Document b5d96dqngpDXnzLo08azN0xYg

ARXfc-omi International Research and Development Corporation SPONSOR: TEST MATERIAL: SUBJECT: 3M Company Fluorad Fluorochemical FC-143 Acute Oral Toxicity (LDsn) Study in Rats. 50 Wilson P. Dean, B.A. Director of Acute Toxicolog2/' and Special Studies (Study Director) Collaborators: Gary Thompson, B.S. Group Technical Supervisor Greg Romig, B.S. Unit Technical Supervisor David Powell, B.A. Unit Supervisor, Report Preparation, Acute and Special Studies Department Date: May 5 > I978 137-091 000038 ______ International Research and Development Corporation_____ T A B L E OF C O N T E N T S I. S y n o p s i s ........................................................ II. Test M a t e r i a l ................................................. III. M e t h o d .......................................................... IV. R e s u l t s ........................................................ A. Mortality and LD^q V a l u e s ................................. B. Pharmacotoxic Signs ........................................ C. Body W e i g h t s ............................................... D. Necropsy Findings ......................................... 1. Rats whichdied during the study p e r i o d ............... 2. Rats which were sacrificed following 14 days of o b s e r v a t i o n ........................................... Table No. 1. PharmacotoxicSigns ....................................... Page 1 2 3 4 4 4 7 8 9 11 5-6 137-091 000039 International Research and Development Corporation Page 1 I. SYNOPSIS Based upon the data obtained, the acute oral LD^Q values and 95% confidence limits were calculated to be as follows: Male Rats: 680 (399 - 1157) mg/kg. Female Rats: 430 (295 - 626) mg/kg. Combined Male and Female Rats: 540 (389 - 749) mg/kg. 137-091 000040 International Research and Development Corporation Page 2 11. TEST MATERIAL The test material was received from the 3M Company, St. Paul, Minne sota ou October 24, 1977. It was identified as "Fluorad FIuorochemical FC-143, 3M Stock No. 98-0211-0008-0, Lot 340" and was received as a white powder. 137-091 000041 International Research and Development Corporation Page 3 III. METHOD Twenty-five male and 25 female rats of the Charles River CD strain (obtained from Charles River Breeding Laboratories, Inc., Portage, Mich igan), weighing from 180 to 221 grams, were used for this study. The rats were housed by sex in groups of 5 rats per cage, in hanging wiremesh cages in temperature and humidity controlled quarters. They were maintained in accordance with the recommendations contained in H.E.W. Publication No. 74-23 (N.I.H.) entitled "Guide for the Care and Use of Laboratory Animals". Water and Purina Laboratory Chow were available ad libitum, except for an overnight period immediately preceding oral administration during which food, but not water, was withheld. The test material was administered orally by gavage as an emulsion"^ in 40% acetone/60% corn oil at the following dosage levels to male and female rats: 100, 215, 464, 1000 and 2150 mg/kg. Five rats of each sex were used at each dosage level. Volumes of 10 ml/kg of body weight were administered at all dosage levels. All rats were observed for mortality and pharmacotoxic signs during the first four hours after dosing, at 24 hours and daily thereafter for a total of 14 days. Body weights were recorded immediately prior to dosing (control weight) and at 7 and 14 days. All rats which died on study were subjected to gross necropsy examination as were all survivors at the end of the 14 day observation period. 