Document 6B6qdQ7X44yKEV9dvr1EXekLm

F">m'WfA 0/ W- PAPACEOnCE t4 H Co**y g'f^w/hce/e*' 7V f J C. t*'*4*>K 0 /* Oe. \Y t &U*r*/\ W f~ Stftnes /1 <*(!*' HONS 21234 7 hr Sttrarf-uf /hr Tiitnl Cm iroitmtitt LNcvivr Muftlislum; C tunp.uij AnutcrJ im -- Primed in Belgium POTENTIAL ENVIRONMENTAL CHEMICAL HAZARDS PART III. INDUSTRIAL AND MISCELLANEOUS AGENTS L l (SIKH IN .nut W Ci I'LAMM Ntiinumt fm/i/mr af l.iiiirunmrmal Hrnt/h Snenftt, Nat tonal fnstt/tttrs of Health, rnhtir fleal/h Ai r> ur u>u! liejmrttiieni of Hfulth. Lshten/iuii ami Welfare, /tiuanfi Trhwxtr 1`arh, \arth Curahna 2170V {U i A) (Heteivtd May 19th, 197J) 1N7 ItODUCJ ION1 In the previous p.ipcr, the polcDii.il environmental chcimc.il hazards related lo dings1 anti feed medreants and pesticides1 were considered via an a-pnon consideriinon of llteir chemical structure, nature of metabolites and degradation products with lel.tuon to known and hazardous insults and the iDicr-rclntionships and com monality of hazards present in various use categories, 1 he present section focuses on industrial and miscellaneous agents in analagous consideration. Polymer and plastic ntgt cdicnls A wide variety of organic derivatives are used in the polymers and plastics indnstiy us plasticizers, modifiers, emulsifiers, stabilizers and solvents, and their incitncss and/or safety is far from being established Polych/orobiphenyls. Polychlorinated biphenyls (PCB's) arc produced by various maim fact dies and arc represented as "a senes of inert, chemically resistant, firc-ietnrding plasticizers compatible with a wide variety of resins, varnishes, waxes and paints, they vary from mobile, oily liquids to white crystals and hard transparent resins"1. The sciies of Aroclors (Monsanto) are marketed under various numbers and consist of mixtures of chlorinated biphenyls and tcrphenyls. The 1200 senes relates to the biphenyls, the 5400 series to the lerphenyls, and the 4400 series to a mixture ot bt- and tcrphenyls. The annual production of PCB's in the Western world till most nNcmly was estimated at 100 million pounds. In the commercial process for PCB manufacture, biphenyls are chlorinated with anhydrous chlorine with either iron filings or feme chloride as the catalyst, the bypioduct is hydrogen chloride and the product is a mixture of several PCB's In the process of replacing hydrogen atoms with chlorine atoms, a large number of sub stitution combinations arise, viz., S' 6' 2 3 Set Tvtof ISt/urv/r, l (1972) 117 HONS 212385 For example, three monochlorobiplienyl isomers arc possible, 12 dichlorobiphcnyl isomers, 21 mclilorobiphcnyl isomers and so on Theoretically, 210 compounds can be prepared by this substitution process (a typical PCB example would be 2,4,6.2',4'pctuachlorobiphenyll The chemical properties ilt.it make polychlorohtphcnyls desirable industrial m.uenaU me iheu excellent thermal stability, their stiong resistance to both uuchc iintl basic hydrolysis and ilicir general inertness The largest single use of PCH's is related to their electrical properties, as coolant insulation fluids in transformers Other uses of PCB's include impregnation of cotton and asbestos for braided insula tions of electrical wiring, plasticizers of vinyl chloride polymer freons, a plasticizer in wire and cable coatings and in ballasts for fluorescent fixtures. Because of their thermal stability and fire resistance, the PCB's also find application in high-pressure hydraulic fluids, heat transfer agents, machine tool cutting oils, specialized lubricants and gasket sealers Miscellaneous uses include; formulation into epoxy paints, protective coatings for wood, metal and concretes, adhesives and in carbonless repro ducing paper, and as plasticizers in plants, resin and chlorinated rubber and have been recommended for improving lindane residues4; they have also been shown to increase the msecucidal properties of DDT Polychlorinated biphenyls along with DDE (l,!-dichloro-2,2-bts (p-chlorophenyt) ethane) are reported to be the most abundant of the chlorinated aromatic pollutants in the global ecosystem'. Extracts from tissues of sea eagles, pike and salmon' as well as in various species of British wildlife* contained PCB's and in the latter instance it was found that in birds' liver and eggs the PCB residues were greater than the organochlonnc pesticide residues PCB's have also been found in fish, mussels and birds front the River Rhine and the Netherlands costal areas7, in marine animals in Sweden, England and the U-SA7'* and in other wildlife samples4''*'u. Polychlorinated biphenyls have been found in human adipose tissue'7, samples of human milk" and in foods (margarine, vegetable oils and particularly fish)14. Essentially, the same type of residue pattern is becoming apparent for the polychlorinated biphenyls that has been found for the persistent organochlonne insecticides. The PCB's are extremely stable, chemically, fal soluble and hence persis tent in the environment. Polychlorinated biphenyls and polychlorinated tnphenyls have been found lo be cstrogcnically active1' -- in a series of PCB's the compounds containing up to 48% chlorine were active. On a weight basis polychlorinated biphenyl preparations (Aroclor 1221) have been shown to have an estradiol-degrading potential about five times that of/?j'-DDE or technical grade DDT' PCB's are inducers of hepatic enzymes and together with other chlorinated compounds may be responsible for aberrations in calcium metabolism in certain species of birds' and are generally considered to be more of a potent threat than DDT to our declining bird populations, especially for predatory birds that accumulate fairly high levels of PCB's. Hydropertcardium, occasionally accompanied by abdominal edema was 118 Sft Total Fnt trim . \ 11972) MONS 212386 found in chicks'* '* and Japanese quail7 aflcr ingestion of PCB of American (Aroclor) and French (Plicnodor) origin respectively. The occurrence of lesions resembling those oT Lhick-edcmn in birds fed PCB'* 19 lias also been repot led, In most recent work, Vos ct a/.10 described the identification and toxicological evaluation of chlorinated diben/ofurat) and chlorinated naphthalene rn two commer cial polychlorinated biphenyls A combination oT toxicological, pathological and chemical-analytical data (including mass spectroscopy) strongly suggested die identity of tclra- and pcniacltlo, cociizofurans (I and 2, respectively) as toxic factors in the PCB's Clopltcn A-60 and Phcnoclor DP6 i* The occurrence of dibenzofuran derivatives was suggested via a consideration of the manufacture of PCB's and particularly in the procedure for the distillation or crude PCB rn which sodium hydroxide can be used21, PCB can react with sodium hydroxide at elevated temperatutes to yield phenolic compounds and can for example yield polycltlorohydroxybrphcnyls via sapomficanon by sodium hydroxide in a polyhydne alcohol medium22, subsequent loss of hydrochloric acid could then produce chlorinated dibcnzofuran derivatives. The biological interactions of polychlorinated biphenyls and insecticides was reported by Lichtenstein el at. 22 who showed that many of the PCB's were toxic to Drosophila melanogasier Meigen and houseflies Musca domesuca L (but to a lesser extent than dicldnn or DDT, their toxicity increased with a decrease m their chlorine contents). Moreover, sublethal dosages of several of the plasticizer PCB's increased the toxicity of dteldrin and DDT. Although PCB's are not pesticides per se, they are included in about three dozen pesticide products registered by the USDA24. Because of their similarity in structure and chemical properties, PCB's, if present in a sample, are carried through the usual pesticide extraction and screening procedures and are frequently mistaken for DDT in monitoring tests ooo ci ci ODE Phihalate emer plasticizers. Phthalate esters are among the most widely used compounds as plasticizers m a variety of lacquers, varnishes, paints, co-polymcrs and plastics. Sci Total Environ , I (1972) I 19 HONS 212387 C.W. U) general, pliiluil.nc esters li.ivc been reported to have .t lower order ol toxicity for experimental .mmi.ili"* J" and thus have been uppioved lor live in packaging minerals for food intended for human consumption However, Guess and cowoikers11'0 have demonstrated the subtle loxicmcs (tissue culunc cell death or enhanced growth, changes in ji.tibod) reactivity and iruuiion as evidenced by dye cxituvasamm) of pl.ivtiuzeis and stabihrcrs used ill (he mamifastute of polyvmjl plastics Cm,itc and phiL/n. estu plasttu/ers such as 1ns (2-eth)lhe\>l)plnhalate and aceiylaied tii-bmyl uu.ue weic found to be leached fiom plasiict/ed polyvinyl clilonde (PVC)'1 1 be nyiuiicaiuc of exposure lime on the leaching of these pt.isuci/ers fioin PVC is iinporiam since the plastic is commonly used in tn-dwelling surgical devices, c q cadicicrs, and m pliarm.ieciilic.il containers Cullcy cl of 30 described the toxicology of a senes oT plnli.il.ue esters. It lias been previous!} shovvn that certain plastic devices used medically can release one or more mgiedicnts into tissue or solvent systems3 J~3*. The four citric acid esters used as plasticisers {c.g tncthyl, acetyl tnciliylinbutyh and acetyl mbuijl citrate) have well defined and marked pharm.icologic.il activity when administered paremeially (all four have local anesthetic action and can block neural transmission when they conic in direct contact with a nerve iiunk, and also stimulate the ncive trunk)30 Phtluilaic ester plastiet/crs were found to be extracted by blood from plastic tubing and from plastic bags used for blood storage. Bulylglycolbutyl phthalate (UGBP) was found to be metabolized by isolated pci fused rat liver to glycolyl pluhn* late, A second phihulalc ester plasticizer di(2-clhylhcxyl)phlhalaic (DEHP) which is commonly used in plastics in biological and medical practice was found accumulated in the liver unchanged In addition, it was identified in samples of human tissue (spleen, liver, lung and abdominal fat) taken from patients who had received trans fusions of bloodslored in plastic bags31. c-o-c*hs o cOU -ocn.c0 -C*4Hwt BOBP COOCH1CHiCaH1)(CHJlJCHj j^j-COOCHjCHtCjHjXCH, J,CH, DC HP 1 he isolation of plasticizers such as DEHP from the anticoagulant citric acid-dextrose solutions stored in disposable polyvinyl chloride blood bag assemblies has also been documented30-37. In addition to evidence of phthalate ester plasticizers in certain foodstuffs such as milk3*, there has been evidence concerning the presence of these plasticizers in animal tissues such b$ beef pineal gland39 and heart40. The teratogenic effects in the chick embryo caused by esters of phthalic acid was described by Bower et al.*'. Dibutoxyethyl phthalate caused tcratogcnesis in the 120 Sci Tittiti fju'irti/r t (1V72) MOMS 212388 developing chick embryo and also ch-2-mcthoxycihyl- and octa-isodvcyl plnlul.nc were capable of causing damage to the central nervous system of the developing thick embryo Toxigenic cJTuIn m different mammals caused by several esters of pluhulic ucid have been well documented3'''2 4i The effect of chemical sterilization of plastic items and thcircontents with pnmtmly alkylating agents such as ethylene- am. piopylenc oxide adds yet .mothei dimen sion to the loxicilics and potential hazards (hat might occur Tins is especially true in the interaction of these gas siculi/ation agents with rubber and polyvinyl com ponents of many devices For example, the ethylene oxide reaction pioduct [2-(2hydioxyethyl-mcreaptofbcn/othiazolc] of the vulcanization uecclcraiot 2-mcrc.iptohen/othta/olc was found to be more toxic than the precursor using cells in culture mice and rabbits46 O'Leary and Guess47 