Document mmqZjNNDRZqLQenK3nj52D8Yk

AR226-1373 Chemical:. UvisionCW Ci:ii|cr !il.I';iul.Miln jl.i`/il4<1 12/73U 1110 c e r t i f i e d m a i l - k k i u r :: /i:; AP.8.&6 - l 7 3 Mardi 20, 1001 Document Control Officer Chemical Information Division " Office of Toxi cl Substances (WH-557) Environmental Protection Agency 401 M Streut, S.W. Washington, D.C. 20460 Centlemen: Subject: Section 8(e) Toxic Substances Control Act (TSCA) I'erf luoroalkane Carboxylic Acids and Corresponding Ammonium Carboxy1a tes Please find attached 3M Report entitled "Oral Rangefinder Study of T-- 299RCoG i.u Pregnant Rats", dated. Mardi J.2, 1981. Pro! i::.-n information from this study has indicated that oral dosin'; c: the subject ammonium carboxylate mixture produces che described teratogenic effects. This Report and the findings described in the article published in the August 1.980 ..American Tr.rh.*. :_r_: IlyI.iuni- lorn m .'iI .uni re ie ii-iieed as pert of iitiO-O i/'.C , us to :.:ubmit this information pursuant to Section S(e) o: 75CA and EPA's statement of interpretation published in the FcDcRAL REGISTER, Mardi 16, 1978. Perfluoroalkane ammonium carboxylates is a generic chemical ran. for a mixture of hoinologs+which can be expressed by the {'.citerai formula G F^ GOO HU^ . Kadi of these homo logs vas reported on the TyCAlnventory As previously stated in our November 19 submission, our employe record:; and epidemiology data indicate that to date no huma:; health problem:; have been observed nor disease patterns dtecte which are attributable or related to fluorochemical exposure. This mixture of homologous ammonium carboxylates and the corre sponding homologous carboxylic acids are currently commercially available and used as follows: 3M Uraud Fluorochemical Acid FC-26 RECEIVED Emulsifier additive in cr.er cal specialty produces (international market only) APR 23 1981 HASKELL LAB. E1D072034 000016 bwc.Uu.i.'itL (.`oilL I(II 01 1 ii;'*l 2- - Me re .'I a1;, FLUORAl/'^ Brand l'l.uorochemical Surfactant FC-126 (;iii:inimiuni ca rh<>xy.1a t<:::) Additive used in chemical special products FLUORAD Brand Fluorochemical Surfaccanc FC-143 (ammonium carboxylates) Emulsifier used in chemical processing and as an additive in chemical specialty products At our Chcmolite production facility, located at Highway 61 and `.-.'ashingter. County Road 19, St. Paul, MN 55133, the subject chemicals are manufactured from of locally-produced perfluoroalkane carboxylic acids and of the 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 Cheinoliue facility. Approximately of perfluoroalkane carboxylstes 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:; ;nlililion.i I in fo rm:il'ion Ik -i-miiic:: i i v .'i i 1.'ihlf to u:;, v/f plan l:n .