Document 2jgQaBo58d314ogZ2ynZ1LaN6

AR N-Et FOSE alcohol IAcute Toxicity - 0002S8 International Research and Development Corporation SPONSOR: TEST MATERIAL: SUBJECT: 3M Company FM-3422 Acute Oral Toxicity (LD,n) Study in Rats. wilson P. Dean, B.A. Director of Acute Toxicology and Special Studies (Study Director) Collaborators: Gary Thompson, 3.S. Group Technical Supervisor Greg Romig, 3.S. Unit Technical Supervisor David Powell, 3.A. Unit Supervisor, Report Preparation, Acute and Special Studies Department 137-084 Date: June 7, 1978 000253 International Research and Development Corporation T A B L E OF C O N T E N T S Page_ I. S y n o p s i s ..................................................... 1 II. Test M a t e r i a l ...............................................2 III. M e t h o d ....................................................... 3 IV. R e s u l t s ..................................................... 4 A. Mortality and LD^q V a l u e s .............................4 B. Pharmacotoxic Signs .............................. 4 C. Body W e i g h t s ............................................... 9-10 D. Necropsy Findings ..................................... 10 Table No. 1. Number of Rats Showing Pharmacotoxic Signs and Time [Hour] (Day) Observed ( M a l e s ) ................ 5-6 2. Number of Rats Showing Pharmacotoxic Signs and Time [Hour] (Day) Observed(Females) ............... 7-8 137-084 000290 International Research and Development Corporation Page 1 I. SYNOPSIS Based upon the data obtained, the acute oral LD^o va^ues an<* 95% confidence limits were calculated to be as follows: Male Rats: 1615 (818 - 3188) mg/kg, Female Rats: 1333 (715 - 2487) mg/kg, Combined Male and Female Rats: 1467 (923 - 2332) mg/kg. 137-084 0002U1 International Research and Development Corporation Page 2 11. TEST MATERIAL The test material was received from the 3M Company, St. Paul, Minnesota on October 28, 1977. It was identified as "FM-3422, 41-27003422-0, Lot 784/Net-35, RR-1" and was received as an off-white to tan waxy substance. 137-084 000292 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, Michigan), weighing from 171 to 259 grams, were used for this study. The rats were housed by sex in groups of 5 rats per cage, in hanging wire-mesh 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% c o m oil at the following dosage levels to male and female rats: 464, 1000, 2150, 4640 and 10000 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 with the exception of the 10000 mg/kg dosage level which was administered at a volume of 20 ml/kg. 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 examinations as were all survivors at the end of the 14 day study period. 