137-091 C00042 International Research and Development Corporation Page 4 IV. RESULTS A. MORTALITY AND LD^Q VALUES: Dose - Mortality Data Dosage Level mg/kg 100 215 464 1000 2150 Hrs 0-4 MF 13 Number of Deaths Days 1 2 3 4 5 6 7-14 MFMFMFMFMFMFMF 1 22 222 42 1 11 Total Mortalities Male Female Total 1/5 0/5 1/10 0/5 0/5 0/10 2/5 3/5 5/10 3/5 5/5 8/10 5/5 5/5 10/10 The Acute Oral LD^.q Values and 95% Confidence Limits Male Rats: 680 (399 - 1157) mg/kg. Female Rats: 430 (295 - 626) mg/kg. Combined Male and Female Rats: 540 (389 - 749) mg/kg. Slope Male Rats: 1.00. Female Rats: 1.00. Combined Male and Female Rats: 1.00. Statistical References ^Weil, C. S. 1952. Tables for Convenient Calculation of Median Effective Dose and Instruction in Their Use. Biometrics, 8 : 249-263. 2 Thompson, W. R. and Weil, C. S. 1952. On the Construction of Tables for Moving Average Interpolation. Biometrics, 8: 51-54. 3 Eby, R. 1957. Statistical Tables for Dose Evaluation, Report No. 5711. Miles-Ames Research Laboratory, Elkhart, Indiana. B. PHARMACOTOXIC SIGNS: The following pharmacotoxic signs were observed during the 14 day observation period: (see Table 1). 137-091 CO0043 TABLE - 1. COMPOUND - FC-143: NUMBER OF RATS SHOWING PHARMACOTOXIC SIGNS AND TIME [HOUR] (DAY) OBSERVED MALES OBSERVATION Normal Ptosis 100 mg/kg 3 (2 -TTT, 4 (13 - 14) 2 (1) 215 mg/kg 4"(2 - 5), 5 (6 - 14) 2 (1) 464 mg/kg rcr-yr, 3 (6 - 14) 3 (1) 1000 mg/kg 2 (6 - IT) 1 [11. 3 (1) 2150 mg/kg Piloerectlon Hypoactivity 5 [1, 2 1/2, 4], 5 (1) 5 [1. 2 1/2, 41, 5 [1, 2 1/2, 4], 5 (1), 1 (2 - 3) 5 (1), 1 (2 - 3) 1 (1) 5 [1, 2 1/2, 41, 5 [1, 2 1/21, 4 [41 5 (1), 3 (2 - 3),, 2 (4 - 5) Decreased Limb Tone Ataxia 3 [1], 4 [2 1/2, 4], 3 (1) 4 [1], 5 [2 1/2], 2 (41 4 [1, 2 1/21, 3 [4], 2 [11, 3 [2 1/21, 2 [1, 2 1/21, 4 [41, 5 [2 1/21, 4 [41 3 (1) 5 [41> 5 (1) 5 (1), 1 (2 - 3) 4 [11, 3 [2 1/2, 4] 3 [11, 2 [2 1/2, 41, 2 [11, 3 [2 1/2,41, 3 in, 5~ u ~i72t ; 1 (1) 5 (1), 1 (2 - 3) 4 [41 Corneal Opacity 2 (1 - 6), 1 (7 - 12) 2 (1), 1 (2 - 5) 2 (1), 1 (2 - 5) 4 (1) Death 1 (7) 2 (2) 2 (2), 1 (4) 1 [41, 4 (1) 0004 Study No.:___ 137-091 o(Dn <_n TABLE - 1.(Cont.) COMPOUND - FC-143: NUMBER OF RATS SHOWING PHARMACOTOXIC SIGNS AND TIME [HOUR] (DAY) OBSERVED FEMALES OBSERVATION 100 mg/kg 215 mg/kg 464 mg/kg 1000 mg/kg 2150 mg/kg Normal 5 (2 - 14) 5 (2 - 14) 2 (4 - 14) Ptosis 3 (1) 2 (1) Piloerection Hypothermic to Touch Hypoactivity Decreased Limb Tone 3 (1), 1 (2) 5 [1, 2 1/2, 4], 5 O) i [1, 2 1/2], 3 [4], 3 (1) 5 [1, 2 1/2, 4], 5 (1) 1 [1], 2 [2 1/2], 3 [4], 3 (1) 1 (2 - 3) 5 [1, 2 1/2, 4], 5 (1), 3 (2 - 3) 1 [1], 2 [2 1/2], 5 [4], 5 (1), 2 (2 - 3) 1 ~ U , 2 1/2, 4], 3 (1), 1 (2) 2 [1], 4 [2 1/2], 5 [4], 3 (1), 1 (2) 5 [1, 2 1/2], 2 t4] 5 [2 1/2], 2 ]4] Ataxia Corneal Opacity 4 [1], 5 [2 1/2], 3.14] 4 [1, 2 1/2,4 ] 1 2 [1, 2 1/2], 3 [4], 4 [1, 2 1/2], 5 [4], 1 [1], 5 [2 1/2], 3 (1), 2 (2 - 3) 3 (1), 1 (2) 2 [41 1 (1) Death 2 (2), 1 (4) 2 (1), 2 (2), 1 (3) 3 [4], 2 (1) 00004 Study No.: 137-09^_____ f* hj p> " International Research and Development Corporation Page 7 C. BODY WEIGHTS: The following body weights were obtained during the 14 