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U ~~ \ $6tt0.02,00-3 73 ARZZG-0W Bio/clynamics Inc. Division of Biology and Safety Evaluation 000811801J 000190 -1- Bio d y n a m i c s In 78-7186 I. GENERAL An experiment was performed to assess the acute inhalation toxici ty of a dust of T-2307 CoC in S p r a g u e - D a w l e y rats. The test material, received from the Minnesota Mining and Manufacturing Company was labeled "3M Company, T 2 3 0 7 C o C , " and was in the form of a fine, yellow-orange powder. II. EXPERIM ENT AL Two test material exposures were performed. For the first exposure, the test material was placed in a 500-millilite r, threeneck flask, fitted with a stir bar. For the second exposure, the test material was sieved through a 60-mesh sieve and placed in a 1000-milli liter, three-neck flask, fitted with a stir bar. The flasks were plac on a mag ne tic stir plate to prov ide constant a g i t ation of the test material during the exposure periods. Dry air, at the flow rate of 10 liters per minute, was passed through the test material, and the resulting dust-laden airstream was directed into a 26.5-liter glass exposure chamber containing the test animals. The exposures lasted for one hour. The flasks containing the test material were weighed befor e and after the respective ex posure periods. The diff er enc es in weight were equal to the amounts of material consumed during the ex posures. The nominal concentrations were calculated by dividing the weight lost by the total air flow through the chambers during the exposures. 000191 -2- Bio/ ___ /d y n a m ic s In 78-7186 II. E X P ER IME NT AL (cont.) The test animals consisted of two groups of five male and five female Sprague-Dawley rats obtained from Charles River Breeding Laboratories, Wilmington, Massachusetts. On the days of exposure (Day 0 - 10/4/78 and 10/12/78), the pre-exposure weights ranged from 200 to 297 grams. The basic health status of the test animals was established by a pre-exposure examination. The animals were observed for abnormalities at 15-minute intervals during the exposure period, upon removal from the chamber, hourly for four hours post-exposure, and daily thereafter for 14 days. Individual body w e i g h t s were recorded prior to exposure on Day 0 and on Day 1, Day 2 (Group I only), Day 3 (Group II only), Day 4, Day 7 and Day 14 (terminus). On Day 14, all survivors were sacrificed (ethyl ether) and gross necropsy examinations were performed. All animals dying s p o n t a n e o u s l y were ex am ined by gross necropsy as soon as p o s s i b l e after death. III. RESULTS AND DISCUSSION During the first exposure period (Group I), a total of 39.98 grams of the test material was de livered in a total v ol ume of 600 liters of dry air, yielding a nominal exposure concentration of 66.63 milligrams per liter. During the second exposure period (Group II), 13.33 grams of the test material was delivered in the same volume of dry air, yielding a nominal exposure concentration of 22.22 milli grams per liter. 000192 -3- Bio O/ d y n a m i e s I n 78-7186 III. RESULTS AND DISCUSSION (cont.) After 32 m i nut es of the Group I exposure, the cham ber atmosphere remained static for a short period of time (less than five minutes) while the delivery flask was refilled with test material. A b n o r m a l i t i es noted in the Group I animals throu g h o u t the exposure period were mucoid nasal discharge, excessive lacrimation, and excessive salivation. Squinting or closing of the eyes was ob served from 30 minutes of exposure through exposure termination. C h r o m o d a c r y o r r h e a was observed in one animal at exposure term in ati on . Signs ob ser ved in the Group I animals upon their removal from the exposure chamber were excessive lacrimation (eight of ten rats), excessive salivation (one of ten rats), chromodacryorrhea (two of ten rats), mucoid nasal discharge (three of ten rats), and dry rales (one of ten rats). These signs were also observed sporadically during the four hourly post-exposure observation