Document yrVLm5X2DYoLwEo6dLj0Lk21D

AR226-1376 Medido Health Physics Industriai Hygiene Toxicology Medical 0epartment/3M 3M Center St. Paul. Minnesota 55101 612/7331110 March 27, 1981 'Z-ri ffi.a.zn.6 - / 3 7 Blaine C. McKusick, Ph.D. Haskell laboratory Elkton Road Newark, Delaware 19711 Dear Blaine: A copy of the TSCA Section 8(e) notification regarding perfluoroalkane carboxylic acids and corresponding ammonium carboxylates is enclosed. Please contact us if you have further questions. Sincerely, F. D. Griffith, Ph.D. Manager, Toxicology Services FDG:klh Enclosure AJP002950 Mrtn o 1 - n m !i EED079613 v 000099 Frank A. bel, M. D. Medical Director March 20, 1981 Acting Director, NIOSH Park Lawn Building 5600 Fishers Lane Rockville, MD 20855 Dear Sir: Subject: Notice to.EPA Regarding Section 8(e) of the Toxic Substances Control Act Please find fnclnsfd for your information a copy of the subject notice submitted to EPA on this date. You will note from our letter to EPA that we regard certain parts of this notice as trade secret or confidential business information. Therefore, this information should be handled according to Section 15 of the Occupational Safety and Health Act (29 USC 664). Tn the event you determine that it may he uccessury to disclose certain of this information to the general public, we request that you contact 3M prior to such disclosure. Very truly yours, Frank A. bel, M.D ss Enclosure OsaseliOlins/bM 7 M 'A.'J*Cenila Saint Paul. Minnesota S5lOt 612/7335181 EED079614 000100 JP002951 i J. I t! ;t iI I 9n v^ucntivou-'* w 3MOunl!f :;i. Paul, Mini ".Ola VM4 612/7331110 CERT[ FLED MAIL - RETURN RLCEH'T KEOUESTEL) March 20, 1931 Document Control Officer Chemical Information Division Office of Toxid Substances (Wh-557) Environmental Protection Agency A01 M Streut, .W. Washington, D.C. 20460 (JenClemeu : Subject: Section 8(c) Toxic Substances Control Act (7SCA) l'erfluoroalkane Carboxylic Acids and Corresponding Ammonium Carboxylates Please find attached 3M Report entitled ''Oral Rangefinder Study ol' T-2993CoC i.n Pregnant Rats", dated March 12, 1931. Preliminary information from this study has indicated that oral dosing o: Che subject ammonium carboxylate mixture produces the described teratogenic effects. This Report and the findings described ir. the article, published in the. Atip.tt.se 1980 American Tndustj*'. n": Hyp,i`in- .Join ii.iI .mil if.Iui uitccd as pact of 3ElKj-H30-U'J/4li, ic.it.:. us to submit this information pursuant to Section 5(e) o: 7SCA and EPA's statement of interpretation published in the ~ZZ>Z?J-.L REGISTER, March 16, 1973. Perfluoroalkane ammonium carboxylates is a generic chemical name for a mixture of homologs+which can be expressed by the general I'ormul.i (1 l1'.^ COO . Each of Uiusc liomoicign was reported on the l'i>CAuXnventory As previously stated in our November 19 submission, our employee record:; and ep i*1!io Iop.y <lal a indicate licit to date rio human health pro Idem:; have been observed nor disease patterns detected which are attributable or related to fluorochemical exposure. This mixture of homologous ammonium carboxylates and the corre sponding homo logons carboxylic acids are currently commercially available and used us follows: 3M brand Kluorochemical Acid FC-26 Emulsifier additive in chemi cal specialty products (international market only) AJP002952 EID079615 000101 b o c n iu u n t C o n t r o l 01 I i ::" - 2- Merch 10 l-'LUOKAU Brand Fluorocheuiical Surfactant FC-126 (am n io n turn carboxyJato::) Additive used in chemical special products FLUORAD Brand Fluorochemical Surfactant FC-143 (ammonium carboxylates) Emulsifier used in chemical processing and as an additive 1?. chemical specialty products At our CUemolite production facility, located at Highway 61 