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% AR226-3067 SPONSOR ElfAtochemS.A. Cours Michelet La Defense 10 92091 Paris-la-Defense CEDEX France STUDY TITLE ACUTE EYE IRRITATION IN RABBITS TEST SUBS STUDY DIRECTOR Stephane de Jouffrey STUDY COMPLETION DATE 28 January 1997 PERFORMING LABORATORY Centre International de Toxicologie (C.I.T.) Miserey - 27005 Evreux - France LABORATORY STUDY NUMBER 14888 TAL Company Sanitized. Doe& not contain TSCA CBi CONTENTS STATEMENT OF THE STUDY DIRECTOR OTHER SCIENTISTS INVOLVED IN THIS STUDY STATEMENT OF QUALITY ASSURANCE UNIT SUMMARY RESUME 1. INTRODUCTION 8 2. MATERIALS AND METHODS 8 2.1. TEST SUBSTANCE 8 2.1.1 Identification 8 2.1.2 Preparation ' 8 2.2. TEST SYSTEM 9 2.2.1 Animals 9 2.2.2 Environmental conditions 9 2.2.3 Food and water 9 2.3. TREATMENT 10 2.3.1 Selection of the animals 10 2.3.2 Study design 10 2.3.3 Administration of the test substance 10 2.3.4 Date of treatment 10 2.4. OCULAR EXAMINATIONS 10 2.5. DESCRIPTION AND EVALUATION OF OCULAR REACTIONS 11 2.5.1 Conjunctiva! lesions and discharge 11 2.5.2 Iris lesions 11 2.5.3 Comeal lesions 11 _ 2.6. INTERPRETATION OF RESULTS AND CLASSIFICATION OF SUBSTANCES 12 2.6.1 Interpretation of the results 12 2.6.2 Classification of the test substances 12 ' 2.7. ARCHIVES 13 3. RESULTS (table 1) 14 4. CONCLUSION 14 Table 1: Individual ocular examinations and mean values'ofthe scores recorded at each reading (24,48 and 72 hours) for each animal 15 Company Sanitized. Does not contain TSC^S APPENDICES 1. Test article description 2. Diet formula 16 17 19 and 20 Company Sanitized. Does not contain TSCA CBI STATEMENT OF THE STUDY DIRECTOR The study was performed in compliance with the following Principles of Good Laboratory Practice Regulations: . O.E.C.D. Principles of Good Laboratory Practice, Decision Concerning Mutual Acceptance of Data in the Assessment of Chemicals, C(81)30(final) Annex 2. May 12, 1981. . Decret N 90-206 du 7 mars 1990 concemant les Bonnes Pratiques de Laboratoire (Journal Officiel du 9 mars 1990), Ministere de 1'Industrie et de I'Amenagement du Territoire. I declare that this report constitutes a true and faithful record of the procedures undertaken and the results obtained during the performance of the study. This study was performed at the Centre International de Toxicologie (C.I.T.), Miserey, 27005 Evreux, France. Toxicology -t 'S. de^iffrd Study Director Doctor of Veterinary Medicine Head of Short-term and Environmental Toxicology OTHER SCIENTISTS INVOLVED IN THIS STUDY For Pharmacy: J. Richard Doctor of Pharmacy For Toxicology: C. Pelcot Study Supervisor company Sanitized. Does not contain TSCAG STATEMENT OF QUALITY ASSURANCE UNIT 1. Specific study inspections Type of inspections Inspections Protocol Report 21 Oct. 96 20 Jan. 97 Dates Report to Study Director (*) 29 Oct. 96 21 Jan. 97 Report to Management (*) 29 Oct. 96 21 Jan. 97 2. Routine inspections performed on other studies of the same type according to a frequency defined in Q.A.U. procedures Inspected phase Inspections Dates Report toReport to Study Director (*) Management (*) Treatment/test substance Preparation/test substance 20 Aug. 96 25 Sept. 96 23 Aug. 96 25 Sept. 96 23 Aug. 96 25 Sept. 96 The inspections were performed in compliance with C.I.T. Quality Assurance Unit procedures and the Good Laboratory Practice Regulations. (*) The dates mentioned correspond to the dates of signature of audit reports by Study Director and Management. D.u^Tai)V? ^ L. Valette-TaIbi Date: 28 January Doctor of Biochemistry Head of Quality Assurance Unit and Scientific Archives 1997 ^ompan'y' Sanftfzed. '^con^rso^ SUMMARY ^lf^HBBBHHH--------1 At the request of Elf Atochem S.A., Paris-la-Defense, France, the potential of the test substance to induce ocular irritation was evaluated in rabbits according to O.E.C.D. (No. 405, 24th February 1987) and E.C. (92/69/E.E.C., B,, 31st July 1992) guidelines. The study was conducted in compliance with the Principles of Good Laboratory Practice Regulations. Methods The study design was established according to available information on the test substance and the above guidelines. As no irritant effects were anticipated, a single dose of 0.1 ml of the test substance was