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TOXICOLOGY AND APPLIED PHARMACOLOGY 49, 189-202 (1979) URL 20143 Embryotoxicity and Fetotoxicity of Inhaled or Ingested Vinylidene Chloride in Rats and Rabbits'*2 F. J. Murray,5 K. D. Nitschke, L. W. Rampy, and B. A. Schwetz Toxicology Research Laboratory, Health and Environmental Research, Dow Chemical U.S.A., Midland, Michigan 48640 Received March 20, 1978; accepted January 26, 1979 Embryoioxicity and Fetotoxicity of Inhaled or Ingested Vinylidene CMonUc in Rats and Rabbits. Murray, F. J., Nitschke, K. D.. Rampy, L. W., and S-.tiwet?, H. A. t igWj. Toxicol. Appl. Pharmacol. 49, 189-202. The teratogenic potential of inhaled or ingested vinylidene chloride was evaluated in Sprague-Dawley rats and New Zealand white rabbits. Both species were exposed to the test material by inhalation for 7 hr/day at concentrations of 20 (rats only), 80, or 160 ppm. For the ingestion study, rats were given drinking water containing 200 ppm vinylidene chloride. Rats were given vinylidene chloride from the 6th to the 15th days of gestation and rabbits on the 6th to the 18th days. A teratogenic effect was not seen in rats or rabbits inhaling concentrations of up to 160 ppm vinylidene chloride for 7 hr/day or in rats given drinking water containing 200 ppm vinylidene chloride. Toxicity to both the dams and their developing embryos was observed among the rats inhaling 80 or 160 ppm and among the rabbits inhaling 160 ppm. At exposure levels which caused little or no maternal toxicity (20 ppm in rats and 80 ppm in rabbits), there was no effect on embryonal or fetal development. Among the rats given drinking water containing 200 ppm VDC, there was no evidence of toxicity to the dams or their offspring. Vinylidene chloride (1,1-dichloroethylene, -resulted in some weight loss in rabbits and VDC, CHa--CC12) is used in the manufacture monkeys, but not in rats, guinea pigs, or of various plastics, including films and dogs (Prendergast, 1967). Rats exposed for coatings for food packaging. Reports on the up to 4 weeks to 500 ppm vinylidene chloride acute toxicity of vinylidene chloride in exhibited nasal irritation, decreased weight laboratory animals have indicated moderate gain, and liver cell degeneration; at 200 ppm, toxicity when given by inhalation or by the only sign of toxicity was slight nasal gavage (Carpenter et ah, 1949; Rylova, 1953; irritation (Gage, 1970). Siegel et ah, 1971; Jenkins et ah, 1972; Vinylidene chloride has been shown to be Jaeger et ah, 1973). Exposure by inhalation a weak mutagen in certain strains of bacteria to ICO ppm vinylidene chloride for 6 weeks (McCann el ah, 1975; Greim el ah, 1975; 1 This study was supported by the companies sponsoring research on vinylidene chloride and administered by The Manufacturing Chemist's Asso Bartsch et ah, 1975). This effect was seen in bacterial systems only under conditions of activation with microsomal enzymes, impli ciation. 5 Presented, in part, at the 18th Annual Meeting of the Society of Toxicology, San Francisco, Calif., March 12-16, 1978. * Current address: Syntex Corporation, Stanford Industrial Park, Palo Alto, Calif. 94304, cating a metabolite of vinylidene chloride rather than vinylidene chloride itself as the causative agent. No information regarding the teratogenic potential of vinylidene chloride was found in 189 <XM1-008X/79/080IS9-l4$02.00`0 Copyright 1979 by Academic Pre, Inc. AH light* or reproduction in any form received. Printed in Croat Britain -V D. E. (1976b). Effects -mpiKumtne. on the reresponse sequences by /pg.v 49. 245-248, :ictial analyses for single. '*- In Singh Case Expert, xs for Studying Behavior ~i D. H. Barlow. ed$j . New York. i.*\, D, E., and Barlow. mercuric chloride: Behavns. Environ. Res. 14, 424- Befcg%iftfal effects of asympduring neonatal development Pharmacol. 41, 459-471. . H. (1977), The effects of * direct feed exposure on FK Pharmacol. Biochem. Bebay sb Michaelson, I. A. (I97J). >rai catecholamines in leadrats. Science 182, 1022-1024. -vr> Goldberg, a. M. (J974). ^id-induced behavior disorder. -epeet. 7. 