Document DM5wLaDe2mzkeMLQVjvG8x3w5

From th. <fsJr of W. B. iJAPAGEORGE Copies toi , R. S. Bsfctfr HI. . 8. * gzsr o. U *. X. Ksllsr J. v. 8. a. Ns toolf INuird w. v. IjlH j. c. Vobor X. t. Wisolor ia/ MOMS 073130 Tht Sturnrr of the Total Cm tronwct** U'cticr Publishing Conipjn). Amsterdam *-- Primed m Belgium POTENTIAL ENVIRONMENTAL CHEMICAL HAZARDS PART III. INDUSTRIAL AND MISCELLANEOUS AGENTS L riMHjr.lN nd W. Cr. FLAMM Ntummil Iniunnr of Cnrirnninrmnl Hfnlih Srleneer, NuIipimI Itisiintiei of Hnihh, rithlir Itrnllh .Si Cl ice tun! Oi'pnriuient of 11PuliIt, Education and Welfare, Reieureh Tnungh Park, Attrift Carolina 177UV (V.S A.) (Received May I9lh, 1971) INTRODUCTION in the previous paper, the potential environmental chemical hazards related to drugs' and feed medicantsand pesticides1 were considered via an a-pnort consider ation of their chemical structure, nature of metabolites and degradation products with relation to known and hazardous insults and the inter-relationships and com monality or hazards present m various use categories. The present section focuses on industrial and miscellaneous agents in analagous consideration. Polymer and plastic ingredients A wide variety of organic derivatives are used in the polymers and plastics industry as plasticizers, modifiers, emulsifiers, stabilizers and solvents, a,id their inertness and/or safety is far from being established. Pot)chiorobtphenyh. Polychlorinated biphenyls {PCB's) are produced by various manufactures and are represented as *'a senes 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"1. The senes of Aroclors (Monsanto) are marketed under various numbers and consist of mixtures of chlorinated biphenyls and lerphenyls. The 1200 series relates to the biphenyls, the 5400 series to the lerphenyls, and the 4400 senes to a mixture of bi- and lerphenyls. The annual production of PCB's in the Wcsicrn world nil most recently 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, vil., S1 C 23 SfL Total CmirQft, 1 (1972) 117 HONS 072131 I .1 For example, three monochtorohiphcnyl isomers are possible. 12 dichlorohiphcnyl isomers, 21 tnchlorohtplicnyl isomers and so on Theoretical, 210 compounds can be prepared by this substitution process (a typical PCB example would be 2,4,6.2.4'- penuchlorobiphenyl) -_ The chemical properties that make polychJorohiphcnyls 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, at 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 m 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 culling oils, specialized lubricants and gasket sealers. Miscellaneous uses include; formulation into epoxy paints, protective coalings for wood, metal and concretes; adhesives and in carbonless repro- duc.ng 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 (he insecticidal properties of DDT. Polychlorinated biphenyls along with DDE {l,l-dichIoro-2,2-bis (p-ch]oro- phcnyl) ethane] are reported to be the most abundant of the chlorinated aromatic pollutants in the global ecosystem1. Extracts from tissues of sea eagles, pike and salmon1 as well as in various species of British wildlife4 contained PCB's and in the latter instance it was found that in birds* liver and eggs the PCB residues were greater than the organochJorine 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-* and in other wildlife samples* *"". Polychlorinated biphenyls have been found in human adipose tissue11, 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 organochJorine insecticides. The PCB's are extremely stable; chemically, fat soluble and hence persis tent in the environment. Polychlorinated biphenyls and polychlorinated (nphenyls have been found to be estrogenically 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 limes (hut of />,/'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. Hydropericardium, occasionally accompanied by abdominal edema was |]g Sri Total Enrtron . t (H721 M0fS 0 72132 found in chicks'**'* and Japanese quail1 after ingestion of PCB of American (Aroclor) and French (PhenoeJor) origin respecthely The occurrence of lesions resembling those of chick-edema in birds fed PCB"'19 has also been reported. In most recent work. Vos et jl.1<> described the identification and toxicological evaluation of chlorinated