iU U O O C j J This report consists of 33 pages numbered from 1 to 33 including 5 appendices. 1. SUMMARY CONTENTS Page 4 II. EXPERIMENTAL PROTOCOL ADOPTED 11.1 II.2 11.3 II.4 II.5 II.6 11.7 II.8 II.9 11.10 11.11 11.12 11.13 11.14 INTRODUCTION AIM METHOD COMPOUND ANIMALS APPLICATION OF COMPOUND CLINICAL MONITORING OF ANIMALS CALCULATION OF CUTANEOUS IRRITATION INDEX STEPS OF THE STUDY CLASSIFICATION DATA ENTRY OF RESULTS REPORT QUALITY ASSURANCE RECORDS 5 6 6 6 7 7 8 9 9 10 10 11 11 11 11 III. RESULTS 111-1 DEVIATION FROM PROTOCOL N 92.04.10.02 III.2 DATES OF TRIAL III.3 CUTANEOUS TOLERANCE 12 13 13 13 IV. CONCLUSION APPENDIX 1 : Protocol n 92.04.10.02 APPENDIX 2 : Technical data and Analytical certificate concerning compound APPENDIX 3 : Analytical certificate concerning foodstuff APPENDIX.4 : Analytical certificate concerning water _ APPENDIX 5 : Results data sheet . 16 17-23 24-26 27-28 29-30 31-33 Company Sanitized. Does noi confam TSC OBI v ^ u i i - O I y j u I I M U . C 7 Z .U V J 0 C I. SUMMARY The aim of this study was objective determination in the Rab properties and/or degree of corrosion induced by com poundf following single cutaneous application. the irritant 0.5 ml of c o m p o u n c Q I^ B H H B K ^ w e r e applied to the right flank of each of three rabbits. The left flank served as a control for the trial. A dressing held the compound in place for 4 hours on the flank of each animal. Any possible lesions were evaluated approximately one hour after removal of the dressing, then 24 hours, 48 hours and 72 hours later. Mean indices were calculated from results obtained from each rabbit at times 24 hours, 48 hours and 72 hours. Cumulative means of mean indices were : . Erythema : 0. . Edema : 0. Mean indices per rabbit, for the three times together were : . Erythema : 0 in all animals. . Edema : 0 in all animals. mam}In conclusi!on, compoundf _______ as found to be non-irritant for the skin of the Eftnpfty TStsnshad. ioss not contain TSCA ' .O CtKtS - blUUY No. 920083 E II. EXPERIMENTAL PROTOCOL ADOPTED ^Company Sanitized. Does not contain T p o * ~r- CtHB - b IUUY No. 920083 E 0 11.1 INTRODUCTION The protocol used for study of cutaneous primary irritation, complied with requirements of OECD Guideline No. 404 (May 12, 1981) and EEC Directives (67/548, 79/831, 83/467, 84/449) and enabled full evaluation of the reversible or irreversible nature of the effects seen. II.2 AIM The aim of the study was objective determination in the J F ta W ^ ^ ^ tiT ^ rrita n t jrop^rties and/or degree of corrosion caused by c o m p o u n c f | ^ ^ ^ H I H H ^ H [following its single cutaneous application. 11.3 METHOD , DermaMmtatioi^and/or corrosion following cutaneous application of compound f m ^ l i m P J t o the back of the Rabbit were evaluated by grading of the Cutaneous irritation reactions seen, using a predetermined score system. This method is not applicable to substances w ith a pH below 2 or above 11.5, with a predictable cutaneous corrosive action. The protocol n 92.04.10.02 signed by the responsible of the sponsor and by the experimenters may be found in appendix 1. A pre-study was carried out using one rabbit. Results showed no irritation, the study was continued in tw o other rabbits. This study took place in accordance with rules of Good Laboratory Practices as published by : - The French M inistry of Social Affairs and National Solidarity : State Secretariat Responsible for Health Instructions concerning Good Laboratory Practices (GLP) in the field of experimental toxicology. Instruction of May 31, 1983, Official Text No. 1065 ; Reference SN-S83/25. - Directive 87/18/EEC, this directive referring to Recommendation CC81/30 Appendix 2 of the OECD. - The Food and Drug Administration : GLP 21 CFR Part 58 of December 22, 1978 and amendments of April 11, 1980 and September 4, 1987. |pfeBipany .Sanitized. 