demonsttated tbc homolyzang ability of known amounts of ethylene oxide to that of freshly gas-stcnhzcd plastic pharma ceutical products as well as the effects of ester type plastics upon the sorption of ethylene oxide into polyvinyl chloride products Oujano tin rom/ionnth Organo tins are compounds which contain at least one tin-carbon bond and if all radicals attached to im through carbon arc designated R, and all other substituents X, the following series are obtained. R4Sn, R,SnX, RjSnX, and RSnXj (R may be simple aliphatic or aromatic hydrocarbon radicals and X halide, hydroxide, OR. SH, SR or acyl radicals). Most of the organo tins of industrial and pcslicida! utility are the derivatives of quadrivalent tin Organo tin compounds arc used in plastics and polymers as stabilizers of vinyl resins and oxygcu-conlanting polymers and polyamides against degradation by heal and/or u.v. light; to control pore structure in polyurethane films; preserve the trans parency of polyvinyl chloride. Compounds used for this purpose are of the type RjSnX {eg dioctyl tin and dibutyl tin dilauraics, m.ileates, oxides, etc), and are generally present to the extent of 1-2% or the finished polymer The increased use of PVC in the food packaging and disposable medic ,ti articles fields has focused the need to elicit both the amount, and nature, of tin stabil izer residues Organo tin compounds used to stabilize poly (vinyl chloride) during cont.iinci'foifiling operations can migrate into foodstuffs packaged in such containers 'I he FDA permits the presence in certain foodstuffs, as a result of such migration of (wo oig.tno tin compounds, namely di-oclyl SS-b (iso-octylmcrcaptoacclatc) and di-ociyl tin malcnte polymer. The concentration of either, or any combination of both, may not exceed I p.p.m. which represents 0.158 or 0.259 pp.m. of tin (as organo tin), respectively, in the foodstuff. Organo tins are employed tn a host of other applications that include' (a) In i uhber products nnd paints: as antioxidants and anticracking agents; to retard rubber deteriorations and as stabilizers of chlorinated rubbers or chlorinated paints, (6) In ti.insformcrs, capacitors Bnd cables: to prevent corrosion by serving bs scavengers for MCI formed if a short circuit occurred m transformers, etc., using pyranols or chlorinated diphenyls (tetraphcnyl tin is usefully employed for this purpose); (c) In lubricants nnd textile oils: as acute oxidants and corrosion-reducing adjuvants for lubricants, as anti-oxidants for textile oils; (</) As activators and catalysts; in oxida- Scl Total Cm'ran., 1 (1972) 121 HONS 212389 C.W. lion, polyincnmiion (polycstcis and silicone elastomers) ax 7iegler-N.ilt.i type catalysts for polyiticri/.mon of olefins, (c) Tm-contaimng polymers mimcious imcontaiiung polymers and macromolcculcs have been prepared with im in the main chain or as substituent as well as ini analogs of silicons (in which carbon and tin aHc-riiate) (j) Miscellaneous uses of org.mo tins include lic.nment of lihiogl.iss with alkyl and aiyl tin compounds toi adhesion to resms, curing catalysis lor application ol silicons to icxtilcs, paper. I he bioctdal applications of organo tm include (of agricultural fungicides' tnphenyl tin acetate (Brcsl.in, lenun acelale) and luplteityl III) hydroxide (Du-lcr, femm hydioxide) and bis(iri-n-bittyl tin) oxide (TBTO), C 11 -- Sn- O-Sb (/>) General fungicidal action (<r,,<7 Iriphenyl tin chloride): in paints, preservation of m.imla and sisal ropes, leather, textiles, to confer mildew resistance to fabrics, for protection of jute and jute bags; wood preservative, sltmicide; paper production process paper; (c) Bactericides and bioslats, disinfectant (tnantyl tin), bactericides for seeds, (tf) Anthelmintics, against worms in poultry (dibuiyl tin laurate, tin olc.itc, telrntsobuiyl tin), {<) Ncinatocide p-bromophenoxy tricihyi tin. (/) Herbicides' vinyl tin compounds (trivinyl tin chloride); (g) Rodent repcllants: protecting food in treated bags (irtbutyl tin chloride, tnphenyl tin chloride and acetate), (A) Mollusctdcs. in phenyl mis; (/') Ovicides: trialkyl and triaryl tm chlorides (e.g. RjSnCl, R being methyl, ethyl or propyl) as insecticides and ovicides in combination with DDT or pytetlirum The mode of action of organo tins in mammals can be delineated as the degree ot alkylation of the tin compound per sc. In general, in the whole animal, pharmacol ogical and toxicological effects of trialkyl tins are confined to the nervous syslcm4*,4V. For rats, the oral loxicitics50 of the trialkyl tins are in the order trielhyl>tnmethyl> mibOpropyl>tri-n*buiyl. (The decrease of toxicity with increasing length of alkyl chain is analogous to that observed with di- and tetranlkyl tins). The conversion of telraalkyl tins to trialkyl tins*1"1* m vivo (as demonstrated for tetraethyl tin) accounts for the latent toxicity of the telraalkyl tins, with the site of the conversion being the liver4*,iJ From the toxicological point of view, the ictraalkyl tins c.in thus be considered to behave in a manner analogous to their trialkyl tin counterparts'4. (This conversion of a telraalkyl to a trialkyl metal has also been shown for tetraethyl lead4* 55-44, and ntay be a general phenomena) Once tetraethyl tin 122 Set. Toitit Environ t I (IV72) #OHS 212390 V. has been convened to tneihyl tin, it appears to persist in the body in (hat form without apparent further reaction to the dialkyl derivative The trialkyl tm ion iv a stable entity which is toxic per sc and persists for some tune in the tissues'1 Loiitt-icrm feeding experiments with trictliyl tin have disclosed some testicular atrophy in addition to lesions confined to the central nervous system'*'. Tneihyl tms and diethyl tins 101117c 111 aqueous solution'7'** wnh pioditclion of the univalent (C2ll,)Sn* and div.dent (CjHjijSn'* cations, respectively It is