and Washington County Road 19, St. Paul, MN 55133, the subject chemicals are manufactured from of locally-produced perfluoroalkane carboxylic acids and of tiie same acid imported from our European plant in Antwerp, Belgium. Chemical reaction occurs in a closed system. Approximately 36 employees are intermittently exposed to the subject chemicals during production at the Chemolice facility. Approximately of perfluoroalkane carboxylates are exported annually. We plan to inform, by April 1, those customers and 3M employees who have, through uses and/or processing, potential significant exposure to the sub ject chemicals. At that time, we will summarize these findings and outline our recommendations for handling and using these products. We are by copy of this letter advising NIOSH of these new preliminary teratogenic findings. A:; a<hl ir innal In fo riuaf ion ava i1ahl v to u::t wr< plan Un advise* the:;* <:u:;l ami ciup I accordingly. In view of the attached preliminary findings and in line with our ongoing testing and monitoriug program on fluorochemicals, the following program is planned for the ammonium carboxylate mixture: (I.) A teratogenicity study in rats. (2) A subsequent teratogenicity study in rabbits. (3) Continual industrial hygiene program to improve and refine mauufactoring and packaging processes which have been developed to further reduce the exposure to plant employees. Since certain of the information provided herein is considered confidential business information, we are providing a sanitized version of this report for the public file. In addition, we have deleted from the confidential submission inconsequential information such as the names of 3M employees for the purpose of protecting their privacy. " EID079616 > s*3 LNAO U> 000102 Document Control O fficer - 3- March 2, lf: Should additional correspondence be n ecessary on this m atter, please contact: L a rry Magill M anager, Regulatory A ffairs Department Commercial Chem icals Division 3M 3M C e n t e r , 223-6S-4 S a in t P a u l, MN 55144 T elephone: 612/733-7062 Yours yery truly, t / / A i# /\i. K t .</'! George L . H egg,' y Group Vice President Ch em icals, Film & Allied P rod ucts G L H :sue A ttachm ents cc: Acting D irector, NIOSH Park I,awn building 5600 F ish e r s L an e R o c k v ille , MD 20855 lie : R. J. Davis/T. J. Scheuerman - 220-12E W. 0. Kwert - 220-12W F. 0. Griffith/W. C. McCormick - 220-2E C.'Tii. Hanson - 223-6 G. L. Hegg - 220-13C I. . C. Kroglt - 223-6 J. U. LaZerce/R. A. Prokop - 236-1 L. F. Ludford - 225-5N W. ll. Pear Ison - 223-6 I). K. Kicker - 53-/, P F. Klehle -- Chemolite W. F. Scown - 223-6 S. 0. Sorenson - 220-2 P. A. Ubel/D. E. Roach AJP002954 EID079617 000103 n> Report Number: M - 6 0 1 Date: March 12, 19 Oral Rangefinder Study of T-2998CoC in Pregnant Rats Experiment No.: Conducted At: Dosing Period: Study Director: 0680RR0018 St. Paul, Minnesota January 20, 1980 to January 29, 198 2 / z V / S'/ Date Date Date SooNnOa> EID079618 000104 In troduction 1. This oral rangefinder study-- was conducted to determine the upper dose level of T-2998CoC-- for a subsequent oral teratology study in rats. The study was sponsored by 3M Commercial Chemical Division, St. Paul, Minnnesota and was conducted by the Safety evaluation Laboratory, St. Paul, Minnesota. The study was conducted in accordance with the Safety Evaluation Laboratory's Standard Operating Procedures for such studies. The storage location for the raw data and a copy of the final report is maintained in the Safety Evaluation Laboratory's record archives. Method?! Thirty-six time-mated Sprague-Dawley derived female rats from Charles River Breeding Laboratory were used in the study. The animals were indiscriminately removed from the shipping boxes by Animal Care