instilled into the left conjunctival sac of three male New Zealand White rabbits. The right eye served as control. The test substance was used in its original form. The eyes were not rinsed after administration of the test substance. Ocular reactions were observed approximately one hour, 24, 48 and 72 hours after the administration and then daily until reversibility of the ocular reactions. The mean values of the scores recorded for each animal after 24, 48 and 72 hours were calculated. Results Very slight to moderate conjunctival reactions were noted in all animals: very slight to moderate chemosis, very slight to moderate conjunctival redness and clear to whitish purulent discharge were observed from day 1 up to day 4 (one animal) or 6 (two animals). Slight iritis was observed on day 2 in two animals; it persisted for 24 hours in one of them. Very slight corneal opacity was also noted in all animals on day 2; it persisted up to day 4. Reversibility of ocular lesions was noted on day 5-(one animal) or 7. The mean scores calculated for each animal over 24, 48 and 72 hours were 1.3, 2.0 and 2.0 for chemosis, 2.0, 2.3 and 2.3 for redness of the conjunctiva, 0.7, 0.0 and 0.3 for iris lesions and 1.0, 1.0 and 1.0 for corneal opacity. Conclusion Under our considered experimental irritant when I___ conditions, the test substance administered by ocular route in rabbits. was Company Sanitized. Does not contain TSCA CBI RESUME flUBRHBUBBR A la demande de Elf Atochem S.A., Paris-la-Defense, France, 1'imtation oculaire pouvant etre induite par Ie produit, a ete evaluee chez Ie Lapin conformement aux lignes directrices de 1'O.C.D.E. (No. 405, 24th February 1987) et de la C.E.E. (92/69/E.E.C., Bs, 31st July 1992). L'etude a ete realisee conformement aux regles de Bonnes Pratiques de Laboratoire. Methodes L'etude a ete realisee selon les informations disponibles sur Ie produit et les lignes directrices mentionnees ci-dessus. Aucun effet irritant n'etant suppose, une dose unique de 0,1 ml de produit a ete instillee dans Ie cul de sac conjonctival de 1'oeil gauche de 3 lapins males New Zealand White. L'oeil droit a servi de temoin. Le produit a ete utilise tel quel. Aucun ringage des yeux n'a ete realise apres 1'administration du produit. Les reactions oculaires ont ete observees environ 1 heure, 24, 48 et 72 heures apres 1'administration puis quotidiennementjusqu'a la reversibilite des lesions. La moyenne des scores enregistres apres 24, 48 et 72 heures a ete calculee pour chaque animal. Resultats Des reactions conjonctivales tres legeres a moderees sont observees chez tous les animaux : un chemosis tres leger a modere, une rougeur de la conjonctive tres legere a moderee, et un larmoiement clair (ou purulent blanchatre chez 1 animal) sont notes du jour 1 jusqu'au jour 4 (1 animal) ou 6 (2 animaux). Un leger iritis est observe chez 2 animaux au jour 2 ; il persiste pendant 24 heures chez 1'un d'entre eux. Une opacite corneenne tres legere esc egalement notee chez tous les animaux au jour 2 ; elle persiste j usqu' au jour 4, La reversibilite des lesions oculaires est observee aujour 5 (1 animal) ou 7. Les scores moyens individuels calcules apres 24, 48 et'72 heures sont de 1,3 ; 2,0 et 2,0 pour le chemosis, 2,0 ; 2,3 et 2,3 pour la rougeur de la conjonctive, 0,7 ; 0,0 et 0,3 pour 1'iritis et 1,0 ; 1,0 et 1,0 pour 1'opacite corneenne. Conclusion Dans nos conditions experimentales, le produit irritant par voie oculaire chez le Lapin. est considere ^^--------------^o, 1. INTRODUCTION The objective of this study was to evaluate the potential of the test substance to induce ocular irritation following a single administration in rabbits. In the assessment of the toxic characteristics of a test substance, determination of the irritant effects on the eyes of mammals is an important initial step. Information derived from this test serves to indicate the possible existence of hazards to Man likely to arise from exposure of the eyes, and associated mucous membranes, to the test substance. This study was conducted in compliance with; . O.E.C.D. guideline No. 405,24th February 1987. . E.C. Directive No. 92/69/E.E.C, By 31st July 1992. 