Document 3Dv1O0nEZXxyxeR194051bzE

1 ' i i j \ , w~ C '. )t b-b. mV.' omda;;;a-ID `H '.vVJDK if ON MM ALP d: 1 MA 5.; A >' dOll.T pao/a 0 iiM-r.ftT CMA IlbMM CM yoco ;.f) ;t~- a; lAMCX PTC-VliC * AVd X ^ J C" 1 1 J ` ' '.7 .1' )''"J*> r. 1 > j. 07 AMU AfDIV . IMAM 70k: -C'..0,6"-I C *.. 1 ,t r 7 t AM: tc. :: AA. i A / 1 u -t. f-it :-... .'j. nsj . ' 1 D'M 11.;; 0. 1- - 'T :d gamaal co::xv..or.-*. *i c.:-i cm .'doitA n: 3; X iu'v -A * ^ j^.` A'Acr.* A'..-: ::n bioHiOvCATM/AM (Methyler0 chloride; by Dr P.G. Mlins (Consultant) yAj/A/vuio U) dulid; d;l 2ioi2XiiyrX.5yla ftipchemlcxl - vM f? Dichlorcmathaue (CK^Clp) is rapid]y absorbed by tho lungs (70-7A of the inhaled vapour), uniformly distributed in organs end rapidly cm re bed via the lungs arl in the urine. It is largely excreted unchanged (von Cettiurr.n et al., 1949; Plley et al., 1-46). Because chlorinated hydrocaibon e..traction solvents can react vith -Hi groups of protein auinoacids, the reaction of dichf or.r.'.r-thane with L-cysteine ms studied. The theoretical reaction product is d*snkclie acid (l,l--di-(l; l-anir.ocarbo:;/ -2 thioethyj )-ret::are) tilth on acute oral ID-,, of >10 g/kg body uoight in mice. Under normal techno]epical conditions practically none is found in the extracted materiel (hli.-ner, 1970). Absorbed cicnl oronethane is-probably hydrolysed in the live)* to formaldehyde and MCI. Scr.o of it also reacts with -SH groups of liver encyr.co e. g. coenzyue A (Kennel and Porterfield, 1948). Acute toxicity Animal Route ^50 ">100 Reference Mouse Rat Guinea pig inhalation inhalation i.p. s.c. oral oral inlsalation 56 ip.g/l air - 1.5 mlAc 76 ra noles/kg 2 sAc 1.6-2 g/kg - .. 14 500 ppm - -- -- 50 000 ppm Svirbely et al.,19/7 Plury 4 f.r:d.)c, 1931 Klaasser. A Flan,lv66 futob i Plea, 1962 Kliimcr, 1970 Dch* Chemical Co., 196 Muckolls. 1913 Th Iscua of th*K document tiooa not conctltuta formal pi'llcUon. I! thould rot uo reviewed, cf Urr.c'ul or quoted vMGiout the o'lsv.iait of tho V.'s.fd Ho'-lh Orernii.'i.on. Author? elono ua r. .-uor.j. for vu-a j Mrprer.o.jd Ic v crp-J tt tiefr ASI 00004227 Co document ne corrUituo p?.3 -juo publication. If na b-oit flro I'ohiut cVucun corr.|_:e rendu ou rdrumd ni o ausur.G citat.cn eans I'autori.-ation do rOrnanieatmn i/oau .,iu tic la Los opinion exprhido-1 can" tj '-.clca sly-, is n'cnraQjnt mi*. Wiuru auit.btr?,. I H:b)/i-/V.'- 10 (n) Age 0 Animal Rabbit Dog Pou to 01T.1 oral 1-. i.n. E.a, U,50 - -- - ^199 1;9 gAg 3 d/'.g 200 my Am; 0.45 .J 2.7 g/H.g Reference 6 pec cv, 1956 TW'ia aim A be or', 191 / A / Ala" :-ar;n H 11: A J Br.r. :..m 1 fjuan.lVp, K This s' :b:;t race : a ? f ii rv r b'.'. !, v ary a ole tile nave i ic w: i h -n exexterneat star a, sue," cci'_` ,/ : a .11 s uvd do -;a> an I i r.;-card lira A an in rat s (Am..via.-:, 1965; Ellin -b 2 i r'O). ) ic;. 1 f; m to the I vnsour c sentrat or: for 24 hou r and their 8 el eve i-.U n v; j, 1 dot or. iued to a-a RmaatoA c notei f. :1. This vs. " found to bn albuminuria l:v in (Geh r.L_ ' ? 196 504 of :ub. fis J ) Ad;: Vi th a ini dec Tctc: alien i.p. to :.vic Ci sad Ja? excretion / \ of 1.5 Flea i nl/..g produced Larson, 1365). Admini51rution activity. Jiie i.p. of .iiO 10 TO to rice J is* 'i no c fleet on livers a ape VC 4 n 'slolapi cal !y no rmal but R..P the rot sr. tic a or bGPT 1. idn.