'Oom WotContain TS'CCE ucriB - s i u u r imo. avouas b 11.4 COMPOUND The technical data and the analytical certificate concerning the compound are attached to the study report in Appendix 2. - Name - Origin and batch number - Record number (CAL) - Origin ELF ATOCHEM SA - Date received Saturday April 18 1992 - Amount 1 bottle of approximately 107 g - Appearance -pH 11.5 ANIMALS - SPECIES : New Zealand Albino Rabbit. - ORIGIN : CEGAV specialized breeding establishment (Les Hautes Nos, Saint Mars d'Egrenne, 61350 PASSAIS LA CONCEPTION, FRANCE). - WEIGHT : Between 1.5 kg and 2.5 kg at the start of the trial. - SEX : female. - NUMBER : 3. - DATE OF DELIVERY : On 01.04.1992. - ACCLIMATIZATION : For at least 5 days before the trial, in the zone where the experiment was to take place. Animals were selected on the basis of their general condition. - IDENTIFICATION : Animals were identified individually by ear clipping. . - HOUSING : Animals were kept in cages of standard size. Excreta were eliminated by unrolling plastified brown paper which was placed under the cages. These cages were kept in an air-conditioned (17C-21C) animal house, kept at relative humidity between 45 per 100 and 65 per 100, apart from during cleaning, in which non-recycled filtered air was changed approximately ten times per hour. The artificial daylight cycle was 12 hours light and 12 hours darkness. CERB - STUDY No. 920083 E - FOOD : UAR 112. An analytical certificate concerning this foodstuff is provided with the study report in Appendix 3. - DRINKING WATER : Tap water distributed ad libitum in polycarbonate feeder bottles w ith a stainless steel teat. A water sample was obtained every three months and sent to the Direction des Services Vtrinaires, 216 Rue Louis Mallet, 18014 BOURGES Cedex, FRANCE for analysis.The water analytical certificate in Appendix 4 corresponds to the sample obtained on the date closest of the start of the study. . II.6 APPLICATION OF COMPOUND C o m p o u n d | H | [ | H | H H ^ w a s applied to the dorsal cutaneous region. For this purpose, on the day prior to application, the dorsal region of each rabbit was carefully shaved over tw o symmetrical zones, measuring at least 14 cm x 5 cm, in relation to the vertebral axis. An AESCULAP FAVORITA II GT 104 electric trimmer was used, avoiding any damage to the skin. Any animal with damaged skin was eliminated from the study at the time of application. The left flank of each of the animals was left intact. A dose of 0.5 ml of c o m p o u n d ^ ^ H ^ B H B H V w a s applied to the right flank of each of the animals. The non-treated flank of each animal served as a control for the trial. C o m p o u n d y lH H H IH H V jw a s deposited on a gauze square of approximately 6 cm2. The side of the gauze in contact with the compound was applied to the skin. This gauze square was protected by a swab held in place with a URGOPORE microporous and non-allergic non-occlusive dressing, and the whole being held in place by COHEVET coalescent elastic