reasonable to assume that tn.tlkyl and triaryl tins exert their biological action as RjSn* ions or as the undissociatcd hydroxide R3SnOH formed on dissociation. The dealkylation of diethyl tm by the rat has been reported", with dicthylution occurring in both the gut nnd tissues The induction of biliary and hepatic lesions by dibulyl tin stdls in rats has also been dcsctibcd''0 Tnphcnyl tms, (C,,Hs)jSnX, (where X was haltde. hydroxide, alkyl or alkenyl, aryl or ahcychc radicals and ester groups or organic acids) have been found to be clicinostcnlonts61 61 when fed to adult houseflies Many of the tnphcnyl tins were found to be superior as eliemostcril.iiits, to the a/tridmes, if both groups were administered orally. The highest chcmosicriiiztng activity was shown by tnphenyl tins tn which X is mobile and the tnphcnyl ion is obtained, eg halides, hydroxide, sulphide, alkenyl and ester derivatives (but not phenyl or butyl). Tnphcnyl tins are mainly used tn agriculture as fungicides (e.g. Drestan, T3T0) In the finely-divided stale tn which tnphenyl tins are applied to plants, they arc susceptible to light and oxygen". Phenyl groups are gradually split off with step-by-step loss m toxicity. Trtphenyl tins decompose slowly into diphenyl tins Bnd the final stage of non-toxic inorganic quadrivalent tm compounds is probably reached through the unstable intermediate monophcnyl tins**, viz., (CjHjhSn - ---------- ---------- {C.HjSn^ 1 ----------* -Sn- \ \I Pate and Hays6* described several degenerative changes in testicular tissue of mule albmo rats treated with tnphenyl tin acetate and chloride. Complete sterility was achieved after 19 days of treatment following oral administration of tnphcnyl tin ucci,lie, b decrease in the number of cell layers per seminiferous tubule, a decrease in tubule diameter and overall testicular size, a depletion of the more advanced cell forms from the tubules and a closing of tubule lumtnB. Tricyclohcxyl tin hydroxide is used as a mtticide(Plictran, miticide) for apples, pears and citrus fruits. Exposure of trtcyclohexyl tin hydroxide to u.v light lias indi cated that the compound degrades to cyclohexyl tin and inorganic tin66. Also, a has been found that when fruit is harvested bi varying periods after the final spray treatment, the ratio of tncyclohexyl tm to total tm decreases with time. Residue half-lives for tncyclohexyl tin hydroxide in apples and pears were 5-6 weeks for the apples and 2 weeks for pears following application of Pirctran (0 84-1.00 ppm for apples and 0 40-0 99 ppm for pears). SH. Taint Lnvirvtl., t (1972) 123 HONS 212391 Biytheitol Displtcnol A[(2 2-bi,<(/vh)droxyphcn\l) ptopnnc] as a copolymer is an impoilanl monomer in several resins used as lood packaging matcnals for it~idtislri.il processing and consumer use o, The metabolic hue ami piopeines of hisphenol A arc ol importance since some tiimMucd monomci docs migrate lo food The metabolism of bispltcmil A in the iat following oral administration'1' indicates that less ilian 1% of the material pissciit m ui me was free bisphcitol A while the feces contained 35% flee btsphcnol A and an additional 35% was identified as a hydioxylaled product of hisphenol A It is important to also note the marked extrogcntc activity of bisphcnol Ali (ihe minimum effective subcutaneous dose was 0 25 mg in the sensitive ISfi-glycogeti response oT the rat uterus) Rubber (iilihtit a More than 600 different compounds are employed tn rubber technology GencitciiHy, however, the organic additives could be giouped into a dozen or so chemical classifications. Among these are the thturams, duhiocarbamaies, lluazolcs, snllonamidcs, thtourcas, guanidines, amines, amides, quinolines and phenols The c.itegoiics of utility include accelerators, aclivaiois, antioxidants, blowing agents, vule.im/ers, reiuidcrs, reinforcing agents, plasticizers, dusting or dipping agents and ineit ltllcrs Table I illustrates the structures of a number of classes of common rubber additives h is of interest lo note that ethyl selcnac (selenium dicihyldilhtocnrbaniatc) which is used both as rubber accelerator and fungicide is carcinogenic in the mouse6', while the luhbcr additive polymcuzcd )V-n!troso-2,2,4-tiimeihyl-l ,2-dihydroquinolmc has recently been found carcinogenic in the rot69-10. 1 he dilltiocarbamatcs and their metal salts have also wide utility as fungicides and their decomposition ptoducis include, alkyl thiourea, ethylene thiurnm monosulhdc, carlson disulfide, carbonyl sulfide, hydrogen sulfide, metal sulfide suits and elemental sulfur Both iluuram71 and lhiourca arc carcinogenic for the thyroid71, and -h4'-ntclhylcnc bis (2-ntclhylottihnc') and 4,4'-mclhylcne bis (2-chloroanilinc-) are liver and lung carcinogens in the rat71 Jit igbtettmg agents Optical brighteners or optical bleaches were first introduced into household products about 23 ycais ago as dcteigent additives. These compounds were gcncrallv used at levels varying from a few hundredths of I % to a maximum of 0.2% in such products but today's quality detergents contain optical brighteners, often at levels higher than 0.5%, They arc deposited in minute amounts on fabrics during laundering und emit a bluish fluorescence when exposed to ultraviolet radiation, thus improving the appearance of whiteness or brighteners in the fabrics 124 Sci. Total Cin tron . t (1972) HOMS 212392 TAIILC l COMMON RUHI1LR AOOlTivrS Cateuorv Accelerators Telr.imct^yltlmjrarn d/sulfidc Iclrjmelliylllnurjn) nionosutfide Structure Cm .Cm, 'n-C-i-S-C-n CM, n |! cm, Cm,, ,CMj .H-C--S -- C-m' cm,' " l 'ch, D'pcmjnKlhylcncilHurjm hcnasullidc MjC, ,N-C-UL-C-n' ,CM. CH,-C/ jj * vCH,-Ch/ ' MeuHodinU'lhyl- and dicihytditlnoiwbjruwks CH, />, >-C-S-M-S-C-N. CMj" " S CM, M.Cu.PB. Zn caM*\ >-C-S- cci auH*^ Sy H2,Cd <1*4, S.T M Ben/oUiiazy! disulfide a>--co 2- M crcupiobcn/othmolc :V Ohytl>c(liylcncbcn7o[hijzolc-2-$ulfcnaimde AACyelolwxyt-2-bcrt7olhinilemircnaniide 0C`>-"<ch,`c'> ^5'A'N CKj-Ch/ 5#V\ ,CHC>V '(mncihyl thiourea Diphenyl (uamdinc *:m. Cm, 'n-c-n' (:t s :tHaN-CNHCHS H NH irt. Tom! I.nvlrun . 