227-232. *ms Goldberg, A. M. (I97?t *d neurochc/nica! investigation yperactivuy. Neuropharmucaia#> *973). Learning deficits in lead"harmacol. Biochem. Behai, t. u*dwi, H. ., and Cook, M. P Physiologic effects of early lead *hvy$. 175-191. *M> Cook, M. P. (1974). Postnatal v*sure in ms: Possible rc!ation>fi v a* dysfunction. Atner. J. Meat. tk? *. 0973). Repeated acquisition a iseline for studying drug etTcvi* Exp. Ther. 1*4, 506-514. M. (1974). Repeated acquisition A tans under chronic drug condt",,!' . Exp. Ther. 188, 700-713. \1. (1977). Development of tolerance effects of cocaine on rcpcj,J-nd performance of response scque0 Exp. Ther. 203. 294-302. G. Kt Carson. T., Smith, R. M.. 3. (1973). Behavioral toxicologic tr neurologic effect of lead in /. 6,405-418. and Mine, C. H. (1970). Effects of pchavior of conditioned goldish ' feoirh 2ft, 45-51. TOX,COLO0V *TM PHA.M.CDLOCy 47 ***-393 (1979, CJU^JU. Saturable Metabolism and the Acute Toxicity of 1,1-Dichloroethylene1'* Melvin E. Andersen, John E. French,3 Michael L. Gargas, Robert A, Jones, and Lawrence J. Jenkins, Jr. Nava! Medical Research Institute Toxiralw Detachment KS'MMfTD), tyright-Pottersm AfB, Ohio 454JJ Received June IS, !9?8: accepted August JO. I97tt Saturable Metabolism and the Acute Toxicity of1,) D.hli>r<<cthvlenc Amwrvn, M. F, French. J. E., Gargas. M. L., Jonis. R. A., am> itvm>%. L.). In < W?vi 7;*/ Appt Pharmacol. 47, 385-393. The toxic effects of smalt. oral ilisn <>f |.l-du;htofiR;thyWne (l.I-DCE) are caused by its metabolites. When saturable, enzymatic production <ff a n>uc intermediate regulates toxicity, the observed inhalation toxicity. t *uff*trntl> high con centrations, will depend on the duration of rxpouie and ir reUxc(> independent ul the ambient concentration. The inhalation toxicity of f.MH t was cummed m L*vtcd >wk rats to ascertain its dependence on both 1,1-lK i voiwemijiion and the duration sff ex posure. Immature rats (100-150 g) were esposed <> '<*> ppm 1,1 IX 1 i.r duraii/> up to 2 hr. Pentobarbital sleep times (PILST) were MgmtKjnil* usk^V'I jD<> r\p.wuir\ *s t-rKf as 0.5 hr. Intubation ofimmature rats with 1,1 -5H J (VtO,*rdettr;nk d<un..v <id i j. uti lization of the endoplasmic reticulum (( K). \(h>le >ur.g m* wen n>c \w*.cyW'W to 1.1-DCE than older rats (>200 gt, evtenviv; d4.'.j*'r n> iNe IK ulx p*e> nt* of 1.1-DCE metabolism) during exposure prv;.j.iYJ v-c .witf-iMi g i*u ir)uUtu<n dose-effect curves. With older rats. VttSl woe '! i'suid <tp.nw.-< J*v .* centration-mortality curve for 4-br c\p*>*iur* ppm, but was virtually flat (i.c., cotKem.ivu > : ,*. . > The LT50 (the time of exposure required <* W:i t*.*: ki*n tm ;*> **.> .T* * *--j t a * j j- m i"v> ' 'K<n tration) only varied between 4.1 and 2.4 hr a\ mu ppm. Failure ofl,l*DCE to adhere to a concrrtiMr.*u> i. * >:<>* .a s of a role of saturable, enxymalic activation n t <%rio**n ^ `Naval Medical Research and Development Com mand, Research Task No. ZF51.524.025.4003. The 1bCvntx!lt.`v-.4> *r) pnrt*tsUf < henttea) opinions and assertions contained herein are the pri me ones of the authors and are not to be construed l is official or reflecting the views of the Navy Depart* "nt or the Naval Service at large. The experiments | sported herein were conducted according to p*n* ICpJCVntr a c i4 hum'J b) the \hen-A*l ef-J >-*w *Mi-*vt*Ne to n>xtilv'iitc* tV`A,'`*.<2 t`-*> thffnKal by the ;v\*o v-Ur ta ft'.-.-n In mxny f'Plcs set forth in the "Guide for Care and U* *,r ; laboratory Animals." Institute of Laboratory Ke* va-o. s: r v * '<' *'# t ->. t?-,n the \ farces, National Research Council, DHEW Public*' ij * No. 73-23. I * Presented in part at the Seventeenth Annual Mt- ^pal^till Jtf 4 41 (KO*'Na-.thrr.cft;*'*^ "i-1 Atjpi >' * <* * * 4 {1 i ii true )*/.; h/fV (Garnet *> , 'lofthe Society ofToxicology, San Francisco. Caiff, ' >k 1 ^farcfi 12-16, 1978. res. '*> s'W )*> a t `-*< \ *J Bft.ureau of Biologies, Food and Drug Adminivira- t* .N * .4tvr .4 \ n., ) 8800 Rockville Pike, Bethesda, Md. 20014. Jfdpf *4 r.e-.t. - * - vtend.rg .4 MS ,* '** I- . *> ier. J'*' 4 ** <M , , ! ftl M 4 cr yj cO r. .S*.