and cohesive hypoallergenic tape. Dressings were held in place for 4 hours after application. The day of application was taken as D1 of the study. ^Company Sanitized. Does noi contain TSC r* CERB - STUDY No. 920083 E 9 JI.7 CLINICAL MONITORING OF ANIMAI S ^ m g x im a te l^ o n e hour after removal of the dressing and of compound H H ^ ^ ^ H H | | H t h e n 24 hours, 48 hours and 72 hours later, possible cutaneous lesions which may have appeared on the right flank of each of the animals were evaluated using the following score system. ERYTHEM A AND ESCHARS FO RM ATIO N No erythema Slight erythema (scarcely visible) Clearly visible erythema Moderate to marked erythema Severe erythema (reddish purple) with formation of slight eschars (deep lesions) 0 1 2 3 4 FO R M A TIO N OF EDEMA No edema 0 Very slight edema (scarcely visible) 1 Slight edema (contours well defined, visible swelling) 2 Moderate edema (thickness approximately 1 mm) 3 Severe edema (thickness more than 1 mm and area greater than that of application) 4 HJLCALCULATION OF CUTANEOUS IRRITATION INDEX Mean indices are calculated from results obtained for each rabbit at times 24 hours, 48 hours and 72 hours. The following are noted : - for each parameter, mean of indices for each rabbit for the three times (= mean index per parameter, per animal for the three times = Mi) The maximal theorical score is 4 (erythema/edema). - for each parameter, the cumulative mean (= sum of mean indices for the three animals 1 3 = sum of Mi/3). The maximal theorical score is 4 (erythema/edema). Company Sanitized. Does not contain t s c a r CERB - STUDY No. 920083 E 11.9 STEPS OF THE STUDY : A pre-study was carried out using one rabbit. Results showed, no irritation, therefore the study was continued in tw o other rabbits. 11.10 CLASSIFICATION The c o m p o u n d H H H IH ^ B B r lw a s classified irritant or non irritant on the basis of irritation indices obtained in accordance with the Directive 83/467/EEC proposed by the Official Gazette of the European Community. Compound is found to be irritant if : - cumulative mean (Cm = sum of Mi/3) is higher or equal to the values indicated in table I for at least one parameter. - or if, for at least one parameter, mean indices (Mi) are higher or equal to the values indicated in the table I in at least 2 animals. TABLE I PARAMETER Erythema Edema THRESHOLD IRRITATION VALUE 2 2 Company Ban?he. D'eR>fesiiMn ISSC CERB - STUDY No. 920083 E 11.11 DATA ENTRY OF RESULTS All data were recorded as and when obtained using files classified by the study number. 11.12 REPORT The report of experiment included all findings noted during the course of the study, and in p a rticu la r: - cutaneous reaction observed, - cutaneous irritation indices, - classification of the compoun 11.13 QUALITY ASSURANCE The Quality Assurance Unit ensured that working procedures relating to this type of study were strictly adhered to, by periodic inspections of random, over the course of the year. Data included in the report of the experiment were audited by the Quality Assurance Unit, in accordance with standard procedures at the Centre. 11.14 RECORDS The protocol, raw data, the correspondance, the report and a sample of the compound have been stored for five years at CERB, 18800 BAUGY, FRANCE, starting from the date of the final report. A t the end of this period, CERB will contact the sponsor in order to jointly determine to either : - continue the records, - return the data to the sponsor, - destroy the data. CERB - STUDY No. 920083 E w 111. RESULTS C Company Sanitized. Does not contain TSOA '***' CERB - STUDY No. 920083 E ! 