Document R7KoLd46Yz7jamN7eMvVv14E

HAZLETO N LABORATORIES AM ERICA, IMC, AR 226-OM5 Chemical & BioMedical Sciences Division BLVD. P.O.BOX 7545 MADISON, WISCONSIN 53707 PHONE (608) 241-4471 TLX 703956 HAZRAL MDS UD u FINAL REPORT /Af, %,^,*, <VV."AV I I MAT 0 1985 AV, V>~,, *.>.<>.*,'',4*, iLLAS D. ZIMMERMAN NNESOTA MINING & MANUFACTURING COMPANY )XICOLOGY SERUICES . PAUL, MN 55101 SAMPLE NUMBER: 50202473 SAMPLE ENTERED: 02/15/85 REPORT PRINTED: 05/07/85 IMPLE: T-3727 1RCHASE ORDER NUMBER: T357842, REL. #505 ENCLOSED: ACUTE ORAL TOXICITY - METHOD, SUMMARY, PATHOLOGY PRIMARY DERMAL IRRITATION - METHOD, SUMMARY PRIMARY EYE IRRITATION - METHOD, SUMMARY QAU REPORT RAW DATA APPENDIX SIGNED: STUDY DIRECTOR ACUTE TOXICOLOGY BY AND FOR HAZLETON LABORATORIES AMERICA, INC. RAW DATA FOR THIS STUDY ARE KEPT ON FILE AT HAZLETON LABORATORIES AMERICA, INC., MADISON, WISCONSIN. OOllOO @ HAZLETON LABORATORIES AMERICA. INC. 3301 KINSMAN BLVD. P.O. BOX 7545 MADISON, WISCONSIN 53707 Chemical & BioMedicat Sciences Division PHONE (608) 241-4471 TLX 703956 HAZRAL MDS UD iMPLE NUMBER: 50202473 iMPLE: T-3727 PAGE 2 ICD ORAL SCREEN Objective: To determine the acute oral toxicity produced when a test material is administered by oral gavage to rats according to the Organisation of Economic Cooperation and Development's Guidelines for Testing Chemicals, Section 401, Acute Oral Toxicity, adopted May 12, 1981. Test Material: T-3727 Physical Description: Off-white waxy solid Stability of Test Material: Sponsor has purity and stability determinations on file. Test Animal: Young adult male and female albino rats (approximately 7 weeks of age) of the Sprague-Dawley strain were procured, maintained in group cages in temperature- and humidity-controlled quarters, provided continuous access to commercial laboratory feed and water, and held for an acclimation period of at least 7 days. Acclimated animals were chosen at random for the study. Test animals were housed by sex in groups of five and identified by animal number and corresponding ear tag. Food and water were available ad 1ib iturn throughout the study, except for an overnight period just before test material administration when food, but not water, was withheld. Reason for Species Selection: The rat is the animal classically used due to its small size, ready availability, and large amount of background data. Method: Five male and five'female rats weighing between 200 and 298 g were used for each dosage level. The study consisted of four dosage levels (0.20, 0.50, 2.00 and 5.00 g/kg). Preparation and Administration of Test Material: For each dose level, the test material was mixed with corn oil and heated in a water bath to form a uniform suspension at a specified concentration. Each suspension was allowed to cool prior to dosing. An individual dose was calculated for each animal based upon its fasted body weight and was administered by gavage. The dose volume of each teat mixture was 10.0 ml/kg of body weight. 001101 HAZLETON LABORATORIES ANERICA, INC. Chemical & BioMedical Sciences Division 3301 KINSMAN BLVD. P.0. BOX 7545 MADISON, WISCONSIN 53707 PHONE (608) 241-4471 TLX 703956 HAZRAL MDS UD MPLE NUMBER: 50202473 IMPLE: T-3727 PAGE 3 -rCD ORAL SCREEN (CONTINUED) Observations: The animals were observed for clinical signs and mortality at 1, 2.5 and 4 hours following test material administration. The animals were observed daily thereafter for 14 days for clinical signs and twice daily for mortality. All animals were weighed just before test material administration, at 7 days and at study termination. At the end of the study an acute oral LD5Q was calculated for each sex. Pathology: At study termination surviving animals were euthanatized. Animals which died during the study or were euthanatized received a gross necropsy examination and all abnormalities were recorded. 001X02 HAZLETON Chemical & BioMedicai Sciences Division 3301 KINSMAN BLVD. P.O. BOX 7545 MADISON, WISCONSIN 53707 PHONE (608) 241-4471 TLX 703956 HAZRAL MDS UD IMPLE NUMBER: 50202473 IMPLE: T-3727 PAGE 4 :CD ORAL SCREEN (CONTINUED) SUMMARY Teat Animal: Albino Rats - Sprague-Dawley strain Source: Harlan Sprague-Dawley, Madison UII Date Animals Received: 01/22, 02/19 and 03/19/85 Temperature and Humidity of Animal Room: 21 to 25 Degrees c . ; 42 to 54?i Relative Humidity Uehicle: Corn oil Method of Administration: Oral Gavage Date Test Started: 03/01/85 Date Test Comp leted : 04/09/85 Estimated Oral LD50*: Ma 1e - 0.28 g/kg of body weight 95X Conf idence Limits of 0.15 to 0.51 g/kg Female - 0.43 q/kq of body weight 95X Conf idence Limi ts of 0.19 to 0.97 g/kg Mortal ity Summary (Number of Deaths) Dosage Level (g/kg) Hours 0-4 MF Days 1 2 3 4 5 61 M F M F MF MF MF M F 7-14 MF Total M F Both 0.20 0.50 2.00. 5.00 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 0 1/5 0/5 1/10 0 0 0 0 1 0 1 0 1 1 0 0 0 0 2 2 5/5 3/5 8/10 0 0 23 3 2 - - 5/5 5/5 10/10 0 0 32 2 3 - - 5/5 5/5 10/10 Dosage Level ( g/kg) Average Body Ueights (g) Initial Day 7 Terminal Male 0.20 0.50 2.00 5.00 262 271 254 249 277 236 -- -- 346 -- -- -- Fe m a le 0.20 0.50 2.00 5.00 225 226 242 229 220 189 -- ----- --- 240 220 -- -- *Thakur, A. K. , and U. L. Fazio, 1981. A computer program for esti- mating LD50 and its confidence limits using a modified Behrens- 0 0 1 J.0 3Reed-Muench cumulant method. Drug and Chemical Toxicology 4 (3) 297-305. 3 HAZLETON LABORATORIES ANIERICA, INC. 3301 KINSMAN BLVD. P.O. BOX 7545 MADISON, WISCONSIN 53707 Chemical & BioMedical Sciences Division PHONE (608) 241-4471 TLX 703956 HAZRAL MDS UD itiPLE NUMBER: 5 0202473 tMPLE : T-3727 PAGE 5 ICD ORAL SCREEN (CONTINUED) Cl in ica Signs Hours 1.0 2.5 4.0 Days 1 2 3 4 5 6 7 8 9 10 11 12 13 14 Dosaae Level - 0.20 g/kg Males Appeared normal 5 5 5 Diarrhea 000 Dark/red/brown-stained anal/ genital area 0 0 0 Red-stained face 0 0 0 Ocular discharge 0 0 0 Hypoact ivi ty 000 Ataxia 000 High Carriage 000 Hypersens itivi ty to touch 000 Hyperactivity 0 0 0 Clonic convulsions 000 Alopecia in abdominal reg ion 000 Red-sta ined abdomen 000 Piloerect ion 000 Ve 1lou-sta ined genital area 0 0 0 Swollen genitals 0 0 0 Prost rat ion 000 Death 000 000000000 0 0 0 0 0 2 00111000 0 0 0 0 0 444444332 2 2 1 1 1 143333 001 1 1 0 0 0 0122 22 000 0 0 0 0 0 333444 000 0 1 0 0 0 0 0 02 2 2 0 0 0 0 1 0 0 0 0000003 10 0 1 0 0 0 000000011 0 0 0 0 0 000000111 0 0 0 0 0 000000000 1 0 0 0 0 000000444 4 4 4 4 4 111111000 0 0 0 0 0 001111000 0 0 0 0 0 1112 22 1 11 1 1 1 1 1 000111000 0 0 0 0 0 000000000 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 0 0 0 Animal died in p .m 001104 HAZLETON LABORATORIES AMERICA. INC. Chemical & BioMedical Sciences Division 3301 KINSMAN BLVD. P.O. BOX 7545 MADISON, WISCONSIN 53707 PHONE (608) 241-4471 TLX 703956 HAZRAL MDS UD IMPLE NUMBER: 50202473 IMPLE: T-3727 PAGE 6 :CD ORAL SCREEN (CONTINUED) Clinical Signs (continued) Hours 1.0 2.5 4.0 Days 45 67 8 10 11 12 13 14 Dosage Leve 1 - 0.20 g/kg Fama 1es Appeared normal 5 5 5 1 1 0 0 0 0 3 4 4 4 4 4 4 4 Diarrhea 0 0 0 2 00000000 0 0 0 0 0 Hypoact ivi ty 0 0 0 0 12 3 4 4 0 00 0 0 0 0 0 Ataxia 0 0 0 000011000 0 0 0 0 0 Red-stained face 0 0 0 4 4 3 3 3 3 0 0 0 0 0 0 0 0 Dark-sta ined anal area 0 0 0 022 222 00 0 0 0 0 0 0 Ve 1low-stained abdomen/ genital area 0 0 0 1 1 1 2 2 2 1 0 0 0 0 0 0 0 Red-s ta ined gen ita 1s 0 0 0 111111000 0 0 0 0 0 Alopecia in abdominal reg ion 0 0 0 00000111 1 1 1 1 1 Ocular discharge 0 0 0 0 0 1 1 1 1 0 0 0 0 0 0 0 0 Piloerect ion 0 0 0 000111000 0 0 0 0 0 001X05 HAZUStOIM LABORATORIES AM ERICA, INC. Chemical & BioMedical Sciences Division 3301 KINSMAN BLVD. P.O. BOX 7545 MADISON, WISCONSIN 53707 . PHONE (608) 241-4471 . TLX 703956 HAZRAL MDS UD iMPLE NUMBER: 50202473 iMPLE: T-3727 PAGE :CD ORAL SCREEN (CONTINUED) Clinical Signs (continued) Hours Days 1. 0 2.5 4. 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 Dosaae Level - 0 .5 g/kg Ma les Appeared normal 4 3 2 0 0 0 0 0 0 0 0 - - - - - - Diarrhea 1 2 3 443 00000-- -- -- -- -- -- Hypoact ivi ty 0 0 0 543222 10- - --- Ataxia 0 0 0 12 10000 0- - -- -- -- Dyspnea 0 0 0 10000000 Red ocular " d ischarge 0 0 0 00 1000 0 0- -- -- -- -- -- Red-stained face 0 0 0 4 4 3 1 1 1 0 0 Brown-stained anal area Red-s tained 0 0 0 44322210 "" genital region 0 0 0 0 2 2 1 0 0 0 0 Hypersens it ivi ty "" to touch 0 0 0 00001100-- -- -- ------ Piloerect ion 0 0 0 00000110- - - - - - Thin appearance 0 0 0 0 0 1 0 0 0 0 0 - -- - -- -- Dea th 0 0 0 01 1100 1 1-- -- -- -- -- -- Females Appeared normal 4 3 4 0 0 0 0 0 0 0 0 0 0 0 0 0 0 Diarrhea 1 2 1 453000000 0 0 0 0 0 Hypoact ivity 0 0 0 555422222 2 2 1 2 1 Ataxia 0 0 0 000122222 3 3 2 2 1 ConvuIs ions 0 0 0 000000011 0 0 0 0 0 Subconvu1s ive jerking 0 0 0 000010000 0 0 0 0 0 Hypersens it ivi ty to touch 0 0 0 000000000 2 2 1 2 1 Piloerect ion 0 0 0 000000000 2 2 1 2 1 Brown-sta ined anal area 00 0 345444444 4 4 3 2 2 Red-sta ined gen ita 1 reg ion 0 0 0 0 1 1 0 0 0 0 0 0 0 0 0 0 0 Red ocular d ischarge 0 0 0 001111111 0 0 0 0 0 Red-stained face 0 0 0 3 3 4 2 2 2 2 2 2 3 3 2 2 1 Thin appearance 0 0 0 0 0 0 0 0 0 0 0 1 3 3 2 2 1 Death 0 0 0 0 0 0 1 0 0 0 0 0 0 0 1 1* 0 *Animal died in p.m. 001106 HAZLETON LABORATORIES AMERICA, INC. Chemical & BioMedical Sciences Division 3301 KINSMAN BLVD. P.O. BOX 7545 MADISON, WISCONSIN 53707 . PHONE (608) 241-4471 . TLX 703956 HAZRAL MDS UD 1PLE NUMBER: 502 02473 MPLE: T-3727 :CD ORAL SCREEN (CONTINUED) Clinical Signs (continued) Hours 1.0 2.5 4. 