dibenzofuran and chlorinated naphthalene in two commer cial polychlorinated biphenyls. A combination of toxicological, pathological and cJicnuiaj-anulylical data (including mass spectroscopy) strongly suggested the identity of telra- and pcniachlo.d.ocnzofurans (1 and 2, respectively) as ioxic factors in the PCU's Clophen A-60 and Phenoclor DP6- sa 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 used11. PCB can rcaet wnh sodium hydroxide at elevated temperatures to yield phenolic compounds and can for example yield polychiorohydroxybiphenyls via saponification by sodium hydroxide in a polyhydnc alcohol medium11, subsequent loss of hydrochloric acid could then produce chlorinated dibenzofuran derivatives. The biological interactions of polychlorinated biphenyls and insecticides was reported by Lichtenstein et at. 11 who showed that many of the PCB's were toxic to Drosophila melanogtssler Meigen and houseflies Mxtsca Homestica L. (but to a lesser extent than dieldnn or DDT: their toxicity increased with a decrease in their chlorine contents). Moreover, sublethal 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 USDA1*. Because of their similarity in structure and chemical properties, PCB's, if present in a sample, are earned through the usual pesticide extraction and screening procedures and are frequently mistaken for DDT in monitoring tests. Cl Cl ooo ooe Phiholate ester plasticizers. Phthalale esters are among the most widely used compounds as plasticizers in a variety of lacquers, varnishes, paints, co-polymers and plastics. Sri Total nr4root> I (1972) 119 MOMS 072133 i i * c.w. developing chick embrjo and also di-2-meihoxvclhyl- and ocia-isodccvl phthalatc were capable of causing damage 10 che ccnlral nervous system of the developing chick embryo Toxigenic efftM* m difTercin mammals caused by several esters of pluhalic acid have been well documented1* *J'*4. _ _ The cfTcct of chemical sterilization of plastic items and theirconlenjsvviih prim arily nlkyl.-itmg agents such as ethylene- ant- propylene oxide adds yet another dimen sion to the lOMcmcs and poicntial hazards that mighi occur This is especially true in the interaction of these gas sterilization agents with rubber and polyvinyl com ponents of many devices. For example, the ethylene oxide reaction product (2-{2- hydroxycthyl-nicrcapio'lbcnzothiazolc] of the vulcanization accelerator 2-mcrcapto- bcnzotlihizole was found to be more tovic than (he precursor using cells in culture mice and rabbits*''. O'Leary and Guess*' 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. Organr nn compoundr. Organo tins are compounds which contain at least one tin-carbon bond and if all radicals attached to tin through carbon are designated R, and all other substituents X. the following senes are obtained: R^Sn, R3SnX, 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 pcsticidal utility arc the derivatives of quadrivalent tin. Organo nn compounds are 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 ihis purpose arc of the type RjSnX (e g. dioctyl tin and dibutyl (tn dilaurates, nuJeates. 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 nn stabil izer residues. Organo tin compounds used to stabilize poly (vinyl chloride) during container-forming operations can migrate into foodstuffs packaged in such containers. The FDA permits the presence in certain foodstuffs, as a result of such migration of two organo tin compounds, namely di-octyl SS-b (iso-octylmercaptoacetate) and di-octyl (in malcate polymer. The concentration of either, or any combination of both, may not exceed 1 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: (a) In rubber products and paints: as antioxidants and anttcracking agents; to retard rubber deteriorations and as stabilizers of chlorinated rubbers or chlorinated paints, (b) In transformers, capacitors and cables' to prevent corrosion by serving as scavengers for HC1 formed if a short circuit occurred in transformers, etc., using pyranols or `hionnaicd diphenyls (tetraphenyl tin is usefully employed for this purpose); (e) In lubricants and textile oils: as acute oxidants and corrosion-reducing adjuvants for lubricants; as anti-oxidants for textile o*ls; (d) As activators and catalysis: in oxida