-ys showed occasional!;7 r;: nival re cro els of cnr.'olu ted tubules (iCLaassen 1 me; 196b). Administration s.c. to mi.ce of the L1.),.- ceased r-.c...o prolongation of pentobarbital sleeping time, little change in ISP retention with noroul liver histology (ilutob & Plaa, 1962). Oral administration to rats of 11.o m molos/kg by. gnvago had no effect on liver glutathione levels (Johnson, 1965).- Inhalation of 5090 pp.:i in air by rats for 7 hours depressed the activity of ruin as measured on activity drums although nor;.ul inspection shoved no obnor.aliiy (Hepcel 1 heal, 1944). Higher levels reduce blood pressure and may injure the myocardium (ven uettinren, 1955). Adninistiaiion i.p. to dogs of the ID,.,, produced elevation of nGfl in 504 of animals. Ho histo logical liver necrosis Aas seen but moderate neutrophil infiltration of the sinusoids. Renal histology use nerval (Klaassen 1 Flua, 1967). Use as anaesthetic in man caused prenarcotie excitement but no other ill effects (Grasset end Gauthier, 1950). Excessive inhalation (2300 pun) produces nausea, vomiting, also acute bronchitis and irritation of the conjunctiva end nose with some anaemia (iioskowitz and Shapiro, 1952). Host commonly drunkenness is produced (Patty, 1958). If confined cn the slain it is only absorbed to a small degree but causes considerable irritation (Torkolson et al., 1966). The TL7 is 500 ppm (Patty, 195S), Spice oleorecins nay hafe 30 ppm and decaffeinated coffee io ppn as residue (FDA, 19o7). Short-term studies Ra 4O- Pour groups of 30 male and 30 female rats received either platn water, 44 alcohol, beer made wiih natural hops and beer made with a hop extract containing 2,24 dichloror.ctbanc for 13 weeks. However, no residues of dichloromethane were detectable in the beer. Ho difference was noted between test and control groups as regards haematology, urine analysis, major organ weights, blood chemistry and histology except for the expected fatty changes in the linn of the three test groups, 'flic thyroids of the two test groups on beer had significantly smaller weights than the other two gro"ps. He evidence of toxicity appeared in beer made with hop extract using dichloromethan? (normnun et al., 196s). ASI 00004228 vn 'wah w ,--lv- '-cr 2 nun'.'.1:-. -i.3 dfluid llh'u V.'-fcr, tv ' in:s Lou I. - ` O.-f'/'ll!.!- or 0.01.'; 1 of upw.-.-an uieh] .y~-- not Vi.-v. i-o ri ~i.l:'Lv..~ v to ';r ;n w. iwn tt; an.; conor.-l t;.0 n'.i rrfarls ,UV'.,'.-h 0i` alio Hole ;ie::!. findIny. (lorn; if-...-;). 1:: j-'-'.r-" ov ]' H-rorr u of mis received u-illy by ruvnac 0,0*5 r.l or 1 ill of an a nr sou a- s.-flvtanu liil o 0,9 0-5 or 0.'. diem v mui `no for 2 years. bn j-r i 1. o:r : 1 - 'an. r : or afvwrro r--' /.els on far'd .lily -ups oi l v-r fn fi.k . ' f .i :crr' in :--r: y Pi can V'.'-.-r, ' .~i-ft ryin, o-.c.-uSeop,' a and .. Lm raoe.uv appear non of raj or or3. ns. ror.. f-Cij o.