111.1 DEVIATION FROM PROTOCOL N 92.04.10.02 : No deviation from the protocol was recorded during the study. The study was performed according to protocol n 92.04.10.02. III.2 DATES OF TRIAL - Date of start of the pre-study : 23.04.1992. - Date of end of the pre-study : 26.04.1992. - Date of start of the main study : 28.04.1992. - Date of end of the main study : 01.05.1992. III.3 CUTANEOUS TOLERANCE The results of findings are shown in Tables II (irritation indices at 24 hours, 48 hours and 72 hours and mean indices per parameter) and III (cumulative means for the three animals) as well as in the results sheet included in Appendix 5. Cutaneous application of compound reaction. caused no irritation rp'3pany Sanittie'a. tioes tfo!conia*TfiCACB CERB - STUDY No. 920083 E ; -+ Rabbit No 920457 TABLE Irritation indices (24h - 48h - 72h evaluations) and mean indices per parameter EVALUATION TIME 24 H 48 H 72 H MEAN INDEX (Mi) mm OO II II oo m 30 II O m D II o mmm DDO II II II oO o ooo II II II DLUC DLUC DLUC oO li II DLUC aLU o ooOO II II II II II QLU DLUC QLU DLUC aLU o ooO II II il II oLUc oLUc QLU DLUC 920458 ER = 0 oo II II cUcJ QLU 920459 ER = erythema ED = edema ERYTHEMA EDEMA TABLE III Cumulative means for the three animals Sum of mean indices of three animals 0 0- ' Cumulative mean (sum/3) = CM 0 0 cr; CERB - STUDY No. 920083 E - Cumulative means (Cm) of mean indices were : . Erythema : 0. . Edema : 0. - Mean indices per rabbit (Mi), for the three times together were : . Erythema : 0 in all animals. . Edema : 0 in all animals. Classification of the compound is : non-irritant compound for the skin of the Rabbit. Pompany Sanitized. Does not contain TSCA C!T CERB - STUDY No. 920083 E IV. CONCLUSION Cutaneous primary irritation following application of compound was evaluated in the Rabbit. ,Ur experimental conditions adopted, the classificatior sof: ncoonm-iprroiutanndt *compoundf0rth^lafH )O T eR aD D it * contain SCowpany San'f1eed.Dsnu* r.r- CERB - STUDY No. 920083 E APPENDIX 1 Protocol n 92.04.10.02 18 CERB - PROTOCOL N 92.04.10.02 Page 1 of 6 TRIAL Cutaneous primary irritation index. SPONSOR : ELFATOCHEM La Dfense 10 - Cedex 42 92091 PARIS LA DEFENSE SITE OF TRIAL : CENTRE DE RECHERCHES BIOLOGIQUES Chemin de Montifault 18800 BAUGY, FRANCE APPROBATION : SPONSOR CONTACT : Mr REGNIER 22/04//92 Date Signed RFSPONSIBI E STAFF FOR CERB : Scientific and Technical Director : S. RICHARD Pharmacien, Docteur de 3me Cycle Matre en Pharmacologie - 16/04/92 Date . Signed Head of Toxicology Department : C. AUDEVAL-GERARD Docteur Vtrinaire 16/04/92 Date Signed Study Director : C. BESSON 14/04/92 Date Signed Quality Assurance : C. VIGIER 16/04/92 , Date Signed 'CompanySanitized. Does noi contain TSCA * CERB - PROTOCOL N 92.04.10.02 Page 2 of 6 CUTANEOUS PRIMARY IRRITATION INDEX I AIM The aim of the study is objective determination in the Rabbit of the irritant properties and/or degree of corrosion caused by com pound^ following its single cutaneous application. II METHOD Dermal irritation and/or corrosion following cutaneous application of compound J U M M ^ H H B t o the back of the Rabbit are evaluated by grading of the ^ fo m e o u ^ ^ n a tio n reactions seen, using a predetermined score system. The protocol used for