1 (1972) I2S HONS 212393 TABLE I (continued) Cutrstury AitUa vi/JtintX Plienyi'/i-ndphliiyi.immc Structure CQT Oiplienyl-p-pliirnyleneili.mil ntf p-liopropony dlphenyluminc J lydroqumonc monobenzyl ether I,2-Diliydfo-3.2,4-trimcihyi qinnolinc AJOoI-k miphlhyljnlinc -r*O"0"cMC* ^-CH,-Q-^^-OH CH, CO;- 1 t- H, H 06pNeCH--C Mj-C~h-CHi OK OH 2(2Msrtl'iylcnc*bi$*(4*mcihyl-6*irr/*buiyl phenol) 'CH,),-C^.CM)_0j,CtCH,)1 CH, CMj A\ NDi{2 octyl)-p-pJKnykne du ni me HH HH C,H,,-C -N-^VN-C-CtH,, Cm, CH, A-(I.VDimcthylbulyl)-W'-phcnyl>p-pheny(cne( 1,1 mine HH c^c-ch,-c - 7-''?- CH, CH, H H Bhnt mg agents Azodtcu rbonamide rU*N-Cil - N = N-Cii -NH', oo Dtmtrokopc n I amethylene tetranune (1.7* Dimtro*o-l, 3|5,7-lc<razabtcyclo(3,3,Il ium,me) H,c -N-CH, 1 t1 ON-N CH-N-HO h,C1 -nI -CI h, 126 Sc! Total Enrlron, 1 (1972) 212394 I TAIlLt I (continued) Cilti/fxrry Rcturdets P/-Niiro^odipltuiyJjnunc S.ilnJyltC acid Structure COOM I'lasitciiers Dibulylphlhalalc COOC4h, &' ,COOC4H Dioclylphlhalale (bis(2-clhylhexyl)phihalaic] COOCHjCHfCjHjHCNjljCH, jL COOCjCH -(CHjijCH, ciHi Vulcancitif agents 2,i-Dis((f*buiyl pcroxyW.S'dimeihyi hexene CM* C*3 ch'-cI -ch* ch^-Ic-ch' 4-cn*-d -ch*-ch*-c-ch' Cm1 Cm3 Fnrrglcttles N'T rid>loromclhyllhin-4'Cyclohexene-l,2' dicjrboxmudc (Captan) ) Miscellaneous athlttii'cs I'oiymcri/cd A/'nitro$o-2,2,4>truncthyt-1,2 diliydroquinoltnc 4,4-Diemmodiphcnyimclhene i I i ! Sri, Total Fm'trott, l (1972) C.W. 127 MONS 212395 TABLC 1 (fconii/>UL'il) Citfcnof} 4,4'A1clhyUvne bjs-fi^bloro.mrhnc) 4,4 Mi.lhyUno bis {2 mo|h>l milmc) Structure The most commonly used collon bnghlcners, shown in Fig. IA arc btstiiu/inyl derivatives of 4,4'-diaminosliibcnc*2,2'-disiilfonic acid. These so-called CC/DAS bnghlcners are picparcd from 2 moles of cyanunc chloride (CC) and I inolc of Ihc disodium sail of diammoslilbcne disnlfomc acid (DAS). Willi the exception of briglitener DMDDE.A all arc reaction products of 1 mole of CC/DAS wnli 2 moles of aniline Bnghtener DMDDEA is the reaction product of 1 mole of CC/DAS and 2 moles of sulfamlic or metamllic acid A number of typical structures of brighteners that are stable to chlorine bleach in ihc wash liquor arc shown in Fig IB. These arc benzidine sulfonc disnlfomc acid (bnghtener BS), naphlhotnazoylstilbcne sulfonic acid (brightcucr NTS, ft * II) and bcnztmidnzolyi (brightener BBI) derivatives. The general structures of typical nylon and wool brighteners arc shown in Fig 1 C and include the derivatives of amino coumarm (bnghtener AC) and diphenylpyra/olmc (bnghtener DP), none of winch are stable to chlorine blench. The general structures of polyester brighteners (hat also have affinity for polyamide fibers are shown in Fig, 1 D and include btsben/oxazolyl (brightener BBO), naphthoxazolyl (bnghtener NOS) and naphlhotnazolyl (brightener NTSA) derivatives. The (CC/DAS) brighteners behave like direct, dyestuffs on cotton14 Brighte ning of hydiophobic fibers such ns nylon, polyester and acetate m an alkaline deter gent liquor takes place by a procedure similar to the dyeing of these fibers by dispersed dyestuffs74. Although the solubility of the commonly used brighteners tn a detergent wash liquor is relatively low, it is still high enough to allow a sufficient amount to dissolve. The exhaust of brightener onto the fiber and migration into the fiber allow nioie brightener to dissolve in the liquor. It is claimed that the total concentration of brightener in the liquor of the modern American home laundry would be only 3-10 mg/litcr, even if all the bnghtener were in solution at one lime1*. Of all laundering aids commonly added to the wash liquor apparently only active chlorine products affect the stability of some brighteners. The extent of attack on the so-called bleach unstable bnghlcners depends on their chemical structure, temperature, amount of blench used, etc Differences in stability to hypochlorite and dtchloroisocyanuratc bleaches I2S Sd Total fftdron.t 1 (1972) moms 212396 r-.\ exist also among the CC/DAS briglncncrs This would appear to indicate lb.it ilie bleach stability of these compounds is directly or indirectly related to the amine which is used for the reaction with the second reactive chlorine on the truzmc ring SOjNa J- ar'*T s-^ 6 ~Qf-V T R NM I S03Ha 1 H,Cn ^CH, ' CH, 0 OH Bragpiitner oes->go>tioo Ta DM T " i HpC1 HjC Oh C! Hp CHj Oh h ODEA I N HjC VCH. h,c in, OH OH SOjH* OMOOEA Bngnt#r BS .a: ftr<Qhtntr AC 0 R^Uvc'CHlCH JOi* CHR 6Brigfttantr OP I in I. Siruclurea of optical bnthlcncrs. A, Bis triaztnyl derivatives of 4,4'-diammoslilbcnc-2,2'. UtuUfomc acid (CC/IMS cotton brighteners) B. Bleach-stable bn#htencrs. C. Nylon and wool brifihtencrs. D, Polyester and polyamide brighteners. The combined action of optical brighteners and ultraviolet light in the produc tion of tumors has been reported by Bingham and Falk76. The optical brighteners studied were: 3-bcnzyl-4-roethyl-7-hydroxy coumnnn (3), disodmm-4,4'-bis (2,4-dimeihoxybcnzamido)-2,2'-sulbenedisulfonatc (4), diso- diiim-4,4`-bis {4,6.dianiImo-5-tnazin-2-yl)-ammo-2,2'-stilbeneditulfonate (5). Set Total frtnuro/t , 1 (1972) 129 HONS 212397 * I I I Tumors weie not found in any mice receiving topical application of the optica! bnghtenerm DM SO alone, bui with addition of ultraviolet light (6 h/day on 5 days/week to a germicidal lamp having 60% of its energy at 254 nip) a high incidence of tumors I developed that resembled grossly the tumors (squamous cell carcinomas) arising I from repeated application of carcinogenic polycyclid aromatic hydrocarbons I Since the use of optical brighlencrs is widespread in laundry products such as detergents, starches, fabric softeners, in