day observa- tion period: Dosage Level (mg/kg) Individual Rat Number Sex Control Weight (grams) 7 Day Weight (grams) 14 day Weight (grams) 100 76888 Male 194 242 296 76889 Male 189 228 275 76890 Male 210 Died Died 76891 Male 190 240 285 76892 Male 198 246 304 76908 76909 76910 76911 76912 Female Female Female Female Female 198 192 186 204 188 217 240 212 226 208 227 225 244 191 212 215 76893 Male 214 266 318 76894 Male 213 267 330 76895 Male 212 254 312 76896 Male 210 252 290 76897 Male 203 234 298 76913 76914 76915 76916 76917 Female Female Female Female Female 195 182 190 185 182 218 243 203 232 209 230 205 222 203 236 464 1000 76898 76899 76900 76901 76902 76918 76919 76920 76921 76922 76903 76904 76905 76906 76907 Male Male Male Male Male Female Female Female Female Female Male Male Male Male Male 215 202 216 218 200 180 180 182 192 194 188 194 192 186 192 Died 249 239 Died 245 200 Died 204 Died Died 208 Died Died Died 223 Died 330 296 Died 302 227 Died 223 Died Died 270 Died Died Died 290 137-091 C00046 International Research and Development Corporation Page 8 Dosage Level (mg/kg) Individual Rat Number Sex Control Weight (grams) 7 Day Weight (grams) 14 Day Weight (grams) 1000 76923 76924 76925 76926 76927 Female Female Female Female Female 202 180 184 198 196 Died Died Died Died Died Died Died Died Died Died 2150 77208 Male 206 Died Died 77209 Male 213 Died Died 77210 Male 208 Died Died 77211 Male 211 Died Died 77212 Male 213 Died Died 77213 77214 77215 77216 77217 Female Female Female Female Female 221 213 217 219 206 Died Died Died Died Died Died Died Died Died Died D. NECROPSY FINDINGS: Gross necropsy observations were noted as indicated on pages 9, 10 , 11. 137-091 000047 International Research and Development Corporation Page 9 1. Rats which died during the study period: Dosage Level (mg/kg) Number Exhibiting Sign/Number Necropsied Gross Necropsy Observations: Yellow stained urogenital region Lungs, conges tion Lungs, pitted Lungs, red foci Stomach, dis tension Stomach, fluid filled Stomach, mu cosa, hyper emia Stomach, mu cosa, thick ened Stomach, con tains dark red fluid Stomach, glan dular mucosa, erosion Stomach, con tains dark red parti culate ma terial Stomach, red fluid filled 100 Male Female 1/1 215 Male Female 464 Male Female 2/2 1/3 1/3 1/3 3/3 2/3 1/3 1/3 1000 Male Female 2/5 2/3 4/5 2/3 4/5 1/3 1/5 2/3 2150 Male Female 3/5 2/5 4/5 5/5 2/5 1/5 5/5 3/5 5/5 4/5 4/5 1/5 1/5 1/5 137-091 000048 International Research and Development Corporation Page 10 Dosage Level (mg/kg) Number Exhibiting Sign/Number Necropsied 100 215 464 1000 2150 Gross Necropsy Male Female .Male Female Male Female Male Female Male Female Observations: Intestines, red fluid filled 2/5 1/5 Liver, pale coloration 1/5 Partially, cannibalized 1/1 Red stain around nose/ mouth 3/5 4/5 137-091 000049 International Research and Development Corporation Page 11 tion: 2. Rats which were sacrificed following 14 days of observa- Dosage Level (mg/kg) Number Exhibiting Sign/Number Necropsied Gross Necropsy Observations: No gross lesions Lungs, foci Stomach, mucosa, thick ened Stomach, glandular mucosa, hyperemia Uterus, hydrometra Kidneys, mottled coloration 100 215 464 1000 Male Female Male Female Male Female Male Female 1/3 1/2 1/2 1/5 4/4 5/5 5/5 4/5 2/3 1/2 1/2 1/4 2/5 1/5 1/5 1/5 2/5 1/2 2/4 2/5 3/5 4/5 1/3 1/2 137-091 000050