0 1 2 Days Dosaae Level - 2 .00 g/kg Appeared normal 3 Diarrhea 2 Hypoact ivi ty 0 Ataxia 0 Brown-stained anal/ genital area 0 Death 0 2 3 0 0 0 0 2 3 0 0 0 0 Males 00 10 30 20 20 23 Appeared normal 3 2 2 Diarrhea 233 Hypoact ivity 000 Ataxia 000 Red-stained face 0 0 0 Dyspnea 000 Lacrimat ion 000 Yellow-stained abdomen/ana1/ genital area 0 0 0 Death 000 Feme 1es 00 30 40 40 30 10 20 30 3* 2 Dosaae Level - 5 .00 g/kg Appeared normal Diarrhea Hypoact ivi ty Ataxia Brown-sta ined anal region Dea th 5 0 0 0 0 0 4 1 0 0 0 0 4 1 0 0 0 0 Appeared normal 4 0 0 D ia rrhea 044 Hypoact ivi ty 111 Ataxia 000 Dark-stained nose and mouth 012 Dea th 000 *Two animals died in p.m. Males 00 20 30 30 20 23 Feme 1es 00 30 30 30 10 23 PAGE 8 10 11 12 13 14 001JL07 HAZLETON LABORATORIES AMERICA, INC. Chemical & BioMedical Sciences Division 3301 KINSMAN BLVD. P.O. BOX 7545 MADISON, WISCONSIN 53707 PHONE (608) 241-4471 TLX 703956 HAZRAL MDS UD IMPLE NUMBER: 50202473 IMPLE: T-3727 PAGE 9 ORAL SCREEN (CONTINUED) PATHOLOGY Dosage Level: 0.20 g/kg of body weight Date Dosed: 03/26/85 Animal Number Test Day Sex Died Sacrificed Necropsy Comments C28605 M 14 Diffuse alopecia on vent ra 1 abdominal region. C28574 M 14 No visible lesions. C28604 M 14 No visible lesions. C28547 M 11 Red perinasal discharge} perineum stained brown. C28414 M 14 Diffuse alopecia on vent ra 1 abdominal region. C28329 F 14 No visible lesions. C28394 F 14 No visible lesions. C28395 F 14 No visible lesions. C28346 F 14 No visible lesions. C28399 F 14 No visible lesions. 001108 HAZLETON l a b o r a to r ie s a jv epic a , in c . Chemical & BioMedical Sciences Division 3301 KINSMAN BLVD. P.O. BOX 7545 MADISON, WISCONSIN 53707 PHONE (608) 241-4471 TLX 703956 HAZRAL MDS UD IMPLE NUMBER: 50202473 IMPLE: T-3727 PAGE 10 :'CD ORAL SCREEN (CONTINUED) PATHOLOGY (continued) Dosage Leve 1: 0.50 g/kg of body weight Date Dosed: 03/"12/'85 Animal Number C29302 Test Day Sex Died Sacrificed M4 Necropsy Comments Periocular, perinasal, and perineal areas stained dark brown; lungs diffusely dark red. C29313 M 2 - Stomach - multiple, dark brown foci, up to 3 mm in length, on glandular mucosa. C27575 M 3 Dark red periocular discharge (bilateral); perineum - stained dark green; stomach - glandular mucosa diffusely red, with multiple, dark green foci, pinpoint up to 1 mm in diameter, on nonglandular mucosa. C28418 M 8 - Stomach - raised, tan areas, up to 2 x 2 x 1 mm, on nonglandular mucosa. C27576 M 7 Perineum/periana 1 area stained dark brown; stomach - contains dark brown material, glandular mucosa diffusely red, with multiple, raised areas, up to 1 mm in diameter, on nonglandular mucosa; small intestine contains dark brown, mucoid material. C28529 F 12 Stomach - dark brown areas, up to 1 x 5 mm, on glandular mucosa, with raised, white areas, up to 1 x 3 x 2 mm, on nonglandular mucosa. C28534 C28537 F F - 14 4-- No visible lesions. Brown perinasal stain; stomach dark brown foci, up to 2 mm in diameter, on glandular mucosa. C28532 F - 14 No visible lesions. C28533 F 13 -- Animal thin; stomach - multiple brown areas on glandular mucosa; liver - accentuated on all 1obes. lobular patter t - O l i O i ) ?)HAZLETON Chemical & BioMedical Sciences Division 3301 KINSMAN BLVD. P.O. BOX 7545 MADISON, WISCONSIN 53707 . PHONE (608) 241-4471 TLX 703956 HAZRAL MDS UD IMPLE NUMBER: 50202473 IMPLE: T-3727 PAGE 11 :CD ORAL SCREEN (CONTINUED) PATHOLOGY (continued) Dosage Leve 1: 2.00 g/kg of body weight Date Dosed: 03/06/85 Animal Number Test Day Sex Died Sacrificed Necropsy Comments C29326 M 1 Stomach - contains normal food and tan granular material; small intestine - filled with tan/yellow, mucoid semifluid. C29328 M 1 Stomach - contains normal food and tan granular material; small intestine - filled with tan/yellow, mucoid semifluid. C29330 M 2 - Stomach - glandular mucosa diffusel red; liver - accentuated lobular pattern. C29335 M 2 - Liver - accentuated lobular pattern C29331 M 2 - No visible lesions. C28664 F 1 C28497 F 1 - Stomach - contains normal food and tan granular material; small intestine - filled with tan and cle< mucoid semifluid. No visible lesions. C28695 F 2 - No visible lesions. C28693 F 2 - C28687 F 1 _ Liver - accentuated lobular pattern Liver - accentuated lobular pattern conio HAZLSTOIM l a b o r iu m ie s a m e b ic a , in c . Chemical & BioMedical Sciences Division 3301 KINSMAN BLVD. P.O. BOX 7545 MADISON, WISCONSIN 53707 PHONE (608) 241-4471 TLX 703956 HAZRAL MDS UD IMPLE NUMBER: 50202473 )MPLE: T-3727 PAGE 12 :CD ORAL SCREEN (CONTINUED) PATHOLOGY Dosage Leve 1: 5.00 g/kg of body weight Date Dosed: 03/01/Q5 An ima 1 Number Test Day Sex Died Sacrificed Necropsy Comments C28545 M 1- Perineum - stained brown. C29314 M 1- Perineum - stained brown. C28198 M 1- Perineum - stained brown. C29319 M 2 - Red perinasal discharge. C28456 M 2 -- Perineum - stained brown; red periocular discharge (bilateral); red perinasal discharge. C28498 F 1 Perineum - stained brown; lungs dark red and firm; thoracic cavity contains a light tan granular material. C28501 F 1- Perineum - stained brown. C28500 F 2 - Perineum - stained brown; red perinasal discharge. C28499 F 2 - C28503 F 2 _ Perineum - stained brown; red perinasal discharge. Perineum - stained brown; red perinasal discharge. Deviations from the protocol: Some rats received a commercial laboratory feed other than Purina Rodent Chow. During the study period the temperature of the animal room ranged from 21 to 25 degrees C. These deviations are not considered to have had an effect on the validity of the study. References: Organisation for Economic Cooperation and Development's Guidelines for Testing of Chemicals, Section 401 Acute Oral Toxicity, adopted May 12, 1981. conn HAZLETON LABORATORIES AIVERICA. in c . 3301 KINSMAN BLVD. P.O. BOX 7545 MADISON, WISCONSIN 53707 Chemical & BioMedical Sciences Division PHONE (608) 241-4471 TLX 703956 HAZRAL MDS UD IMPLE NUMBER: 50202473 IMPLE: T-3727 PAGE 13 .'CD SKIN IRRITATION Objective: To determine the relative level of primary skin irritation/ corrosion of a test substance on rabbits under semioccluded conditions according to the Organisation of Economic Cooperation and Development's Guidelines for Testing Chemicals, Section 404, Acute Dermal Irritation/ Corrosion, adopted May 12, 1981. Test Material: T-3727 Physical Description: Purity and Stability: Off-white waxy solid Sponsor has purity and stability determinations on file. Test Animal: Young adult rabbits (approximately 14 weeks of age) of the New Zealand UJhite strain were procured, maintained individually in screen-bottom cages in temperature- and humidity-controlled quarters, provided continuous access to Teklad Laboratory Rabbit Diet and water, and held for an acclimation period of at least 7 days. Three acclimated female animals, weighing from 2640 to 3112 g, were chosen at random for the test,, treated, and maintained during the observation period as specified for the acclimation period. Test animals were identified by animal number and corresponding ear tag. Approximately twenty-four hours before treatment the hair was clipped from the back of each animal. Reason for Species Selection: Historically, the New Zealand White albino rabbit has been the animal of choice for evaluating the effect of chemicals on the skin. Preparation of Test Material: The sample was dosed as received. Treatment: The test material was applied to the intact skin of each rabbit in the amount of 0.5 g per site and moistened with 0 .996 saline. The treated area was covered with a 2.5 x 2.5-cm gauze patch secured with paper tape and overwrapped with Saran Wrap and Elastoplast tape to provide a semiocclusive dressing. Collars were used to restrain the test animals for the 4-hour exposure period. 001X12 HAZLETOOf t-A e o R ffro F iiE s a /v p ic a . |Njc Chemical & BioMedical Sciences Division 3301 KINSMAN BLVD. P.O. BOX 7545 MADISON, WISCONSIN 53707 PHONE (608) 241-4471 . TLX 703956 HAZRAL MDS UD IMPLE NUMBER: 50202473 IMPLE: T-3727 PAGE 14 :CD SKIN IRRITATION (CONTINUED) Observt ions : After the exposure period, the patches were removed. The test sites were washed using lukewarm tap water and disposable paper towels. The test material was removed from the test sites as thoroughly as possible without irritating the skin. Thirty minutes following removal of the test material, the degree of erythema and edema was read according to the Draize* technique. Subsequent examinations were made at 24, 48 and 72 hours after patch removal. Individual body weights were taken just prior to study initiation. Pathology: At study termination all animals were euthanatized and discarded. *Draize, J. H. , "Appraisal of The Safety of Chemicals in Foods, Drugs and Cosmetics - Dermal Toxicity." Association of Food and Drug Officials of the U.S., Topeka, Kansas, pp. 46-59 (1959). 001113 HAZLEXOIM LABORATORIES AM ERICA, INC. Chemical & BioMedcal Sciences Division 3301 KINSMAN BLVD. P.O. BOX 7545 MADISON, WISCONSIN 53707 . PHONE (608) 241-4471 TLX 703956 HAZRAL MDS UD iMPLE NUMBER: 50202473 1MPLE : T-3727 PAGE 15 :CD SKIN IRRITATION (CONTINUED) SUMMARY Test Animal: Albino Rabbits - New Zealand Ulhite Source: Hazleton Research Products, Inc., Denver PA Date Animals Received: 02/05/85 Temperature and Humidity of Animal Room: 20 - 22 Degrees C. J 40 - 44X Relative Humidity Date Test Started: 03/01/85 Date Test Completed: 03/04/85 Animal Numbe r F07819 F07816 F07800 Mean Individual Dermal Irritation Scores Test Material: T-3727 Erythema Score Hours 4 24 48 72. Edema Score Hours 4 24 48 72 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 o o 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 Primary Dermal Irritation Scores Observation Period 3 Rabbit Mean 4 Hours: 24 Hours: 48 Hours: 72 Hours: 0.0 0.0 0.0 0.0 ResuIts: No dermal irritation was observed at any time during the study period. Deviation from the protocol: The test material was moistened with 0.9X saline rather than deionized water as stated in the protocol. This deviation is not considered to have had an effect on the validity of the study. 