2. MATERIALS AND METHODS 2.1. TEST SUBSTANCE ^U^B^Bf 2.1.1 Identification_____ The test substance used in the study was supplied by ElfAtochem S.A. Documentation supplied by the Sponsor identified the test substance as follows: . name: . ^^^^^^^^^^ . batch number: ^^^^^ ^^HHw . Elf Atochem filing number: . description: dark brown liquid , container: one plastic flask . date of receipt: 11 October 1996 . storage conditions: at room temperature and protected from light. Data relating to the characterization of the test substance are documented in a test article description (presented in appendix 1) provided by the Sponsor. At the beginning of the study, the analytical certificate was not available. The pH of the test substance as mentioned in the safety data sheet was 8.5. 2.1.2 Preparation The test substance was used in its original form. cm"u"sanlt^eao^^^^ 2:2. TEST SYSTEM 2.2.1 Animals Sex, species, strain: male New Zealand White rabbits. Reason for this choice: species commonly requested by the international regulations for this type of study. Breeder: Elevage Cunicole de Val de Selle, 80160 Prouzel, France. Number of animals and identification: three animals were used, as recommended by the international regulations and taking into account that a good correlation of results can be obtained with either three or six animals (i). The animals were identified individually with a metal tag in the ear. Weight: on the day of treatment, the animals had a mean body weight standard deviation of 2.4 0.2 kg. Acclimatization: at least five days before the beginning of the study. 2.2.2 Environmental conditions During the acclimatization period and during the main test, the environmental conditions in the animal room were set as follows: . temperature: 183C . relative humidity: 30 to 70% . light/dark cycle: 12 h/12 h . ventilation: approximately 12 cycles/hour of filtered, non-recycled air. The temperature and relative humidity were recorded continuously and records retained. The housing conditions (temperature, relative humidity and ventilation) were checked monthly. The animals were housed individually in polystyrene cages (35 cm x 55 cm x 32 cm or 48.2 cm x 58 cm x 36.5 cm). Each cage was equipped with a food container and a water bottle. 2.2.3 Food and water All the animals had free access to 112 C pelleted diet (U.A.R.., 91360 Villemoisson-sur-Orge, France). Each batch of food was analysed (composition and contaminants) by the supplier. The diet formula is presented in appendix 2. Drinking water filtered by a F.G. Millipore membrane (0.22 micron) was provided ad libitum. Bacteriological and chemical analysis of the water and diet and detection of possible contaminants (pesticides, heavy metals and nitrosamines) are performed periodically. Results are archived at C.I.T. It was verified that no contaminants in the diet or water at levels likely to influence the outcome of the study were present. (1) Talsma, D.M.; Leach, C.L.; Hatoum, N.S.; Gibbons, R.D.; Roger, J.C.; Garvin, J.P.: Reducing the number of rabbits in the Draize eye irritancy test: A statistical analysis of 155 studies conducted over 6 years. Fundamental and Applied Toxicology. 10: 1, 146-153 (1988). poffip^ Sanity,o^oneosntnc,ont^scACBl 10 2.3. TREATMENT 2.3.1 Selection of the animals The day before treatment, the eyes of each animal were examined in order to use only animals without any signs of ocular irritation. Animals showing signs of ocular irritation, ocular defects or pre-existing comeal injury were not used. 2.3.2 Study design The study design was established according to available information on the test substance and according to the O.E.C.D. and E.C. guidelines. As no irritant effects were anticipated, the test substance was evaluated in three animals. 2.3.3 Administration of the test substance The test substance was used in its original form. A single dose of 0.1 ml of the test substance was instilled into the conjunctival sac of the left eye after gently pulling the lower lid away from the eyeball. The lower and upper eyelids were held together for about one second to avoid any loss of test substance. The right eye, which remained untreated, served as a control, The eyes were not rinsed after administration of the test substance. 