te/ Total Eiiuron , 1 <1972) 121 MGKS 072135 1 t I 1i In general, phthalate esters have been reported to have a lower order of toxicity for experimental animals'5 and thus have been approved for use in packaging materials for food intended for human consumption. However. Guess and coworkers,,-J0 have demonsiraiedjhc subilg loxicmes (tissue culture cell deaih or enhanced growth, changes in antibody reactivity and irritation as evidenced by dye extra vasation) ol plasticizers and stabilizers used in the manufacture of polyvinyl plastics Citrate and phth.il.iu ester plasticizers such as bis (2'Ctliylhe\\ l')plvi Ival.tic and acclytaicd In-butyl citrate were found to be leached front plasticized polyvinyl chloride (PVC)*1. The sigmlicancc of exposure lime on the leaching of these plastici zers from PVC is important since the plastic is commonly used in in-dwelling surgical devices, e.g. catheters, and in pharmaceutical containers Calley ei aL>a 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 systems**-'*. The four citric acid esters used as plasticizers (e.g tricihyl, acetyl triclhylHbutyl- and acetyl inbutyl citrate) have well defined and marked pharmacological activity when administered parenterally (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)*0. Phthalate ester plasticizers were found to be extracted by blood front plastic tubing and from plastic bags used for blood storage. Buiylglycolbutyl phthalate (BGBP) was found to be metabolized by isolated perfused rat liver to glycolyt phthalate. A second phthaUle ester plasticizer di(2-cih)lhex)l)phtha)aic (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 bags**. C-0-C4h, a C-OCH,C-C4M, && obi* COOK GtyiOlyi pntltMt* COOCHtCM(CtHtHCM}l|CH] COOCH, CHI C ,H*HC H, If H, DEHP ' The isolation of plasticizers such as DEHP from the anticoagulant citric acid-dcxtrose solutions stored in disposable polyvinyl chloride blood bag assemblies has also been documented**1*'. In addition to evidence of phthalate ester plasticizers tn certain foodstuffs such as milk**, there has been evidence concerning the presence of these plasticizers in animal tissues such as beef pineal gland" and heart**. The teratogenic effects in the chick embryo caused by esters of phihahc acid was described by Bower ei a/.*1. Dibuioxyeihyl phthalate caused te-a agenesis in the 120 ScL Ttttoi E*nroti,t \ (1972) HONS 072134 tion, polymerization (polyesters and silicone elastomers) as Ziecler-Nattn type catalysts for poly mcrt/jiton of olefins, (r) Tin-coiti.nnine polymers. numerous till' containing polymers and mucrotnolccules ha\e been prepared with tin in the main chain or as substituent as wcl]_as tin analogs of silicons (in winch carbon and tin alternate): (/) Miscellaneous uses of organo tins include, treatment of fibreglass 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: (a) agricultural fungicides' triphenyl tin acetate (Brcslnn; fail in acetate) and irtphcnyl tin hydroxide (Du-tcr, fenun hydroxide) and bts(iri*n*butyl tin) oxide (TBTO); C, H,-- Sn-O-Sn TBTO (6) General fungicidal action (e.g triphenyl tin chloride)' in paints, preservation of manila and sisal ropes, leather, textiles, to confer mildew resistance to fabrics, for protection of jute and jute bags; wood preservatise, slimicide, paper production process paper; (c) Bactericides and biostats: disinfectant (triantyl tin), bactericides for seeds, (if) Anthelmintics: against worms in poultry (dibutyl tin lauruie, tin olcaie, letraisobutyl tin), c) Nemaloctde. p-bromophenoxy methyl tin; (/) Herbicides: vinyl tin compounds (trivinyl tin chloride); (g) Rodent repellants: protecting food in treated bags (tributyl tin chloride, triphenyl tin chlortde and acetate), (A) Molluscides. triphenyl tins; (0 Ovicides: trialkyl and iriaryi tin chlorides (e.g. RjSnCI, R being methyl, ethyl or propyl) as tnsecucides 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 perse. In general, in the whole animal, pharmacol ogical and toxicological effects of tnalkyl tins are confined to the nervous system4* **. For rats, the oral toxictlies30 of the trialkyl tins are in the order: tneihyl>irimethyl> triisopropyl>tri*n-bulyl. (The decrease of toxicity with increasing length of alkyl chain is analogous to (hat observed with