001X14 HAZLETO N LABORATORIES AM ERICA. IMO. 3301 KINSMAN BLVD. P.O. BOX 7545 MADISON, WISCONSIN 53707 Chemical & BioMedical Sciences Division PHONE (608) 241-4471 TLX 703956 HAZRAL MDS UD IMPLE NUMBER: 50202473 IMPLE: T-3727 PAGE 16 :CD SKIN IRRITATION (CONTINUED) References: 1. Organisation for Economic Cooperation and Development's Guidelines for Testing of Chemicals, Section 404, Acute Dermal Irritation/ Corrosion, adopted May 12, 1981. 2. Draize, G.H., "Appraisal of the Safety of Chemicals in Foods, Drugs, and Cosmetics - Dermal Toxicity", Association of Food and Drug Officials of the U.S., Topeka, Kansas, pp. 46-59 (1959). 00115 3 HAZLETON LABORATORIES AMERICA, INC. Chemical & BioMedical Sciences Division 3301 KINSMAN BLVD. P.0. BOX 7545 MADISON, WISCONSIN 53707 PHONE (608) 241-4471 TLX 703956 HAZRAL MDS UD IMPLE NUMBER: 50202473 IMPLE: T-3727 PAGE 17 ICD EYE IRRITATION Objective: To determine the level of ocular irritation produced following a single exposure of a test substance to one eye of albino rabbits according to the Organisation for Economic Cooperation and Development's Guidelines for Testing Chemicals, Section 405, Acute Eye Irritation/ Corrosion, adopted May 12, 1981. Test Material: T-3727 Physical Description: Purity and Stability: Off-white waxy solid Sponsor has purity and stability determinations on file. Test animal: Young adult rabbits (approximately 14 weeks of age) of the New Zealand Ulhite strain were procured, maintained individually in screenbottom cages in temperature- and humidity-controlled quarters, provided continuous access to Teklad Laboratory Rabbit Diet and water, and held for an acclimation period of at least 7 days. Three acclimated female animals, weighing from 2666 to 3000 g, were chosen at random for the test. The animals' eyes were examined within 24 hours prior to test material administration using sodium fluorescein dye procedures. Only those animals with no sign of ocular injury or irritation were used. Test animals were identified by animal number and corresponding ear tag. Reason for Species Selection: The New Zealand Uhite albino rabbit is the animal of choice based upon its large orbit and nonpigmented iris. Preparation of Test Material: The sample was dosed as received. A bulk density determination was made to determine the weight equivalent of a 0.1 ml dose. Based upon the density determination, an individual dose of 0.09 g was weighed out for each animal. Treatment: Each rabbit received 0.09 g (0.1 ml weight equivalent) of the test material placed on the everted lower lid of one eye, with the contralateral eye serving as the untreated control. The upper and lower lids were gently held together for one second to prevent loss of material and then released. The eyes of the rabbits remained unflushed. coins HAZLSTOIM t-ASORTORies ATVEBICA, INC. 3301 KINSMAN BLVD. P.O. BOX 7545 MADISON, WISCONSIN 53707 Chemical & BioMedical Sciences Division PHONE (608) 241-4471 TLX 703956 HAZRAL MDS UD IMPLE NUMBER: 50202473 IMPLE: T-3727 PAGE 18 ICD EVE IRRITATION (CONTINUED) Observations: The treated eyes were observed for ocular irritation at 1, 24, 48, 72 and 96 hours after treatment. At the 72-hour reading, sodium fluorescein was used to aid in revealing possible corneal injury. Irritation was graded and scored according to the Draize* technique. Animals were weighed just prior to test material administration. Pathology: At study termination all animals were euthanatized and d iscarded. *Draize, J.H., "Appraisal of the Safety of Chemicals in Foods, Drugs, and Cosmetics - Dermal Toxicity." Association of Food and Drug Officials of the U.S., Topeka, Kansas, pp. 49-51 (1959). 0-01117 HAZLETON l a b o r a t o r ie s AIVERICA, INC. 3301 KINSMAN BLVD. P.0. BOX 7545 MADISON, WISCONSIN 53707 Chemical & BioMedical Sciences Division PHONE (608) 241-4471 TLX 703956 HAZRAL MDS UD )MPLE NUMBER: 502 02473 iMPLE: T-3727 PAGE 19 ICD EVE IRRITATION (CONTINUED) SUMMARY Test Animal: Albino rabbits - New Zealand White Source: Hazleton Research Products, Inc., Denver PA Date Animals Received: 02/05/85 Temperature and Humidity of Animal Room: 19 to 22 Degrees C.j 40 to 44% Relative Humidity Test Material: T-3727 Date Test Started: 02/28/85 Date Test Completed: 03/04/85 PRIMARY EYE IRRITATION SCORES* OBSERUATION PERIOD 3 Rabbit Mean 0.09 g (Unwashed) 1 Hour : 24 Hours: 48 Hours : 72 Hours: 96 Hours : 7.0 3.7 3.0 2.3 0.0 * The Primary Eye Irritation Score is the total eye irritation score for all the animals divided by the number of animals (3) at each observation period. Comments: No pain response (vocalization) was elicited from any animal following instillation of the test material. No corneal irritation was observed during the study. C1JL1 LA BO RATO RIES A M ER IC A . INC. 3301 KINSMAN BLVD. P.0. BOX 7545 MADISON, WISCONSIN 53707 Chemical & BioMedical Sciences Division PHONE (608) 241-4471 TLX 703956 HAZRAL MDS UD IMPLE NUMBER: 50202473 IMPLE: T-3727 PAGE 20 ICD EYE IRRITATION (CONTINUED) Table 1 Ind ividua 1 Eye Irritation Scores Animal Number Observat ion Period Cornea Score A B AXBX5 Iris Score Con june tivae Sco A A X 5 A B C (A +B F07813 1 Hour 24 Hours 48 Hours 72 Hours 96 Hours 00 0 1 5 111 6 00 0 1 5 110 4 00 0 1 5 110 4 00 0 1 5 100 2 00 0 0 0 000 0 F07814 1 Hour 24 Hours 48 Hours 72 Hours 96 Hours 00 0 0 0 111 6 00 0 0 0 100 2 00 0 0 0 000 0 00 0 0 0 000 0 0 0 .0 0 0 0 0 0 0 F07815 1 Hour 24 Hours 48 Hours 72 Hours 96 Hours 00 0 0 0 11Q 4 00 0 0 0 000 0 0Q 0 0 0 000 0 00 0 0 0 000 0 00 0 0 0 000 0 Table 2 Sod ium Fluorescein 1Examint ion Animal Number Observat ion Period Pre- initiation 72 Hours F07813 NEG NEG F07814 NEG NEG F07815 NEG NEG NEG No stain retention POS - Positive stain retention (area of cornea invo1v e d ) Re ferences: 1. Organisation for Economic Cooperation and Development's Guidelines for Testing Chemicals, Section 405, Acute Eye Irritation/Corros ion, adopted 0 0 1 1 1 9May 12, 1981. 2. Draize J.H., "Appraisal of the Safety of Chemicals in Foods, Drugs, and Cosmetics - Dermal Toxicity", Association of Food and Drug Official Officials of the United States, Topeka, Kansas, p p . 49-51 (1959). PAGE 21 QUALITY ASSURANCE STATEMENT Study No. 50202473 The report as herein attached for the above-mentioned study has been reviewed by the assigned Quality Assurance Unit of Hazleton Laboratories America, Inc. in accordance with the Good Laboratory Practice Regulations as set forth in 21 CFR 58.35 (b) (6) (7). It has been found to accurately identify and/or describe the authorized methods and standard operating procedures followed in the conduct of the study and that the reported data accurately reflect the raw data of the laboratory study. Furthermore, the Quality Assurance Unit has conducted the following inspections of the testing facilities utilized in the conduct of this study and has submitted written reports of said inspections to the study director and/or management. Date of Inspection Type of Inspection Acute Oral Toxicity Study in Rats 2/25-26/85 3/26/85 5/01/85 Process Audit Process Audit Report Review Primary Dermal Irritation Study in Rabbits 2/25-26/85 5/01/85 Process Audi t Report Review Primary Eye Irritation Study in Rabbits 2/25-26/85 5/01/85 Process Audit Report Review Date Issued to Management 2/26/85 3/26/85 5/01/85 2/26/85 5/01/85 2/26/85 5/01/85 Inspector, Quality Assurance Unit Date 001120 6 Test Haterial T - 3 7 A 7 Bulk Density_ -63---- (g/ml) 9<ACUTE ORAL TOXIC! (LD50) record .Vehicle _-- filL_2ji Species-- fco-A Source Mo-r (a.a 6 -------RT No . S 0 2 0 J M 7 3 Date Received _ i 5 1 _ Sex J Dosage 0 . 2 0 (e/ke) Dose Volume |0.0 (ml/ka) Animal No./Ear Tag No.CA Prefasted Bodv Welshr i a \ 4)/-- Pasted Body Weight ( r ) Actual Dose (ml ) Day 7 Body Weight (g) Day 14 Body Weieht (a) 337 ip ih 3SO Ml an Dose Time || % Tech. DkVi ScYfP'sed : *y7 1HH tin te 77f5 2ww. NA X-- 21% ? i \ A L o 17 \ 'fcwTM. 3*5\o Kt x2^ 5 2 2 9 ,3*1 319 gs ff te JllOj >?.L> 3|7 <7. 5 \ % \ .qT yr idus- 3 ? l ** \ "e* U<f1O Jr Y-? Doses Verified bv iMiT * rr NA 1 30/0 k.4yo*i /r/9 NA Dosage O . a O (g/kg) Dose Volume |0.O (i/kg) Animal No./Ear Tae No .C^ f n Prefasted Bodv WelRlit (r ) JA - Fasted Body Weight ( r ) 23M Actual Dose ( Bi ) Day 7 Body WelRht ( r ) Day 14 Body Weight (g) ' 1n o Doae Time__ i3 '& 0-Vk > W o * S345- II Iff) V \ <? 2 0 0 a*r z*fa \ 31.2. 31. \ r9*0 JJ.A 3 . H Q &\ \q 0 a w | \ \ A M *L _ 2 0 9 a t L * A LL " 3 Doaea Verlfled-hy MORTALITY (NO. DIED/NO. DOSED) Tech. ^Mm. aU 1b Scale Used: 3 ~2<p NA .. S K ln0 5 J & NA \^ \0 I 0 M is 0 1 9 ___ MA________ e if o H" L 10 P NA - Not Applfeeble * - Dosage calculated, but not administered Unused animal returned to stock Reviewed b y , i 11 12 1 13 I 14 1Total IW 3A. O R EUR na am pm pm f r & yf * fs % % HA- Y r /s% % fc r< r % k % CfL s t SP Y s f 05 i S t t y % % % % % t % NA % oste Sex c? ACUTE ORAL TOXICITY (LP5Q) RECORD Teat Material--T ' 3 7 ' 2 ' 7 -- .----------------- Vehicle---- C a & t i Q jL . nr Ho.,5&ao<3/73 Bulk Density-- ---- (g/al) Species-- fto^V* Source a Date Received Dosage O . f t i fg/ke) Fasted* Date -II-SS" Tiae 3*`0D p*i.Tech. R o n . Nn 3 Dose Voluae /O.O (al/kg) Dose Tiae 2J5 Ol.vw . Tech. & Scale Used: Animal No./Ear Tan No.Cot |30% ^313 i & Prefasted Body Ueisht (%\ MItnA h r . VI 7ST7L m v\ t 3-I3L # NA Fasted Body Weight (g) ASS' i*7*f 3S(p \ 3-/a KnfieA/530 Actual Dose (si ) LKCuCf fAiv?lb f**0 Day 7 Body Weight (g) 3^-sr i- t s - d a d *Day 14 Body Weight (g)___ TW*" if + 2,7 <3.0 \ 3 -/a Pend 0-K- Who V CA \ 373 Doses tttr. Verified bv ___C L . -3-/7 a3?0 NA tiro H S Z 2 ____NA_______ Dosage 0 , 5t> (ff/kg) / S ' Dose Volume / ) , 0 G*l/kg) Pose Tiae ^ ' 3 0 A. m .