fabrics and paper and in miscellaneous products such as toilet soap and all-purpose cleaners, questions relating to the poten tial hazard of dermal contact and/or penetration of the above brighteners as well as those listed in Fig I A-D, arc germane. Also of importance is the recent finding77 that the optical brightening agent (6) has been recovered from fish in Sweden suggesting a potential hazard of wash liquors conitiming other optical brighteners being concentrated in marine organisms and fish and hence available for human consumption. Another interesting brightening agent is 4-methyl umbciliferone (7-hydroxy-4-nicthyl coumann) (7) that is used as a whitener in laundry detergents as well as I ! e- . a briglitcncr in dcntrifrices. ft ts related to umbciliferone (7-hydroxy coumarin) (8) which is used in sunscreen lotions and creams. Both coumann derivatives had been shown to induce chromosome breakage in allium cepo7*'79. Miscellaneous agents Trichloroethylene and tetrachloroeihylene. Both trichloroethylene and tetra- chlorocthylenc (pcrchloroethylene) are used extensively as industrial solvents (pn1 maiily for dryclcnmng and degreasing), the latter has been finding increasing use since ihc advent of coin-operated drycleanmg Trichloroethylene is also used wnh other chemicals such as polymerized resins of phenol-formaldehyde, urea-formal- 130 Set Total Entttron , | (1972) C.W. #OHS 212393 S'" dchydc and epoxides in the production of special fiber glasses Tciucltloroctltslene is used m small amounts as a commodity fumigant Both trichtoro- and icir.iehloroethylene have been shown to be ncuroioxic10""J, but ictrnchlorocthylcnc is beliesed to be more hepatoxic than the trichloro derivative The metabolism of ,<'C-labcled tncMoio* and tctrachloroctltylcnc was simlied by Daniel*4 who found th.n both compounds arc lurgcly excreted through the lungs It is well known that tnchlorociliylcnc is exoeted in the urine as tncliloroticenc acid and triehlorocthtinol in all species of experimental animals studies In addition to these compounds, monochloroaeetic acid is also a urinary metabolite of man, A point of major importance is the nature of the rearrangement which results in the formation of2,2,2-trichlorocthanol and tiichloroaccuc acid from 1,1,2-trichloroctltylcnc. This has been shown to be an inlra-molecular rearrangement of trichloro ethylene and no exchange of chloride with the body chloride pool. Fig 2 illustrates the metabolic pathways of trichloroethylene and tetrachloroethylenc C!aC=CHC* EpOMidai'On 1 ------- Tfsen!Oro<hyl*ft Irnetraamrro^lencwulaar1. ^ ^ CUC - -CMC! vy' \ CCljCHjOM Triehiorcelnanol CCljCOOH Tnchiorolit acifl T#jr*emorotnyi*** -ecu Jntr#<rioiecur*r rearrange fr* m CCl,COCl Hy0r--V*'1, CCljCOOH Tr*cnioroacety! criorioe Trichloroacetic acid pig. 2 Metabolic f>>ilJmiy of iNihioroethylene and JetrachloroalbyJenc in iJic Ml The formation of the Intermediate oxide was postulated by Powell**. Trichloro ethylene oxide is believed to be formed m vitro when trichloroethylene is oxygenated in the presence of actinic radiation Rearrangement of the oxide yields trichloroacetaldchyde (chloral) The formation of chloral in men exposed to trichloroethylene vapor has been reported'6. Chloral appeared in the blood within 30 nnn of exposure but subsequently underwent rapid metabolism. The oxidation of chloral to trichloro acetic acid is reported to be carried out by an enzyme present in the liver of a variety of experimental animals'7. The reduction of chloral to tnchlorocthanol would involve alcohol dehydroge nase, The metabolism of tetrachlorocthylene may also involve the intermediate oxidation formation. For example, following exposure of tetrachlorocthylene vapor for 2 h in mice, the urinary metabolites included 52% trichloroacetic acid, 11% oxalic ncid and traces of dichloroacelic acid An epoxide intermediate was postulated to account for these products'* as shown in Fig. 2. icf. Totut Liu*nmt 1 (1972) 131 MOMS 212399 The acid chloride would be rapidly hydrolyzed to trichloroacetic acid and neither tnchlorocihanol or oxalic acid would be formed. In all of the above discuSMon of the metabolism of mchloio- ,md iaui- chloroethylcnc u is impoit.uu to note the mutagenicity ol the intermediate chloi.il hydrate11''1,0 as well as the potential mutagenicity and carcinogenicity of epoxides in general wait epee i lie jilcicnce to tctnu.liloiocihylcnc ovule postulated abo'C li is ol added impoii.ince to consider the smiilaiity ol types of metabolic pioducts (to those discussed above) of the important anesthetics halothanc (1,1,1- tn[luoin-2-bronio-2*clilo>oothanc) (S>) and fiuoioxcito (2.2,2-lrinuoroclhy| vinyl ether) (10) It I CFj-C-Cl CFjCH,OCH--CH, I Br 9 ID Titfluoroctltanol. ivifluoroacctuldehydc hydrate and irifluoroncciicncid arc the nictabolncs of both anesthetics and thetr foimation may proceed via an intcnncdutie cpoxid.mon and intramolecular rearrangement as described for tnchloro- and tcttachlorocthylenc in Fig. 2 Little ts known of the chronic toxicmes of the above fluoro-mctaboiitcs. Trinzena Certain tria/enes have technical importance as intermediates in the " Rnpidogen " dyeing process91 and aryl dialkyl iriazenes have been patented for use as rodent repcIUints and herbicides91*94. Other iriazenes have been evaluated as cnrcmostatic agcnts9,-9,. l-Phcnyl-3,3-dinicihyltriazcne is both a potent carcinogen99 and tcraiogcn m rats100 101 Certain other l-aryl-3,3-dialkyl triazencs of the general formula' ' ^jilkyl i : jNjayi .ire .ilso potent ncmotropic carcinogens in rats,oa. The potency increases in the ordci, phenyl, 3-pyndyl, pyridyl-At-oxidc, and methyl and ethyl, respectively. In acid medium, aryldmlkyltriuzcncs arc hydrolyzed to yield aiyl duizomum stilts and a secondary amine, (ft is of importance to note that methyl phenylmirosamme and phenylniirosourcn are both