di- and tetraalky! (ins). The conversion of tctraalkyl tins to trialkyl tins"*31 m iko (as demonstrated for tetraethyl tin) accounts for the latent toxicity of the teiraalkyl tins, with the site of the conversion being the Iivcr**,3J. From the toxicological point of view, the tetraal- kyl tins can thus be considered to behave in a manner analogous to their trialkyl tin counterparts3* (This conversion or a tctraalkyl to a trialkyl metal has also been shown for tetraethyl lead**-33,3*, and may be a general phenomena). Once ittraelhyl tin 122 Sri Toro/ Em iron., 1 (1972) HONS 072136 i has been convened to methyl itn h appears 10 persist in tlie body in that form without apparent further reaction to the dmlkyl derivative The matkyl tin ton is a stable entity which is toxic per se and persists for some lime in the tissues'2. Long-term feeding experiments with methyl tin have disclosed some testicular atrophy in addition to lesions confined to the central nervous system4*. Tncihyl tins and diethyl tins ionize in aqueous solution'* '* with production of the univalent (CjHj)Sn* and divalent (C:H,),Sn'* cations, respectively It is reasonable to assume that trialkyl and triaryl tins exert their biological action as RjSn* tons or as the undissociated hydroxide R^SnOK formed on dissociation. The dealkylation ofdiethyl tin by the rat has been reported'*, with diethylntion occurring in both the gut and tissues. The induction of biliary and hepatic lesions by dibutyl tin salts in rats has also been described*4. Triphcny! tins, (C*H j)jSnX, (where X was halide, hydroxide, alkyl or alkenyl, aryl or altcyclic radicals and ester groups or organic acids) have been found to be chcmostcrilants*1 41 when fed to adult houseflies, Many of the iriphcnjl tins were found to be superior as chemostcrilants, to the azmdincs, if both groups were administered orally. The highest chcmosteriltztng activity was shown by triphenyl tins in which X is mobile and the triphenyl ton is obtained. e.g. halides, hydroxide, sulphide, alkenyl and ester derivatives (but not phenyl or butyl), - Triphenyl tins are mainly used in agriculture as fungicides (e.g. Bresun, TBTO) In the finely-divided state in which triphenyl tins are applied to plants, they are susceptible to light and oxygen41. Phctiyl groups are gradually split off with step-by-step loss in toxicity. Triphenyl tins decompose slowly into diphenyl tins and the final stage of non-toxic inorganic quadrivalent tin compounds is probably reached through the unstable intermediate monophcnyl tins44, m, tC.H,),Sn- /(C.U,),Sn: \ (C.H.Sn/ ) \ --Sn-- Pale and Hays45 described several degenerative changes m testicular tissue of male albino rats treated with triphenyl tin acetate and chloride Complete sterility was achieved after 19 days of treatment following oral administration of triphenyl tm 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 lubule lumina. Tricyclohexyl tin hydroxide is used as a miucide (Pliclran, miitcide) for apples, pears and citrus fruits. Exposure of incyclobexyl tin hydroxide to u.v light has indi cated that the compound degrades to cydohcxyl tm and inorganic tin44. Also, it has been found that when fruit is harvested at varying periods after the final spray treatment, the ratio of tncyclohexyl tin to total tm 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). Set Total Environ., 1 (1971) 123 MON5 0 7213 7 c w. c,w.' i Bitpltcnol. Bisphcnol A[(2 2-bis(/>-hydrox\phcnyl) propane) as a copolymer is an important monomer in several resins used as food packaging materials for industrial processing and consumer use. CM, The metabolic fate nnd properties of huplionol A are of importance since some unreactcd monomer does migrate to food. The metabolism of bisphcnol A in the rat following oral administration*7 indicates that less than IV* of the material preseni in urine was free bisphenol A while the feces contained 35% free bisphcnol A and an additional 35V* was identified as a hydroxy latcd product of bisphenol A. Ii is important to also note the marked estrogenic activity of bisphcnol A1* (the minimum effective subcutaneous dose was 0.25 mg in the sensitive I8h*glycogen response of the rat uterus). Rubber atMu n'cs More than 600 different compounds are employed in