-y_ a ora". croicans au:i urine lysis (a . singer, 1506). ct Iffii'.v Groups of bowsiarc reaei/ur by daily r;rvn;,o 0;0.3 rdL or 1 rl. of nav-eous solution ovr u.b-uL uo 9, 9,G;'J or 0.1 r aiahlom a-thane for ? rears, lo reverse flr-linm v. wit!, rep .rd vo i monr ircio, fortfj. Ity. a.r 0aranee of 'J i ^ , 'alien, y- naral Vehavtwr, weight pair*, macroscopic and raicrusoopic ^T5]y.ri7Tuics major or-, hn.ruiol:(g/`, oer.on proteins and urinalysis (Idslayer,Ifca) 114-111Juki K-ata, rabbits. docs and guinea pigs were ewmosed to dichlorcuathane up to 5000 r.pn for \ drying tvriods up to 6 r.cjvlh?. 1c serious adverse effects were seen except for occns/ioral pulmonary o adera -with focal necrosis and fatty defeneration of the liver.. Reproduction was unaffected (Keppel et al., 1944). Rabbit shin was treated with 0.5 g/kg for 5 clays per week for 90 days wit heut any adverse effects (Dow Cha.vical Co,, i960). 1444411111:114:40:411 4 hmnn subjects had the slain of their thurra iiumrrvi in nsthylcnechloride for .90 r.inuta a. the neon peak alveolar concentrat`d on;!--uring exposure was 3 ppn. This fell to 0.7 ppm 2 hours after the corposurs (btc-uart 1 Dodd, 1964). I ASI 00004229 /V:. pi-.- 4 (-0 " ; \ or n .-ameer., 0.6. -li l -and, (1034) 'y.'u'b, 'T. I3l?rear: real,, y1,7 205 Born .-ann, G. , :6."&V!, 1., Loeser, A. a::d Ogiic, A. (1963) Lined. Lebeusn,- landrod- 'i, b/. "'-J7 3 re-Mil A. (i'6y: Tonicity ar. I dnratolimi of li. duririal bolvonts, 41savior, A: 'L< - m.. bcr.: CdmievL dm (VA'd) i e./ad.mhod Ida 0: i 4 .did to '1.0 inhJ'.r, 4.9. [ '.scry r. elciy, AiV-*y Ac\! lor-: : ivl l-:-" tor Flury. id out A'-ort, 7, (V;3l) ocl lit Gase, tm'ycxrd Le-rlin food and drag titloriiy (1 767) FV.c-r:! 1 . :::d.--v, H.B.A. .121, 1U39 Gchrir:, P.J. (A/A) Toxic. .''.'1. Fdr raced. , /% At? Grama o, J. r--d Gv:ih;.er; . /950), 6,--.. dOr,.', 1- ir, /, 1239 bcm, Hepy/, L.A. ov: Ac.a. I, P.A. (l//) J. .11 h3_ Hyr,, Toric. 26, 1? cal, H.A. , i'orr In, V.L., Or Id.L. and i arteri'iold, V. T, (19/ h * : iv-b and rord-rf ieid, 7-7. (lv/. J Biol. Chc:r. 176, ?6? (1965) Piece on r'"acd. , ; . and pGaa, G.L, (1967) F o:cLc . and Finn, UiL, (1966) Tonic Xlimor, C.A. (1970.) report to trordcwriton Ascior. LAO 5/7/66 . Hutob, n .D. and Flm, G.L. (196,2) Toicic. avpl. Fharraccl., A., 354 Looser, A. (1366) crusted by -.lim-er (1970) l.'osinyar, {1?66) quoted by Aliw.er (1970) ^^ioskovitz, S. -and -ibapiro, 4. (1932) Arch. Inc', dry., 6, 116 ^Bluckollc, A. Id. (1933) irdeivriiem1 Laboratories Acot, .rLsceilanoous hazards ^ no 2375 Patty, F.A. (1954) industrial Hygiene r.r-d Tcnieolony, II cd., Interscience, - sw York Plan, G.L. and Larson, II.3. (idol) Toc-cic. uprol. rhar.vaool., 7, 37 Id ley, d. C., Faucctt, D.A. and button, A.L. (1966) brer. Xr.d. Hyp. Asa. J., 27, 341 Spcctor, .do. (1956) Handbook of toxic cloy, Tol.I. launders, Philadelphia Ltevurd, R.D. and Load, II.C. (1964) Ar-er. Ind. Hyp. -osoc. J., 2% 439 Svirbcly, J.L., Hi/mrn, B., Alford, A'.G. and von Ccttinyen, A,id (1947) J.~nd.Hyp.To;/,?9.332 Torkelson, I.It., Hoyle, H,H. arid Eov;e, 7.4. (1966) Pest Gor.trol, July 1966 von Gottingen, A.?. (1955) Publ. :11th. 001"/. Publ. 414 von Octtinqen. Ad?., Pduell, G.C., Sharplcss, 4.id, Alford, A.C. and Fecora, L.J. (1949) Hatl, Inst. Health Bull., no 191 ASI 00004230