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International Research and Development Corporation SPONSOR: TEST MATERIAL: SUBJECT: 3M Company FM-3422 Acute Oral Toxicity (LD..J Study in Rats. 2 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 Deoartment 137-084 Date: June 7, 1978 International Research and Development Corporation T A B L E OF C O N T E N T S Pa,ge I. Synopsis................................................ 1 II. Test M a t e r i a l .......................................... 12 III. M e t h o d ..................................................3 IV. R e s u l t s ................................................^ A. Mortality and LD^q V a l u e s ..........................4 B. Pharmacotoxic Signs ............................... 4 C. Body Weig h t s .......................................... 9-10 D. Necropsy Findings ................................. 10 Table No. 1. Number of Rats Showing Pharmacotoxic Signs and Time [Hour] (Day) Observed (Males) ............... 5-6 2. Number of Rats Showing Pharmacotoxic Signs and Time [Hour] (Day) Observed(Females) ............. 7-8 137-084 ______ International Research and Development Corporation Page 1 I. SYNOPSIS Based upon the data obtained, the acute oral L D ^ values and 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 International Research and Development Corporation Page 2 II. TEST MATERIAL The test material was received from the 3M Company, St. Paul, Minnesota on October 28, 1977. It was identified as "FM-3422, 41-2700 3422-0, Lot 784/Net-35, RR-1" and was received as an off-white to tan waxy substance. 137-084 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 grains, 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 International Research and Development Corporation Page 4 IV. RESULTS A. MORTALITY AND LD,-q VALUES: Dose - Mortality Data Dosage Level mg/kg 464 1000 2150 4640 10000 Hrs 1 0-4 1 M Fmf Nnmhp.r of Deaths _______ Days___________________ Total 2 3 4 5 6 7-14 Mortalities mfmfmfmfmfmf Male Female Total 11 21 1 11 11 2 112 12 2 2 2 3 2 1/5 2/5 2/5 5/5 5/5 0/5 1/10 4/5 6/10 2/5 4/10 4/5 9/10 5/5 10/10 The Acute Oral L D ^ Values and 95% Confidence Limits: Male Rats: 1615 (318 - 3188) mg/kg, Female Rats: 1333 (715 - 2487) mg/kg, Combined Male and Female Rats: 1467 (323 - 2332) mg/kg. Slope: Male Rats: 0.80, Female Rats: 0.80, Combined Male and Female Rats: 0.80. Statistical References: '"Weil, C. S. 1952. Tables for Convenient Calculation of Median Effective Dose and Instruction in Their Use. Biometrics, 8: 249-263. ^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. PHAKMACOTOXIC SIGNS: The following pharmacotoxic signs were observed during the 14 day observation period: (see Table 1). 137-084 TABLE - 1. COMPOUND - FM-3422: NUMBER OF RATS SHOWING I'HARMACOTOXTC SKINS AND TIME [HOUR] (DAY) OBSERVED MAl.l'.S OBSERVATION 464 mg/kg 1000 mg/kg 2150 mg/kg No i'm1] 3(6-7), 4(8-14) 1(1], 3(12-16) Bnulyeurd 1n lliiirrliea Urine St lined Abdomen 2(1) 1(2) I' l 1o e r e c t i o n Hypoactlvlty Decreased Limb Tone At a x i 1 Aggressive H ostility 5 [ 1 , 2-j, Aj , 5 (1 -5 ), 1(7) 3 i 1,2*2 ],/,(/, 1, 3 ( 1 ) , 5(2), 3(3), 2(4-5), u3[f 1i ,=2n*2], AIA ], 5 ( 1 - 2 ) 3(3-5), 2(6). 