2.3.4 Date of treatment Animal number 01 02 03 Date of treatment (day 1) 12 November 1996 12 November 1996 12 November 1996 End of the observation period 16 November 1996 18 November 1996 18 November 1996 2.4. OCULAR EXAMINATIONS The eyes were examined approximately one hour, 24, 48 and 72 hours after administration of the test substance. Following the O.E.C.D. and E.C. guidelines: . when there is no evidence of irritation after 72 hours, the study is ended. . when there is persistent ocular irritation after 72 hours, the observation period is extended to a maximum of 21 days (until day 22) in order to determine the progress of the lesions and their reversibility. . when severe irritant effects are observed, the animals are killed on humane ground. Any change in the animals' behaviour was noted. Company Sanitized. Does not contain TSCACBE 11 | I ^^ ^y 2.5. DESCRIPTION AND EVALUATION OF OCULAR REACTIONS Ocular reactions were evaluated for each animal according to the following numerical scale; 2.5.1 Conjunctival lesions and discharge Chemosis (lids and/or nictitating membranes) . no swelling ............................................................................................................... 0 . any swelling above normal (includes nictitating membranes) ................................. 1 . obvious swelling with partial eversion of lids ......................................................... 2* . swelling with lids about half-closed ......................................................................... 3* . swelling with lids more than half-closed ................................................................. 4* Redness (refers to palpebral and bulbar conjunctivae, cornea and iris) . blood vessels normal ............................................................................................... 0 . a number of blood vessels definitely hyperaemic (injected) .................................... 1 . diffuse, crimson colour, individual vessels not easily discernible .......................... 2* , diffuse, beefy red ...................................................................................................... 3* Discharge . absence of discharge ................................................................................................. 0 . slight discharge (does not include small amounts normally found in inner canthus) ....................................................................................................... 1 . discharge with moistening of lids and hairs adjacent to lids .................................... 2 . discharge with moistening of lids and hairs on wide area around the eye ............... 3 2.5.2 Iris lesions 0 . normal....................................................................................................................... . markedly deepened rugae, congestion, swelling, moderate circum-corneal hyper- aemia, or injection, any of these or combination of any thereof, iris still reacting to light (sluggish reaction is positive) ...................................................................... I* . no reaction to light, haemorrhage, gross destruction (any or all of these) ............... 2* 2.5.3 Corneal lesions Cornea (direct examination or, if necessary, with an Ultra-Violet lamp) To determine the presence or absence ofcomeal opacification and to evaluate the affected area, one or two drops of 0.5% sodium fluorescein solution can be instilled into the eye (however, this must be performed before the 24-hour reading). If corneal opacification is difficult to determine, the eye can be examined under a U.V. lamp (a clear fluorescence is visible in the areas of opacification). Opacity (degree of intensity: area most dense taken for reading) . no ulceration or opacity ............................................................................................ 0 . scattered or diffuse areas of opacity (other than slight dulling or normal lustre), details of iris clearly visible ................................................................................... I* . easily discernible translucent area, details of iris slightly obscured ........................ 2* . nacrous areas, no details of iris visible, size of pupil barely discernible ................. 