___ Tech. Date Scale Used: Anlaal No./Ear Tas N o . Q ASJ) 8S3*( ^ 3 7 HOT Prefasted Body Weight (s) nMnA Fasted Body Weight (g) 3 5 1 2 3 (a _ \v j i l 9 lO (? \ Actual Dose ( . 1 ) Day 7 Body Weight (g) Day 14 Body Weight (g) 2 .5 fU d -?*/ QSlJuL_ 3 ? 3 p .a Petu/ _ 3-ib-VS !% ns+ Q .\ i f lis t g* *m \ \ \ @wrr|ikA cctttC tu * Doses Verified bv IbO ' ' MORTALITY (NO. DIED/NO. DOSED) Wl fifcA /C ' A , ... / * ? 3 - L 3 -/0 1 2 -/? 3 -a < r ? -(2 NA -- ---------------------- rs. KTfUJJ NA J th ^ n K fr O n S3Q<t, ____ NA_______ Dose Level Hours 0 - 4 i S> 2 3 AIMpa flBPB c? o.3k,/t<.4 % ft ? ft & 2_ O.fXIka. Technician fg % * & f t f**v $p r sp sp 1 1 9 1 io 1L u J RB. ULBA SA i f Ky W DA B--A D A a. _ DA 12 aa. D A 1aa13PB1aai f 1Total J2B UA_ * ts * * ff ft- f t 2k "4 f c k f t f t 1A 7 s & im sp 0: ik CK sp CK- M M Date m s ... .jjy- % % k f c k N NA - Not Applicable * - Dosage calculated, but not administered Unused nnlinn] returned to stock Ik 2 y 1 i 4 Reviewed by y k L 2s ^ 5 '/a Date *fr//P /iffT 0*01 c> ( ACUTE ORAL TOXICIT1T(LD50) RECORD o Test Material "T:~3*7ot'7 -----------------Vehicle;___C / i & t i OlL. .RT Ho. ^ O J O p W 3 Bulk Penalty (g/al) q? . Q O (a/ka> S p e c ie a ^ a.4 ' S o u rc e -- M t u dl&JQ. _ Date Received * '*7~ SS~ Faated: p a t e T i n e ' * O pm Tech. Rqq- No . 3 _______ Dose Volune /b.O (nl/kg) Dose Tine |p.wr tmi__ ____ Tech. ii Scale Used: Sex Anlnal No./Ear Tag NojCS naifi 9330 13*1 1335" 13.$ ?33 \ 3-6 NA Prefaated Bodv Uelohr ta\ -- \-- j f Faated Body Weight (g) 767 2?7 37o 71) AM 7 \ 3 "6 KtcaJ Actual Dose (nl ) Day 7 Body Weight (g) Day 14 Body Weight () \51 5.1 21 5.7 5.5 5.5 5.5 ^Dh bead 0&*D a<?<? ST \W rnoABW '0 J57>0 tXOLd m>&JaW 07 \15" Xfry* sr 3*14l1 j rxn W wjsfnsr 36-jr ie*n Poeee TP-- *a/ Veriff Ld by _/r 3-6 NA ' hie. ____NA_______ d o SL o r: CO Doaage <3?,D O (g/kg) Dose Volune (0,0 (nl/kg) Doge Tine H-'op r d m _________ Tech. .fill Scale Used: Anlnal No./Ear Tag No.05 ^663 1 M 1 t i l 1 8615 Prefaated Body Weight (g) Faated Body Weight (g) 7 5 1 533 553 AOl Actual Dose ( Hi ) Day 7 Body Weight (g) Day 14 Body Weight (g) 5.3 5.5 5. 5 5. `I Tbaud RSq 0EO s-n-R 3-1- 3-i-yi Sf * Carl k& 5 * ICIwABtflfcwSWS \J Ji87 \ V *V \ .5 5.A wd o t ' \ \ jT 3-1' .'Sn^> \ S*m T-6 5n?n_ 57H 3-6 NA K m * i i3vs NA Baaek-Sf&Tf Id by _ l z L d ^ L . ____ NA_______ Dose Level lloura 0-4 <?.0. fI.t^u . 5.GCKjU* TeclinltiWn % % lawi MORTALITY (NO. D1ED/N0. DOSED) TStuidy Bax 7 | 8 | 9 I 10 I 11 I 12 | 13 14 Ifotal fmrnmCTfHTi f?nmTinn?nf?nmmrnr^?riff^PrimE!3n3EiTiim y> U 7n ate /9 & T NA - Not Applicable * - I S Z5SH&S5 S v(iii*rwdrryy eernroriD^ ^'--> ^Re^vileewweedd Kbyy Sk. pate NA ~a d.i. --- s. - TOO tu " } Teat Material Bulk Density_ ~r- 3 ^ a T A h --- (g/el) O ACUTE ORAL. TOXICITY (Lp^) RECORD Species t f f i f .Vebicle_2LH_aLl Source-- H a / I a * r> RT Mo. 5 a o a y ~ ? * Date Received 1-Jj-^.r Ubsaxe g . f i n (a/ka) Fastedt Date_g? Tine O ' O O ^ a Tech. 5*tL Boon No. Dose Volute |(\D (sl/kl) ____ !___ ________ Doae Tine A Tech. Date Scale Used: Sex Aninal No./Ear Taa No. ( A Prefasted Body Height (g) f i t * Fasted Body Height (i) p i 7 Actual Dose (nl ) M Us Day 7 Body Height (g) Day W Body Heisht (a) (Imi & H `1 7?.5 \ \ VM l 7lO \J.5 P.M M Ss \\4/Mrt tyiN * * fimi ititm * i Y!Iptav 3 /i AninvA ftfA uSrfA, tax -i's J n ^ J 1 5 Poses Verified by __ NA > isort NA MA_______ | Uoaa8e 5.00 (g/kg) nfooioOtnOort/e'd&/dotenct/e/>/nS-3-&?S _________________________________ Dose Volune | , (a l/k l) Dose Tine la ` tinAninal No./Ear Ta* No.* isaO 9193 m i 5bl 5D3 S5W \Prefasted Body Height (a) fitf\ V \S - Fasted Body Ueiaht (a) jns 230 J07 M l -H a \Actual Dose ( ! ) M - ??> JM 7.5 2,1 J.z \Day 7 Body Height (a) Di(H( M iri A M * (Vrtl Tech. Wl u itt* Scale Used: Y i NA J\ 5/l Mitw) ISM l 3 /, NA Day 14 Body Height (g) ** Doaca Verified.by _______ ^L_ NA_______ MORTALITY (NO. DIED/NO. DOSED) ro im i litu i T m . S Q 2 Q j > n*> TIUT HATMtlAL T~-^ 7 .3 "7___________ fy.Ae. OrvJ__Ti' `Vfy L. 0O80H IHVII. o a Q j/* 3- AlflMAL/lA* TAO HO. C j - f S 7 . . . 300. STUNVl>A| # SIMKINHIWNATI xArmilo MOBMAL T 1 XftfVCf)u\liajAwfClMkctao..c^a^! ft-t fa-c-f. * i 3t 3 V s (r *7 ? 70 ii la w2TL7 , *u&I/IfIfc w% %, w. i. Mi, JE % %[Nife A\/V%E l \ J Ait J y y/ L a/e }& y/ y y y ( y y T 13 i i aA V\ 5 i/ Hi jvi *>h* y y l/ OJ&ujuplaoVa-cfVi- V v/ 7 7 _ 7 y Alt k5^ fi* N y a) |0 i/ i \ ^hhnn^mA-e y |sj^ tt ty T \t\iX\\ppe>,rsQePn^JtVMi*>. . y y y fjk/ d y y JE n C/o/) .' , CbOMMlfrioA -- -- ----------- -- -- ---- _____ -- y iE y i Atdiii c. o rn o t io u iic ia n fai! & a l ZZI s ta ri. ' m r^ rr-ifT J ^Irsfjo T V\ MTB %k KN % .J y-U n IraiHiiit NI - Mot KwMaat I - V ii Ir w iM t, tfllfclit MA Nat Appi (calila (Ddied w m se i-L'&s v\ 1-,-r v \ =U _____ _l \ V3 A--x 4v /i STUM T i m . ...flctAt, ut m . S 0 ^ ^ 7 TKtiT MATEAIAI. T ___________ GnA POSAOH u w il 0 . 3 0 fb- animal/ kab tag no. CZrJb'i... 001126 TUM Tifili J lc u k s . OnJ. TUST MATCMIL T~-A 7 _________ WMGK lUVil Q . 3 Q ^ ^ ANIHAlVlU TAC M 0.O - f t L O S ft ITUaV TlTUl W *-.3230^71, m T MAYKMIAL T-^7J~7________ _ jjg ik __Qkl-- To* `Cijy. i n ri* POgAGit U V tt. o - a o ^ l ^ _ AljlMAL/lU* TAG N . - _ $ * / # . . . H s; :S: ION - VW Jwh - un >H*MH *l - I* iww| " -^ 1 % al i W M M m n K *% TJ TT im "% ~w> s w MW wmimun biyhi Vs * ww r r377 w w w rr ST tip avi w w 37TW 5f W s* 7* l --rr L Z1 m wW W w W mw mm ? 517 'hL t% * % W Fh 7T- V /> W W m 57? 3L * f 'S n Lfi ?** % M ri II 01 "Tp^y. ^"uUp pavas jAl-atToAy] TTRRRiiViijf 1 M n mniMnncis I AVd M U S WRfR - 7 ? * H Y* lYJIflYHlilY ~ ^ f 9 O V ' MT* W W W * -p-TM ^9 !m 'T * > 0 TCPZCar irimuw m i " Z'ATOTO^-i m tru iA M MI I - YM " H * * *ll - Ml 1M*IW > * ll - I jhm m m j vtt|| -y\ _ s sz_____ _____ _____ \ f'vi"JITA %%y1?1 j 1TWm1 TSC%T1fys"36"73TB*1"M3T[rb"s1"rwat giva NYMimKieViiaftxl s;\ S ~" r* \\ u V SH VX V Q W W "irt 3rt 3N3fi 3rl VI 3N s/Wfi 3f1W 3N 3W3ti WW 3AI 317 3iV 3N 3rl 3y/i T 3P^9(vs A P 3C* 3V3PZ1 r A JTp 3(1/7 ---- r /, A Z"' /* z'/* r 91* /" Z<5/V' // -- ---- ---- ------ ------ ------ -----T-- b v^oj^ojy T/?W1i 3C'\Yi'v h{\ ^orq % % % %SISI EEJ EZH ElfiWSEU K M T A WS WSkS&f E L 6Zu W S W H P53 1% MCl tl I 01LS *& b '4 Ki *> s b *C* If *1*L3-Tb*a3 Sm*3Mp1M 1 IVMuHtlVIMT liranranxicis iyMmmus - T j 'iih wrx vnrvmnf m u n moymmi * L ' T 0 -- 73F Tf rrrenr iyiwaym i m ~ 2 J F 0 f f % r-m in i r u i l JUNTO TC TT-00 \ nu Tit /s.Af, ** g30?V 7 3 .T W HATUIIAt. T- ^7J ~7__________________* f ira.l To* ,oJy m OOSAOK uvu. Q.30 ^ ANIMAL/KAft TAC N Q .C - _ ^ 3 3 V . TUDY TITUIl n m.j22QjfZ3_ nur HATIMIAL T - ^ 7 J ~ 7 flcirk, Dc&A g,aj/*3DQ8A0K UtVIL U )IH U y iU I TAO STUUY NAY s 1 1 1 J 3 * S i 9 UIMUUUUINAY AFFEAIEB MODUL %-T % WAiVu \u.t. W<1 sUi.'J ^ aiUj utlloui sfc.ift<4 1a,uw.trt |U<P n/<- m ***' i . atYtfi/ninaP .M rY"e/n",/"^ y/jL & &%& y y yJ y i/ -y j J jj i/ J %t $ y iv) y MF, toe y Alfc.foe y yiy K & j <0 II ia 13 m X% y/7 i 4 > v /i/feHC Ulf M. HC A A/ ne Ne NL Jf (Jk MC Ne NE HC b HC N6 Nf, A/ y y ix y . ~ > v\ V .... DEATH TECMMICIAM * n3s" fauU H i itgu. J'JL QJL L s H %I 1 & & %>%kk k Ho --- r/ SF s/* rO t V - MJtf* r n m M w t I - Mifti fdiMNt, ttll|tlit NM - Hat KvMmit NA - Hai Aj>|it!:|tln -- \| \ [3 1 ~~ ccoo H H O O $Q co 'S t4 O - 7 2 'im o r i m / it w ik t T T F U n u n aovroti r* n r m r itnauvt u m ' U pTJp u t i l a i m u I i O STUD T lH A i bt . a a a o a n : ^ TSST MATESIAL ~ T - M 3 7 ___________ /)g jL j4t O n d --T o ^ i ^ ^ y POSAOS IJtVBL SMINAI*/BAI TAO MO. C J - .. CTTOO coi13i c STUOV TITIJIl . UT UO.S Q 3U U W 73> m T HATEMIAL T v M 3 7 ___________ Dro,\ Ta%i(L\^j DOSAMI U V IL IKK tJ L J^ AMIHAI./EAK TAC Hft. C J " 9 SL3 o oo ITW 1 TITU l . / ) c u \ i t . a a a o a n ?> T8T HATEAIAl. T - ^ 1 3 . 1 ___________ Drft.1 . X o ^ i + y SKI DOSAS* UtVU. O.SOfl) C? AMIHAlVlAS TAC NO. C j J - 7 % Oo STUBV T lT L fl / ) < L u \ l O r < ^ \ T o ^ ' C - d w -------------- TU T HATEHUL T - ^ 3 7 _______________ UA8ACM LIVU. m_x2_ Ju^ AMIMAI^Mi TAC NQ - C - * J S . 7 S ' 8CTT00 o oo sTuov r im i kt Mu-5oaoiim^ M HAT*IAL T - 37,21______ /1caj\<- D a ' ' T a % c . A yj SKI J OOSAGK LftVIL iS?^ |.K^ AljlHAL/lUl TAC N O . C J - ^ 3 . 0 Gll*0 ----- s z \ ion - VN PI* aM - N s% K & y? '- J? 7h -- *11 '* | - i - ,,1 J }b *f i/o 7>KMPMMFHlInki R Hii EMHB120 m , I lim im eli HiViNI s ;> V -- 5 \ A i_ * AV Z /* / / 3N T # ^/V art 37 'lA Z / Z " ^TJrpvTrr^f" V r z\ /* Z Z yZ /i ?A 'A 3<H A Z z' Z Z Z / /zZ Z i A Z nryv-j vT^j P^9 V X a 3 9/V */V 3JV W 9 # 3 !i P w T P ?n W 9N W J3rf / N. 9CS W id Z P ?/nr / ~w Z -i m rm m s r N * k % tc4 M a ti % <% % II Of b S % L 4 ? S *1 Ae h% SI If 1 L*xaw !* n fMf f nun mnimaiitis frt ABUS 'fa S $ -Z> **H ** /IWIHf 37"* *11A n OVSO'I . \ U->G T W E f K T T i m M W unu TIFVfcSrW 1 r u t i awu* oo ,i TIO) c *t w>.. s o a o a n > TKST NATISIAL STIMMT T i m i . __________ Oo Or<>^\ . T & * C ' \ b j posaos w l C S . S ^ J r^ AlfMAL/SAft TAC MQ. C j J r Cr o a 0TU0 TITLHi NT W I . 5 0 M l 2 _ TUST MATCHI AL T - V ^ T __________ /lg ju V < Dro>.\ T o x iC -ify DOSACI! u n c u . MX ANIMAL/CAS TAC NO. g$T 3 - O Oo n u n titijii T m.SOZOJ'tTK TEST HATEAIAL *T - X 7 J3~7__________ /lc u \t Tci'tiC.'j SKI Q`% ^ rDOSACK LKVSL ANIHAL/kAK TAC coi143 oc - STIMM TITIA l . MT m .SO A O A H T S TWIT HATCMIAL T - ^ 7 3 7 ______________ / IcjlA i O r A - \ _ X q x C.Ij~y OOSAGK UIViL O .S d ^ K^ _____ an ih a iVsak t a c no. C?- f lS 3 T I 001144 GhUjEmrr fifB-ir-tr oo STUDY TITIJtl dt m. S O L Q M l S TUT MATS*IAL cok. C ^ L -- POSAOS UVSL su o ANIMAL/KAS TAC ... 