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The SeieueNof the Total environment Llscvicr I'uhtivl'inu Comp.my. Amsterdam -- Primed in Belgium POTENTIAL ENVIRONMENTAL CHEMICAL HAZARDS PART III. INDUSTRIAL AND MISCELLANEOUS AGENTS L. I ISIIlll lN ;iml \V. Ci. ri.AMM National Institute of Environmental Health Sciences, National Institutes of Health, Public Health Service ami Department of Health, Education am! Welfare, Hesearch Triangle Park, North Carolina 2770V {U.S. A.) (Received May I9(l, 1971) INTRODUCTION In the previous paper, the potential environmental chemical hazards related to drugs' and feed nicdicanis and pesticides2 were considered via an a-priori consider ation of their chemical structure, nature of metabolites and degradation products with relation to known and hazardous insults and the inter-relationships nod com monality of hazards present in various use categories. The present section focuses on industrial and miscellaneous agents in anaiagous consideration. Polymer am! plastic ingredients A wide variety of organic derivatives are used in the polymers and plastics industry as plasticizers, modifiers, emulsifiers, stabilizers and solvents, and their inertness and/or safety is far from being established. Poiyc/iiorobiplienyls. Polychlorinated biphenyls (PCB's) are produced by various manufactures and arc represented as "a series of inert, chemically resistant, fire-retarding plasticizers compatible with a wide variety of resins, varnishes, waxes and paints; they vary from mobile, oily liquids to while crystals and hard transparent resins'0. The series of Aroclors (Monsanto) are marketed under various numbers and consist of mixtures of chlorinated biphenyls and tcrphenyls. The 1200 series relates to the biphenyls, the S400 series to the terphenyls, and the 4400 scries to a mixture of bi- and terphenyls. The annual production of PCB's in the Western world till most rcccmly was estimated at 100 million pounds. In the commercial process for PCB manufacture, biphenyls are chlorinated with anhydrous chlorine with either iron filings or ferric chloride as the catalyst; the byproduct 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' S' 23 Set. Tolul Environ., I (1972) 117 MUNS 087154 For example, three monochlorobiphcnyl isomers arc possible, 12 dichlorobiphcnyl isomers, 21 trichlorobiphenyl 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'pcntachlorobiphenyl). The chemical properties that make polychlorobiphcnyls desirable industrial materials arc their excellent thermal stability, their strong resistance to both acidic and basic hydrolysis and their general inertness. The largest single use of PCB's is related to their electrical properties, as coolant insulation fluids in transformers. Other uses of PCD's include impregnation of cotton and asbestos for braided insula* lions 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 insecticidal properties of DDT. Polychlorinated biphenyls along with DDE [l.l-dichloro*2,2-bis (p-chloro* phenyl) ethane] are reported to be the most abundant of the chlorinated aromatic pollutants in the global ecosystem9. Extracts from tissues of sea eagles, pike and salmon9 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 organochlorinc pesticide residues. PCB's have also been found in fish, mussels and birds from the River Rhine and the Netherlands costal areas7, in marine animals in Sweden, England and the U.S.A.7,8 and in other wildlife samples6,*-n. Polychlorinated biphenyls have been found in human adipose tissue13, samples of human milk13 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 organochlorinc insecticides. The PCB's are extremely stable; chemically, fat soluble and hence persis* tent in the environment. Polychlorinated biphenyl and polychlorinated triphenyls have been found to be cstrogcnically active" -- 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 />,/>'DDE or technical grade DDT9. 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 birds9 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. Hydropericardium, occasionally accompanied by abdominal edema was 118 Scl. Total Environ.* t (1972) HONS 087155 found in chicks161* and Japanese quail7 after ingestion of PCB of American (Arodor) and French (Phenoclor) origin respectively. The occurrence of lesions resembling those of chick-edema in birds fed PCB'*`<* has also been repotted. In most recent work, Vos ct aI.20 described the identification and toxicological evaluation of chlorinated diben/ofuran and chlorinated naphthalene in two commer cial polychlorinated biphenyls. A combination of toxicological, pathological and chemical-analytical data (including mass spectroscopy) strongly suggested the identity of tetra- and pcnlachlordmcnzofurans (l and 2, respectively) as toxic factors in the PCB's Clophen A60 and Phenoclor 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 of crude PCB in which sodium hydroxide can be used1'. PCB can react with sodium hydroxide at elevated temperatures to yield phenolic compounds and can for example yield poiychlorohydroxybiphcnyls via saponification by sodium hydroxide in a polyhydric alcohol medium22, subsequent loss of hydrochloric acid could then produce chlorinated dibenzofuran derivatives. The biological interactions of polychlorinated biphenyls and insecticides was reported by Lichtenstein el al. 21 who showed that many of the PCB's were toxic to Drosophila me/anogaster Meigen and houseflies Musca domestica L. (but to a lesser extent than dicldrin or DDT: their toxicity increased with a decrease in their chlorine contents). Moreover, subielhal dosages of several of the plasticizer PCB's increased the toxicity of dieldrin 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 testa. ! C.W. DOO DOE Pluliafate ester plasticizers. Phthaiate esters are among the most widely used compounds as plasticizers in a variety of lacquers, varnishes, paints, co-polymcrs and plastics. Set. TomI Environ., I (1972) | ]9 hQNS 007156 In general, phthalate esters have been reported to have a lower order of toxicity for experimental animals25,2" and thus have been approved for use in packaging materials for food intended for human consumption. However. Guess and cowor kers27 50 have demonstrated the subtle toxicitics (tissue culture cell death or enhanced growth, changes in antibody reactivity and irritation as evidenced by dye extra vasation) of plasticizers and stabilizers used in the