carcinogenic10J-104 forming probably phcnyldm/onmmion as a reactive intermediate.) Preussmann vi at.xai studied the enzymatic dealkylation by rai liver and lung microsomal fraction hi ittrn l-Phcnyl-3,3-dinieihyl triazene was found to be oxidat ively dcalkyluted to loun the corresponding aldehyde (formaldehyde} and aniline was also shown to be a metabolite. The results suggest that carcinogenic aryl dialkyl triazencs arc dealkyiated to form aryl-mono alkyl iriazenes as pioxnnatc carcinogens Aryl mono-alkyl triazencs arc known alkylating agents and the carcinogenic activity of tna/cncs was explained by alkylation of biopolyincrs (nucleic acids) Fig 3 illus trates n proposed activation mechanism of carcinogenic phenyl dimethyl tnazcnc 132 Sci Tutu! miron , [ (W2) HONS 212400 I lo form phenyl monomethyl iriozcnc as proximate carcinogen and carbomum ion as ultimate alkylating agent. The proposed reaction mechanism, however, docs not exclude that certain iriazcncs may act by a purely chemical heterolysis to form aryl diii/onium ions as reactive intermediates (for example, the very local sarcomas after subcutaneous injection of ] -pheny 1-3,3-dmactliyl trtazene may be explained on this basis) 1-Ph#riyi - 3 -rftttftyl * 3 ' rtyOf&ayfftttnyHrtann# Frmld#hyd Ad prt*nyimriom*lfty*tn*l*A Annin-,* * M*lhyWi*ior>ydroxW* Cirborium tn as Otyifttmg Apart i"n 3, Proposed activation mechanism of carcinogenic phcnytdrmcihyltnazenc to form phenyl mononictWyliriurcnc as proximate carcinogen, and carbomum ion * ulirnute ilkyiaimg agent101, The m vitro alkylation of guanosinc, RNA and DNA with aryl-monoalkyltru/cnes to form 7-alkylguanine was demonstrated by Preussmann and von Hodenberg106. Aryl monoalkylinazcnes are alkylating agents107-1* as shown, -HH-XtM-CH, + H* -- * Nj + CHj* The alkylation of biopolymers was earlier proposed as the first step in carcino genesis by arylduilkyltriazcnes105. Reactions of l-phenyl-3-monomethyl- and mono ethyl iriazcncs, respectively, with gun nosine, RNA and DNA resulted tn the formation of 7-mcihyl and 7-ethyl guanine. It is germane to consider the closely related carcinogenic alkylating substances consisting of: A-nitroso, hydrazo-, azo-, and azoxyalkancs since, as we have discussed previously, many environmental agents either possess the above moieties or are trans formed via metabolic and/or degradative pathways lo them. Set. Total CitOifotUy l (1972) 133 I ! C.w. ( -v The first and decisive slop in the activation of these groups tn an enzymatic a-C-hydroxylation of an alkyl residue, which is then cleaved oifas the corresponding aldehyde {an alkyl diazohydroxide or an alkyl diazomum ion is probably formed as an alkylating intermediate) The naturally occurring azoxyalkanc cycasin {mclhyl- azoxyniethanol giucundc) (II) is transformed to its mcihylazoxymcihnnol (12) + CM,-N-N CN*0 P-O-CJIuOi I o- II + CHj-N *N-CH4OH ! o- 12 This proMnuic carcinogen is then easily hydrolyzed to formaldehyde and an alkylating agent, probably methyl dnntine oxide, which is a tautomer of mcthyl- diazohydroxidc Azoalkancs cottld possibly be oxidized m live to yield azoxyalkancs. Dcatky- lation of alkanes could form alkyl dununes which could possess alkylating activity. Fig 4 illustrates the proposed reaction mechanism of hydrazo-, azo-and azoxyalkancs according to Preussmann er a!}11. R-C Mj- NH - NH -ct~ a R-CHj-NzN-CHj-B o R-CHa-NsN-CHa-R a-C-nyorcmyHt* R-Cm*-nxn-Ci m -R OH . a-C-hyoroxyi*** O t OH R-C 'h O H |-,t. 4. proposed reaction mechanism of hydrazo-, azo- and azoxyalkancs The alkylatton of nucleic acids, particularly at N-7 in guanine, and the resulting change of the genetic code in cells is considered as the initiation of their carcinogenic tionsformation. Since the "active forms" in all three groups of substances (mi, (a) nilroso compounds, (b) hydrazo, azo, and azoxyalkanes, and (c) 1-aryl-3,3-dmIkyl triazencs) arc the same, t.g. alkyldiazonium compounds, the specificity of the effects must most probably be attributed to the whole molecule of the "transport forms" or to their 134 Sti. Total Fan iron , 1 (1972) MOHS 212402 enzymatic activation Tlic dctcciion of carcinogenic properties in diaromctlunc ami diuzoacci.iic as well as in directly acting alk> kiting agents Sue It as alkyl halides, a/indmes. dialkyl sulfates and 1,3-propane sulfone gives considerable support to the alkylation theory101 A number of rcpoitcd reactions of mono-nucleic acids with dsazenuum salts in i'tiro arc informative112114 For example, the arylation of guanine in the 8-posmon by dia/oniuni salts has been demonstrated11J, o ^ ypical compounds formed include 3-p-bcnzolsuifoguanine (13) Guanine reacts with diazomum sails to yield guanine <5-azo compounds which can further reduce to 5-atmno guanine and arylaminel',,n while adenine docs not undergo the analogous reaction. Kbsscl111 described the icaction of mononucleotides with diazonium stilts to proceed as shown: o Qisrotmo Jk >L * >Vll*ntilC ftC`d R GutnyJiC ACK* ^3 M-O N -N, 4 HjO XtnlttidyliC C10 The mononucleotides guanyl-, ndenyl and cytidyltc acid react with diazoti/cd sulfamile acid at pH 10-11 forming colored dyes (pigments) which absorb strongly at 370-440 nri|i. Guunyhc acid reacts more rapidly than adenylic or cyndyhc acid while uridyl- and thynudylic acids show no reacton with diazontum salts. At pH 3 all the pigments decompose again to the starting materials. The pigment formation is inhib ited in the presence of formaldehyde. The reaction products are suggested to be diazoanuno compounds. Sri. Tviul Outrun., 1 <197') 135 MOWS 212403 i .. Reactions of dni/oimini suits wiili nucleic acids were investigated by Pochon 11 nd MicJiclsonMT Dwi/omun mIis obumed Irom 2~animo-/)-benzene disutphonic acid and 2-aiiiinonaphihalenc-l,5-disulphomc acid were found !o be highly specific giving 8-subxiitmcd guanine residues. This type of rcageiu has