intervals. Seven of ten rats from Group I died during the 14-day observation period. Pre-death signs in these animals were m u c o i d nasal discharge (five of seven rats) red nasal discharge (five of seven rats), dry rales (one of seven rats) excessive lacrimation (one of seven rats), excessive salivation (one of seven rats), labored breathing (five of seven rats), yellow staining of the ano-genital fur (seven of seven rats), brown staining of the ano-genital fur (one of seven rats), reduced activity (seven of seven rats), poor general condition (seven of seven rats), spasms (one of seven rats), coldness of the body (two of seven rats), brown nasal discharge (one of seven rats), hair loss (one of seven rats), and rapid bre athing (one of seven rats). Signs observed in the th**ee surviving animals during the 14-day in-life period were red nasal dis charge (two of three rats), mucoid nasal discharge (three of three rats 000193 -4- B io / / d y n a m i c s In 78-7186 III. RESULTS AND DISCUSSION (cont.) excessive lacrimation (two of three rats), dry rales (one of three rats), labored breathing (three of three rats), yellow staining of the ano-genital fur (three of three rats), brown staining of the ano genital fur (two of three rats), reduced activity (three of three rats) poor condition (three of three rats), spasms (one of three rats), loss of righting reflex (one of three rats), rapid breathing (one of three rats), and pilo erection (one of three rats). Individual body weights and necropsy observations of the G r o u p I animals are pres ented in Table I. Animals dying during the stu dy lost we igh t steadi ly prior to death. Two of three surviv ing rats also exhibited steady weight losses. One male rat (#14), however, was gaining weight by termination of the study. Necropsy observations of the Group I animals were liver discoloration (nine of ten rats), lung discoloration (six of ten rats), adrenal discoloration (one of ten rats), adrenal enlargement (two of ten rats), gaseous distention of the stomach (three of ten rats), gaseous distention of the intestine; (one of ten rats), stomach discoloration (one of ten rats), and intes tinal discoloration (two of ten rats). A b n o r ma li ti es noted in the G roup II (22.22 mg/1) rats during the exposure period were excessive lacrimation, excessive salivation, squinting or closing of the eyes, mucoid or red nasal discharge, and/or labored breathing. Upon removal of the animals from the exposure chamber, dry rales (three of ten rats), mucoid nasal discharge (two of ten rats), excessive salivation (one of ten rats), excessive lacrimatior (two of ten rats), and yellow staining of the ano-genital fur (nine of ten rats) were observed. These signs w e r e also o b s erved in the rats 000194 -5- /cB i o d y n a m i c s In 78-7186 III. RESULTS AND DISCUSSION (cont.) during the four hourly post-exposure intervals. Other signs observed sporadically during those intervals were labored breathing and re duced activity. Observations made during the 14-day in-life period were dry rales (seven of ten rats), mucoid nasal discharge (seven of ten rats), rapid breathing (two of ten rats), yellow staining of the ano-genital fur (eight of ten rats), brown staining of the ano-genital fur (two of ten rats), orange staining of the ano-genital fur (two of ten rats), reduced activity (two of ten rats), pilo erection (one of ten rats), hair loss (one of ten rats), coldness of the body (two of ten rats), and generally poor condition (ten of ten rats). Individual body weights and necropsy observations of the Group II animals are p r e s en ted in Ta ble II. All Group II rats expe rienced w e i g h t loss following exposure to the test material. Though weight gains were retar ded , all male rats exceeded their Day 0 body weights by t e r m i nation of the study. None of the female rats recovered their original weights by Day 14, though three of five females were gaining weight by the end of the study. Necropsy observations of these animals revealed lung di sc oloration in eight of ten rats. 