rubber technology. Gencncally, however, the organic additives could be grouped into a dozen or so chemical classifications Among these are the thiurams, dtihiocarbamates. thiazoics, sulfonamides, thioureas, guanidines, amines, amides, quinolines and phenols. The categories of utility include accelerators, activators, antioxidants. Mowing agents, vulcnnizcrs, retarders, reinforcing agents, plasticizers, dusting or dipping agents and inert fillers Table I illustrates the structures of a number of classes of common rubber additives. It is of interest to note that ethyl selcnac (selenium diethyldithiocaibamate) which is used both as rubber accelerator and fungicide is carcinogenic in the mouse*1, while the rubber additive polymerized A'-miroso-2,2,4-tnmcthyl-l,2-dihydroquino]inc has recently been found carcinogenic in ihe ral*9-70. The dithiocarbamatcs and iheir metal salts have also wide utility as fungicides and their decomposition products include alkyl thiourea, ethylene thiuram monosulftde, carbon disulfide, carbonyl .sulfide, hydrogen sulfide, ntetal sulfide sails and elemental sulfur. Both ihiuram71 and thiourea are carcinogenic for the thyroid71, and 4,4 '-methylene bis (2'melltylaniline') and 4,4'-methylene bis (2-chloroanihne) arc liver and lung carcinogens in the rat71. 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 varying from a few hundredths of IV* 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, ihusimprovtng the appearance of whiteness or brighteners in the fabrics. 124 Sel. Total Emiron., 1 (1972) HONS 072130 1 ' . 1 I C.w, 4 i TAIILE 1 COMMOV RUPtlir.R ADDtTIVFS Cuirfary Stntfturr Acceiertrlorj TciraRicihyHhiuram disulfide CMK,H-C-S-S-C-n'-ch, CH," f >' 'CH, Teiramclhylthiuram monotul/idc Dipcnumclhylcnclhiuram hcnatulfidc CM\ N-C S C-n'CH-' ch/ 8 fi CH, CHj-CH, CHj--CH| H,cv ;n-C -(S*L-Cjj -nCSCH,-CH,'''cm, Meullodimcthyl- and diclhyldithiocarbamaict CH, a CM, ^n-C`S-m*s-c*n: Ch/ J CH, MaCu.Pft. In c.mk 1 -uA u _ctM* % Jm n.2.Cd * nt. it.Tt Bcnialhtazyl duulAd* 2`Mcrcapiobcnmhiazoit 5>- A'-Oiydicthy lentbcnzothniok-2-ulfnmid eCfVXS>.-5`W^CH'CH,S N-Cyc lohe*yl-2-bcnzoihiitolew Ifcnamidt Trimethyl thiourea Diphenyl (uuudlnt Ch,CH, * H H CHCH* -H. ,CH 'n-C-nn cm/ E m ^HtN-CNHC,H, H NH . , Sri. Total Environ.. 1 (1972) 125 MONS 072139 c w. i TABLE t (continued) Ciurg iff Antioxidant* Pheftyf /^naphihytamirt* Structure -- 'OCT Diphenyl-p-phcnyiertedijmine A-JiOpropOXy dtphenyfomihc Hydroquinone roonobentyl ether l,2-Oihydro*2,2,4*iHfTV6ihy| quinotint Aldol-a-naphthylamine O7^0-cmC! ^-C^-O-Q^Otj a5& H phlrCMHCM^-CH-CH] 0Q ~ l12-MclhylciK-bii-(4-n>ethyJ-6-rf'buty] phenol) Oh OH CH, CH, dmf-e.'MMtt N,A''-Di(2.oclyl)-p-phenylen diamine MH CH, MH Ch, S-(1,3-Dimethy(buty()-A'-pheny)-/.phny!eie' ^Mininc MH CM, CH H M Sionirf oftun AcodicerboiMflud* H*N"-C *NbNC*NM| * rt it O0 Dimuo*opentameihy!ene letramine (3,7-Dmitroto-l,3.5,7-ictrtaubicyelolJi J.l)nonane) H.C -- M--CH, 111 ON-N CH, N-NO Hj1C-N1-1CH, 126 Scl, Total Enriran f 1 (1972) MOhS 072140 I TABLE I (continued) Cvtogvff Reorders N*Njlr0sod]phhyfamine Salicylic ocid Masfteltert Dibutyiphth'ilaie Structure G-i-O HO COOH gr COOCtHt 0COOC4H' Dioctylphlhalalc |Pii(2-ethylhcxyl)jihtha1aic] COOCHfCHtCjHjKCHjljCMj JL coocwjCm *(ch,ijch, QT C,M, Vutcamzing agenn 2,5-Bu(wr`bulyJ ptroky)-2,S-<limc(hy1 hcunc CH* CH* C N^-C -CH* CH*-C-CH* 11 0O 11 0y CM,-C1 -Ch'-Cm*-C1 - C m' CM* CM* Funftcldrj A,-Tnchloromcih>iihif'-4-cyclo(iexene-K2- dKarboximide (Capian) MucrHanrota addltlctl Polymerized N-nnroto-2,2,4-trimethyl-1,2 dihydr oquinolinc o 0^y*-ce'. o i"* Cr 2"ch* NO 4,4-Diammodiphcnylmclhanc ScL Total m iron., I (1972) 127 HONS 072141 TABLE 1 (eominutd) Cutesor* 4,4'^Methylene bS'C-eh1oroartiUftc) S<ruefare 4,4'-Methylene bi**{2'nKlhybni1inc) mn-0'ch-^- MM, Cm7 iC>M, The most commonly used cotton brighicners, shown in Fig. IA arc bistriazinyl derivatives of 4,4'-diaminosiilbcnc-2,2'-disuirontc acid. These so-called CC/DAS brighicners are prepared from 2 moles of cyanuric chloride (CC| and I mole of Ihe disoc.um salt of diamwostilbene disulfonic acid (DAS) With Ihe exception ofbrightener DMDDEA all are reaction products of I fnole of CC/DAS wilh 2 moles of aniline. Brightcner DMDDEA is the reaction product of I mole of CC/DAS and 2 