study of cutaneous primary irritation, complies with requirements of OECD Guideline No. 404 (May 12, 1981) and EEC Directives (67/548, 79/831, 83/467, 84/449) and enables full evaluation of the reversible or irreversible nature of the effects seen. This method is not applicable to substances with a pH below 2 or above 11.5, with a predictable cutaneous corrosive action. A pre-study is carried out using one rabbit. . .. If results shows no irritation or only slight irritation, the study is continued in two other rabbits. , ,, . . If results reveals an irritant effect (grade > 3 erythema and/or edema), the pre study can be continued until D8 and D15 to indicate the possible reversibility of lesions, though the study is not repeated in two other rabbits. This study took place in accordance with rules of Good Laboratory Practices as published by : - The French Ministry of Social Affairs and National Solidarity : State Secretariat Responsible for Health , Instructions concerning Good Laboratory Practices (GLP) in the field of experimental toxicology. 0 0 0 /0 r- Instruction of May 31, 1983, Official Text No. 1065 ; Reference SN-S83/25. - Directive 87/18/EEC, this directive referring to Recommendation Appendix 2 of the OECD. CC81/30 - The Food and Drug Administration : GLP 21 CFR Part 58 of December 22, 1978 and amendments of April 11, 1980 and September 4, 1987. III. COMPOUND FORAPERLE 321 : DATA SUPLIED BY THE SPONSOR : .... .. The substance information sheet and the analytical certificate were received on April 10,1992. DATA TO, BE SUPPLIED BY THE SPONSOR : please fill in the test substance information sheet. AM UNT OF COMPOUND TO BE SUPPLIED : 5 ml of compound bre required for the study. CERB - PROTOCOL N 92.04.10.02 zu Page 3 of 6 IV - GENERAL CHARACTERISTICS OF STUDIES : IV-1 ANIMALS - SPECIES : New Zealand Albino Rabbit. - ORIGIN : From CEGAV specialized breeding establishment (Les Hautes Noes, Saint Mars d'Egrenne, 61350 PASSAIS LA CONCEPTION, FRANCE). f- WEIGHT : Generally between 1.5 kg and 2.5 kg at the start of the trial. - SEX : male or female. - NUMBER : 3. - ACCLIMATIZATION : For at least 5 days before the trial, in the zone where the experiment is to take place. Animals are selected on the basis of their general condition. - - IDENTIFICATION : Animals are identified individually by ear clipping. - HOUSING : Animals are kept in cages of standard size. Excreta are eliminated by unrolling plastified brown paper which is placed under the cages. These cages are kept in an air-conditioned (17C-21 C) animal house, kept at relative humidity between 45 per 100 and 65 per 100, apart from during cleaning, in which non-recycled filtered air is changed approximately ten times per hour. The artificial daylight cycle is 12 hours light and 12 hours darkness. - FOOD : UAR 11 2 foodstuff. An analytical certificate concerning foodstuff is included in the study report. Company Sanitized. Does not contain TSCA CERB - PROTOCOL N 92.04.10.02 Page 4 of 6 - DRINKING WATER : Tap water distributed ad libitum in polycarbonate feeder bottles with a stainless steel teat. A water sample is obtained every three months and sent to the Direction des Services Vtrinaires, 216 Rue Louis Mallet, 18014 BOURGES Cedex, FRANCE for analysis. A water analytical certificate is included in the study report. IV-2 APPLICATION OF COMPOUND C o m p o u n c H ^ f lii^ H V l'S applied to the dorsal cutaneous region. For this