Document a42nqr4dG12Jzv0ONdwR6zYzb

THE HALOGENATED ALIPHATIC, OLEFINIC, CYCLIC, ARO MATIC. AND ALIPHATIC-AROMATIC HYDROCARBONS INCLUDING THE HALOGENATED INSECTICIDES, THEIR TOXICITY AND POTENTIAL DANGERS by W. F. von Oottingtn, M.D., Pb. D. Notional ImHMm of Hoaltk NaHooal ImtiM* ol Artkrltb and Moiaboll* DImum If. I. DEPMTMENT OF HEALTH, EDUCATION AND WELFARE Ftffc ItaRR Onto HONS 076X71 PREFACE Since (he ehort review, "The halogenated hydrocarbons: their toxicity end potential dengue," wee published in 1B37 (J. Ind. Hyg. Tox., 19, 340,1037) ,.much investigative work on the mechanism of their action and numerous reports on thoir toxicity have been published. Since that time not only new halogenated aliphatic hydrocarbons have found new fields of use in industry and our daily life but also cyclic and aromatic hydrocarbons have gained in importance from both the practical end the toxicological point of view. It appears, therefore, timely that these are included in the present review, especially since there exists no synopsis of their toxicology. In the following peges the chemistry, analytical procedures, potential uses, investigative toxicology, elinieal toxicology, and the prophylaxis and treatment of such poisonings will be discussed. It is hoped that this review will help to reduce the incidences of such poisonings, facilitate their diagnosis and treatment, and stimulate research on the many prob lems which still remain unanswered. W. F. vow Osmwoxw. r Mu i IMS Ln Printbit OIRm ill MOMS 076172 BiufiociiLOitODiru70uro Benzochlorodifluoride, w-chlorodifluorotoluene, Ooo,,` has, according to Swarts (1808), the molecular weight 162.90 and is a colorless liquid of irritant odor and a density of 1.26445 18* which boils st 142.6* C. (770 mm.) and which is somewhat hygroscopic. According to Lehmann (1028) doses of 0.7 to 1.0 mM (114 to 168 mg.) per 100 gm. body weight are fatal to frogs, causing paralysis without in creased motor activity, increased reflex excitability, and convulsions. . BIBLIOGRAPHY Flury, F.. sod F. Zsralk, Bchftdllcbe Gase, J. Springer. Berlin. 1981. p. 849. Lehmann, F., Arch. ezpU. Path. Phanaakol., 199,200.1928. Bwerta. F. Bull. seed. rep. ad. da Belgique. 8rd atr., 88, 875,1808. 4. HALOGENATED XYLENE DERIVATIVES Of tlie halogenated xylene derivatives only bromoxylene has been in vestigated toxioologically. Whereas the pure product has not been studied, Flury and Zernilc (1981) stated that a mixture of C^lI.CHtBrCII,Br and C,HCHaCHBra has been used as lacrimator in chemical war fare under tlte name of T-stoff or lilac gas, which has a boiling range of 216* to 220* C. and, according to Uttermark (1037), a specific gravity 1.31. The vapors of bromoxylene produce in animals severe irritation of tho eyee and a lest severe irritation of the lungs. High concentrations will produce edema of the mucous membranes, pulmonary edema, and, after several days, somnolence, loss of appetite, and death. Man can tolerate concentrations of 40 mm.* per m.' (0.56 mg,/liter) for only one minute and, according to Vedder (1926), concentrations of 0.00878 mg. per liter render a man unable to fight As stated by Uttermark (1987) concentrations of 0.016 mg. per liter are intolerable and such of 0.0018 mg. per liter are the lower limit eausing irritation. BIBLIOGRAPHY Fluty, F, end F. Bernik, Bcfaldllcke Case, J. Springer. Berlin, 1031. p. 840. Uttermark, W., Die fhemlerhee Kempt stefla u. IndnetrlegUte. O. Uelseaer, Hamburg, 1887. Vedder, BL B.. The --dleel lepirts e( riieiilrel wurfkre, Wllllaais and WUklse, Baltimore, 19M. 5. HALOGENATED DIPHENYL DERIVATIVES A. Monohalogenated Diphenyl Derivatives MoKocHix>ioozrKSim Monochlorodipbenyl exists in 8 isomeric forms, depending upon the position of the chlorine atom in 1 of the 6-carbon rings o-Chloro<jj. ! i l ha# the inolf*' ! boil at 2C7* i*. .. : in ligroine. m-Chlorodir... has