3* . opaque cornea, iris not discernible through the opacity .......................................... 4* * indicates positive effect Company Sanitized. Does not contain TSCA CB? 12 Area of opacity . one quarter (or less) but not zero ............................................................................ 1 . greater than one quarter but less than a half ........................................................... 2 . greater than one half but less than three quarters .................................................. 3 . greater than three quarters up to whole area .......................................................... 4 Any other lesions observed were noted. 2.6. INTERPRETATION OF RESULTS AND CLASSIFICATION OF SUBSTANCES The results obtained were evaluated in conjunction with the nature and the reversibility of the scores observed, whilst taking into account all the reactions of the treated animals. 2.6.1 Interpretation of the results Criteria for irritation A substance or a preparation is considered irritant for the eyes if, when applied to the eye of the animal, significant severe ocular lesions are caused within 72 hours after exposure and which persist for 24 hours or more after treatment with the test substance. All the scores at each reading time (24, 48 and 72 hours) and for an effect are used by calculating the respective mean values. 2.6.2 Classification of the test substances - Xi symbol, indication of danger "irritant", - phrases indicating the nature of special risks: R 36: "Irritating to eyes" Ocular lesions are significant if the mean score has any of the following values: . opacity of the cornea > 2, but < 3, . lesion of the iris >. 1, but ^ 1.5, . redness of the conjunctivae S 2.5, . oedema of the conjunctivae (chemosis) > 2. Or else, if the test is performed on three animals, if at least two of them show lesions equal to one of the following values: . opacity of the cornea > 2, but < 3, . lesion of the iris > 1, but $ 2, . redness of the conjunctivae >. 2.5, . oedema of the conjunctivae (chemosis) >. 2. R 41: "Risk of serious damage to eyes" Ocular lesions are severe: if the mean score has any of the following . opacity of the cornea > 3, . lesion of the iris > 1.5. values: Or else, if the test is performed on three animals, if at least two of them show lesions equal to one of the following values: . opacity of the cornea > 3, . lesion of the iris = 2. EnmftaTW Sanitized. Does not contain TSCA CBB Or if they persist at the end of the observation period. If the test substance or preparation induces irreversible colouration of the eyes, the phrase R 41 should also be applied. 2.7. ARCHIVES The study documentation and materials, namely: . protocol and possible amendments, . raw data, . correspondence, . final report and possible amendments, are stored in the archives of C.I.T., Miserey, 27005 Evreux, France, for five years after the end of the in vivo phase of the study. At the end of this period, the study documentation will be returned to the Sponsor. Company Sanitized. Does not contain TSCA CBB 14 3. RESULTS (table 1) Very slight to moderate conjunctival reactions were noted in all animals: very slight to moderate chemosis (grades 1 to 3), very slight to moderate conjunctival redness (grades 1 to 3) and clear to whitish purulent discharge were observed from day 1 up to day 4 (1 animal) or 6 (two animals). Slight iritis (grade 1) was observed on day 2 in two animals; it persisted for 24 hours in one of them. Very slight comeal opacity (grade 1) was also noted in all animals on day 2; it persisted up to day 4. Reversibility of ocular lesions was noted on day 5 (one animal) or 7. The mean scores calculated for each animal over 24, 48 and 72 hours were 1.3, 2.0 and 2.0 for chemosis, 2,0, 2.3 and 2.3 for redness of the conjunctiva, 0.7, 0.0 and 0.3 for iris lesions and 1.0, 1.0 and 1.0 for comeal opacity. 