moles of sulfamltc or metamllic acid. A number of typical structures of brighicners that are stable to chlorine bleach m the wash liquor are shown in Fig. IB These are benzidine sulfone disutfomc acid (brigluencr BS), naphihoinazoylsiilbene sulfonic acid (bnghiener NTS, R * H) and benzimidazolyt (brightcner BBl) derivatives. The general structures of typical nylon and wool brighicners arc shown in Fig I C and include the dematives of amino coumarin (bnghiener AC) and diphcnytpyraeolinc (brighicncr DP), none of which are stable to chlorine bleach The general structures of polyester brighicners that also have affinity for polyamide fibers are shown in Fig. ID and include bisbenzoxazolyl (brightener BBO), naphthoxazolyl (brightcner NOS) and naphihoiriazolyl (brightener NTSA) derivatives. The (CC/DAS) brtghieners behave like direct, dyestuffs 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 dyemg of these fibers by dispersed dyestuffs74. Although the solubility of the commonly used bnghteners 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 brightcner to dissolve in the liquor. It is claimed that the total concentration of brightcner in the liquor of the modern American home laundry would be only 3-10 mglluer, even if all the brightener were in solution at one time7'. Of all laundering aids commonly added lo the wash liquor apparently only active chlorine products affect the stability of some brighicners. The extent of attack on the so-called bleach unstable bnghteners depends on their chemical structure, temperature, amount of bleach used, etc Differences in stability to hypochlorite and dichloroisocyanurat: bleaches 128 Total m iron,, I (1972) H0*s C?21<,2 exist also among the CC/D,\S 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 marine ring SOjktJ .iQ-tm-v s^- ? :i-Q-yV s-Q -- I 'r* NM -- O X- h m ftnghl*n*r CrtignaltQfl TA om A,, CH, CH, CH, ` OH H DUE* n>rR ,n '--r N H,C^ 'CH, Mf' '`CH, H,C in, '' H<f CH, OH Oh OH OH H ,** ODEA OMODEA H*OjS ft-N tOyN* -NHB BrlgrM *n*f BS N*0,S CON H iITI ^C-CHSCH-CV * liorr 4 Bngftitrwr NTS Bngntvftvr BBt >-00CH Br*gntftr AC th-? 'v & Bngnientr DP .-0>-chcm-c^0- l^C-CH=CH-H Brigiuwwr BBO BriQMtrwr MOS A IV C* -c H N--N " Hjo- BrigiM*n*r NTSA Fig - Slruciurci of optical bnghicner* A, Bu majinyl derivative* of 4,4'-didminolilbcne-2t2'* duulfomc tuid (CC/DAS cotton brightcner*). B, BJcactvnablc bnghicncn. C, NyJon ynd wool brighicncr>, D, Polyester And polyarmdc brtghtcnen, The combined action of optical brighteners and ultraviolet light in the produc tion of tumors has been reported by Bingham and Falk1*. The optical brighteners studied were- 3-benz)l-4-mcthyl-7-hydroxy coumarm t3), disodiuin-4,4'-bis (2.4-dimelhoxybenzamido)-2,2'-stilbenedisuironate (4), disodtum-4,4'-bis (4,6-dian]J]no-5-iriazin-2-yl).amino-2,2'-stilbenedisuironale (5), Sri TewI Ciwiron., I (1472) 129 HONS OTZl1*^ w. Tumors were not found in any mice receiving topical application of the optical bnghtcncr in D MSO alone, but with addition of ultraviolet light (6 h/d.iy on 5 days/wcek to a germicidal lamp having 60V* of ns energy at 254 m/0 a high incidence of tumors developed that resembled grossly the tumors (squamous cell carcinomas) arising from repealed application of carcinogenic polycycltd aromatic hydrocarbons Since the use of optical brighteners is widespread in laundry products such as deicrgcnis, starchcv. 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. are germane. Also of importance is the recent finding77 that the optical brightening agent (6) has been recovered from fish jn Sweden suggesting a potential hazard of wash liquors containing other optical brighteners being concentrated m marine organisms and fish and hence available for human consumption. Another interesting brightening agent is 4-mcthyl umbelliferone (7-hydroxy-4-mclhyl coumann) (7) that is used as a whitener in laundry detergents as well as OS-ft-CO -0^,0 - CM, a brightener in denirifrtces. It is related to umbellifcrone (7-hydroxy coumarin) (S) which is used in sunscreen lotions and creams Both coumann derivatives had been shown to induce chromosome breakage in allium cepa1*'1*. Miscellaneous agents Trichloroethylene and teiracliloroethylene. Both trichloroethylene and tetra- chlorocihylene (perchloroethylene) are used extensively as industrial solvents (pri marily for drycleaning and degreasing), the latter has been finding increasing use since the advent of coin-operated drycieamng. Trichloroethylene is also used with other chemicals such as po<ymerized resins of phenol-formaldehyde, urea-formal- 130 -Tc Tqfat Environ , 1 0972) MQNS 07214* 1 dchydc and epoxides in the production of special fiber glasses, Tcirachloroethvleiic is used in small amounts as a commodity fumigant Both tnchloro- and teir.it.hioracihylcnc have been shown to be neurologic"'-", bui icirachlorocthylcnc is believed to be more heputoxic than the tnchloro derivatives The metabolism of J*C-labeled tnchloro- and tetrachlorocihvlcnc was studied by Daniel** who found that both compounds are largely excrcicd through the lungs. It is well known that trichloroethylene is excreted in the urine us trichloroacetic acid and irichlorocihanol in all species of experimental animals studies. Tn addition to these compounds, monochlorojccnc acid is also a urinary metabolite of man, A point of major importance is the nature of the rearrangement which results in the formation of 2,2.2-trichlorocthanol and trichloroacetic acid from 1,1.2-tnchloroethylcne This has been shown to be an tntra-molecular rearrangement of trichloro ethylene and no exchange of chloride with the body chloride pool. Fig, 2 illustrates the mcubolic pathways of trichloroethylene and letrachloroeihylene. C'tC=CWCl TricnjfrrMinynn* lntr*moi*eyi*r - ClyC ---- CmCI ------------------ cot, CHO A*CWC1Ion/ \oOSMMtien cci,ch,om rfidiiwMintwi CCIjCOOH Tr^iwyottHit cJ Ci,C*CCU t*ir*ehwfrti Esomoation Cl.C -ecu lntran*oleul*r rrrr>5mnl CCi,COCi Hyaretyvs - cci,cooh TnciMoro*c*tyl ctuoria* Tr,cmorotmt iti Fi( 2 Metabolic pathways of irichloroeihylent and leiraehloroethylcne in the rat The formation of the intermediate oxide was postulated by Powell**. Trichloro ethylene oxide is believed to be formed in ntro when trichloroethylene is oxygenated in the presence of actinic radiation. Rearrangement of the oxide yields trichloroace(aldehyde (chloral). The formation of chloral in men exposed to trichloroethylene vapor has been reported**. Chloral appeared in the blood within 30 mtn of exposure but subsequently underwent rapid metabolism. The oxidation of chloral to tnchloro 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 irichlorocihanol would involve alcohol dehydroge nase The metabolism of letrachloroeihylene may also involve the intermediate oxidation formation. For example, following exposure of letrachloroeihylene vapor for 2 h in mice, the urinary metabolites included 52% trichloroacetic acid, !J% oxalic acid and traces of dichloroacctic acid. An epoxide intermediate was postulated io account for these products" as sho-* n tn Fig. 2. Sc/ Toioi Emttrvn , J (19*72) 131 1 I i HONS 072245 c.w. The acid chloride would be rapidly hsdroly/ed to trichloroacetic acid and neither tnchloroctHanoi or ovulic acid would be formed. In all of the above discus-ion of the metabolism of trichloro- and tetra* chlorocihylcnc it is nnpori.ijjt to notf ihc mutagenicity of ihe lnicrmcdi.itc chloral hydrate*'* vo as well as the potential mutagcmciiy and carcinogenicity of cpovidcs tn general with xpccific rclerence to tetrachlorocthylcne oxide postulated above. h is of added nnpoitancc to consider the similarity of types of meiubohc products (to those discussed above) of the important anesthetics haloihanc (1,1,1mnuoroO'bromoO-chloroeilianc) (9) and lluoioxcne (2,2,2-induorocthyl vinyl ether) (10) H I CF.-C-Cl I Br CFCHiOCH=xCH, 9 10 '1 nfluoroethanol. trifluoroaccinldehyde hydrate and tnfluoroacctic and are the metab olites of both anesthetics and their formation may proceed via an intermediate cpoxidation and intramolecular rearrangement as described for trichloro- and tctrnchloroethylene in Fig, 2 Little is known of the chronic io\iciiies of the above fluoro-mctab* ohies. Triaiews Certain tn.izcnes have technical importance as intermediates in the " Rapidogen" dyeing process*1 and aryl dtalkyl tnazenes have been patented for use as rodent repcllants and herbicides*1-*4. Other trtazenes have been evaluated as carcmostatic agents**-**. l-Phcn>l-3,3-dimethyltnnzcne ts both a potent