manufacture of polyvinyl plastics. Citrate and phthal.ite ester plasticizers such as bis (2-cthylhe\yl)phlhalale ami acciylatcd tri-butyl citrate were found to be leached from plasticized polyvinyl chloride (PVC)31. The significance of exposure time on the leaching of those plastici zers from PVC is important since the plastic is commonly used in in-dwelling surgical devices, c.ff. catheters, and in pharmaceutical containers. Callcy ct al.i0 described the toxicology of a series of phthalate esters. It has been previously shown that certain plastic devices used medically can release one or more ingredients into tissue or solvent systems32'34. The four citric acid esters used as plasticizers (c.cj. tricthyl. acctvl tricthyltributyl- and acetyl tributyl citrate) have well defined and marked pharmacological activity when administered parcntcrally (all four have local anesthetic action and can block neural transmission when they come in direct contact with a nerve trunk, and also stimulate the nerve trunk)30. Phthalate ester plasticizers were found to be extracted by blood from plastic tubing and from plastic bags used for blood storage. Butylglycolbulyl phthalate (UGBP) was found to be metabolized by isolated perfused rat liver to glycolyl pluhalate. A second phthalate ester plasticizer di(2-clhylhexyl)phthalaic (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 blood stored in plastic bags39. c-och,c-c4h9 &8 BO0P QC ^>^c-och9cooh a Glycolyl phthaiatt COOCH2CH{C*H,)(CH2>,CH, j^jj-COOCH,CH(C2H5)(CH# ),CH, DEHP ' The isolation of plasticizers such as DEHP from the anticoagulant citric acid-dextrose solutions stored in disposable polyvinyl chloride blood bug assemblies has also been documented3037. In addition to evidence of phthalate ester plasticizers in certain foodstuffs such ns milk3*, there has been evidence concerning the presence of these plasticizers in animal tissues such as beef pineal gland39 and heart40. The teratogenic effects in the chick embryo caused by esters of phihnlic acid was described by Bower et a!V. Dibutoxyethyl phthalate caused tcratogcncsis in the 120 Scl, Total Environ., \ (1972) MONS 08715 7 developing chick embryo and also di-2-mcthoxyclhyl- and ocla-iscnlccyl phthalutc were capable of causing damage lo ihc central nervous system of the developing chick embryo. Toxigenic effect s in different mammals caused by several esters of phthalic acid have been well documcmcdi`,-4J 4S. The cfTect of chemical sterilization of plastic items and their contents with prim arily alkylating agents such as ethylene- am. propylene oxide adds yet another dimen sion lo the toxicities and potential hazards that might occur. This is especially true in the interaction of those gas sterilization agents with rubber and polyvinyl com ponents of many devices. For example, the ethylene oxide reaction product (2-(2hydroxycthyl-mcrcaplo)benzolhiazolo] of the vulcanization accelerator 2-mcroaptobcn/olhiazolc was found to be more toxic than the precursor using cells in culture mice and rabbits46. O'Leary and Guess4' demonstrated the homolyzing ability of known amounts of ethylene oxide to that of freshly gas-sterilized plastic pharma ceutical products as well as the effects of ester type plastics upon the sorption of ethylene oxide into polyvinyl chloride products. Organo (in compounds. Organo tins are compounds which contain at least one tin-carbon bond and if all radicals attached to tin through carbon arc designated R, and all other substituents X, the following series are obtained: RjSn, R,SnX, RjSnX2 and RSnX3. (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 pcslicidal utility are the derivatives of quadrivalent (in. Organo tin compounds arc used in plastics and polymers as stabilizers of vinyl resins and oxygen-containing polymers and polyamides against degradation by heat and/or u.v. light; to control pore structure in polyurethane films; preserve the trans parency of polyvinyl chloride. Compounds used for this purpose arc of the type RjSnX (eg. dioctyl tin and dibutyl tin dilaurales, maleates, oxides, etc.), and are generally present to the extent of 1-2% of the finished polymer. The increased use of PVC in the food packaging and disposable medical articles fields has focused the need to elicit both the amount, and nature, of tin stabil izer residues. Organo (in compounds used to stabilize poly (vinyl chloride) during container-forming operations can migrate into foodstuffs packaged in such containers. 'I hc FDA permits the presence in certain foodstuffs, as a result of such migration of two organo tin compounds, namely di-octyl SS-b (iso-octyimcrcaptoacctatc) and di-octyl tin malcale polymer. The concentration of either, or any combination of both, may not exceed I p.p.m. which represents 0.158 or 0.259 p.p.m. of tin (as organo tin), respectively, in the foodstuff. Organo tins are employed in a host of other applications that include: (<2) In rubber products and paints: as antioxidants and anticracking agents; to retard rubber deteriorations and as stabilizers of chlorinated rubbers or chlorinated paints; (b) fn transformers, capacitors and cables: to prevent corrosion by serving as scavengers for HCt formed if a short circuit occurred in transformers, etc., using pyranols or chlorinated diphenyls (letraphcnyl tin is usefully employed for this purpose); (c) fn lubricants and textile oils: as acute oxidants and corrosion-reducing adjuvants for lubricants; as anti-oxidants for textile oils; (<f) As activators and catalysis: in oxida se/. Total Environ., 1 (1972) 121 c.w. MGNS 08715* lion, polymerisation (polyesters and silicone elastomers) as Zicglcr-Nulla type catalysts for polymerization of olefins; (e) Tin-containing polymers: numerous tincontaining polymers and mucromolcculcs have been prepared with tin in the main chain or as substituent as well as tin analogs of silicons (in which carbon and tin alternate): (/) Miscellaneous uses of organo tins include: treatment of librcglass with alkyl and aryl tin compounds for adhesion to resins; curing catalysts for application of silicons to textiles, paper. The biocidal applications of organo tin include: (o) agricultural fungicides: triphenyl tin acetate (Brestan; femin acetate) und iriphcnyl tin-hydroxide (Du-tcr; fentin hydroxide) and bis(tri-n-butyl tin) oxide (TBTO); ^V c,,h9 IBTO \ 04 c4h, (/>) General fungicidal action (e.g. triphcnyl tin chloride): in paints, preservation of maniln and sisal