the molt';.' boil at 284* to . p-Chlorodi]., ha# the molec;.i and boil ut 2-. ligroine. Smyth (IfC, , rabbits and gi. 20 to 40 hourwhereas the ].r causing eonvu; Smyth, H. F.. J : C. Of thu dihr ` been studied to thep,p' dcrivai:\ p,p -Difiuori .; has the moh* .! specific gravit 254 to 253* C. ether, and chit:- Kempf, Gn diet containing voloped neith* r cell count or o!; Kampf, Q. A., D. A. HONS 076173 V and it t Ihich boil* B ItS me.) without Tn- hO. been innot been ItCH.Bruical war[ rang* of avity 131. ion of tha liona mill and, attar Mar) for ationa of Jttarmark id aush of Ellaabai* La wuktas. upon tlio o-Chlorodiph*nyl, o> hna tin molecnlnr weight 188.CS and forma cryntale which melt at 34 and boil at 807 to 808 G. and which an insoluble in watar but vary aolubla in ligroina. m-Chlorodiphanyl, od has tha molaoular weight 188.8S and forma crystals which melt at 88* and boil at 884 to 880 a p-Chlorodiphsnyl, oo~ , haa tlia molecular weight 188.05 and forma Ieaileta which melt at 77-5 C. and boil at 888 C., and which are inaolubla in watar but aolubla in liproina. Smyth (1831) atudied the toxicity of the ortho- and para-compounde in rabbit* and guinea pine and found that the former killed animal* within 80 to 40 hour* with doses of 83 gm. per kg., canning mild convulsion*, where** the latter waa fatal in 40 hour* in doaca of 8.5 gm. per kg. without causing convulsions. 8EFHENCE intftb, h. r.. j. tea. Bra., /, *7. leai. B. Dihalogenciled Diphenyl Derivatives Of the dihalogenated diphenyl derivatives only difluorodiphenyl has been studied to some extent. It exists in two isomeric forma, of which only the p,p' derivative haa been studied lexicologically. p,p-Difluorodiphenyl, 'OO haa the molecular weight 180.18. It forms monoclinio columns of the apeoiAc gravity 1338 8S/4 which melt at 80 to 85 C., end boil at 854 to 865 C., and.which arc insoluble in watar and soluble in alcohol, ether, end chloroform. Kempt, Greenwood, end Nelson (1857) reported that rata kept on a diet containing 0.05 percent of this material (calculated es fluorine) de veloped neithsr mottled enamel of the teeth nor change* of the red blood oall oount or of the hemoglobin. EEFEEENCI mbs*, O. X, D. *. Oreanwee*, sad V. . Nelson, J. Lab. Clio. 1M,, St, lit*, 1T. JOS HONS 07617b I C Polychlorinated Diphenyl Derivatives 1 lip In iil ih.y . Polychlorinated diphenyl derivatives ere of eonmdnntlile toxicological intermit bonuise they era conatitnonle, together willi chloronaphthalenee, of curtain synthetic mm mod extensively in industry u for Uia insula tion of oloetrical equipment. " Penning (1030) doneribaii (lie proems by which those products ore pro- pnml. In Ilia conrao of tliin procedure fifst a mixture of 2- and 4- chlorodiphenyl is formed, mid M Ute chlorination proeoeds tiio mixture bocouica more ami more viscous and finally solid. Those products are marketed under the name of "Aroclor" and represent mixtures of differ ent isomers. "Aroclor" is insoluble in water and glyoerol, not very solu ble in lower aloohols, but very soluble in oils and other organic solvents. The "Aroclors" are solvents for sulfur, rubber, asphalt, paraffin, and natu ral waxes, and are used for protective coating, waterproofing of wood, and for electric insulation. Hie toxicological evaluation of these products is difficult because of their variable composition. Drinker,Warren, imd Bennett (188T) used a prepa ration which contained 85 percent of chlorine and Hiller (1844) used a viscous, almost white material of the empirical formula CuHtCI. of a specific gravity 1.S74 to 1.883. The toxicity of chlorodiphony2 for eoporimantal animals was first studied by Smyth and Smyth (1881) who found that their product proved nontoxic by oral administration to guinea pigs and rabbits in doses of 4 gm. per kg. given as a paste. Drinker, Warren, and Bennett (188T) and Bennett, Drinker, and Warren (1888) found that feeding rata about 0.8 gm. daily waahighly toxicwhan given over a period of 6 days, } changes in b 11 1 lion. 