0 0 1 .1 4 6 O I T U M TITUIl T o. S n ' n S m r MTCNiAi. T oo OMC* u n til. (Q^ivc>Vy . CT _____ ANIMAL/KAI TAC M . ^ 3 ~lQ . o oo STUBY TITI.il WT M 0 . _ 5 M Q . a i 2 3 TST MTCBIAL - T - y n D 7 _________ r t c o .k C W L T q & i C.'V ^ MMACa I M I . . aiti d L Jj(3 AI)IMAL/BM TC _ o TOM VITIJU "T MO. S O A O J H lZ TUST MTOMIl. T - S l D y c o .k o ANIMAL/KAM TAC H O . ^ 3 cr o o STUDY TITIJIl ut m. S'nJH7 3 TUST HATIMIAL T V V 7 . 0 7 _______ vc^N C O W . __ Q l A ---- loll 008AGU IJIV IL AMIHAL/KA* TAC * ._ C A / ? 3 < 2 1 L - O i i Oo STUDY TITIJIi ST MO. S o L O J H l* TUST HATi*IAL 'T ~ X 7 D ~ J cAik Ui&ifci DOSACI utvu. SKI ANIMAL/BAS TAC N Q . j ^ T k j 5 7 ) TOO ot i A n im a l died in Oo STUDY TITLN* T MU. S C A O J H lS TUST MATEMIAL T - . V / 3 7 & ik o ANIMAL/CAC TAC N Q - . C ^ i k C ^ . . _ TSTTOO I - Sign f n i M t , l l l |k l MK - Mot K v IJ e a t NA - N at p |) |l t : t b l oo TIMIV TITUI t m . S 0 O * W l 3 TIMIT MAttUHAL T V V 7 .3 7 __________ $ ca k Q fl&A Tq ^ jc.; su _ DOSAGN LBVIL t^blr o ANIMAL/RAB TAC ... o CTUOV TITIJIl *- S J . O J H 1 3 TfcST HAYUtlAt. " T - K T J _ o O ^ l __ l o A i b . . DOSACI! UtVIL su o AIJIHAL/SA1 TAC m - l Q T i i ? . . . - 001153 I - ll|a ftaatmt, SlljtAt 0Pnw iJ dieci in >ni.3->-S 3~dw Hit - Nat KvMnt ' MA - Mot ApiIlcalti 00X154 TUM TITIJ T M. SLOJHl3i TWIT HATEAU l. T W ? ^ x ik IW o MSfiM UVIL SKI _ aijih aiV ia a ta c ? ... -o A CTUBV TITIA l MT MO. SD>H 7 \ TUST MATMIAL T - ^ 7 ^ /?<u l e Q g - 1 Io x . ' c M POSACK lA V K L______5* o iyiNAL/KAt TAC N * Tunv T i m i HT MO. S C &O JH 7 <. m t i n m i A L T - a ?L2 ----------------- /?<>>->-k. Q cq- l o ^ / c i T y -------------------- ^ M0SA6M WWW. 8" -- -- _ __u AlUML/ltAM TC M Q .^ _ ^I^e 9STT00 Y^ * TUM m u . T i. SJO'S>H7 % ruar h a t m i a l . t ^ 7 c?~7_________ -o o AlfltUl/KA* TAC M Q._^'<pr 057 I - Al tmamut. M ig h t NK - Mat K vl4ct NA - N at Applicai*! o * o o tuo m u l i , . u i s . T MO. s c & o a m *> TOT MATCMIAL T - ^ 7 ^?'?_________ Qr^l to/Vo^y I SW OOSAGtt UWU. (T AMINAL/KA TAU m . _ 3 _ $ 1 j$ _ . * * -O STIW TITLKl T MO. Q J D J H 7 *> TINT MATMUAL T - A 7 ^ ~ 7 ___________ ffcu k .Q t y-l IMklflK U N O . i Kl d * 5 ,0 ^ 1 H* ANIMAL/RAI TAC M O .^ j? _ f 6 S IT 0 0 A CTUOV TIT* KT MO. S O J D J H 7 S TWIT MATCMIl. T - U J l _________ /?eo -t- Qr^-1 l o ^ c M y ______ uosAGK mm. m i m U t * * TAG W - J ? J ? 7 . 1 l i > . . - 03TT09 A (TUOI TITlJli UT Mft. S O D J H 7 S TUST MATUUL T-A7J~_______ /?Co 4^C, O c c J I o * . c i j y DOSAOK invi. U jlM A L/lta TAG M O .^cp 1 I1 .T -o 4 STUDY TITIJU UT MO. S J D H7*> TUST MATKUUl. T - _____________ /?q 4 Org-I loy-i'cT-l SKI uouACs unni. SCq Jh^ AMINAL/KAU TAC N Q ..^ ? _ . `M4M tl.-iMMl'4 .tno H H O O losR -- dy1 W,/1IMI',T niun w anm .^v-x iv im w u n V L h e a & > '* * r i m ani* 001164 STUM TITIA l MT M0. S C & D JH 7 S T O T HATWIUL T l .A l s O -------------- Q r o - 1 I O/Vci . IMSAOK IA V IL ----------------------------- 'O 8" MIMAlV*A* TC M O ..^ _ . - S o s ty PRIMARY SKIN IRRITATION SCORING SCALE (1) Erythema and Eachar Formation No erythema Very slight erythema (barely perceptible) Well-defined erythema Moderate to severe erythema Severe erythema (beet redness) to slight eschar formation (injuries in depth) Highest possible erythema score 0 l 2 3 4 4 (2) Edema Formation No edema Very slight edema (barely perceptible) Slight edema (edges of area well-defined by definite raising) Moderate edema (raised approximately 1 am) Severe edema (raised more than 1 mm and extending beyond area of exposure) Highest possible edema score 0 1 2 3 4 4 I oo o o H cn cn Tutti UuMI i S rn k j a - s - % sb a ld Au l u i a B acai a d 3 - 2 1 - t Ita la A a la u la U llp p e d l S k ia t i'u |M iia llu a l ______-- . Taciti m i n a i DONAI. UITATIOM STUDI __________________________ MIA Nuabacl & 0 < S lV ? .3 m o l b + l n l d uJiBi O ^lo t ealti _ . _ f ________ laureai /fettA/Ah Products Dana /(ol~ I C.IC. lattiate* kn C*_ Datai 3 - / " ^ Deviane* kfi Datei 3 - 1 - 4 5 fo- Au Intu N u ./k lu i I n i t i a l Ikaly l b l | k l . ( | ) U dlM llM fe fu rim i --------------- EryirST" 4 td ue. M lluui a B rf lltaaa y| m "" n iiuuta ttjrlb eaa ta u . B rylbaaa 9a Mutua 1 "- try lb iM J jj. tifllum tdaaa albo o > r> o t> 0 '? HK* arvo o 7 O o n o0 ,, 3 //o , o 0 V" \ \ V> 1 O\ n\ O > o 41 \ \ 7 bay Body N e ig lil ( | ) w i / 3-I-S5" O MA - u til tt|A |>lIcuble. A * ttulM UlttUUAAMtt U m o InII ll * blIM (:iilu|. JJ iwciullc arena ltv l M 4 byt Datai Tacita Ic la a CK fP P CfL In itia l Dy C.K 6A ms~ D a ta 3> S cala uaedi < M m I I r r i t i l i Im Score 3 - / Q-OS? t i *y 1 dvMr CK 3 -a . 3 -3 O .O s,, . ..... (TIA) o O O' 3W 15 BEST COPY AVAII ABLE (1) Cara t. I fPSHBTX I (A) o--c itr - dagru of doaaltr (a rt* aost d<nit tabu fa r roadinc) Ha OpMitT . --............. i i ...... . . . -- -- i........ . m m m m m m m m ii u. ... . SoattarU or llffuao araa, datalla af Irla olaarljr rtalblo EaaUf diaaarnlbla tru a lo e u t arau , datalla of Irla a U c ttlr obuor - ' ................ .......... Opaloaaaot arau , aa datalla of Ir la rla lb ls , alaa of pupll b artlr diaaarnlbla ................... -- -- ---- ---- Opoqu, Ir la larla lb ia ..........--...................., ..... . ........ 0 1* 2* 3* * <i> l e u st a m i laiBlTrt Oaa qaortor (or loas), bot aet u ro ru ta r tina m quortor, bofe lo u tb u b alf - .... . . . . . . . . . . . . ... ru ta r tb u balf, bvt lo u tb u tb ru oaartars i i ru ta r tb u tb ru qurtars, ta U alska ru ,... . . 111.. i 2 3 lili] Total Harta 80 (2) M i (2) m a n . laida aban aar u l . aaagaatlu, aaalllac, olrooanoraool la jo a tlu (aar or a ll of tbaas or o a a U u ttu of ar tboroaf) Ir la a t lll raaatlai ta 1Kb* (alaqtab ru a tlu la positivo) ................ 1 1* la r u a t lu u U bt, baaarrbaa, rau taatru t l u (aay r a ll a r tfeaaa) .. - - .... ....... . ........... ........ ...........-- 2 * It 9 TSU I Hwrta a 10 (3> fiM.nattin* (A) n^aamam (rafors ta polpobrol a u ju a tlu a oaly>) Yoasala a a ru l ---- -- 1 .. . ...... - -- Yaaaala d elaltaly lajootod abar a aaraal 1- 1 .. ... Kara dlffuu , doapar artaa u r U , ladlrldaal n u l a aab aaatly Usoarolblo ....... ' M ffU o baaty ra l . 1 0 1 32** (I) a m u la uaU la " .----i. . . . . -- ...- lfl|P g fiU 4 fl| iiM vt oovsiiL (IboI imIb - O^VjUMM M U IB I l^tdl p lftlftl WTSlflfll of X14| uaauaaun la a llla Itb Uda aba* balf ol oau . ni.. flinULlsc Mifcll XSsM o lo n l (9 M p l l t i l f olotMl 0 1 32** t* (e> t t a t o m Aar auoa* oifforoat fe rn aaraal (dou aot laoludo aaall aaauts obaarrad la laaor e u tb u of iwraol aalaals) 1 ... Uaobtrsa ltb u la tu ln of tba lu a ud balra J u t adjaout tS UdS ... .. ...... . Maabana Itb aalatoala of tba Uda aad balra* ud ooaaldoroMo a ru arooad tba ora -- - ....... . .. .......... - ............... . . 0 1 2 3 Saara (1 I C) s 2 Total H u la 20 Tba tatal aoora f t r t b a o r o l a t b a a u o f a l l aaoru obtatnodfar tba tarnu . Ir la , aad aoajuotlrao. * S cirrid t l i u r u lndlcaeo .poalelr affaee. 001167 Primary Eye Irritacin Tese Inicial Sodium Fluorescein Exam and Animal Body Weights Tese Compound___ T - _____________ RT Ho. S 2 0 3 ^ 1 3 pH Result D* (8) 0- Q,$ , LtfiL-tfuiyaIsrt) Dose (ml) N O ft Oats Animals Received 2- HazJeW Iteaaarch TVtsducb Room Ho. )(oI- 1 Dosed By /y? Reviewed By Dace ?/? &/#r~p*te H - No 001168 Primary Ey Irritation Teat Observations Test Compound / ** 3*7o2~7 a He. S O O S V 7 .3 Tese Ey* % \ o \ rV (Oft Washed Group &. __ Seconda following instillation of test eterici, the test eye was washed with f O A 1 of KJ A for K^n seconds Unwashed OBSERVATION PERIOD; \ K n U J T Animal No./ ci Ear Tag No. location of Sornaal Lesions \Om o oCeil ... . .... > Head 7 ??/s- (() o Ocular Structure Cornea - Ogaeity Area Iris Conjunctivas - Redness Cheaosia Discharge Sodium Pluoreseein Exam Technician Recorded Bv r> n y \\SS \ \ \6 rr & n n n \ 1 (Oft YV rr7 o 0. o t_ _ n tofl- */3f \ \ \ \ \ \ .\ \ A P a m lent Discharge B Clear Discharge C Petite Hemorrhage D Blanching 1NJ Injected NEC - Negative. POS Positive E Feeling f - Corneal Epithelial Daaage, Filing C Corneal Epithelial Damage, Fitting H - Fannus I - Corneal Neovasculariaation HA - Hot Applicable Reviewed By: Sc osta: 3-M-3S* Eye Irritation Score: T Q Sv^> '--I 001169 Primary Sy Irritation Tase Observation ^ V tC Compound 4 T- 3 1 2 1 Tst Eye R.>a V A . Croup /oA w Mo. S D D V r l Oft Hashed Oft Saeonds followinc instillation ai east material, tha test eye was washed with , b m ! of - ^ A for Oft- saeonds Unwashad A Parulane Discharfa B Claar Discharge C Patita Bamorrhaga 0 Blanching INJ Injaeead NEC Nagativa POS * Positiva Reviewed By: -- ^Data: E Coraaal Epithaliai Damage, Pealing P - Corneal Epithelial Damage, Piling G Corneal Epithelial Damage, Pitting ' B Pannua X Corneal Neovascularization HA Not Applicable ^ Eye Irritation Score: (1311A) G01170 Primary Eye Irritation Teae Obaervaeiona 4 Taac Compound r- ?mi no. S'osa s v 7J Taac Eya ^ vOkVrV Group &2 (Oft ,Waahad Saeonda following inatillation of eaae Unwaahed ,19m.a6t.erailal,*_th_a__ea^ae aya waa or wOaafhtad wieh aaconda Raima1 No./ iar Tag No. .oeaeion of Corneal Laaiona \0~ 7JI3- f ) W- W (> () Dcular Structura Cornea - Opaciev Area Erie n. n O h , '/o.. D \ \\ Conjuaeeivae * Radnaaa t Chemoaia 1 Diaeharre A JASodium Fluoraaeain Exam a Technician W.- Recorded Bv Lea, mS 3k. A * Parulane Diaeharga B * Claar Diaeharga C Paeiea Hemorrhage D Blanching IMJ * Xajeceed toe - Negative POS Poeieiva h. rs ' n (O ' \s| nA Aid O *in_ . ........ \ \ \ - VP J k ____ 3/k \ \ AnWT 3 Corneal Epiehelial Damage, Peeling F a Corneal Epiehelial Damage, Piling G Corneal Epiehelial Damage, Pieeing H Pannua I " Corneal Neovaacularixaeion IU Hoe Applicable Reviewed By: 5<.