personnel and placed in the rack of cages from the left to right starting at the top and working down. Later the Study Director assigned dose groups by vertical rows. The rats were housed individually in hanging stainless steel cages with wire mesh floors and fronts in a temperature and humidity controlled room. Purina Laboratory Chow and water were available ad libitum. The lights were on a 12 hour light/dark cycle. The animals were observed daily from day 3 through day 20 of gestation for abnormal clinical signs. Body weights were recorded on days 3, 6, 9, 12, 15 and 20 of gestation and the rats dosed accordingly using a constant done volume of 1 ml/kg of body weight. T*299UCoC wan uu^pondud in corn oil and administered daily by oral intubation at doses of 150, 100, 75, 50 or 25 mg/kg/day to groups of 6 rats on days 6 through 15 of gestation. A control group of 6 rats received only corn oil by oral intubation on the same days._ On day 20 of gestation the rats were killed by cervical dislocation and each uterus, including its contents, was examined immediately to determine if the animal was pregnant. Because two previous teratology studies ( Experiment Nos: 0680TR0008 and 0680TR0010) with chemically related compounds resulted in fetuses with teratogenic changes in the lens of the eye, a few fetuses were also taken at day 20 of gestation and examined for eye abnormalities. Blood samples from three rats in each dose group were taken before the first dose and at day 20 of gestation. Liver specimens were also taken from the same rats on day 20 of gestation. The plasma samples and liver specimens were frozen and submitted to the sponsor. Results and Discussion The oral administration of T-2998COC at 150, 100, 75, 50 or 25 mg/kg/day to rats during the period of organogenesis (days 6 through 15 of gestation) did not result in any deaths. A toxic effect of reduced body weight gain occurred between day 6 fid 9 of gestation in the 150 mg/kg/day dose group (Table 1). The two nonpregnant 150 mg/kg/day rats had a more severe effect on body - Experiment No. 0680RRQ018 - FC-143 EID079619 AJP002956 oooios weight on day 9 of the study than the pregnant high dose dams (Appendix X). They lost a considerable amount of weight and one was observed to have urinary incontinence on days 11, 12 and 13. The pregnant dams of the 100, 75, 50 and 25 mg/kg/day dose groups did not have abnormal clinical signs and gained weight at comparable levels to the 0 rag/kg/day group. Four fetuses were examined from each of four dams in the 150 and 25 mg/kg/day dose groups for eye changes. All of the readable fetuses sectioned had eye changes consisting of one or more of the following: large lens clefts, dark streak running one-half to three-quarters of the way through the lens or disorganized lens fibers (Table 2). The lens abnormalities occurred in the same location as those observed in the two previous teratology studies ( Experiment Nos: 0680TR0008 and 0680TR0010) on chemically related compounds. The abnormalities in this study appeared more pronounced than in the previous studies. In the previous studies, the teratogenic effect was a developmental eye abnormality which appeared to be an arrest in development of the primary lens fibers forming the embryonal lens nucleus, followed by secondary aberrations of the secondary lens fiber of the fetal nucleus. The same general morphological changes occurred in this rangefinder study with T-2998COC. Conclusion The objective of determining an upper dose level for an oral rat teratology study was met in this study. The above results suggest that the 150 mg/kg/day dose level would be an appropriate high dose in a rat teratology study because of the toxic effect of reduced body weight gain. In addition to the toxic effect of reduced body weight gain, the teratogenic effect of lens abnormality was observed and is likely to be reproduced in a teratology study. AJP002957 EID079620 000106 Table 1 Oral Rangefinder Study of T-2998CoC in Preonant Rats Mean Body Weight Gains of Pregnant Rats With Standard Deviations (g) Control 150 mg/kg/day 100 mg/kg/day 75 mgAg/day 50 my/ky/Uuy 25 mg/kg/day Day 6 8 12 It. 26 21 28 76 4. 