4. CONCLUSION Under our experimental conditions, the test substance I was considered irritant when administered by ocular route in rabbits. Company Sanitized. Does not contain TSCA CM 15 Table 1: Individual ocular examinations and mean values ofihe scores recorded at each reading (24,48 and 72 hours) for each animal RalAit nurober Region of eye 01 Conjunctivae Descripriori Scon;S of ocular reactions Ih 24h 48h 72h Dl D2 D3 D4 D5 D6 D7 Chemosis 2 2 1 1 0 Redness 1 3 2 1 0 Mean irritation score (1) 1,3 2,0 Interpretation (+) (-) (-) (-) Discharge E 2 0 0 0 0,7 Iris 0 1 1 0 0 0,7 (-) Comeal opacity Intensity Area 0 1 1 1 0 0 3 2 1 0 1,0 (-) 2,0 02"" Other Fluorescein Conjunctivae Chemosis Redness * * * * * / U U """3""" ,.....3y"..".". '"""2"" .".....iH"... " i 2 3 2 2 i - - """i"""" ""6"""" ""'""2,0""" i 0 2,3 """"""""C+T""""" (-) Discharge E S S 0 0 0 0 (2) Iris 0 0 0 0 0 0 0 0,0 (-) Corneal opacity Intensity 0 1 1 i 0 0 0 1,0 (-) Area 0 3 2 i 0 0 0 2,0 Other * 4) * * + 4 * Fluorescein 1 U U U U 1 i 03" Conjunctivae Chemosis 3 3 2 1 1 1 0 2,0 (+) Redness 2 3 2 2 1 1 0 2,3 (-) Discharge E 2 0 0 0 0 0 0.7 Iris 0 1 0 0 0 0 0 0,3 (-) Comeal opacity Intensity 0 1 1 1 0 0 0 1,0 (-) Area 0 3 2 1 0 0 0 2,0 ' Other Fluorescein * * * * 4 * * / U U U U / / (1) mean of scores on days 2, 3 and 4 h = hour D =day (+) = irritant according to E.E.C. criteria (-) ~= non-irritant according to E.E.C. criteria * = None (2; = not calculated U = Fluorescein batch No. 5253 / ' = Fluorescein not used ^E = Scoring obscured by residual test substance > = Whitish purulent discharge = Ocular examination not performed Company Sanitized. Does not contain TSCA CBS 16 APPENDICES Company Sanitized. Does not contain TSCA CB& 17 1. Test article description Company Sanitized. Does not contain TSCA CBi 18 TOXICOLOGY DEPARTMENT CONFIDENTIAL 10 October 1996 elf atochem s.a. La defense 10, cedex42 92091 Paris-la-Defense, France TEST ARTICLE DESCRIPTION IDENTITY Test article name Chemical name CAS number EINECS number Purity Origin and batch Batch Elf Atochem filing number PHYSICAL AND CHEMICAL PROPERTIES Appearance Melting point Boiling point Flash point Solubility brownish liquid -22C 95C 50C water TOXICOLOGICAL INFORMATIONS AND USE SAFETY See safety data sheet __ STORAGE AND DISPOSAL Storage Expiry date Disposal_____________ in dark and ai room temperature December 1997 incineration ^PanySani&cA Does not WafnTSCACBg 19 2. Diet formula Company Sanitized. Does not contain TSCA C58 j 20 Ref: 112 COMPLETE DIET RABBIT MAINTENANCE DIET Appearance: 4.5 mm diameter granules Conditioning: bags of 25 kgs Daily portion: in accordance with race and body weight. Rabbits 100-150 g, water ad libitum. t-UKMULA % Cereals .................................... Grain biproducts and legumes ................................... Vegetable proteins (soya bean meal, yeast) ............................ Vitamin and mineral mixture ... AVERAGE ANALYSIS % 43.8 49 4.2 3 Calorific value (KCal/kg)........ Moisture ................................. Proteins ................................... Lipids ..................................... Carbohydrates (N.F.E.) .......... Fibre ....................................... Minerals (ash) ........................ AMINO ACID VALUES (calculated in mg/kg) 2200 10 13 2.7 49.3 17 8 Arginine .... Cystine ...... Lysine ....... Methionine Tryptophan Glycine ..... FATTY ACID VALUES (calculated in mg/kg) 6800 2100 4600 1600 1400 5200 Palmitic acid...... Palmitoleic acid., Stearic acid......... Oleic acid........... Linoleic acid...... Linolenic acid.... 6400 0 600 6400 12100 2400 MINERALS (c alculated nmg/kg) Nat. CMV val. val. Total P.......... .... Ca .... K ......... .... Na ....... Mg ...... .... Mn ...... FP Cu ....... Zn ....... Co ....... I .......... 3500 4500 11600 400 2100 40 160 12 30 0.1' 0 snn 3500 4500 0 1600 100 40 140 15 45 1.5 0 3000 7000 9000 11600 2000 2200 80 300 27 75 1.6 0 3500 vnFAMINS (c;alculated perkg) Nat. CMV val. val. Total Vitamin A Vitamin D3 Vitamin B 1 Vitamin B2 Vitamin B3 Vitamin B6 Vitamin B 12 Vitamin E Vitamin K3 Vitamin PP Folic acid ' Biotin Choline Meso-Inositol 2850 IU 30 IU 4.3 mg 3.8 mg 16 mg 1 mg Omg 16 mg 6mg 55 mg Omg Omg 850 mg Omg 6500 IU 1000 IU Omg Omg Omg 1 mg Omg 10 mg 1 mg 5mg Omg Omg 200 mg Omg 9350IU 1030 IU 4.3 mg 3.8 mg 16 mg 2mg Omg 26 mg 7mg 60 mg Omg Omg 1050 mg Omg Available under quality "Control Ref.: 112 C" U.A.R., 7 rue Gallieni, 91360 Villemoisson - Tel: 69.04.03.57 - Fax : 69.04.81.97 (Ref. Doc. UAR: 1992) ^WSanitized. Does not contain TS6A CM --