000195 -6- AB i o d y n a m i c s In 78-7186 IV. CO NCL USI ON A pair of exposures were performed on Sprague-Dawley rats to de termine the acute inhalation toxicity of different con ce ntrations of a dust of T-230 7 CoC. The first exposure (Group I) y i e l d e d a nominal test material exposure concentration of 66.63 milligrams per liter. Seven of ten animals of this group were dead by Day 10 of the study. The second ex posure (Group II) y i elded a nominal expo sur e test material concentration of 22.22 milligrams per liter. There was no m o r t a l i t y in the second group. However, all animals e x p ose d to the test material in this study displayed a definite r e s ponse to their exposu re to the dust of T-2307 CoC. In-life o b s e r v a t i o n s showed the animals to be in poor condition following the exposure and post-e xp osu weight gains were markedly depressed. Necropsy examination of the Gr oup I animals revealed liver d i s c oloration in nine of ten rats, marked lung d i s c ol or ati on in six of ten rats and adrenal e n l a r g e m e n t in two of ten rats. The main findings on necropsy of G r o u p II animals after 14 days was lung d i s c o loration in eight of ten rats. These fin dings, es pe ci all y in Group I, would appear to be indica t i v e of a residual effect of the test material exposure. y George M. Rusch, Ph.D. Director, Inhalation Technology Written by: Ilona R. Jupina /mes U'yuL- F William E. Rinehart, Sc.D. Vice President, Science 000196 Table I An Acute Inhalation Toxicity Study of T-2307 CoC in the Rat Individual Body Weights and Necropsy Observations Group I - 66.63 mg/1 78-7186 000197 Animal ______________ Body Weights (g) Number Sex Day 0 Day 1 Day 2 Day 4 Day 7 Day 14 10 M 248 221 207 195 Dead^ 11 M 270 242 226 209 Dead3 12 M 297 273 260 241 245 216 13 M 269 251 247 228 197 Deadc 14 M 297 271 267 257 202 236 20 F 208 198 194 173 149 Deadc 21 F 206 194 187 185 183 179 22 F 234 207 199 184 172 Deadd 23 F 228 215 208 183 163 Deade 24 F 238 220 205 194 175 Deade * N.O.A. - no observed abnormalities. Key: R = right; L = left; B = bilateral. ? Spontaneous death Day 6. D Spontaneous death Day 7. j Spontaneous death Day 8. Spontaneous death Day 9. e Spontaneous death Day 10. _____________Necropsy Observations*______________ B. lungs red in color. Liver mottled tan and red. Stomach distended with gas. B. lungs red in color. Liver mottled tan and red. All lobes of liver mottled tan and red. B. lungs red in color. All lobes of liver mottled red and grey. All lobes of liver mottled red and tan. B. lungs red in color. All lobes of liver blackred with tan and grey patches. B. adrenal en larged in appearance and red in color. N.O.A. R. lobe of liver mottled red and tan. B. adrenals enlarged (1.5 x normal size) in appearance. B. lungs red in color. All lobes of liver ab normally dark red in color. Stomach distended with gas. Small intestines yellow in color, distended with gas. B. lungs red in color. All lobes of liver ab normally dark red in color. Stomach pale yellow in color, distended with gas. Small intestines yellow in color. I Table II An Acute Inhalation Toxicity Study of T-2307 CoC in the Rat Individual Body Weights and Necropsy Observations Group II - 22.22 mg/1 78-7186 Animal Body Weights (g) Number Sex Dav 0 Hav 1 flaw T * 30 M 281 253 265 256 250 31 M 288 266 255 258 272 32 M 266 238 234 237 246 33 M 276 267 262 260 265 34 M 282 275 277 274 284 40 F 214 207 200 194 189 41 F 206 179 175 175 177 42 F 200 196 196 188 188 43 F 224 219 222 210 220 44 F 207 182 179 175 164 291 301 272 282 314 202 169 187 220 195 Necropsy Observations* Scattered red foci on B. lungs. B. lungs mottled pink and red with scattered grey foci. B. lungs mottled tan and red with scattered grey foci. B. lungs mottled pink and tan with scattered grey foci. Scattered red and grey foci on B. lungs. Scattered red foci on B. lungs. B. lungs mottled pink and red. N.O.A. N.O.A. B. lungs mottled pink and tan. * N.O.A. - no observed abnormalities. Key: R = right; L = left; B = bilateral. 86T000 i CD I