ropes, leather, textiles, to confer mildew resistance to fabrics, for protection of jute and jule bags; wood preservative, slimicide; paper production process paper; (c) Bactericides and biostats; disinfectant (trianlyl tin), bactericides for seeds; (</) Anthelmintics: against worms in poultry (dibulyi tin laurate, tin oleate, tclraisobuiyl tin); (<?) Ncniatocide: /*-broniophenoxy iricthyl tin; (/) Herbicides: vinyl tin compounds (trivinyl tin chloride); (g) Rodent repcllants; protecting food in treated bags (tributy! tin chloride, triphenyl tin chloride and acetate); (h) Molluscidcs: triphcnyl tins; (/) Ovicides: trialky) and triaryi tin chlorides (e.g. RjSnCI, R being methyl, ethyl or propyl) as insecticides and ovicides in combination with DDT or pyrethrum. The mode of action of organo tins in mammals can be delineated as the degree of alkylation of the tin compound per se. In general, in the whole animal, pharmacol ogical and toxicological effects of trialkyl tins are confined to the nervous system4*'49. For rats, the oral toxicilics90 of (he trialkyl tins are in the order: triethyl>trimcthyl> triisopropyl>tri*nbutyl. (The decrease of toxicity with increasing length of alkyl chain is analogous to that observed with di- and tetraalkyl tins). The conversion of tciranlkyl tins to trialky] tins51'55 in vivo (as demonstrated for tetraethyl (in) accounts for the latent toxicity of the tetraalkyl tins, with the site of the conversion being the liver48,99. From the toxicological point of view, the tetroal- kyl tins can thus be considered to behave in a manner analogous to their trialkyl tin counterparts94. (This conversion of a tetraalkyl to a trialkyl metal has also been shown for tetraethyl lead48,95 9*, and may be a general phenomena). Once tetraethyl tin 122 Set. Total Environ., t (1972) HONS 087159 has been converted to trielhyl tin. it appears to persist in the body in that form without apparent further reaction to the dialkyl derivative. The trialkyi tin ion is a stable entity which is toxic per sc and persists for some time in the tissues52. Long-term feeding experiments with trielhyl tin have disclosed some testicular atrophy in addition to lesions confined to the central nervous system4*. Trielhyl tins and diethyl tins ionize in aqueous solution57'** with production of the univalent (CjHj)Sn4 and divalent (CjH5)2Sn* + cations, respectively. It is reasonable to assume that trialkyi and irinryi (ins exert their biological action as RjSn+ ions or as the undissociated hydroxide R,SnOH formed on dissociation. The dealkylation of diethyl (in by the rat has been reported59, with diethylation occurring in both the gut and tissues. The induction of biliary and hepatic lesions by dibutyl (in salts in rats has also been described*0. Triphcnyl tins. (CfcHs)jSnX, (where X was halide, hydroxide, alkyl or alkenyl, aryl or alicyclic radicals and ester groups or organic acids) have been found to be chcmosterilanis61 61 when fed to adult houseflies. Many of the triphcnyl tins were found to be superior as cheinostcrilanis, to the aziridines, if both groups were administered orally. The highest chemostcrilizing activity was shown by triphenyi tins in which X is mobile and the triphenyl ion is obtained, e.g. halides, hydroxide, sulphide, alkenyl and ester derivatives (but not phenyl or butyl). Triphcnyl tins are mainly used in agriculture as fungicides (e.g. Brestan, TBTO). In the finely-divided stale in which triphenyi tins are applied to plants, they are susceptible to light and oxygen63. Phenyl groups are gradually split off with step-by-step loss in toxicity. Triphenyi tins decompose slowly into diphenyl tins and the final stage of non-toxic inorganic quadrivulcnl tin compounds is probably reached through the unstable intermediate monopheny! tins64, viz., / /I (C*Hf)jSn - ---------- <C*H,),S< --------- (C.H.Snf }----------- * -Sn- \ \i Pale and Hays65 described several degenerative changes in testicular tissue of nude albino rats treated with triphenyi tin acetate and chloride. Complete sterility was achieved after 19 days of treatment following oral administration of triphcnyl tin acetate, a 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 lurnina. Tricyclohcxyl tin hydroxide is used as a miticide (Plictran, miticide) for apples, pears and citrus fruits. Exposure of iricyclohexyl tin hydroxide to u.v. light has indi cated that the compound degrades to cyclohexyl tin and inorganic tin66. Also, it has been found that when fruit is harvested at varying periods after the final spray treatment, the ratio of tricyclohexyl tin to total tin decreases with time. Residue half-lives for tricyclohexyl tin hydroxide in apples and pears were: 5-6 weeks for the apples and 2 weeks for pears following application of Plictran (0.84-1.00 ppm for apples and 0.40-0.99 ppm for pears). Sri. Total Lnt'iroa., I (1972) 123 C.W.' hqns 8?160 Bisphenol. Bisphenol A((2.2'bis(/>*hydroxyphcnyD propane] as a copolymer is an important monomer in several resins used as food packaging materials Tor industrial processing and consumer use. C Hj tliipftcnoi * The metabolic fate and properties of bisphenol A arc of importance since some unreactcd monomer does migrate to food. The metabolism of bisphenol A in the rat following oral administration''7 indicates that less than 1% of the material present in urine was free bisphenol A while the feces contained 35% free bisphenol A and an additional 35% was identified as a hydroxylated product of bisphenol A. It is important to also note the marked exirogenic activity of bisphenol A13 (the minimum effective subcutaneous dose was 0.25 mg in the sensitive 18h*glycogen response of the rat uterus). Rubber additives More than 600 different compounds are employed in rubber technology. Gcncrically, however, the organic additives could be grouped into a dozen or so chemical classifications. Among these arc the thiurams, dithiocarbamntcs. thiazolcs, sulfonamides, thioureas, guanidines, amines, amides, quinolines and phenols. The categories of utility include accelerators, activators, antioxidants, blowing agents, vuleani/crs, retarders, reinforcing agents, plasticizers, dusting or dipping agents and inert Idlers. Table I illustrates the structures of a number of classes of common rubber additives. It is of interest to note that ethyl selcnac (selenium dicthyldilhiocnrbamatc) which is used both as rubber accelerator and fungicide is carcinogenic in the mouse6, while