'Ilit: skin linn of tlot |. i mirnmiiiliiig !, striicl.inn nf lit* ! Tho Inpunt .- CIMIWhI IK, ||K'!|.' cuvcnioun vii: The Insirifff I. ' Warren,and I.' a ruts. They ( * concentration < fnr a probin'.'* but when the a | showed puli', - . lion of I In: li Vi increased vnci. . is more toxic : . . totoxic action . * in the molecul a There are ii- . * phenyl alone, c ture with chin, eminent Induperm.1 asthn- and that even 0.06 gm. per rat waa definitely toxic, causing injury to the liver, elthough no yellow atrophy of the liver wae observed. Miller (1844) found that feeding guinaa pig* 8 doses of 68 mg. 1 week opart wee fetal in 11 to 88 days after the first doss, tad that the animals showed marked liver changes. Hiller (1844) reported that tha snbcvtanstms injection of a single dose of 0.6 cc. (68 mg.) caused in guinea piga local necroses at the gits of in jection, followed by encapsulation, and after 8 days fatty infiltration of the liver, moderate central atrophy and, rarely, focal necroeee and JAm. Conf. Gov. : 200, 1933. Bcimr-ir, a. .\., i . 1 Drinker, C. K.. ,\.V I Miller. J. W.. l'M. . I>do1d. C. II.. In- 1 Bttjth, H. F. uul .. some congestion of the kidneys. Them injuries were more severe after dosee of O.l to 0JI oo. (188 to WO mg.) ana, whan given aa a 60 percent 6. H/ . solution in oil, 846 mg. killed all animals within 18 days The sub cutaneous injection of 61 mg. into rabbits produces fatty infiltration of A. IKs the liver earlier than observed in guinea pige but with,lam marked central atrophy. On tha other hand, congestion of tha spleen was seen more i frequently end often then was a myelosis of the pulp. Doses of 600 mg. i Monochloroi ; produced marked fatty changes in the liver and considerable hypertrophy f chioronaphthu'. of the spleen. With repeated administration 10 doses of 68 mg. gave I double ring;. i definite pathologic changes in the liver, and 10 doses of 880 mg. and of Alphaciilorur. 1880 mg. given on oonseoutive days caused delayed death and marked fatty infiltration and sometimes focal necroses of the liver. With tmiansous application Hiller (1844) found that in guinea pip daily doeas of 34.6 mg. for 11 days wars fatal after various intervals 30* i iii i miW Ff>: i HQHS 076175 ^yEBh |U- r* 4ir iro w* lu ll* toml, ir |M1 II f ft rst Mil. Ill Hilt 'K 1 Ih* H) i4nl lUHl kiM in* i*Mi Mil ri*r mil mb* i of (nil ini m. I'l'.V uvo I of kl i>>8 tain l tip to 21 days, Die animals allowing essentially tho aamo pathologic > changes in livsr ami oDwr organs as obsanrod witli subcutanoous injeoi lion. The akin at the sit* of Die application showed occasionally congos' (ion of the capillaries, thickening of tho epidermis, edema of the dermis surrounding the blood roseola, end with prolonged administration UeI struction of the epidermis. Tile topical application to tie cornea of rats on 2fi consecutive days { caused no local changes but slight central atrophy of the liver and slight | rarmmoua venous congest ion of the spleen. I The toxicity of chlorodiphenyl by inhalation was studied by Drinker, | Warren, and Bennett (1937) and Bennett, Drinker, and Warren (1088) in a rata They found that exposure of rats for 10 hours daily to an average f concentration of 0.57 mg. per m.' or for 8 hours daily to 0.93 mg. per m.' for a prolonged jieriod of time caused no apparent ill effects during life, . lint when Die animals wet* killed after various periods of exposure they rhowed pale, slightly yellow, somewhat mottled liven, hyaline degenera tion of the liver cells, increased prominence of cytoplasmic granules, and increased vacuolisation. The same authors thought that chlorodiphenyl is more toxic than chlorinated naphthalenes and believed that the.hepai