purpose, o ^ t n ^ d a y prior to application, the dorsal region of each rabbit is carefully shaved over tw o symmetrical zones, measuring at least 14 cm x 5 cm, in relation to the vertebral axis. An AESCULAP FAVORITA II GT 104 electric trimmer is used, avoiding any damage to the skin. Any animal w ith damaged skin is eliminated from the study at the time of application. The left flank of each of the animals is left intact. A dose of 0.5 g of c o m p o u n d ^ H l H H B H ^ i s applied to the right flank of each of the animals. The non-treated flank of each animal serves as a control for the trial. The substance is deposited on a gauze square of approximately 6 cm2. The. sida of the gauze in contact w ith the compound is applied to the skin. This gauze square is protected by a swab held in place with a URGOPORE microporous and non-allergic non-occlusive dressing, and the whole being held in place by COHEVET coalescent elastic and cohesive hypoallergenic tape. Dressings are held in place for 4 hours after application. The day of application is taken as D1 of the study. Steps of the study : A pre-study is carried out using one rabbit. If results shows no irritation or only slight irritation, the study can be continued in tw o other rabbits. If results reveal an irritant effect (grade > 3 erythema and/or edema), the pre study can be continued until D8 and D15 to indicate the possible reversibility of lesions, though the study is not repeated in tw o other rabbits. IV-3 CLINICAL MONITORING OF ANIMALS Approximately one hour after removal of the dressing then 24 hours, 48 hours and 72 hours later, possible cutaneous lesions which may have appeared on the right flank of each of the animals are evaluated using the following score system. Observation can be continued until D8 and D15 if signs of irritation persist at 72 hours. "Zorn, not contain TSCft Gft CERB - PROTOCOL N 92.04.10.02 Page 5 of 6 ERYTHEMA AND ESCHARS FORMATION No erythema Slight erythema (scarcely visible) Clearly visible erythema Moderate to marked erythema Severe erythema (reddish purple) with formation of slight eschars(deep lesions) 0 1 2 3 4 FORMATION OF EDEMA No edema 0 Very slight edema(scarcely visible) 1 Slight edema (contours well defined, visible swelling) 2 Moderate edema (thickness approximately 1 mm) 3 Severe edema (thickness more than 1 mm and area greater than that of application) 4 IV-4 CALCULATION OF CUTANEOUS IRRITATION INDEX Mean indices are calculated from results obtained for each rabbit at times 24 hours, 48 hours and 72 hours. The following are noted : - for each parameter, mean of indices for each rabbit for the three times (= mean index per parameter, per animal for the three times = Mi) The maximal theorical score is 4 (erythema/edema). - for each parameter, the cumulative mean (= sum of mean indices for the three animals / 3 = sum of Mi/3). The maximal theorical score is 4 (erythema/edema). IV-5 CLASSIFICATION The c o m p o u n d P H H i s classified irritant or non irritant on the basis of irritation indices o b ta in e ^ in accordance with the Directive 83/467/EEC proposed by the Official Gazette of the European Community. Compound is found to be irritant if : '' - cumulative mean (Cm = sum of Mi/3) is higher or equal to the values indicated in table I for at least one parameter. - or if, for at least one parameter, mean indices (Mi) are higher or equal to the values indicated in the table I in at least 2 