the rubber additive polymerized A'-nitroso-2,2,4-tiimelhyM,2-dihydroquinolinc has recently been found carcinogenic in the rat69,70. The dithiocarbamatcs and their metal salts have also wide utility as fungicides and (heir decomposition products include: alkyl thiourea, ethylene thiuram mono* sulfuic, carbon disulfide, carbonyl sulfide, hydrogen sulfide, metal sulfide salts and elemental sulfur. Both thiuram71 and thiourea are carcinogenic for the thyroid72, and 4,4'*mcthylene bis (2-mclhylnnilinc) and 4,4'*methylene bis (2-chloronnilinc) are liver and lung carcinogens in the rat73. Brightening agents Optical brighteners or optical bleaches were first introduced into household products about 23 years ago as detergent additives. These compounds were generally used at levels vurying from a few hundredths of 1% 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 are deposited in minute amounts on fabrics during laundering and emit a bluish fluorescence when exposed to ultraviolet radiation, thus improving the uppcnrancc of whiteness or brighteners in the fabrics. 124 Sd. Total Environ., 1 (1972) 087161 TABLE I COMMON RUHUf:R ADDITIVPS Catenary Accelerators Tdramoihylilmiram disulfide Structure CM Cm. '>-C-S-S-C-N/ ' CH, S jj CM, TciromcihyMItiurum monosulfide DjpctUamclhylcnelhiuram hcxasulfidc ,, ,C H, ^N-C-- S -- c-w' 3 CHJ s S CHJ CHj-CM, C H--CH, HjC; ,N-C-<SL-C-< ;ch, CHrCH,' * SCH,-Ch/ * MtMullodimclhyl- and diclhyldilhiocorbiimulcs CH, CH, )n-c-s-m-s-c-n; CH,' 'l CH, M.Cu.Pft. Zn ]CH*\>-C-S- M Jn5H * ft2;Cd Aid;S*,T Ilcn<ro(1iiu7.yl disulfide oo---<X3> J'McrcuplobcnzothUitolc /V-Oxydic(J)yfcncbctt>(hiuzole-2-sulfcnaniide CM.-CM, . I c-s-nk ;o ^N CM,.CM, A^Cydnlwxyl-2-bcn*othiui'(ilcsulfcnamide {?v\v /ch,cm, Csjl. ,cc-s-N-cC ;ch, M M CH.CM/ Trimclhyl ihiourcu Diphenyl guanidine :Hv ,CH >-C-N. :h, u h ^.6HsN"CNHC,Hfc H NH . Set. Total linvlroa., 1 (1972) 125 HONS 087162 TAHLE I (continued) Category /Uitiovii/nnis Pltenyl'/f-miphlhylaminc Diphony l*p-pbeyletwtliiintmc /*lsopropoxy diphenylumine Structure COT O'i'O'V'O o-v-o-o-C llydroquinonc monobenzyi ether 1,2-Dihydro-7,2,4-trimethyl quinoline Aldol-anaphlhylumino CH, CCe1 CH, M f-NsCH-C Mj-CK-CH, 2,2-Mcthylenc-bis-(4-mcthy|.6*f<v7*butyl phenol) Oh OH CM, CH, Ainl-tuononts A,A''Di(2>octyl)>p>phcnylone diamine HH CH, HM CH, 1 ..t-DimcthylbulyO-A'-phenyl-p-phenylenetiiiiminc HH CH,-C-CH,-C CH, CH, H fl/oHing agents Azodicarbonamidc N,N-C-N8N-C-NH. * (1 It 00 H DinitrosopcntanKlhylcnc tctraminc (.\7-Dinitroio-l,3,$,7-tctraarabicyclo{3,3,I)nomine) H.C -N -- CH, 111* ON --N CHjN-NO H,C --N--^H, . 126 Scl. Total Environ., I (1972) TABLE I (continued) Culogvry Retarders iV-Nilrosodipl'cnyluminc Salicylic acid . Plasticizers Dibutylphlhalntc Structure OvO NO COOH 6-"" COOC4H9 ^rcooc`H* Dioctylphlluilulc [bis(2-cthy1hxyl)phthalulc] COOCHjCHiCjHjXCHjJjCH, X^COOCHaCH-iCHjJjCH, uu Vulcanizing agents 2,5-Bis(f<vr*butyl pcroxy)-2,5*dmicthyl hexane CH> CH> CH*-C-CHJ CH^C-CH3 0O 9 <j> ch^c-ch^ch'-c-ch* CH* CH* Fungicides /V-TrichloromcthyUhlo-4cydohcxcne*l,2- ilicarboximidc (Captun) Miscellaneous additives Polymerized Mnltroso-2,2,4*trimcthyM,2 dibydroquinoline H OC'>-s-ca, O CHj G`>s: NO 4,4*Dlaminodiphcnylmcihane Set. Tola/ Environ., I (1972) C.W. 127 HONS 087164 TADLC 1 (continued) CtitCflory 4,4'-Methylene bis*(2*ehloroum`hne) 4,4' Methylene bs-(2-melhyl;miJh)c) Structure Cl Cl CH, CHj The most commonly used cotton brighteners, shown in Fig. IA arc his triaWnyf derivatives of 4,4'-diaminoslilbcnc*2,2'-disulfonic acid. These so-called CC/DAS brighteners arc prepared from 2 moles of cyanuric chloride (CC) and I mole of Hie disodium sail of diaminoslilbcnc disulfonic acid (DAS). With the exception of brighIcncr DMDDEA all arc reaction products of J mole of CC/DAS wiiJ* 2 moles of aniline. Brightener DMDDEA is Ihe reaction product of I mole of CC/DAS and 2 moles of sulfanilic or mctanillic acid, A number of typical structures of brighteners that are stable to chlorine bleach in the wash liquor arc shown in Fig. IB. These arc benzidine sulfonc distil* Ionic acid (brightencr BS), nnphthotriazoylstilbene sulfonic acid (brightener NTS, R -- H) and bcnzimidnzolyl (brightener BBl) derivatives. The general structures of typical nylon and wool brighteners arc shown in Fig. I C and include the derivatives of amino coumarin (brightener AC) and diphcnylpyrazolinc (brightener DP), none of which are stable to chlorine bleach. The general structures of polyester brighteners that also have affinity for polyamide fibers arc shown in Fig. ID and include bisbcn/.oxazolyl (brightener BBO), naphthoxazolyl (brightener NOS) and napluhotriazolyl (brightencr NTSA) derivatives. The (CC/DAS) brighteners behave like direct, dyestulTs on cotton74 Brighte ning of hydrophobic fibers such as nylon, polyester and acetate in 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 in 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 more brightener to dissolve in (he 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 brightener were in solution at one time75. Of all laundering aids commonly added to the wash liquor apparently only active chlorine products affect (he stability of some brighteners. The extent of attack on the so-called bleach unstable brighteners depends on their chemical structure, temperature, amount of bleach used, etc. Differences in stability to hypochlorite and dichioroisocyanuratc bleaches 12$ Sri. Total Eoriron., I (1972) MONS OU7165 exist also among the CC/DAS brighteners. This would appear to indicate that the 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 triazinc ring. SO)Na TR NH I SO,H* I TR i , OH Brightri#f assignation NaOjS __ ySQ3N H o* *0 BHgntnr BS OH OH B OH OH SO.Na DMODEA NaOjS -0> Brigntvw n is i 4 ^N'a^X*`0'X'*0 Y '--' N CH V G" "CXn>'ch"ch'cCX^" 0righ(*n*r BBO XR <^-CH = CH^>-N-N |T jC-CH= CH-R Ao Brlgniner NOS Brigntenr NTSA |;ig, I. Structure* of optical brighteners. A, Bis trinzinyl derivatives of 4,4'-diuminosiilbcnc-2,2'dintlfonic acid (CC/tMS cotton brighteners). B, Bleach-stable brighteners. C. Nylon and wool brighicncrs. 