-it!v i-.c- L:;**. Oi:;( <iiu<*r:; ami cuip 1uyi-r:. .ii.cunl ing 1j . T.n view of the attached preliminary findings and in line with our ongoing testing and monitoring program on fluorochemicals, the following program is planned for the ammonium carboxylace mixture: (J.) A teratogen i.city study in rats. (2) A subsequent teratogenicity study in rabbits. (3) Continual industrial hygiene program to improve and refine mauui ar.tur ing 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 3H employees for the purpose of protecting their privacy. EID072035 000017 Document Control Officer - 3- March 0, Should additional correspondence be n ecessary on this matter, please contact: L a rry Magill Manager, Regulatory Affairs Department Commercial Chemicals Division 3M 3M C e n t e r , 223-6S-04 S a in t R aul, MN 55144 Telephone: 612/733-7062 Y o u r s yery truly, n ,i Group Vice President Chem icals, Film & Allied P roducts GLH : sue Attachments c c : A ctin g D irecto r, NIOSM Park Lawn liuilding 5000 F ish e rs Lane R o c k v ille , MD 20855 R. J. Davis/T. J. Schcuerman - 220-12E W. 0. Kwert - 220-12W F. D . Criffitli/W. C. McCormick - 220-2E C.'V. Hanson - 223-6 G. L. Hegg - 220-13C I. . 0 . Krogl* _ 223-0 J. . LaZertte/K. A. Prokop - 236-1 L. F. Ludford - 225-5N W. II. Pearlson - 223-6 I). It. Kicker - 50-4 l*. F. Ridile - Cliemolite W. F. Scown - 223-6 S. I). Sorenson - 22-2 1*. A. Ubcl/D. E. Roach EID072036 OOO1 Report Number: M-6C1 Date: M a r c h 12, 19 Oral Rangefinder Study of T-2998CoC in Pregnant Rats Experiment No. : Conducted At: Dosing Period: Study Director: 0680RR0013 St. Paul, Minnesota January 20, 1930 to January 29, 199 z * /? y / t / Date 3 / 2 V /?; p /P f/s / Ca-. EID072037 000019 Introduction 1. This oral rangefinder study^ was conducted to determine the upper dose level of T-299UCoC- for a subsequent oral teratology study in rats. Toe study was sponsored by 3M Commercial Chemical Division, St. raul, Minnncsota 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 ouch 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 cays 3, 6, 9, 12, 15 and 20 of gestation and the rats dosed accordingly using a constant done volume <>t 5 ml/ky of body weight. T-299tlCoC w m suspended 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 or 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: 0600TR0008 and GGU0TU0010) 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 <i through 15 of gestation) did not result in any deaths. A toxic effect of reduced body weight gain occurred between days G and 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 r- Experiment No. 0600RR001 2 FC-143 * EID072038 00002a 2. weight- on day 9 of the otudy than the pregnant high dose dams (Append i.< I). 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 Sos: 0680TR0003 and 0680TR0010) on chemically related compounds. Tne 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 weiyr.t gain. In addition to the toxic effect of reduced body weight gain, tr.s teratogenic .effect of lens abnormality was observed and is likely to be reproduced in a teratology study. . EID072039 000021 Table 1 Oral Rangefinder Study of T-2998CoC in Preanant Rats Mean Body Weight Gains of Pregnant Rats With Standard Deviations (g) Control 150 mg/kg/day 100 mg/kg/day 75 mg/kg/day 50 mg/kg/day 25 mg/kg/day Day & 1.2 lil. 2'J 2t> l* 21 2* '/c. 4. 2 7. 4 ?. 1' 1. 6 Itv ?' .-1 L-. !- 1/. 2'.-2. 12 M V. i: 12. 12. 1 2? i A x `2. 1 7 1? H J i ! .12 e. 12. 