animals. Company Sanitized. Does not contain TSCA cm CERB - PROTOCOL N 92.04.10.02 23 Page 6 of 6 PARAMETER Erythema Edema THRESHOLD IRRITATIO N VA LU E 2 2 V - RESULTS All data are recorded as and when obtained using files classified by the study number. VI - REPORT The report of experiment includes all findings noted during the course of the study, and in particular : - irritation reaction observed, - cutaneous irritation indices, - classification of the studied compound. VII - QUALITY ASSURANCE The Quality Assurance Unit ensures that working procedures relating to this type of study are strictly adhered to, by periodic inspections of random, over the course of the year. Data included in the report of the experiment are audited by the Quality Assurance Unit, in accordance w ith standard procedures at the Centre. VIII - RECORDS The protocol, any possible amendments, raw data, the correspondance and the report, and a sample of the compound are stored for five years at CERB, 18800 BAUGY, FRANCE, starting from the date of the final report. A t the end of this period, CERB will contact the sponsor in order to jointly determine to either : - continue the records, - return the data to the sponsor, - destroy the data. IX - PI ANIFICATION : Date of start of study : Week of April 27, 1992. Results by telex : at the end of the study. Date of submission of the draft report : end of May 1992. Date of submission of the English summary : at the final report submission. womp?* n-yt coriia*n CERB - STUDY No. 920083 E APPENDIX 2 Technical data and Analytical certificate concerning compound Company Sanitized. Does not contain TSCA CBI SERVICE DE TOXICOLOGIE CONFIDENTIEL Avril. 1992 -J eif atachefn sa La Dfense 10, cdex 42 92091 Paris-La Dfense France FICHE D'INFORMATIONS IDENTIFICATION Nom commun Nom chimique Origine; n de lot N d'archivage (CAL) PROPRIETES PHYSICO-CHIMIQUES Apparence Viscosit Temprature bullition pH Densit Point d'clair Solubilit INFORMATIONS TOXICOLOGIQUES ET PRECAUTION D'EMPLOI Aucune information'disponible._____________________ CONDITIONS DE CONSERVATION ET DE DESTRUCTION Conservation Stabilit Destruction ' : A l'obscurit et l'abri de la chaleur. : Stable jusqu'en Avril 1993 dans ces conditions de stockage : Incinration- conta* TSC & D<>es n o t elf atochem sa 4, cours Michelet, cedex 42 92091 Paris La Dfense 10 France BULLETIN D'ANALYSE AT Jean-Franois Rgnier Service de Toxicologie APPENDIX 3 Analytical certificate concerning foodstuff CampmjrSmlllxe'l.Dossi'''" TM ' ' " " Kt. 3 AUMENT COMPLET LAPINS - ENTRETIEN Granuls : 4.5 mm Ration journalire du Lapin : suivant la race.-de 100 150 g -- Eau volont. FORMULE % Crales, 's u c r ...................................... 42,8 Issues'et lgumineuses-...................... - 49 Pirptines'vgtales (tourteaux)........... 4,2 Compos -minral vitm ins.............. 4 ANALYSE MOYENNE % V Valeur calorifique (C a l/k g ).......... -.. 2.200 ` Eau '. . I ............................................... 10 Protides .............................................. "13 '.Lipides - ................. 2.7 ` Glucides (EM AT't,'':...... .............. , . 4 9 .3 . ; 'Cellulose ^Wende);'.-................. 1 7 '. :Minraux . . -----v . . . . . : . : ; l v . 8 ; ` -- itLiv''.''.' M IN E R A U X 1 . . (calculs.e n m g /k g ) App. Nat. . (">oyJ App. par CM* TOTAUX P ........................... C a ....... ................... 4.100 4500 3500 4500 '7500 S.100 K ......... ..................... 