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-benzyl*4-methyl-7-hydroxy coumarin (3), disodium-4,4'-bis (2,4-dimethoxybenzamido)-2,2'*stilbenedi$ulfonate (4), disodium-4,4'-bis (4,6-diani]ino-S-lriazin-2-yl)-amino-2,2'-stilbenedisuIfonate (5). Sd. Tolu/ lindroii., I (1972) 129 HONS 087166 C.W. $ Tumors were not found in any mice receiving topical application of the optical brightener in DMSO alone, but with addition of ultraviolet light (6 h/day on 5 days/wcck to a germicidal tamp having 60% of its energy at 254 m/i) a high incidence of tumors developed that resembled grossly the tumors (squamous cell carcinomas) arising from repeated application of carcinogenic pofycyclid aromatic hydrocarbons. Since the use of optical brighteners is widespread in laundry products such as detergents, starches, fabric softeners, in fabrics and paper and in miscellaneous products such as toilet soap and alt-purpose cleaners, questions relating to (he 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 containing other optical brighteners being concentrated in marine organisms and fish and hence available for human consumption. Another interesting brightening agent is 4-methyl umbelliferone (7-hydroxy-4-methyf coumarin) (7) that is used as a whitener in laundry detergents as well as a brightener in dcmrifrices. Tt is related to umbelliferone (7-hydroxy coumarin) (8) which is used in sunscreen lotions and creams. Both coumarin derivatives had been shown to induce chromosome breakage in allium cepa'*`19. Miscellaneous agents Trichloroethylene and telrachloroethylene. Both trichloroethylene and tetra- chlorocthylene (pcrchloroethylene) are used extensively as industrial solvents (pri marily for dryclcnning and degreasing), the latter has been finding increasing use since the advent of coin-operated drycleaning. Trichloroethylene is also used with other chemicals such as polymerized resins of phenoldormaldehyde, urea-forroaJ- 130 Set. Taint Environ., 1 (1972) MONS 087167 dchydc und epoxides in the production of special fiber glasses. Tctrachlorocthylenc is used in sirtall amounts as a commodity fumigant. Both trichloro* and tctrachloro cthylenc have been shown to be neurotoxic10"*3, but tctrachlorocthylenc is believed to be more hepatoxic than the trichloro derivative. The metabolism of 3<,C-labclcd trichloro* and tctrachlorocthylenc was studied by Daniel*4 who found that both compounds arc largely excreted through the lungs, Jl is well known that trichloroethylene is excreted in the urine as trichloroacetic acid and trichlorocthanol in all species of experimental animals studies. In addition to these compounds, monochloroacctic acid is also a urinary metabolite of man. A point of major importance is the naittrc of ihc rearrangement which results in the formation of 2,2,2*lrichloroctlianol and trichloroacetic acid from 1,1,2-trichlorocthylcnc. This has been shown to be an intra-niolecular rearrangement of trichloro ethylene and no exchange of chloride with the body chloride pool. Fig. 2 illustrates the metabolic pathways of trichloroethylene and telr8chioroethylcnc. CiaCCHCl -- Trichierotnyi*nt CI.C----- CHCl CCIjCHjOH Trichiorotnno( CC1,COOM Tricnioroacttic ckJ CijCsCCl, EeOKlflSl'On ------------------- Ttre>u**o#thyi#fw CltC----- CCl* 1 intramolecular rearrangement CCljCOCl Tncmoroacetyi cniono CCljCOOM Trichloroacetic acid Fig. 2. Mctubollc pathway* of trichloroethylene and tetrachloroethylcne in Un? rut. The formation of the intermediate oxide was postulated by Powell85. Trichloro* ethylene oxide is believed to be formed in vitro when trichloroethylene is oxygenated in the presence of actinic radiation. Rearrangement of the oxide yields trichloroaceluidchyde (chloral). The formation of chloral in men exposed to trichloroethylene vupor has been reported8*. Chloral appeared in the blood within 30 min 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 animals87. The reduction of chloral to trichloroethanol would involve alcohol dehydroge nase. The metabolism of tetrachlorocthylene may also involve the intermediate oxidation formation. For example, following exposure of tetrachlorocthylene vapor for 2h in mice, (he urinary metabolites included 52% trichloroacetic acid, 11% oxulic acid and traces of dtchloroacelic acid. An epoxide intermediate was postulated to account for these products88 as shown in Fig. 2. Set. Total Em irtnt., I (1972) 131 HONS 067168 The acid chloride would be rapidly hydrolyzed to trichloroacetic acid and neither trichloroclhanol or oxalic acid would be formed. In all of the above discussion of the metabolism of trichloro- and tetra- chloroethylcnc it is important to note the mutagenicity of the intermediate chloral hydrate8" 1,0 as well as the potential mutagenicity and carcinogenicity of epoxides in general with specific lel'ctcnee to tctrachlorocthylenc oxide postulated above. It is of added importance to consider the similarity of types of metabolic products (to those discussed above) of the important anesthetics halothanc (1,1,1- lri(luoro-2-bromo-2-chiorocihunc) (9) and Huoroxene (2.2,2-trifluoroethyl vinyl ether) (JO). It I CFj-C-CI I Br CFjCHjOCH--CH, 9 10 Trifluorocthanol. trifluoroaceialdehydc hydrate and trifluoroacetic acid arc the metab olites of both anesthetics and their formation may proceed via an intermediate epoxidation and intramolecular rearrangement as described for trichloro* and ictrachlorocthylcnc in Fig. 2. Little is known of the chronic toxicitics of (he above fluoro-metabolites. Triazenes. Certain triazenes have technical importance as intermediates in the " Rnpidogen" dyeing process91 and aryl dialkyl triazenes have been patented for use as rodent repcllants and herbicides91-94. Other triazenes have been evaluated as carcinostatic agents95-98. 1-Phenyl-3,3-dimcihyllriaz.cnc is both a potent carcinogen99 and teratogen in ruts100,101. Certain other l-aryI-3,3-dialkyl triazenes of the general formula: * ^.Hlkyl aryl-N-N-N I 2 3Nilkyl arc also potent nemoiropic carcinogens in rats102. The potency increases in the order: phenyl, 3-pyridyl, pyridyl-A/-oxide, and methyl and ethyl, respectively. In acid medium, aryldialkyltriazcnes arc hydrolyzed to yield aryl diazonium salts and a secondary amine. (It is of importance to note that methyl phenylnitrosamine and phcnylnitrosourca are both carcinogenic102,104 forming probably phcnyldiazoniumion as a reactive intermediate.) Preussmann el al.l0i studied the enzymatic dealkylation by rut liver and lung microsomal fraction in vitro. l-Phcnyl-3,3-dimcthyl triazene was found to be oxidat ively dealkylated to form the corresponding aldehyde (formaldehyde) and aniline was also shown to be a metabolite. The results suggest that carcinogenic aryl dialkyl triazenes arc dealkylated to form aryl-mono alky] triazenes as proximate carcinogens. Aryl mono-alkyl triazenes are known alkylating agents and the carcinogenic activity of triazenes was explained by alkylation of biopoiymers (nucleic acids). Fig. 3 illus trates a proposed activation mechanism of carcinogenic phenyl dimethyl triazene 132 Set. Totui Environ., t (1972) MONS 087169 to form phenyl monomethyl trinzcnc as proximaie carcinogen and carbonium ion as ultimate alkylating agent. The proposed reaction mechanism, however, docs not exclude that certain triazencs may act by a purely chemical heterolysis to form aryl dia/.onium ions as reactive intermediates (for example, the very local sarcomas after subcutaneous injection of j-phenyl-3,3*dimelhyl triazene may be explained on this basis). O-......... 