1(7) 2(9) M U , 5 [ 2 !j, A1, 5(1-3), 6(6-5) , 3(6-11) 5(1,24,4], 5(1-5), 4(6), 3(7-11), 1(12-14) H U , 5 (2*2,6 ], 5(1-3), 4(6), 3(5-9) 43((26*)2,,4 31(, 7 -51(11)- 5 ) , 2(10-11) HI], 5(24,4], 3(24,4], 5(1-5), 5 (1-3), 4 ( 4 - 5 ) , 316 4 (6), 3(7-9) 2(7), 3(8-9), 2(10-11) 1(9), 2(12-14) 4640 mg/kg 10000 mg/kg 1(1) 1(1-4) 2(2) 511,24,4], 5 (1-4), 3(5), 2(6), 1(7-8) 5(2 4 4], 5(1-4), 3(5), 2(6), 1(7-9) 5(24,4], 5(1-4), 3(5), 2(6), 1(7-8) 5(1,24,4], 5(1-2), 3(3-4), 2(5-6) 3(1], 5(24,4], 5(1-2), 3(3-4), 2(5-6) 3(1], 5 (24,4], 5(1-2), 3(3-4), 2(5-6) 3(1], 5(24,4], 5(1-2), 3 (3-4), 2(5-6) l .o i non I (11,u I I y 2(2-6), 1(8), 1(10) 3(2), 1(3-4) 3(2-4), 1(5-6) Study No.: 137-084 OfnQt>) u TABLE - 1. (Cont.) COMPOUND - EM-34 22 OBSERVATION Death 464 mg/kg K7) NUMBER OF RATS SHOWING PIIARMACOTOXIC 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) Page Study No.: 137-084 TABLE - i. (cent.) COMPOUND - FM-3A22: NUMBER OF RATS SHOWING PIIARMACOTOXIC SIGNS AND TIME [HOURl (DAY) OBSERVED FEMALES OBSERVATION Normal Bradycardia At>4 mg/kg 3(6), 5(7-14) 1000 mg/kg 2 ( 1 ] , 1 (12-1 A) 2150 mg/kg 1 (12-1 A) Sa1ivation DIarrhea U rAi nbedomSetna i n e d Piloerection Hypothermic to Touch 1(3) 1T9) llypoactivity D e c r e a s e d Limb 'lone Ataxia -^( 1 . 2-2, A] , 5 ( 1 - 3 ) , 3 ( 4 --5 ) , 2 ( 6 ) 2 ( 1 , 2 *2) , 3 [A], 2 ( 1 ) , 5 ( 2 - 3 ) , 3 ( A--5) 2 [ 1 , 2bJ, 3[A] , 5 ( 1 - 2 ) , A( 3 ) , 2 ( A- 6 ) 3 ( 1 ] , 5 [ 2*5, A1, 5 ( 1 , A] , 5 ( 1 - 8 ) 5 (1 -3 ), A(A) , 3(5-7 2(8), 1(9-11) A( 9 - 1 1 ) , 2 (1A) 3(12-13), M U , 5 [ 2 ij, A] , 5 0 - 3 ) , A(A) , 3(5-6), 2(7), 1(8-9) A12 Ij, A], A( 1 ) , 5 ( 2 --A) , A(5) , 5 (6-8), A(9-11), 1(12-13) 15 H( 1I- 3 ) ,5(2A1(2A, A) ], , 3(5-6), 2(7-8), 1(9 Study No _1_3__7__-_0_8__A_________________ A6A0 mg/kg 1 [2!$, A] 10000 mg/kg 1(1) 2(8) 1(1-2) 1(1A) 1 (1 ), 4(2), 2(8) T T 1 ) , A( 2 ) , 2TFT 2(8) 5 U ] , A(2*5, A] , 5 ( 1 - 5 ) A( 6 ), 3 ( 7 - 9 ) , 1(10-1A) 5 [ 1 , 2lj, A], 5 ( 1 - 2 ) , 3(3-4), 2(5-8) M 2 *5, A] , 5 ( 1 - 5 ) , A(6 ), 3 (7 -9 ), 1 ( 1 0 --1A) 3 ( 1 1 , 5 [ 2 lj, A] , 5 ( 1 - 2 ) , 3 ( 3 --4 ) , 2(5-8) V in 00 TABLE - 1. (Cont.) COMPOUND- FM-3422: OBSERVATION Prost rat ion Clonic. Convulsions Corneal Opacity High Carriage Aggressive Hostility De a th 464 mg/kg NUMBER OF RATS SHOWING PHARMACOTOXIC SIGNS AND TIME [HOUR] (DAY) OBSERVED I'EMALES (Cont.) 1000 mg/k|> 2150 mg/kg TT5-7) 1(4), 1(5), 1(8), 1(9) K9), 1(14) 4640 mg/kg 1(2) 1(12-14) 10000 mg/kg 2 [2'5,4 ] TTT)--- ----------- 3(2) 1(6), 1(7), 2(10) 1(3), 2(5), 2(9) Page Study No.: 137-084 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 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 (grains) 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 I N - 1422 TAIU.K 2. S i tl.efH (till Nuillhc | IH`l l o p s I od No p . i o s s l e s i o n s Kxt ei na I y e l l o w s t a i n e d u i np ,c n 11 a I i !(> I o n c le a r s t a in aro und month pa 1 1 I a I 1y c a n n I Ita I I zed red/hrow n s t a in around nose S t oHia< li flu id filln d d is t oils loll im icosa, th ic k e n e d m ucosa, hyperem ia c o o l a I n s a m h er mat o r i.i I foeI g la n d u la r im irosn, e ro s io n m u c o s a , 1111o r a l I o n non - u I .nulul a i im u o s a , p o r f o r a t Ion I.iiiik k ll|;h t p rey a re a s c onge st ion c oiiko I Id at Ion Intest Ies mucosa, hyperemia c o n ta in s daik red mucoid m ate ria l K tdney.s p a I e c o I cm a I I o u mot t I e d c o l o t a t I o n I.Iver pa Ie co I o ia t Io n SpI con e n l a i ) ! I hymns congest Ion lit ei ns hydrnmel ia Ar ul i - III ill T n x l i I t y (I.I) ) S t u d y In K i l l s . 4fi'i <b/J?.c M I Sunm iiiiy o f C r u s K Ni-i:ru|>Hy O lis e r v a t I m is . 1000 ni g/ kg MF Ill-ill 11M 2I SO nig/ kg Mi 4040 m g / k g MF 1(1000 mg/ MF 2 42 2 > 4S 5 2 24 22 2 11 12 2 15 2 44 1 4 1 1 2 21 4 I 1 1 21 2 11 1 1 2 I II) I | | II I | j j I I / OH/* W i mg/kg Mr 4S 2 T im h i I i i i i I S ; i f i I f l< p 1000 mg/kg h I- m o lug/kg HF 4040 mg/kg 1 1) I) ) 2 I 1 2I 2 I Page 11