137-084 000293 International Research and Development Corporation IV. RESULTS A. MORTALITY AND LD.q VALUES: Dose - Mortality Data Page 4 Dosage Level mg/kg Hrs 0-4 MF 12 M FM Number of Deaths Days 34 5 FM FM FM F 6 MF Total 7 -14 Mortalities M F Male Female Total 464 1000 2150 4640 10000 1 I1 IL 2 1 12 2 112 3 21 12 22 1/5 2/5 2/5 5/5 5/5 0/5 4/5 2/5 4/5 5/5 -T-h-e--A-c-u-t-e---O-r-a-l--L-D,5,,0--V-a-l-u-e-s--a-n-d---9-5-"--C-o-n-f--i-d-e-n-c-e--L-i-m-i-t-s-: !Iale Rats: 1615 (818 - 3188) mg/kg, Female Rats: 1333 (715 - 2487) mg/kg, Combined Male and Female Rats: 1467 (923 - 2332) mg/kg. Slope: Male Rats: 0.80, Female Rats: 0.80, Combined Male and Female Rats: 0.80. Statistical References: 1/10 6/10 4/10 9/10 10/10 Hieil, 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, Re port 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). 137-084 000234 TABLE - 1. COMPOUND - FM-3422: NUMBER OF RATS SHOWING PllARMACOTOXIC SIGNS AND TIME [HOUR] (DAY) OBSERVED MALES OBSERVATION 464 mg/kg 1000 mg/kg 2150 mg/kg 4640 mg/kg 10000 mg/kg Normal 3(6-7), 4(8-14) 1(1], 3(12-14) Bradycardia Diarrhea Urine Stained Abdomen 2(1) 1(2) PiJoerection Hypoactivity Decreased Limb Tone Ataxia 2(9) 5 1 1 , 4 ] , 5(1-5), 1(7) 4(11, 5[2<j,4r, 5(1-3), 4(4-5), 3(6-11) 511,2*2,4], 5(1-5), 4(6), 3(7-11), 1(12-14) 3(1,2*21,4 f4 ], 3(1), .1(11, 5[2*i,4], 3(2*a.A]. 5(1-5), 5(2), 3(3), 2(4-5), 5(1-3), 4(4), 3(5-9) 4(6), 3(7-11) 1(6-7) 2(10-11) 3[ 1,2'iJ, 4(4], 5(1-2) H U , 5(2*4,41, 312*4,4], 5(1-5), 3(3-5), 2(6). 1(7) 5(1-3), 4(4-5). 3(6 4(6), 3(7-9) 2(7), 3(8-9), 2(10-11) Aggressive Hostility 1(9), 2(12-14) 1(1) 1(1-4) 2(2) 5(1,2*2,41, 5 (1-4), 5(1,2*4,4], 5(1-2), 3(5), 2(6), 1(7-8) 3(3-4), 2(5-6) 5(2!* 4], 5(1-4), 3(5), 2(6), 1(7-9) 5(2*2,4 ], 5(1-4), 3(5), 2(6), 1(7-8) 3(1], 512*5,4], 5(1-2), 3(3-4), 2(5-6) 311], 5 [2*5,4], 5(1-2), 3(3-4), 2(5-6) 3(1], 5[2*5,4], 5(1-2), 3 (3-4), 2(5-6) Corneal Opacity 1__ Study N o . : j 37-084 2(2-6), 1(8), 1(10) 3(2), 1(3-4) 3(2-4), 1(5-6) tj OrQo 09 000295 TABLE - 1. (Cont.) COMPOUND - FM-3422: OBSERVATION Death 464 mg/kg 1(7) NUMBER OF RATS SHOWING P11ARMAC0T0XTC SIGNS AND TIME [HOUR] (DAY) OBSERVED MALES (Cont.) 1000 mg/kg 1(4), 1(6) 2150 mg/kg 1(6), 1(7) 4640 mg/kg 2(5), 1(6), 1(7), 1(9) 10000 mg/kg 2(3), 1(5), 2(7) 962000 Study No.: 137-084 OrQe O' TABLE - l. (Cont.) COMPOUND - FM-3422: NUMBER OF RATS SHOWING PHARMACOTOXIC SIGNS AN!) TIME {HOUR] (DAY) OBSERVED OBSERVATION Normal Bradycardia Salivation Diarrhea 4b4 mg/kg 3(6), 5(7-14) 1000 mg/kg 2|11, 1(12-14) 2150 mg/kg 1(12-14) 4640 mg/kg 1(2*5,4] 10000 mg/kg KD 2(8) 1(1-2) Urine Stained Abdomen Piloerection 1(3) 1791 1(14) 1(1), 4(2), 2(8) n i ) V 4(2), 2(8)--- Hypothermic to Toucli Hypoactivlty Decreased Limb Tone 511,2*4,41, 5(1-3), 3(4-5), 2(6) 2(1,2sl, 3141, 2(1), 5(2-3), 3(4-5) 3(1], 5(215,4], 5(1,2*4,41, 5(1-8) 5(1-3), 4(4), 3(5-7 4(9-11), 3(12-13), 2(8), 1(9-11) 2(14) 1(1], 5(215,4], 5(1-3), 4(4), 3(5-6), 2(7), 1(8-9) 4(215,4], 4(1), 5(2-4), 4(5), 5(6-8), 4(9-11), 1(12-13) 2(8) 5(1], 4(2*5,4],5(1-5) 5(1,2*5,4], 5(1-2), 4(6), 3(7-9), 3(3-4), 2(5-8) 1(10-14) 4(215,4], 5(1-5), 4(6), 3(7-9), 1(10-14) 3(1], 5 [2*5,4], 5(1-2), 3(3-4), 2(5-8) Ataxia oc> o<) Study No.: 0) 137-084 211,2*41, 3(41, 1(11, 512*4,4], 5(1-2), 4(3), 2(4-6) 5(1-3), 4(4), 3(5-6), 2(7-8), 1(9 Om(QI) TABLE - 1. (ConC.) COMPOUND - FM-3422: OBSERVATION Prostration Clonic Convulsions Corneal Opacity High Carriage Aggressive Hostility Death 464 mg/kg NUMBER OF RATS SHOWING PllARMACOTOXIC SIGNS AND TIME [HOUR] (DAY) OBSERVED