'c SCHj Illfnnityymmaattiie lrD>yoarooxyyiii*iion 1f\.n=n-n(CM' \=/ ch#-ohJ Pr*r>y>dm*thyltrlai*n* 1-Ph*nyl-3-m*thyl-3hyeroxym*thyltnl*n ^/7~^V\ nsN-n' 'll " + CH,0 = N --CH j Formaio*>)yd* ntf Ph*nyiroor>om*tPyltrl*x*ft* + [HO-N = N-CH,J -OH* -M, Amitn* Mctrtyieiaxoftyeroxie* Carbonium ion alkylating agant Pig. y. Proponed activation mechanism of carcinogenic phcnyldimcthyitriazcnc 10 form phenylmonomcthyltriazcnc as proximate carcinogen, and carbonium ion as ultimate alkylating agent10*. The in vitro alkylation of guanosinc, RNA and DNA with aryl-monoalkyltriazcncs to form 7-alkylguanine was demonstrated by Prcu&smann and von Hodenberg106. Aryl monoalkyltriazcnes arc alkylating agents10,",1 as shown: + H* -------- " (^J^-NHa + Na CH,* The alkylation of biopolymers was earlier proposed as the first step in carcino* genesis by nryidialkyllriazcnes10*. Reactions of l-phenyl-3-monomethyl- and mono ethyl triazencs, respectively, with guanosine, RNA and DNA resulted in the formation of 7-mcthyl and 7-ethyl guanine. Jl is germane to consider the closely related carcinogenic alkylating substances consisting of: A'-nitroso, hydrazo-, azo-, and azoxyalkanes since, as we have discussed previously, many environmental agents either possess the above moieties or are trans formed via metabolic and/or degradative pathways to them. Sri. Tulul Environ., \ (1972) - 133 C.W. MONS 087170 The first and decisive step in the activation of these groups in an enzymatic cr-C-hydroxylnlion of an alkyl residue, which is then cleaved off as the corresponding aldehyde (an alkyl diazohydroxide or an alkyl diazonium ion is probably formed as an alkylating intermediate). The naturally occurring azoxyalkanc cycasin (methylazoxymetlumol glucuride) (11) is transformed to its mcthylazoxymcthanol (12). CHj-N-N CMjO-0-O-C*ftMO| I o- II CHj-N N-CHiOH I o- 12 This proximate carcinogen is then easily hydrolyzed to formaldehyde and an alkylating agent, probably methyl diimine oxide, which is a tautomer of mcthyldiazohydroxide. Azoalkancs could possibly be oxidized in vivo to yield azoxynlkancs. Dealky lation of alkanes could form alkyl diimines which could possess alkylating activity. Fig. 4 illustrates the proposed reaction mechanism of hydrazo-. azo- and azoxyalkancs according to Preussmann et o/.,N. a-CHj-NN-NH-CHj- R-CH,-N=N-CHj-R O \ r-ch2-'N: fl-C-nydroxyi*** R-CHj-nsN-Ch-R OH . -C-hydroxyiM 0 1 R-CHj-NsN-^H-R OH l-'ig. 4. Proposed reliction mechanism of hydrazo-, azo- and azoxyalkancs. The alkylation 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 transformation. Since the "active forms" in all three groups of substances (vi2.t (a) nitroso compounds, (6) hydrazo, azo, and azoxyalkanes, and (c) l-aryl-3,3-dialkyl triazenes) arc the same, e.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 Sri. Tolu! Environ., 1 (1972) HONS 087171 enzymatic activation. The detection of carcinogenic properties in diazomcthanc and diuzoucctatc as well as in directly acting alkylating agents such as alkyl halides, a/iridincs. dialkyl sulfates and 1,3-propane sulfone gives considerable support to the alkylation theory101. A number of reported reactions of mono-nucleic acids with diazonium salts in vitro arc informative112 -M4. For example, the arylation of guanine in the 8-posilion by diazonium salts has been demonstrated"5. X jCK>**h r OH OH HOCHj is rh, is r. HO HO Typical compounds formed include <$-/>-bcnzolsulfoguanine (13). Cuaninc reacts with diazoniuni salts to yield guanine 5-azo compounds which can further reduce to d-amino guanine and arylamine"3"* while adenine docs not undergo the analogous reaction. KOssel"4 described the reaction of mononucleotides with diazonium salts to proceed as shown: aiatot.ita r Ousnylie *CH3 it N SO H-tAl'V "" 'H> The mononucleotides guanyl-, adenyl and cytidylic acid react with diazotized sulfa* nilic acid at pH 10-11 forming colored dyes (pigments) which absorb strongly at 370-440 mft. Gunnylic acid reacts more rapidly than adenylic or cytidylic acid while uridyl* and thymidylic acids show no reacion with diazonium salts. At pH 3 all the pigments decompose again to the starting materials. The pigment formation is inhib* ited in the presence of formaldehyde. The reaction products are suggested to be dia zoamino compounds. Set, TulaI Environ., I (1972) 135 *QNS oanit C.W. Reactions of dia/onium salts with nucleic acids were investigated by Pochon and Michcl$onM\ Diazomum salts obtained from 2-amino-/vbcnzcnc disulphonic acid and 2uminonaphthalcnc-l,5-disulphonic acid were found to be highly specific giving {{-substituted guanine residues. This type of reagent has been employed to mark DNA for studies by electron microscopy'1B. Polyphenyls. Certain polypheny! compounds have been used as moderator coolants in nuclear reactors for some years and their toxicity is of importance should they be accidentally released. The chronic toxicity of polyphcnyl mixtures have been rcportcdnv,i:t>. At a duily dietary intake of 350 mg/kg or more Santowax 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-tcrphcnyl (64.1%), nttcrphcnyl (25.1%) and yMcrphcnyl (6.1%); while OMRE High Boilers consists of high boilers>98%, biphenyl (<0.l%), o-terphenyl (0.1%), //Mcrphcnyl (<0.I%, /Mcrphcnyl (<0.7) and inorganic (<0.l%). At a daily dietary intake of 33 mg/kg or more an OMRE High Boiler Sample (consisting of tcrphcnyl and radiolytic and pyrolytic products derived thereof) induces a marked reticuloendothelial hyperplasia in rats following chronic oral adminis tration, leading to an irreversible monolobular cirrhosis. The toxicity of the above reactor coolant to fish was described by Guthrie and Acres'31. The acute toxicity in rabbits of polyphcnyl compounds used as atomic