10.600 0 10.600 N a ........................... M g ........... ............... 1.150 2.100 1J9S0 130 3.100 2230 M n ........................... 40 40 80 Fe ........................... 160 140 '.300 Cu ........................... 12 15 27' Zn .......................... . 30 45 75 C o .......................... ' I ............................... ' 0.1 1.S 1.6 apport cous forme assimilable par atQoe mer!ne. j i i 1 1 | 1 J j j I j 1 j l : V IT A M IN E S ^ B ^ ^ ^ g g - ; . (calcules au App. N at (m oyj App.Syrrtht TOTAUX V ctam . A __ . 2 5 5 0 . U l - ' 0*3 -30 . - .i . 430 - - 82 - 3.80 ' - 83 . 16 - - 8 6 .: 1 - . E ... '16 - ' - K3 - 6- PP . . 55 - C h o lin e ........ 850 - 6500 Ul 1500 - 0.00 mg . 0.00 - 0.00 110 15200 - 9350 Ul ij0 3 0 - 430 mg 3.80 16 2. 26 " 760 - * 1.050 - ..H CERB - STUDY No. 920083 E APPENDIX 4 Analytical certificate concerning water Physicochimie T urbidit en U Jackson Conductivit jiS/cm PH O xydabilit KMn04 mg/1 D uret en 'Franais T..C en "Franais Ammoniaque en m g/i N itrite s en m g/l N itra te s en mg/1 Sulfates en mg/1 SpChlorures en mg/1 F e r en mg/1 Manganse en mg/1 F lu o r en mg/1 Rsultats Normes* Bactriologie Rsultats 0 .3 652 7 .5 1 37 25 0 O 57 65 20 O <2 U 6 .5 -9 <5 < 0.5 < 0.1 < 50 < 250 < 200 < 0.2 < 0.05 < 1.5 Coliformes th erm o lo l ra n ts/ 100ml Streptocoques fcaux/ 100ml C o lifo rm e s /100ml Dnombrement des bactries arobies revivifables 3 7 C/ml ` - 22* C/ml Spores de bactries anarobies sulfito-rductrices/20m l - ' /100m l Salmonelles Staphylocoques pathognes : : : : : 0 0 2 < 2 0 *:Selon decretN89-3 etsuivants. <5 Normes* 0 0 0-95/2 ' si 0. 0 0 0 Bourges,le: Lundi 18 Mai 1992 Adj. Dir. du Laboratoire Le Directeur du Laboratoire Company Sanitized. Does not contain r*snn r pwpang Sanitt*.DoesnotcontainTS'OC5 CERB - STUDY No. 920083 E APPENDIX 5 Results data sheet CERB IRRITPARTOIDOUNITPRCIHMIMAIIQRUEECUTANEE Co ?.-- - > A ' " '" M u t " ' - 'I VjJ ETUDE N : c) ^ 0 0 % 3 ESPECE : Lapin Neo - Zlandais PRODUIT SEXE :-jftie. / femelle N LOT : DEBUT D'ETUDE : ? VOLUME -ewMASSE ADMINISTRE^ : O. HEURE DE DEBUT DE L'APPLICATION / FIN D'ETUDE . H. ^ _ r PARAPHE \ J O / c> -c>&9z. HEURE DE DEBUT DU DEMAILLOTAGE / PARAPHE :J U > & / C.S UMES LECERE N IE T O IfiPIN 5$ O L S f r EKEAEEE HEURE 24 H LATE .ce E= O 0=0 E= O= E= 0= J ^ lo /c s 48 H fflffi zia< E= 0= O E= 0= E= 0= [h 72 H TM z2(.(A E = C? E= 0= E= 0= 4 *30, ^ TO/TWNHylNLDICE D'OECE' NKEN * E= O o=0 E= 0=0 E= 0= 0= E = ` = 0= 0= C5 ^6 IM O IO 0 <W0I OOI' CBSERffiHaC DIVERSES -- T.TH3IJRB NIAEIN ^ 2 o L 57- HEREELAEEEHE 5H Q-oU. E= O= E= 0= J8 E= O= E= 0= E= 0= J15 E= O= E= 0= E= 0= // Company Sanitized. Does noi contain tro r w om il h Qo C.c.j CERB CE* T !Pns IRRITATION PRIMAIRE CUTANEE PRODUIT CHIMIQUE ETUDE N : 3 2 PRODUIT ESPECE : Lapin No - Zlandais SEXE : madr / femelle N LOT DEBUT D 'ETUDE : 6 $.ok-3t VOLUME m . MASSE ADMINISTREE : FIN D'ETUDE :'-/ O 5 -3 HEURE DE DEBUT DE L'APPLICATION / PARAPHE :3 \ / c 6 HEURE DE DEBUT DU DEMAILLOTAGE / PARAPHE S t i S o y c TEZS LECKRE N IE E O IP2N QhOkSd %0k&> EHERUHREEBE OO wIl oI ouIl ooI 24 H DKDE E= , 0= rt3o/ c s 0oI wIl oII 0 wIl 48 H EKIE z)Cfi{ E= 0= /c s 72 H DAEE :^S E= O 0= E= O 0= o E= 0= Ji"c& -/ totm/ qvdice H d C E /A N D A L MUKEN * E= O O=o E = <9 E= O 0=0 E=0 0=0 E= 0=6 -E = 0= 0= c6 5H l$-ok-32 J8 E= J 15 E= E= Q E= 0= E= 0= E= 0= E= 0= E= o oII o= 0= 0= ^//0 /c6 / / 'SanSriad. Uhs Kot tnisin Tca B?