been employed to nurk DNA for studies by electron microscopy11*. Pol)/ihcn\h Cerium polyphcuyl compounds have been used as moderator coolants in nuefeur reactors for soi ^ years and ilieir toxicny is of importance should they bo accidentally released The emoiiic toxicity of polypheny! mixtures have been reported11" 1". At a daily dietary intake of 350 mg/kg or more Samowax OM, a mixture of tcrphcnyls used as a coolant, causes severe and to some extent irreversible chemical nephrosis and interstitial nephritis in rats following prolonged ingestion Santowax OM consists of a mixture of biphenyl (4.7%), o-tcrphenyl (64.1%), hitciphenyl (25.1%) and />-ieiphenyl (6 1%), while OMRE High Boilers consists of high boilcrs>98%, biphenyl (<Q 1%), o-lerphenyl (0.1%), //i-lcrphcnyl (<0 1%, /i-tcrphcnyl (<0.7) and inorganic (<0 1%) At a daily dietary intake of 33 mg/kg or more an OMRE High Boiler Sample (consisting of (crphcnyl and radiolylic and pyrolytic products derived (hereof) induces a marked reticuloendothelial hyperplasia in rats following chrome oral admtnisnation, leading to an irreversible monolobular cirrhosis The toxicity of ihe above reactor coolant to fish was described by Guthrie and Acres131. The acute toxicity in rabbiis of polyphcnyl compounds used as atomic reactor moderator coolants was described by Haley et al133 Ortho* and ineta terphenyls were the only poly phenyls that caused death after inhalation. Dnsocyanates and polyurethanes The dnsocyanatcs such as ioluene-2,4dnsocyanatc (TDI) and methylenediphenyldiisocyanate (MD1) are representative of chemically hghly reactive moieties that will combine with many organic compounds The industrially useful reactions involve the combination with a resin, usually an organic polyhydric alcohol, to form a high molecular weight polymer of the polyure* ethane type. Polyurethanes are used as paints and varnishes, surface coalings, flexible and rigid foams, wire coverings and in thermal and sound insulation nco TO l MDt TDI is usually prepared from toluene-2,4-diamine and phosgene in a solvent such as o-dichlorobcnzene or toluene. In the process where TDI is used on a very large scale in the manufacture of flexible foams, the highly exothermic reaction is controlled by the addition of appropriate catalysts (e g, blowing agents such as arodicarbonamide). As a result of the exotherm, significant quantities oflDI vapor may appear in the atmosphere and in concentrations substantially above the present threshold limit value of 0.02 p p.m.l3J. Prolonged exposure of workers to low air concentrations of TDI (0 I p p m.) have been reported to produce a variety of acute and chrome respiratory effects134*13". 136 Tvtflt Lntiroti.. \ 0972) MOMS 212404 i ** Crude MD( used in rigid urcili.mc foam formulations is prepared by ircatmg the condensation product of .mill nc and formaldehyde wuh phosgene Any uncoiidciised aniline initially present will be converted to phenyl isocyanate, which because of its volatility, is more toxic than the dnsocyanntes The h.i/iirds involved m the decomposition of polyurethanes have been suggested by l'aisley,, For example the decomposition of polyurethanes used in wne insulation occurs at 220 Q-275C, producing iso-cy,males and Af-oxides (The temperature of a soldering iron m normal soldering operations is approximately 30Q"C.) The possibility of a serious incipient hazard in combatting fires involving buildings and rcfi igcratcd compartments, etc , where large quantities of polyurethane foams arc used was also raised by Paisley130, The effects of physiologically active niraia on polyurethanes were studied by Lipatova and Vcrclovsku13' to determine the potcnttal use of polyurethanes as substitutes for tissues in surgery The mechanical strength of polyurethanes were declined by 40-80% after a S-month treatment tn lest solutions (e.g. physiological solution, gastric juice and pure HCI) The degradation of polyurethane lit the model solution occurred os a result ofclcavage of CO-bonds in the urethane group affording RNCOOil and R'OH The degradation rate was inversely proportional to the number of intcrmolccular bonds in the polyurethane. SUMMARY We have examined but a small number of selected chemical agents from a spectra of environmental areas, m , drugs', feed medicanls and pesticides1. polymer and plastic ingredients, rubber additives, brightening agents and industrial chemicals with a view toward elaborating their potential hazard via a primary consideration of their structural analogies to known carcinogens, mutagens and/or teratogens Eflorts were made to cite wheie possible, the areas of primary environmental concern to man in terms of water, soil, air and food residues and attendant portals of entry of these agents as well as to sircss their known biological and toxicological effects. Recognition was also made wherever feasible to the interrelationships and commonal ity of metabolites and degradation products from within the classes of compounds examined. We stress the fact that not only are chemical pollutants (both synthetic and naturally occurring, as well as their metabolic and/or degradation products) capable of producing any one or more of a variety of acute and chronic toxiciucs, but they may also interact in vitro and m vivo to produce synergistic or potentiating effects. Clearly the problem is staggering when one considers the myriad of new agents introduced into (he environment annually on top of an already staggering number of present and potential hazards, but the time may also be short in eliciting the hazards of these agents to man. Sri Tiftut Lnnrott., | (1972) 137 ^5 212405 /.. references 1 L. Fnhhein and W C FI mini Set T/ifnl Em iron , I <1972) J5 c2 L Flshbein and W lljmm.iii T<n<il Liu iron , 1 (1972) 31 3 Monsanto Tc.ll. Dull C PL to*. 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