reactor moderator coolants was described by Haley et ai.11*. Ortho and meta terphenyls were the only polyphenyls that caused death after inhalation. Diisocyanates and polyurethanes. The diisocyanates such as toluene-2,4diisocyanale (TDI) and methylenediphenyldiisocyanate (MOI) are representative ofchemically 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 polyureethane type. Polyurethanes are used as paints and varnishes, surface coatings, flexible and rigid foams, wire coverings and in thermal and sound insulation. NCO TOI TDI is usually prepared from toluene-2,4-diamine and phosgene in a solvent such ns 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 uzodicarbonamide). As a result of the exotherm, significant quantities of TDI vapor may appear in the atmosphere and in concentrations substantially above the present threshold limit value of 0.02 p.p.m.133. Prolonged exposure of workers to low air concentrations of TDI (0.1 p.p.m.) have been reported to produce a variety of acute and chronic respiratory effects'34'13*. )3(5 Sci. Tout! Em-iron., 1 (1972) HONS 087173 Crude MDI used in rigid urethane foam formulations is prepared by treating the condensation product of aniline and formaldehyde with phosgene. Any uncondcnsed aniline initially present will be converted to phenyl isocyanate, which because of its volatility, is more toxic than the diisocyanates. The hazards involved in the decomposition of polyurethanes have been suggested by Paisley130. For example the decomposition of polyurethanes used in wire insulation occurs at 220'C-275C, producing iso-cyanalcs and /V-oxidcs. (The temperature of a soldering iron in normal soldering operations is approximately SOO^C.) The possibility of a serious incipient hazard in combatting fires involving buildings and refrigerated compartments, etc., where targe quantities of polyurethane foams arc used was also raised by Paisley130. The effects of physiologically active media on polyurethanes were studied by Lipatova and Vcrclovskii131 to determine the potential use of polyurethanes as substitutes for (issues in surgery. The mechanical strength of polyurethanes were declined by 40-80% after a 5-month treatment in test solutions {e.g, physiological solution, gastric juice and pure HC1). The degradation of polyurethane in the model solution occurred ns n result of cleavage of CO-bonds in the urethane group affording RNCOOM and R'OH. The degradation rate was inversely proportional to the number of intcrmoIccuJar bonds in the polyurethane. SUMMARY We have examined but a small number of selected chemical agents from a spectra of environmental areas, viz., drugs'; feed medicanis and pesticides2; 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. Efforts were made to cite where 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 stress 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 toxiciiics, but they may also interact in vitro and in vivo to produce synergistic or potentiating effects. Clearly the problem is staggering when one considers the myriad of new agents introduced into the 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. Scl. Total Environ., 1 (1972) 137 HUNS Od7I7<, REFERENCES 1 L. Fishbein unci W, C. Flnmm, Set. Total Environ., I (1972) IS. 2 L. Fishbein and W. C. l-'lamm, S<i. Total Environ., 1 (1972) 31. 5 Monsunio Teel*. Dull. C PL-206, Arachlar Plasticizers, 1968. 4 I. Ilornslcin and W. N. Sullivan, J. (icon. Entoniol., 46 (1953) 937. 5 It. W. Rkcbrmigl*, P. Rcicbe, IV 1), Pcukult, S G. Herman ami M. N. Kirven, Nature, 220 (1968) 1098. 6 D. C. Holme', J. II. Simmon* and J. O. G. Tatton, Nature, 216 (1967) 227. 7 J. II. Koemun, M. C. Dcllruuw and R. H. dc Vos, Nature, 221 (1969) 1126. 8 S. Jensen, A. C. Johnok, M Okson and G. Ottcrliiul, Nature, 224 (1969) 1126. 9 S. Jeiiwti. New Scl., 32 (1966) 6(1 10 G. li, Nunley, W. L. ReichcJ and E. Cromantic, J. ^,r.r. Oflic. Anal. Client., 53 (1970) 251. 11 A. V. Holden and K. Marsden, Nature, 216 (1967) 227. 12 I'. J. Niros, A. C. Walker and A. Medbury, Bull. Environ. Contain. Toxicol., 5 (1970) 317. 13 R. Rixebrough and V. llrodinc, Environment, 12 (1970) 16. 14 C. Wesloo, K. Noren and M. Anderson, Var Faedtt, 2-3 (1970) 10. 15 J. Hitman und II. C. Cecil, J. Aar. FontI Client., 18 (1970) 1108, 16 D. K. Hick. R. G. O'Dell and V. A. Childs, Poultry Sri., 44. (1963) 1460. 17 U, L. MvCunc, J- E. Savage und B. L. O'Dell, Poultry Set. 41 (1962) 295. 18 J. G. Vos and J. H. Koemun, Toxical. Appf. Pharmacol., (7 ((970) 636. 19 A. Huang, D. Firestone and A. D. Campbell, J. Ass. OJJic. Anal. Chon., 50 (1967) 16. 20 J. G. Vos, J. H. Koemun, H. L. Vandermuus, M. C. Ten Noever dc Brauw und R. H. dc Vos, Foot! Cosmo, Toxicol., 8 (1970) 625. 21 J. W. J. Fay and J. M. Richards. Onicc Tech. Serv. PB Rcpi. 75859, Bios Finul Rept. (1947) 893 22 S. A. Progil, Brit. Put. 779,221, july 17, 1957. 23 E. P. Lichtenstein, K. R. Schulx, T. W. Fuhremann and T. T. Liang, J. Eevn. f/irtmio/., 62 (1969) 761. 24 Anon, Environ. Action Bull., April 25, 1970. 25 II. C. Hodge, Proc. Soc. Exp. Biol. Med., 53 (1943) 26. 26 C. P. Carpenter, C. S. Weil and H. F. Smyth, Arch. hid. Hyg. Oceup. Med., 8 (1953) 219. 27 W. L. Guess and S. Haberman, J. Biomtd. Mater. Res., 2 (1968) 313. 28 J. Ncmmolluhl, W. L. Guess and J. Autiun, J. Phann. Sci., 56 (1967) 1446. 29 D. Calley, 3. Autian and W. L. Guess, /. Phanu. Scl., 55 (1966) 158. 30 D. B. Myers, J. Aulian and W. L. Guess, J. Phann. Sci., S3 (1964) 774. 31 O. Schvttino and M. I. Lurotondo, Bull. Soc. Ital, Biol. Sper., 45 (1969) 1337. 32 W. H. Lawrence, J. L. Mitchell, W. L. Guess and J. Aulian, J. Phann.Sci., 52 (1963) 958. .3.3 W. L. Guess and J. Autian, Ant. J. Hosp. Phttrm., 2J (1964) 26). 34 S. A. Koscnblulh, G. R. Wcddlngton, W. L. Guess and J. Autian, J. Phann. Scl., 54 (1965) 156. 35 K. J. Jaeger and R. J. Rubin, Science, 170 (1970) 460. 36 W. L. Guess, J. Jocob and J. Autiun, Drug Intell., 1 (1967) 121. 37 Y. L. Marcell and S. P. Noel, Lancet, l (1970) 35. 38 J. Ccrbulls and J. 3. Ard, J. Ass. OJJic. Anal. Chem., 50 (1967) 646. 39 R. J, Titborsky, J. Agr. Food Chem., 15 (1967) 1073. 40 D. J. Nu/ir, M. Dcroza and P. P. Nui, Fed. Proc., 26 (1967) 412. 41 R. K. Bower, S. Ilubcrmun and P. D. Minton, J. Phann. Exp. Therap.,171 (1970)314. 42 C. If. Sltufer, C. I*. Carpenter and H. F. Smyth, J. lad. Hyg. Toxicol., 27 (1945) 130-135. 43 II. F. Smyth, Jr., C. P- Carpenter, C. S. Weil and U. C. Poizani, Arch. hid. Hyg. Oceup. Med., 10(1954 ) 61-68. 