2 7. 4 7. ! 1. 6 1. 7 2 1 *j a 12 84 b. 6 l/. 8 8. 8 12. 8 12. 1 28 4i 18 17 18 84 1 4 4 12. 8 12. it x X 21 18 74 t*. O Xt 0 2. 7 18. 8 12. 6 !'; l_ l. M . l' l' t*. s. 7 t<. 6 7. 2 16. 8 A 10 2. Kf 0. v- b. 8 8. 2 S. 8 -- Significantly higher than the control (Dunnett's t test p <0.05) AJP002958 EID079621 000107 Table 2 Oral Rangefinder Study of T-2998CoC in Pregnant Rats a Ratios of Fetuses with Eye Changes to Fetuses Examined-- High Dose Group (150 mg/kg/day) 16/16 Low Dose Group (25 mgAg/day) 15/15- 4 Four fetuses examined from each of four dams One fetus not examined because eye architecture destroyed in sectioning Itrio* AJP002959 EID079622 000108 1 V. `` 4 1 < . % Appendix I Oral Rangefinder Study of T-2998CoC in Pregnant Rats Individual Body Weights (g) and Mean Body Weights with Standard Deviation for Pregnant Rats Day 2 6 8 12 15 20 O t'Ki tTi N ik N ik N IK N1R N lR 216 217' 310 218 246 124 186 182 207 180 222 214 217 228 221 244 228 227 200 207 262 202 208 280 287 282 211 282 270 265 360 * 268 MEAN 180 220 242 264 282 S T A N . J>EV 7. 7 1 0 . 2 1 1 . 5 1 0 . 5 1 1 . 5 NON PREGNANT AN TMALS 368 8. 2 N1R 184 224 2 l5 221 222 Day - o *4 1 2 i5 1 5 0 MG.'KG.-' L-'tt 01k O ik O ik O iR 221 224 221* 247* 202 183 177 206 '2 2 216 181 222 216 21? 226 MEAN 180 216 ST AH. DEV 1 2 . y 1 7 . 5 NON PREGNANT AN I Mttt.S 220 4. 6 01k o ik 222 222 207 181 t">j* .* 200 181 257 257 244 262 28? 261 241 278 C,Cl. 7 7. 7 18. 4 200 218 18c .2 1 5 267 344 314 378 251 Is 246 231 5 AJP002960 "--- -- - . - - _ \ r..- * . EID079623 O, ... .... . . 000109 Appendix I (Continued) Oral Rangefinder Study of T-2998COC in Pregnant Rats Individual Body Weights (g) and Mean Body Weights with Standard Deviation for Pregnant Rats o Dajr V & * 12 15 20 .iMtl I'H.I.'I'll.'1!1 PIP 226 164 1*2 210 22* s / 327 1. PIP 22,'' 214 240 243 263 265 221 PIP 323 262 23 302 317 24* 452 P1K 325 200 23`J* 24b 236 252 P1K 320 135 213 34 43 63 33 PxR 343 13* 213 240 262 2*6 371 1. MEON 02 32 47 264 32 366 SI HU. DfcV 3'3. e 21. 2 20. 4 2*. 6 34. * 45. t. Day 6 * 12 15 20 ( 75 MG.' KG/DfiV ---- -- WlR 221 1 *2 z> 243 263 246 CllP 322 1*3 213 223 24* 271 246 < 0.1R 322 172 202 215 2 5 263 246 i.ilR 224 211 24 2 61 2?U CU.fi 335 1 *2 216 225 44 263 231 CUR 2 4 * 200 221 4 3 6 5 2*2 232 ME.MN 1*4 221 2 2 252 272 24 . S I fiN. L'hV U . * 14. 1 13 2 12. 4 l o 6 0. *- < AJP002961 EID079624 000110 Appendix I (Concluded) Oral Rangefinder Study of T-2998CoC in Pregnant Rats Individual Body Weights (g) and Mean Body Weights with Standard Deviation for Pregnant Rats Day 3 6 9 12 15 20 50 MG. `KG/l-'RY RlR 336 193 219 236 253 276 350 R1R 337 17? 201 213 235 259 338 RlR 338 226 251 262 283 314 397 Rift 339 170 198 218 237 254 RlR 340 IS? 226 245 26? 304 3?S RlR 350 192 229 243 276 308 382 MERN 191 221 236 259 286 359 STRN. DfcV 19. 4 19. 6 IS. 2 20. 1 26. 2 33. 0 ______Day_________________ 6 9 12 15 20 25 HG/KG/DHY SIR 342 216 239 26o 283 304 SIR 343 20V 234 249 279 304 V *3*V SIR 344 185 208 22? 253 292 SIR 345 200 219 233 249 270 SIR 351 205 233 238 268 307 'li MERN 203 227 243 266 295 STRN. DEV 11. 4 12. 8 15. 4 15. 2 15. 3 13. 4 NON PREGNRNT RNIHRLS SIR 341 IS? 203 213* 220 228 238 7 AJP002962 EID079625 000X11 DISTRIBUTION JLXST C. G. Gortrier (original + 1) E. G. Lamprecht R. A. Nelson - M. T. Case W. C. McCormick -* F. D. Griffith -* F. A. Ubel (5) AJP002963 EID079626 v 000012