^ Daea: Eye Irrieaeioo Seora: 3. Oiva C1311A) C 01171 Primary By Irritation Teat Observations ,/"^Teat Compound / ** *3*1 * 6. .riO JOJV7J Test Eye ft'v & V * Group lOfl. lOft Washed Seconds following instillation of test fOA A Oftnotarial, the test eye was washed with al of KJ for seconds Unwashed Animal No./ Ear Tat No. Location of Zorneal Lesions rO" fail <--- > Head Zcular Structure Zornea - OgAcit^ Area Iris Conjunctiva * Redness OBSERVATION PERIOD; 73 V\nUT<; W3 f) t) Q Oo \O \\f /A/5 o & \/ c n r) n Chemosis Diacharre On n n_ . n C) . Sodium Pluoreseein R a n Technician Recorded Bv P.eS-- , AjV/1 . hn _ JtWi 1 $Vr /Oip/i I $ () \\\ \ \ A Purulent Discharge B Clear Discharge C Petite Hemorrhage D Blanching XNJ Injected MEG Negative POS Positive E Corneal Epithelial Damage, Peeling f - Corneal Epithelial Damage, Piling G Corneal Epithelial Damage, Pitting R * Pannua I Corneal Neovascularization NA * Noe Applicable Reviewed By: Dace: Eye Irritation Score: 2 , ^ sva U 3 iia; 001172 Priaary Eye Irritation Tese Observacin O 1**' Ccpouod ! ~ 3721 po. S o o o sy 7J Tase Eya ^ ^<xV V *0 shad Group o ft _ Seconds following instillation of east notarial, tha tase aye was washed with -fc. ! - fo r wconds Unwashed Aninal Mo./ Ear Tat Mo. .ocacion of Corneal Lesions -- vO" Wl Scalar Structure 'lEj o O OW - Q ornea - Ogaciey Area Iris Conjunctivas - tedness Cheaosis 0 00 o0 00 oo 0 o 0 n \ \\ \| Oischarxe 0 At ft 0 AlA O m \ \ Tachnician CK _ CUL \ Recorded Bv 6 * cu. .\ Data /9S5"* 3N 3Af 3M \ A Purulent Oiacharga B Clear Oiacharga C Patita Banorrhage 0 Blanching IMJ Injected MEG negative FOB Poaieive E Corneal Epiehalial Denego, Peeling 7 Corneal Epithelial Denega, Piling G Corneal Epiehalial Daaaga, Pitting H Panata 1 Corneal Neovaseulariaaeion NA * Hot Applicable Reviewed By: T Date: 0.0 Eye Irritacin Score: (l311A 001173 BEST COPY AVAIl ABLE HAZLETON LABORATORIES AMERICA, INC. 3301 KINSMAN BLVD. P.O. BOX 7545 MADISON, Wl 53707 (60S) 241-4471 TLX 703956 HA2RAL MDS UD February 25, 1985 Dallas D. Zimmerman, PhD Manager, Toxicology Services International 3M Center St. Paul MN 55144 i i FEB ',i 1, \. Dear Dallas Enclosed please find two copies each of the following protocols for sample T-3727, HLA No. 50202473: Protocol No. Study______________ -___________________________ . TP-2069 TP-2072 Tp-2071 Acute Oral Toxicity Study in Rats Primary Eye Irritation Study in Rabbits Primary Dermal Irritation Study in Rabbits These studies will be conducted in accordance with the OECD testing guidelines and GLP regulations. Please sign all copies, retain one set for your file, and return the others to me. We can initiate these studies upon your verbal authorization. Should you have any questions, please feel free to call. Sincerely Steven M. Glaza Study Director Acute Toxicology SMG/mvh Enclosures Chemical & BioMedical Sciences Division 001174 HAZLETON LABORATORIES AMERICA, INC. 3301 KINSMAN BLVD. P.O. BOX 7545 MADISON, Wl 53707 (608) 241-4471 TLX 703956 HAZRAL MDS UD PROTOCOL TP2071 /' Primary Dermal Irritation Study in Rabbits (OECD Guidelines) Study No. 50202473 '. 'V for 3M St. Paul, Minnesota by Hazleton Laboratories America, Inc. Life Sciences Division 3301 Kinsman Boulevard Madison, Wisconsin 53704 February 25, 1985 1985, Hazleton Laboratories America, Inc. Chemical & BioMedical Sciences Division 001175 1 PROTOCOL TP2071 Primary Dermal Irritation Study in Rabbits (OECD Guidelines) Study No . Study Location 50202473 Hazleton Laboratories America, Inc Life Sciences Division 3301 Kinsman Boulevard Madison, Wisconsin 53704 Test Material T-3727 Sponsor's Representative Study Director Dallas D. Zimmerman, PhD Steven M. Glaza Proposed Timetable Starting Date Completion Date Final Report Date Week of February 25, 1985 Week of February 25, 1985 Week of April 1, 1985 001176 OBJECTIVE The objective of this study is to determine the relative level of primary skin irritation of a test material on rabbits under semioccluded conditions. All aspects of this study will conform to the Organisation for Economic Cooperation and Development's Guidelines for Testing Chemicals, Section 404, Acute Dermal Irritation/Corrosion, Adopted May 12, 1981* and the U.S. Food and Drug Administration's Good Laboratory Practice Regulations for Nonclxnical Laboratory Studies. All procedures will be done according to Hazleton Laboratories America, Inc. (HLA) Standard Operating Procedures (SOPs) referenced in this protocol. TEST MATERIAL Test Material: Physical Description: T-3727. Off-white solid. Purity and Stability: Sponsor has purity and stability determinations on file. Storage Conditions: Store at room temperature. Test Material Retention: Any unused test material will be discarded 30 days after issuance of the final report. Safety Precautions: Laboratory personnel will take the normal necessary precautions in handling a substance of unknown toxicity. Laboratory clothing, latex gloves, Safety glasses, and a particle mask approved for toxic dusts must be worn. TEST SYSTEM Test Animal Young adult albino rabbits of either sex of the New Zealand White strain, approximately 14 weeks of age, will be obtained from Hazleton Research 001177 2 Products Inc., Denver, Pennsylvania. An adequate number of extra animals will be purchased so that no animal in obviously poor health is placed on test. Historically, the New Zealand White albino rabbit has been the animal of choice for evaluating the effect of chemicals on the skin. Acclimation Upon receipt, the animals will be taken to a designated animal room where they will be acclimated for at least 1 week before being placed on test (OP-GENB 36). During acclimation, the animals will be examined for clinical abnormalities indicative of health problems (e.g., diarrhea, ectoparasites, rough hair coat, nasal or ocular discharge, evidence of injury, etc.). Any animals regarded as unsuitable for study purposes because of poor physical condition will not be released from acclimation and the reason(s) will be documented. Identification Each animal in the study will be assigned a permanent identification number and will be identified with a metal ear tag (OP-GENB 24). All data collected from an animal will be recorded and filed under its identification number. Housing and Maintenance The following environmental conditions will be maintained in the animal room used for this study (OP-TARC 230). o Temperature: 21C +2 o Relative humidity: 50% +20% o Air change: At least 10 changes an hour of filtered 100% outsiae air o Light cycle: 12 hours light/12 hours dark 001178 3 Temperature and humidity will be monitored throughout the study. Variations from prescribed environmental conditions will be documented. Animal husbandry and housing at HLA comply with standards outlined in the 3 "Guide for the Care and Use of Laboratory Animals." Care will be taken to ensure that the animals are not disturbed for reasons other than data collection and routine maintenance. The animals will be housed individually in screen-bottom stainless steel cages (heavy gauge) held on racks, with absorbent pan liners in the urine- and feces-collecting pans. Pan liners will be changed at least three times each week. Feed and water will be provided ad libitum. The diet will be Teklad Laboratory Rabbit Diet. No contaminants are expected to be present in the feed or water which would interfere and affect the results of the study. Study Design Three rabbits will be selected at random based upon health and a body weight of 2.0-3.5 kg. Each animal will serve as its own control. PROCEDURES Preparation and Administration of Test Material TWenty-four hours prior to test material administration, the hair will be clipped from the back and flanks of each animal. The treatment sites will be inspected for interfering lesions, irritation, or defects that would preclude the use of any of the animals. 2 The test material will be applied to the test area (approximately 6 cm ) on each rabbit, in the amount of .5 g and will be moistened with deionized water. The treated area will be covered with a 2.5-cra x 2.5-cm gauze patch 001179 4 secured with paper tape and loosely overwrapped with Saran Wrap and Elastoplast tape to provide a semiocclusive dressing. Collars will be used to restrain the animals during the 4-hour exposure period. Reason for Route of Administration 4 Historically, the route of choice based on the method of Draize. Ob servations After the 4 hours of exposure the patches and the test material will be removed as thoroughly as possible using water or an appropriate solvent without irritating the skin. Thirty minutes after removing the patches, the degree of erythema and edema will be recorded according to the Draize Technique (Attachment 1). Subsequent readings will be taken at 24, 48, and 72 hours after patch removal. Further observations may be recorded, as necessary, to establish reversibility. If irritation is increasing in severity at the 72-hour examination period, observations will be repeated at 96 hours and at 7 and 14 days, if applicable. Body weights will be taken just prior to test material administration and at weekly intervals during the study. Observations and body weights will be recorded in the study notebook. Pathology All animals, whether dying on test or sacrificed at study termination, will be discarded. O O iJ L S O 5 Repor t The final report will present a description of the test material, a description of the test system, dates of study initiation and termination, a tabulation of irritation data, and a description of any toxic effects other than dermal irritation. Maintenance of Raw Data and Records Original data or copies thereof will be available at HLA to facilitate auditing the study during its progress and prior to acceptance of the final ' report. When the final report is completed, all original paper data, as well as the final report, will be retained in the archives of HLA, Madison, Wisconsin (OP-GEN 44). REFERENCES 1. "Acute Dermal Irritation/Corrosion", OECD Guidelines for Testing Chemicals, Section 404, May 12, 1981. 