2 X' X J 2.1 1 * v W t-. X'-' t> 2. 2 J ij.2 1.-:. If. tel. l' ' m t. a. ? 2. 7. 2 10. 2*1 . 2y 2 2. * t-. 2 2. 2 2*. i' 3. -- Significantly higher than the control (Dunnett's t test p <0.05) EID072040 000022 \ Table 2 Oral Rangefinder Study of T-2993CoC in Pregnant Rats Ratios of Fetuses with Eye Changes to Fetuses Examined-- Hiqh Dose Group (ISO mg/kg/day) 16/16 Low Dose Group (25 mg/kg/day) 15/15- < Four fetuses examined from each of four dams One fetus not examined because eye architecture destroyed in sectioning ieri EID072041 000023 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 e- *-4 12 10 'IJ 0 t'Hi.'lO V D i-iVi Nik Nik NIK Nik NiR ale217 21V 217 24*. 174 1 ** 172 >1J'/ 175 2l4 2-17 'V*- 221 244 toJw`` 25? .'if.y < t*o..iJC..*. 200 -jI *r** c.* 2*5 211 17 0 2e-`l J.l-.l'j 2c*5* MEkN 175 225 24 2 2 if.4 v'4y S*lHN. DEV l, ' 10. 2 11. 2 10. 5 11. o NON PkEuNrif .'i O N I M m L - Nik 1.2 -1 211 224 2l5 7 '. w. 7V' Day j. r. * 12 a5 Jl;l 150 HG.V.O. 'Dm * 01k 01k 01k Oik 221 224 2 2 '.. 24 7' 2 O'2 17a 177 2>5*. 222 212 171 222 210 217 VK, 257 257 24 4 2 .I* I!>' 2*-l 2-1a *7 24-1 114 "c* HEh N .130 21E SI MN C41V 12. 7 17. 5 4. * NON PkEONHN'l HNil lHfr 255 if*'.'' 151 *. i' 13 4 OJ R 01k 227 2t 7 77 :: \ 200 217 24*. 221 i v i 2 1>' 215 221 EID072042 \ 000024 Appendix I (Continued) O ral R an gefin d er Study o f T-2998CoC in Pregnant flats Individual Body Weights (g) and Mean Budy Weights with Standard Deviation for Pregnant Rats ' Day t- Cj 1 2 1 0 .-O ,|Mti Hii.. '1 11. 1-i i FMK f'lP P IP P IP P IP PxP. j'. w*r. 'WJ i' * **V* 2 'sU 3-IS: 104 2:1 -1 202 .'jo 18*:. 1 *7 17a 24U "-Ir. 220 217 210 24 0 1 0 224 24 U 22i* 17 2 0 c. 240 202 200 :;> iy Vr.X 2c.2 21 4 22 w- !!: 271 t-1EHN 2C' 2 ^ ^ 2 4 7 6 4 * M> o o STFlN. DhV i i . 2 0 4 27. 0 24. 7 4 0. 0 '< 6 Day 12 10 *J 70 Mij/KU/DhV t!lK C'lP CilP Clll-: i!JP 21P 221 222 222 224 220 24 7 172 172 172 211 iv: Ulj > 212 202 24 2 210 221 24 2 'c*. 210 22c- 24 0 200 247 220 201 244 200 c*"j 271 2J1. 27 u 240 4 6 240 w *7* 22.1 20 2 MEW 174 221 Cm mm'2.'* to-VW tw1*m- 24 0 71 hr.'. L-LV l..\ O 14. 1 12 2 12. 4 io 0 J. -* EID072043 000025 Appendix I (Concluded) Oral Rangefinder Study of T-2993CoC in Pregnant Rats Individual Body Weights (g) and Mean Bcdy Weights with Standard Deviati on for Pregnant Rats Day *v 6 Ci 12 10 .1 >0 MG.'IG.'l 'HY RlR RlR R1R R1R R1R R1R 226 237 23 s' 2 2S' 340 3v0 IS*3 177 226 170 10*7 192 2 IS* 201 21.1 190 220 212 CL* 21.0 240 24 2 21>2 220 w *2* ** 267 276 1*W* 2S*r* 21 21-4 204 30>' 2r..i ^ .M 37: 26 HEHN IS'l 221 O 09 2"6c.- %: STHN. I'cV IS*. 4 19. 6 10. 2 20. 1 . k Day 46 12 I1.. o 21'. MG. 'KG.'L'l-tV SIR SIR SIR SIR SIR 24 2 24 2 244 243 21.1 21.6 OV` 160 200 00 2j;Ci 224 20 219 222 2C 249 2 2 1 ?' tm 2* 279 03 249 2o& 204 204 :.- U 270 207 34*0 -- 246 '-!*." 1 MEHN 203 243 2c*r. 2!r*0 Jl* 1 1 STHrl. t'EV 11. 4 12. 6 10. 4 15. 2 10. 2 19. 4 N O N PRE GNHM'f Hl11ilML'. SIR 341 IS? 203 219 220 E1D072044 000026 DISTRIBUTION LIST E. G. Gortner (original + 1) E. G. Lamprecht R. A. Nelson -* M. T. Case W. C. McCormick F. D. Griffith *> F. A. Ubel (5) E1D072045 000027