FEMALES (Cont.) 1000 mg/kfc 2150 mg/kg 4640 mg/kg 1(2) 1(12-14) 10000 mg/kg 2[2li,4] 1(7) 3(2) iiiir r(5)7 Trsr, 1(9), 1(14) 1(9) 1(6), 1(7), 2(10) 1(3), 2(5), 2(9) 862000 Study No.: 137-Q84_________ OAQ) ,, International Research and Development Corporation Page 9 C. BODY WEIGHTS: The following body weights were obtained during the 14 day observation period: Dosage Level mg/kg Individual Rat No. 464 77218 77219 77220 77221 77222 77223 77224 77225 77226 77227 1000 77060 77061 77062 77063 77064 77065 77066 77067 77068 77069 2150 76858 76859 76860 76861 76862 76873 76874 76875 76876 76877 4640 76863 76864 76865 76866 76867 Sex Male Male Male Male Male Female Female Female Female Female Male Male Male Male Male Female Female Female Female Female Male Male Male Male Male Female Female Female Female Female Male Male Male Male Male Control Weight (grams) 220 214 228 234 236 232 216 230 224 224 258 225 259 221 254 202 209 213 200 201 196 193 185 192 183 194 185 183 174 200 182 182 182 191 195 7 Day Weight (grams) Died 185 257 263 259 204 216 237 220 221 220 209 Died Died 249 156 Died Died 186 150 Died 140 140 Died 140 170 160 142 130 150 Died Died Died 154 Died 14 Day Weight (grams). Died 236 298 284 304 240 228 242 238 250 280 268 Died Died 310 Died Died Died 231 Died Died 248 190 Died 218 215 202 176 Died Died Died Died Died Died Died 137-084 000299 International Research and Development Corporation Page 10 Dosage Level (mg/kg) 4640 10000 Individual Rat No. 76878 76879 76880 76881 76882 76868 76869 76870 76871 76872 76883 76884 76885 76886 76887 Sex Female Female Female Female Female Male Male Male Male Male Female Female Female Female Female Control Weight (grams) 176 184 176 178 185 171 191 192 190 178 192 197 176 172 173 7 Day Weight (grams.) 120 140 Died Died 148 Died Died Died Died Died Died 145 Died 138 Died 14 Day Weight (grams.) 130 Died Died Died Died Died Died Died Died Died Died Died Died Died Died D. NECROPSY FINDINGS : Gross necropsy observations were noted as indicated on Table 2. 137-084 000300 Page 11 ir* \ i 1^ [ if1-1422: TABI.K 2. S i tl.ees Ion Number nee tops led No g r o s s l e s i o n s Kxl e r n a l yellow si .lined urogenital region c l e a r s t a i n around moutli partially cannibalized red/brown stain around nose Stomach dUinsttieln sfiiol lne d mucosa, thickened mc oucnot a a a, in s h yper c amber mi a ma t e r i a l !UICi1iidtiIvir Mucosa, e r o s im i mucosa, ulceratim i nonp-e!r fI.onrualoi lhanii imicosi, l.ungs CliObIiIlgieSgl rIeolyi .ireos rousol (dal lon IlltCSt Ines mucosa, hypereiula coulains dark reti mucoIil m aterial Klilneys mloalleI lecdo loc roalio riaoin lon I.! ver pale colorailou Spleen enlarged Tbymus congest ton Ut ebyrdurhomct ra 464 nig/kg M 1 Acute (hiil Toxicity 0 * 0 ^) Study In Rats. Summary of ('.ross Necropsy O b s e r v a t i o n s . 1000 H my/kFfi Dual Us 2 ISO mg/kg HK 4640 ii "i g / kKg 1H0000 mg/kFg 2 42 2S 2 ` 2 11 2 12 11 1 2 2 1 i 2 15 2 22 4 2 41 4 1 1 44 BEST COPY AVAILABLE 46M4 nig/kKg 4s 2 Termina 1 Sac r lf le e 1000 ig/kg 2 ISO tag/kg M FH F l 113 1 12 4640 Fmg 1 1 Z 2 2 1 1 l 1 TDO I ? - CIMA