2. 21 CFR 58 3. DHEW Publications No. (NIH) 78-23 (1978). 4. Draize, J. H., "Dermal Toxicity," Appraisal of the Safety of Chemicals in Foods, Drugs, and Cosmetics, Association of Food and Drug Officials of the U.S., Topeka, Kansas, pp. 46-59 (1959). 00181 6 PROTOCOL APPROVAL B l P AVAILABLE V :.v_-. U L v A -A. u'tva',, Dallas D. Zimmerman, PhD Sponsor's Representative 3M Group Leader, Acute Toxicology Hazleton Laboratories America, Ine. (1069S/j g) Date .Date 001182 7 ATTACHMENT I PRIMARY SKIN IRRITATION SCORING SCALE 1. Erythema and Eschar Formation No erythema Very slight erythema (barely perceptible) Well-defined erythema Moderate to severe erythema Severe erythema (beet redness) to slight eschar formation (injuries in depth) Highest possible erythema score 2. Edema Formation No edema Very slight edema (barely perceptible) Slight edema (edges of area well-defined by definite raising) Moderate edema (raised approximately 1 mnO Severe edema (raised more than 1 mm and extending beyond area of exposure) Highest possible edema score 0 1 2 3 _4 4 0 L 2 3 _4_ 4 001183 HAZLBTOIN LABORATORIES AMERICA. INC. 3301 KINSMAN BLVD. P.O. BOX 7545 MADISON, Wl 53707 (608) 241-4471 T U 703956 HAZRAL MDS UD PROTOCOL TP2069 Acute Oral Toxicity Study in Rat/ (OECD Guidelines) P FEB 2 7 Study No. 50202473 V IV / for 3M St. Paul, Minnesota by Hazleton Laboratories America, Inc. Life Sciences Division 3301 Kinsman Boulevard Madison, Wisconsin 53704 February 25, 1985 J 1985, Hazleton Laboratories America, Inc. Chemical & BioMedical Sciences Division 1 PROTOCOL TP2069 Acute Oral Toxicity Study in Rats (OECD Guidelines) Study N o .: Study Location: Test Material: Sponsor's Representative: Study Director: Proposed Timetable Starting Date: Completion Date: Final Report Date: 50202473 Hazleton Laboratories America, Inc. Life Sciences Division 3301 Kinsman Boulevard Madison, Wisconsin 53704 T-3727 Dallas D. Zimmerman, PhD Steven M. Glaza Week of February 25, 1985 Week of March 11, 1985 Week of April 1, 1985 001185 OBJECTIVES To determine the acute oral toxicity produced when the test material is administered by the oral route (gavage) to rats. All aspects of this study will conform to the Organisation for Economic Cooperation and Development's Guidelines for Testing of Chemicals, Section 401, adopted May 12, 1981* and the U.S. Food and Dru Administration's Good Laboratory Practice Regulations . .2 for Nonclinical Laboratory Studies. All procedures will be don according to Hazleton Laboratories America, Inc. (HLA) Standard Operating Procedures (SOPs) referenced in this protocol. Test Material: Physical Description: Purity and Stability: Storage Conditions: Test Material Retention: Safety Precautions: TEST MATERIAL T-3727. Off-white solid. * Sponsor has purity and stability determinations on file. Store at room temperature. Any unused test material will be discarded 30 days of issuance of the final report. Laboratory personnel will take the normal necessary precautions in handling a substance of unknown toxicity. Laboratory clothing, latex gloves, safety glasses, and a particle mask approved for toxic dusts must be worn. Disposal All waste feed, animal wastes, pan liners, and carcasses resulting from this study will be disposed of in a high-temperature incinerator (U.S. Smelting Furnace Company, Belleville, Illinois). 001186 2 TEST SYSTEM Animal Model Young adult male and female albino rats (approximately 7 weeks of age) of the Sprague-Dawley strain will be obtained from Harlan Sprague-Dawley, Madison, Wisconsin. Rats will be selected at random from healthy animals that had been acclimated at HLA for at least 1 week. An adequate number of extras will be purchased in order that no animal in obviously poor health is placed on test. The weight variation in animals used on test will not exceed +20% of the mean weight (i.e., mean * 250 g, range 200 to 300 g). Reason for Species Selection The rat is the animal classically used due to its small size, ready availability, and large amount of background data. Identification Each animal will be assigned an individual animal number and ear tag which will accompany data collected from that animal throughout the study (0P-GENB 24) . Housing and Maintenance The following environmental conditions will be maintained in the animal room used for this study (OP-TARC 230). o Temperature: 2 1 C 2 o Relative humidity: 50% 20% o Air change: At least 10 changes an hour of filtered 10.0% outside air o Light cycle: 12 hours light/12 hours dark Temperature and humidity will be monitored throughout the study. Variations from prescribed environmental conditions will be documented. 001187 3 Animal husbandry and housing at HLA comply with standards outlined in the 3 "Guide for the Care and Use of Laboratory Animals." Care will be taken to ensure that the animals are not disturbed for reasons other than data collection and routine maintenance. The animals will be individually housed in screen-bottom stainless steel cages held on racks, with absorbent pan liners in the urine- and feces-collecting pans. Pan liners will be changed at least three times each week. Feed and water will be provided ad libitum. The diet will be Purina Rat Chow*. No contaminants are expected to be present in the feed or water which would interfere and affect the results of the study. PROCEDURES Experimental Design Initially, a single dose of 5.0 g/kg will be administered to 10 animals (five males and five females). If no test material-related mortality is . produced at this level, no further testing is required. If any mortality occurs at the 5.0-g/kg dose level, at the Sponsor's request, three or four geometrically spaced dose levels may be added. Each dose level will consist of 10 animals (five males and five females). Animals will be assigned to groups according to HLA Standard Operating Procedure OP-TOX 42. Test Material Preparation and Administration The test material will be suspended in an appropriate vehicle. Individual dosages will be calculated based upon the animal's body weight taken just before administration of the test material and administered by gavage. 001188 4 Justification of Route of Administration This is the method for administering a known quantity of test substance and has been the route of choice historically. Observations The animals wil.l be observed individually for clinical signs and mortality at 1.0, 2.5, and 4 hours after test material administration. The animals will be observed daily thereafter for at least 14 days for clinical signs and twice daily (morning and afternoon) for mortality. The duration of observations may be extended when considered necessary. The time of death will be recorded as precisely as possible. Individual body weights will be recorded just prior to study initiation and at 7 and 14 days following test material administration and at death. Changes in body weight will be calculated and recorded when survival exceeds 1 day. Pa th o lo g y All test animals, whether dying during the study or sacrificed at termination, will be subjected to a gross necropsy examination and abnormalities recorded. Report - The final report will contain a description of the test material, a description of how the study was conducted, response data for clinical signs, mortality and body weights by sex, a discussion of the data, and gross pathology findings. 001189 5 Maintenance of Raw Data and Records Original data or copies thereof will be available at HLA to facilitate auditing the study during its progress and prior to acceptance of the final report. When the final report is completed, all original paper data, as well as the final report, will be retained in the archives of HLA, Madison, Wisconsin (OP-GEN 44). REFERENCES 1. Organisation for Economic Cooperation and Development's Guidelines for Testing of Chemicals, Section 401, Acute Oral Toxicity, adopted May 21, 1981. 2. 21 CFR 58. 3. DHEW Publications No. (NIH) 78-23 (1978). 001190 6 PROTOCOL APPROVAL iV-h! . Dallas D. Zifnmerjnan, PhD Sponsor's Representative 3M V...