44 R. S. Harris, H. C. Hodge, E. A. Maynard and H. T. Blonchet, Jr., Arch. Ind. Health, 13 (1956) 259. 43 S. Haberman, Sac. Plust. Eng, J., 34 (1968) 62-69. 46 W. L. Guess and R. K. O'Leary, Toxicol. Appl. Pharmacol., 14 (1969) 221. 47 R. K. O'Leury and W. L. Guess, J. Phann. Scl., 57 (1968) 12. 48 H. 0. Sioncr, J. M. Barnes und J. I. Dult, Brit. J. Pharmacol., 10 (1955) 16. 49 P. N. Mugee, H. B. Stoner and J. M. Barnes, J. Pathol. Bacterlol., 73 (1957) 107. 50 J. M. Barnes und H. B. Sioncr, Brit. J. hid. Med., 15 (1958) 15. 51 J. E. Cremcr, Dlochem. J., 68 (1958) 685. ; 138 Scl. Total Environ., I (1972) HONS 0a7175 52J. E. Crcmcr, Biochem. J., ft7 (1957) 87. 5.1 J. E. Crcmcr, Biochem. J., (>7 (1957) 28P. 54 R. Lccoq, C. R. Acad. Sri. Paris, 2.19 (1934) 678. 55 J. li. Crcmcr, Bril. J. hid. Med., 16(1959). 56 W. Zemun, F. Gaderman and K. Hurdcbcck. Dent. Arch. Klin. Med., 198 (1951) 71.1. 57 J. G. A. Lmjicn ami 0. J- M. van Ucr K iik, A survey of the chemistry and applications of organa tin compounds. Tin Research Insliiulc, ;v52. 58 J. G. A. Luijtvu and G. J. M. van ,!c. .virk, Investigations lit die field of organa tin chemistry, Tin Research Insliiulc, 1951. 59 J. W. Dmlgcs, P. S. Davies and R. O. Williams, Dlachcm. J., 98 (1966) I4P. 60 J. M. Dames and I*. N. Magee, J. Pathol. Bacterial., 73 (1958) 267. 61 li. li. Kem.g.i, Cheat. MV,A, 93 (1964) 64. 62 I:. L:. Kenaga, Uth ltd. Conge. Entomtd., London, July 8 -16, 1964. 6.1 A. K. Sijpcstcijn, Meded. Ltmdhouw hagesch. Opzoekiagssta. Stoat Cent, 24 (1959) 850. 64 E. K roller, Deal. Lebenstn. Rnndsch,, 36(1960) 190. 65 l*. D. I'atc and R. L. Hays, J. Econ. Entomol., 61 (1968) 32. 66 G. N. Smith, F. S. Fisher and R. J. Axelrod, cited in H. O. Corbin, J. Ass. Offic. Anal. Client., 5.1 (1970)140. 67 J. R. Knuak and L. J. Sullivan, Toxical. Appl. Pharmacol., 8 (1966) 175, 68 J. R. M. Innes, D. M. Ulland, M. G, Valerio, L. Potrucclli, L. Fishbejn, E. R, Hart, A. J. Pallotta R. R. Dales, H. L. Falk, J. J. Gart, M. Klein, I. Mitchell and J. Peters, J. Nat. Cancer Insl. 42 (1969) I 101. 69 X, L. Carter and F. J. C. Roc, Food Cosmet. Toxicol., 6 (1968) 821. 70 E. Uoylaiul, R. L. Carter, J. W. Gorrod and F. J. C. Roc, Ear. J. Cancer, 4 (1968) 213. 71 |;, Griopentrog, Beitr. Pathol. Anal. Allg., 126 (1962) 24J. 72 A. Rosin and H. Ungur, Cancer Res., 17 (1957) 302. 71 E. F. Slulla, H. Sherman and J. A. Zapp, Jr., 10th Ann. Meet. Soc. Toxicol., Washington, D. C., March 7-11, 1971. 74 P. S. Stensby, Soap Chem. Spec., 43 (1967) 41. 75 P. S. Stensby, J. Am. Oil Chem. Soc., 45 (1968) 497. 76 E. Oingham and H. L. Falk, Food Cosmet. Toxicol., 8 (1970) 171. 77 C. Arrhenius, personal communication. 78 S. Avanzi, Caryologia, 6 (1954) 134. 79 S. Avunr.i, Caryologia, 6 (1954) 160. 80 R. l>. Stewurt, J. Am. Med. Ass., 208 (1969) 1490. 81 R. J. Vernon and R. K. Ferguson, Arch. Environ. Health, 18 (1969) 894. 82 A. Friborskn, Brit. J. Ind. Med., 26 (1969) 1490. B1 P. It. Gchring, Toxicol Appl. Pharmacol., 13 (1968) 287. 84 J. W. Daniel, Biochem. Pharmacol., 12 (1963) 795. 85 J. F. Powell, Brit. J. Ind. Med., 2 (1945) 142. 86 G. G. Scansetti, G. F. Rubino and G. Trompco, Med. Lav., 50 (1959) 743. 87 J. R. Cooper und P. J. Friedman, Biochem. Pharmacol., I (1958) 76. 88 S. Yliner, V :.,re, 191 (1961) 820. 89 A. Darihclmess, Arznehn.-Forsch., 6 (1956) 157. 90 A. Goldstein, W. 3. Schult (ed)., in Mutations, Univ. of Michigan Press, Ann Arbor, Michigan, I960, p. 172. 91 II. Zollinger, Dlazo and Azo Chemistry, Interscience, New York, 1961, p. 187. 92 Brit. Pat. 941, 489 (1959); C. A. 60 (1962) P6788A. 93 U.S. Pat. 3, 162, 571 (1962); C. A. 61 (1963) 63I2D. 94 U.S. Pat. 3, 138, 521 (1961); C. A. 62 (1964) 14568F. 95 C. S. Rondestvent and S. J. David, J. Org. Chem., 22 (1957) 200. 96 G. A. Utbcck, J. W. Jones and K. K. Robins, J. Am. Chem. Soc., 83 (1961) 1)13. 97 Z. B. Pupunastusiiow, R. T. Druni, E. White and P. L. Levins, J.Med. Chem., 9 (1966)725. 98 Y. F. Shcalcy, C. A. Krauth, L. B. Holum and W, E. Fitzgibbon, J.Pharm. Set., 57 (1968) 83. 99 H. Druckrcy, S. Ivunkovic and R. Preussmann, Natuneissettschaften, 54 (1967) 171. 100 M. L. Murphy, Clin. Proc. Children's Hasp., 18 (1962) 307. ' 101 II. Druckrcy, S. Ivankovic and R. Preussmann, Experlentia, 23 (1967) 1042. 102 II. Druckrcy, Angete. Cheat., 9 (1970) 742. Sel. Total Enclron., 1 (1972) 139 103 11. Druckrcy, R. Prcussmtinn, S. Ivankovic and 0. Schmahl, 7.. Krcbsfonch., 69 (1967) 163. 104 R. Preussmnnn, M. Dru<.i'." ;ij J. Buchckr, 2 Krebsforjch., 7) f)96X) 63, 105 R. Prcussmann, A. Von Hodcnbcrg and H. Hcngy, Biocltcm, Pharmacol., 18 (1969) 1. 106 W. Prcussmann and A. Von Hodcnbcrg, Dioehem. Pharmacol-, 19 (1970) 1505. 107 O. Dimrolh, Ber., 36 (1903) 909. 108 O. Dimrolh, Bcr., 38 (1905) 670. 109 I;. II. While and M. Scherrcr, Tetrahedron Lett. (1961) 785. 110 R. Prcussmann, II. Schneider and F. Epplc, Arzneint.-Forsch., 19 (1969) 1059. IK R. Prcussmann, II. Druckrcy, S. Ivankovic and A. Von Ifodenbcrg, Amt. N. Y. Acad. Sc163 (1969) 697. 112 II. Kernel, /.. Physiol. Cheat. .340 (1965) 210. 113 II. Fischer, 2. Physiol. Client., 60 (1909) 69. 114 H. Kosscl and S. Doehring, Z. Physiol. Cheat., 340 (1965) 221. 115 II. D. Hoffman und W. Muller, Diochim. Biophys. Acta, 123 (1964) 421. 116 l,. F. Cavulicri and A. Bcndich, J. Ant. Cheat. Soe., 72 (1950) 2587. 117 !:. Pochon and A. M. Michelson, Biachltn. Biophys. Acta, 149 (1967) 99. 118 C. M. Moudriumikis and M. Deer, Proc. Nat. Aead. Sci., 53 (1965) 564. 119 A. Pvtknu and J. 1 loogstrautcn, J. Am. lad. Hyp. Ass., 26 (1966) 380. 120 G. Young, A, Pcikau and J. Hongstraaton, J. Am. lad. Hyp. Ass., 30 (1969) 7. 121 i. E. Guihric and O. E. Acres, Ball. Emiron. Contain. Toxicol., 5 (1970) 146. 122 T. J. Haley, L. F. Tciriek, N. Komcsu, P. Williams, H. C. Uphnm and L. Daurmash, Toxicol. Appl. Pharmacol., 1 (1959) 515. 123 U. C. Parkcs. Proc. Roy. Sue. Med., 63 (1970) 10. 124 11. Utkins, G. W. McCarl, H. G. Brugsh and ). P. Fuhy, J. Am. Ind. Hyp. Ass., 23 (1962) 265. 125 A. Munn, Trans. Ass. Ind. Med. Off., 9(1960) 134. 126 G. M. lamu. Arch. Ind. Health, 16 (1957) 232. 127 A. Munn, Ann. Hyg., 8 (1965) 163. 128 K. S. Williamson, Trans. Ass. Ind. Med Off., 15 (1965) 29. 129 J. M. Pcicrs, Proc. Roy. Soc. Med,, 63 (1970) 14. 130 D. P. G. Paisley, Brit. /. Ind. Med, 26 (1969) 79. 131 T. E. Lipatova and R. A. Vcselovskil, Vysokomol. Soedin., Ser. A., U (1969) 1459; C. A., 71 (1969) 105158 B. 140 Sci. Total Environ., I (1972)