totoxic action of chlorodiphenyl increased wiUi the percentage of chlorine * in the molecule. Pl Tilers ere no reports on human poisoning from exposure to chlorodiphenyl alone, although numerous poisonings have resulted from its mix ; tun with clilorinatsd naphtiialenes. The American Conference of Gov ' eminent Industrial Hygienists (1953) accepted a concentration of 1 mg. , perm.'as threshold limit for continued exposure. MBUOGRAFHY . An. Cast. Oev. lad. Hrslealats, Lea Aaseles (IKS), Area. lad. Hys Ore. Mad, 8, 1 290, IMS. Reflect!. Q. A., C. K. Drlalwr, and M. P. Wanes, J. lad. Hys- TeateeL, M, 97.1988. 1 Drlatar, C. X., II. r. Warns, and Q. A. Dennett, J. lad. Hys. TraleoL, it, 288,1987. , Miller. J. W,, Poll, llcaltll Ilcp.. U. 1089, lMt. rrimtnx, O. II.. Iml. Has. Ctieia., 88, llStt lone, mayUt. II. K. ami II. K. Hmylli, Jr, J. lad. lire., 7.1,87,1KI1. 6. HAIOGENATED NAPHTHALENE DERIVATIVES A. Monohologenoted Naphthalene DerivatIvwi HaxocHLoeoiiAnRHAunre . Monochloronaphthslene exists in 2 isamerie forms, alpha- and betachloronaphthalane, depending on the position of the chlorine atom in the double ring. Alphaduoronaphthalene, -naphthyI chloride, 307 Mtii'jpunpM* 11 iBpsi ni i* in 1 i j i M0NS 076176 hss Urn moleoulsr weight 103.01. It if colorkas liquid of the specific gravity 1.134 30*/4* which solidifies et -90* C. end boils et 85BJ* C. end which is insoluble in weter, soluble in eloohol) end miscible with bcnsone, carbon disulfide! end ether. .. oaBota-chloronaphthelene, ff-nuphthyl chloride, .. has the molecular weight 163.61 end forme lesflets of specific gravity 1.266 16* which melt at 66* to 67* C. and boil at 264* to 866* C. (761 mm.) and which are insoluble in wetor and very soluble in alcohol and ether. Nous of these compounds has been studied toueologically, but Gavan- dsn, Gavandan, and Durand (1963) found that the vapors of alphachloronaphthaleno affect the roots of TrlUcm vulgar* with exposures of 1 to 2 bourn, causing ksryokinssia. REFHENCI Oavaadaa. F., It. GavaoSaa. aai J. r. DanaS. Omit read. soc. MaL, MS, 1448,1SSS. FoooaoaArimiAXjiiTa Alpha-fluoronaphthalsoe, naphthyl fluoride, CO hit thi molecular weight 146.16 and it a liquid of tht specific gravity 1.188 19.5*/4* which solidifies at --8* C. and boifa at 818* to 816* C. and it soluble in bensene, alcohol, acetone, and chloroform. Kempf, Greenwood, and Nelson (1987) fed rats levels of 0.1 and 0.05 peroent (at fluorine) in the diet Animals kept on the higher concentra tion died within 80 days without developing abnormalities of the teeth, but thoee kept for a lonipr period of time on a diet containing 0.05 percent of fluoronaphthaleoe developed mottled enamel. They did not reproduce, but showed no-changes in the rad blood cell oount or in the hemoglobin. K8HMNC8 ~ Kempt; 0.i,D.l Greenwood, aad T. m. Nelson. J. Lae. Oita. Met, ft, lltt, UST. ft. Polyhaloganotud Naphthalane Derivatives 'friCHLoaoNArHiHALnni Trichloronaphthalene exists in the form of two isomers differing in the distribution of the8 chlorine atoms in the 6 ring. 808 Okamutry.--l, has the molecular end which are v< ; 1,4,0-Trichlorot. of the seme molt ' and which arc.soi Whereas the Drinker, Warren. (1938) studied tl. contained a tract* . 49.9 percent. Th> l.31 mg. per m.* f .r and when sacrifir* ' changes in liver w. ,, being nomial. K.\ m.* for 16 hoursda.I. during exposure a . and 102 days they -. oral atlmimstrati' i only a very slight i. differed from ti:r pounds. Similar'., naphtlislene wa# showed that the i.x medication with et! Courtoia-Sui&t, T* Mtnetrel and Aubr posure to trichloron. condensers, and rep< (69 percent of the ( the vapors of this m sometimes associate*, oped vesicular edenu of tlie body. After cute eczema which, furuncles, and inflar was followed by a sol most common, 64 p footing mainly tha Other patients dew folliculitis on the ou 0NS 076177