- Steven M. Glaza U Study Director Group Leader, Acute Toxicology Hazleton Laboratories America, Inc (1064S/j g) Date ,ys. Date 001191 HAZLETON LABORATORIES AMERICA. INC. 3301 KINSMAN BLVD. P.O. BOX 7545 MADISON, Wl 53707 (608) 241-4471 111 < > * ~ r a n 9 m B B w i w M B a K a n t J u i J n M R 7 i TLX 703956 HAZRAL MDS UD PROTOCOL TP2072 Primary Eye Irritation Study in Rabbits (OECD Guidelines) Study No. 50202473 for 3M St. Paul, Minnesota by Hazleton Laboratories America, Inc. Life Sciences Division 3301 Kinsman Boulevard Madison, Wisconsin 53704 February 25, 1985 * 1985, Hazleton Laboratories America, Inc. Chemical & BioMedical Sciences Division 001192 I PROTOCOL TP2072 Primary Eye Irritation Study in Rabbits (OECO Guidelines) Study No. Study Location Test Material 50202473 Hazleton Laboratories America, Life Sciences Division 3301 Kinsman Boulevard Madison, Wisconsin 53704 Inc. T-3727 Sponsor's Representative Study Director Dallas D. Zimmerman, PhD Steven M. Glaza Proposed Timetable Starting Date Completion Date Final Report Date Week of February 25, 1985 Week of March 1, 1985 Week of April 1, 1985 001193 OBJECTIVE The objective of this study is to determine the level of irritation produced following a single exposure of a test material to one eye of albino rabbits. All aspects of this study will conform to the Organisation for Economic Cooperation and Development's Guidelines for Testing Chemicals, Section 405, Acute Eye Irritation/Corrosion, Adopted May 12, 1981^ and the U.S. Food and Drug Administration's Good Laboratory Practice Regulations for 2 Nonclinical Laboratory Studies. All procedures will be done according to Hazleton Laboratories America, Inc. (HLA) Standard Operating Procedures (SOPs) referenced in this protocol. Identification Test -Material: Physical Description: Purity and Stability: Storage Conditions: Test Material Retention: Safety Precautions: TEST MATERIAL T-3727. Off-white solid. Sponsor has purity and stability determinations on file. Store at room temperature. Any unused test material will be discarded 30 days after issuance of final report. Laboratory personnel will take the normal necessary precautions in handling a substance of unknown toxicity. Laboratory clothing, latex gloves, safety glasses, and a particle mask approved for toxic dusts must be worn. 001194 2 TEST SYSTEM Test Animal Young adult albino rabbits of either sex of the New Zealand White strain, approximately 14 weeks of age, will be obtained from Hazleton Research Products, Inc., Denver, Pennsylvania. An adequate number of extra animals will be purchased so that no animal in obviously poor health is placed on test. The New Zealand White albino rabbit is the animal of choice based upon its large orbit and nonpigmented iris. Acclimation Upon receipt, the animals will be taken to a designated animal room where they will be acclimated for at least 1 week before being placed on test (OP-GENB 36). During acclimation, the animals will be examined for clinical abnormalities indicative of health problems (e.g., diarrhea, ectoparasites, rough hair coat, nasal or ocular discharge, evidence of injury, etc.). Any animals regarded as unsuitable for the study purposes because of poor physical condition will not be released from acclimation and the reason(s) will be documented. Identification Each animal in the study will be assigned a permanent identification number and will be identified with a metal ear tag (OP-GENB 24). All data collected from an animal will be recorded and filed under its identification number. 001195 3 Housing and Maintenance The following environmental conditions will be maintained in the animal room used for this study (OP-TARC 230). o Temperature: 21C +2 o Relative humidity: 50% +20% o Air change: At least 10 changes an hour of filtered 100% outside air o Light cycle: 12 hours light/12 hours dark Temperature and humidity will be monitored throughout the study.. Variations from prescribed environmental conditions will be documented. Animal husbandry and housing at HLA comply with standards outlined in the 3 "Guide for the Care and Use of Laboratory Animals." Care will be taken to ensure that the animals are not disturbed for reasons other than data collection and routine maintenance. The animals will be housed individually in screen-bottom stainless steel cages (heavy gauge) held on racks, with absorbent pan liners in the urine- and feces-collecting pans. Pan liners will be changed at least three times each week. Feed and water will be provided ad_libitum. The diet will be Teklad Laboratory Rabbit Diet. No contaminants are expected to be present in the feed or water which would interfere and affect the results of the study. Study Design Three rabbits will be selected at random based upon health and a body weight of 2.0 to 3.5 kg. PROCEDURES Preparation and Administration of Test Material The rabbits' eyes will be examined using fluorescein dye procedures within 24 hours prior to test material administration. Only animals with no sign of 001196 4 corneal injury or eye abnormalities will be utilized. One eye of each animal will be treated with the test material and the other eye will serve as the untreated control. Each rabbit will receive 0.1 g (or the weight equivalent of 0.1 mL) of solid test material. If necessary, the solid test materials will be finely ground into a dust or powder. The test material will be placed into the everted lower lid of the rabbit's eye. The upper and lower lids are then to be gently held together for 1 second before releasing to prevent loss of material. The eyes of the rabbits will remain un.flushed for 24 hours following instillation of the test material. After 24 hours, a washout may be used if considered appropriate. Reason for Route of Administration 4 Historically, the route of choice based on the method of Draize. Ob servations The treated eyes of all animals will be examined for ocular irritation at 1, 24, 48, and 72 hours after treatment. If no irritation or injury is present at 72 hours, the study will be terminated. If irritation is present at 72 hours, additional observations will be made at 96 hours and at 7, 14, and 21 days. If at any of these time points there is no irritation, the study will be terminated. If injury is still present at 21 days, the Sponsor will be-contacted to determine whether the study should continue or be terminated. After recording the 24-hour observations, sodium fluorescein may be used to aid in revealing possible corneal injury. Irritation will be graded and 4 scored using the Draize technique (Attachment 1). All eye abnormalities will be recorded. 001197 5 All animals that have a damaged eye producing undue stress or discomfort will be sacrificed for humane reasons after consulting with the Sponsor. Body weights will be recorded prior to test material administration and at weekly intervals throughout the study. Observations and body weights will be recorded in the study notebook. Pa thology All animals, whether dying or sacrificed at study termination, will be discarded. Report The final report will present a description of the test material, a description of the test system, dates of study initiation and termination, a summary table showing the irritation data at each observation period, and any special observations that were recorded. Maintenance of Raw Data and Records Original data or copies thereof will be available at HLA to. facilitate auditing the study during its progress and prior to acceptance of the final report. When the final report is completed, all original paper data, as well as the final report, will be retained in the archives of HLA, Madison, Wisconsin (OP-GEN 44). 00X198 6 REFERENCES 1. "Acute Eye Irritation/Corrosion," OECD Guidelines for Testing Chemicals, Section 405 (May 12, 1981), 2. 21 CFR 58. 3. DHEW Publications No. (NIH) 78-23 (1978). 4. Draize, J. H., Appraisal of the Safety of Chemicals in Foods. Drugs, and Cosmetics - Dermal Toxicity, Association of Food and Drug Officials of the .S., Topeka, Kansas, pp. 49-51 (1959). 001199 7 BEST COPY AVAU ABLE PROTOCOL APPROVAL -- - ->.-A ' Dallas D Sponsor1 3M Zirameitnan, PhD Representative vy Th, Steven M. Glaza Study Director Group Leader, Acute Toxicology Hazleton Laboratories America, Inc (1068S/ j g) Date 2-*s-as Date 001200 PROTOCOL - ATTACHMENT 1 (1) Cornea (A) nrmnitr - degree of density {area most dense taken for reading) No opacity -- -- -- -- -- -- -- ---- -- -- -- --- -- -- -- -- -- -- -------- 0 Scattered or diffuse area, details of iris clearly visible --------- 1 Easily discernible translucent areas, details of iris slightly obscured ------------------ --------------------------------- 2 Opalescent areas, no details of Iris visible, site of pupil barely d i s c e r n i b l e ------------- ------------------------------------ - 3 Opaque, iris invisible -..---------------- ----------- 4 (B) /irea of cornea involved One quarter (or less), but not taro -- -- -- -- -- -- -- -- -- ---- ----- 1 Greater than one quarter, but less than half Greater than half, but less than three quarters -- -- --- 2 -- -- -- --- -------- 3 Greater than three quarters, up to whole' a r e a ----------------------- 4 AxBx 5 Total Maximum * 80 (2) Ida (A) Values Normal Folds above normal, congestion, swelling, circuacorneal injection (any or all of these or combination of any thereof) iris still - reacting to light (sluggish reaction la positive) Mo reaction to light, hemorrhage, gross destruction (any or all of these) ... . ------------------------- ....-- - 0 1 2 Ax 5 Total Maximum * 10 (3) Conjunctivas (A) Redness (refers to palpebral oonjunctlvae only) Vessels normal -- -- -- ------------------------- -- ---------------- -- 0 Vessels definitely injected above normal ---- - 1 More diffuse, deeper erlmson red, Individual vessels not easily discernible -- ----- ----------- - ----------- ---------- ----- ' 2 Diffuse beefy red 3 (B) chgggaia No s w e l l i n g --------------------------- -- ;-- -- -- ------------------------ Any swelling above normal (includes nictitating membrane) Obvious swelling with partial eversion of lids -- -- -------- --- ----- Swelling with lids about half d o s e d -- -- -- .----- --- - - -- Swelling with lids about half closed to completely closed ---------- 0 1 2 3 4 (C) djPlsshantB Any amount different from normal (does not Include small amounts observed in inner canthus of normal animals) -- ----------------- Discharge with moistening of the lids and hairs Just adjacent to lids -- ---------------- Discharge with moistening of the lids and hairs, and considerable area around the eye -- -- ------------ ------------------------- -- 0 1 2 3 Score (A B * C) x 2 Total Maximum 20 The total score for the eye is the sum of all scores obtained for the cornea, iris, and conjunctivas. 001201