carcinogen*' and teratogen m rats'00-101, Certain other l-aryl-3,3-dialkyl trtazenes of the general formula. ' aryl-N-N-N 1 2 3 'alkyl are also potent nemoiropic carcinogens in rats103, The potency increases in the order: phenyl, 3-pvridyl, pyridyl-A'-oxide, and methyl and ethyl, respcciisely. In acid medium, aryldialkyltnazenes are hydrolyzed to yield aryl diazonium salts and a secondary amine. (It is of importance to note that methyl phenylnnrosanunc and phenyl nitrosourea are both carcinogenic103-104 forming probably phenyldiazomumion as a reactive intermediate.) Preussmann w at103 studied the enzymatic dealkylation by rat liver and lung microsomal fraction m niro l*Phcny!-3,3-dimeihyl tnazene was found to be oxidat ively deulkyhtted to form the corresponding aldehyde (formaldehyde) and aniline was also shown to be a metabolite. The results suggest that carcinogenic aryl dtalkyl triazenes are dealkylated to form aryl-mono alkyl tnazenes as proximate carcinogens. Aryl mono-alkyl tnazenes are known alkylating agents and the carcinogenic activity of trtazenes was explained by alkylation of biopolymcrs (nucleic acids) Fig 3 illus trates a proposed activair-n mechanism of carcinogenic phenyl dmethyl tnazene 132 Sa Total Ejinron t I (1972) HONS 072146 to form phenyl monomcthy! tri,i7cne as proximate carcinogen and carbontum ion as ultimate alkylating agent. The proposed reaction mechanism, however, does not exclude that certain trtazencs may act by a purely chemical hetcrolysis to form aryl diazomum ions as reactive iniermcdiaies (for example, the very local sarcomas after subcutaneous injection of l*phcnyl*3,3-dimelhyl triazene may be explained on this basis). rtx. />c*,,*, S'** \ 1H-yP0hr*onAy>ym- 3#-thmyH*irn<y4it-#3rr#' H.O ^-NiN-h' ' + CHjO 'll " Fwmle#t>yw -NIN'CH, Phcnytmensm* thylt riii*A* + H,0 MH, T CMO-McH-CHf} Amur* * Myihytanjohyoronte* -OH" -** Ch * Carbonwim <0" alxyiaune *g*nt Ri 3 Propoied activation mechanism of carcinogenic phenyldtmethyllnwcne to form phenyk nionorndhylinjnifw at proximate carcinogen, and carboruum ion as ultimate alkylating agent1*1. The m mro alkylation of guanosine, RN'A and DNA with aryl-monoalkyl* tnazenes to form 7-alkyIguamne was demonstrated by Preussmann and von Hoden* berg10*. Ary l monoaikyitriazenes are alkylating agents*01-110 as shown: ^.NH-NIN-CH, * H* --------- -- at, + CH,* The alkylation of btopolymers was earlier proposed as the first step in carctno* genesis by aryldialkylmazenes*01. Reactions of l-phenyl*3-monomethyl* and mono* ethyl tnazenes, respectively, with guanosine, RNA and DNA resulted in the formation of 7*methyl and 7-eihyl guanine. It is germane to consider the closely related carcinogenic alkylating substances consisting of. A'-mtroso, 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. Set Total Ejmron, 1 (1972) 133 HGNS 0721*7 o The first and decisive step in the activation of these groups in an enzymatic tt-C-hydro\ylation of an allij 1 residue, which is then cleaved ofi'as the corresponding aldehyde (an alkyl diarohydroxide or an alkyl diazontum ion is probably formed as an alkylating intermediate), The naturally occurring azoxya/kane c>casin (methyIazoxymcthanol glucuride) (II) is transformed to its methylazoxymethanol (12). + CH.-N-N-CH,O-P-O-C.H,,O, + CH.-N-N-CH.OH o- oJ li n This proximate carcinogen is then easily hydrolyzed to formaldehyde and an alkylating agent, probably methyl dtimine oxide, which is a tautomer of methyl- diazohydroxtde. Azoalkanes could possibly be oxidized in rttv to yield azoxyalkancs. Dealky lation of alkanes could form alkyl dumines which could possess alkylating activity. Tig 4 illustrates the proposed reaction mechanism of hydrazo-, azo- and azoxyalkancs according to Preussmann ef a/."1, i R-CHj-NH-NH-CH,-* R-CH.-msw-CH-H *i OH , -C-nyorayim O a-CM*,-N*n-Ci HM -a i -H-C -a-c 'h A CW,-NJN-H 0 1 A-CHj-NSN-H CHj-a Fig, 4 Proposed raetion mechanism or hydrazo-. azo- and azoxyalkane*. The alkylation of nucleic acids, particularly at N-7 in guamne. 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 (tiz , (a) mtroso compounds, (6) hydrazo, azo, and azoxyalkanes, and (r) 1 -aryl-3,3-dialkyl tnazencs) are the same, t.g afkyldtazomum compounds, the specificity of the effects must most probably be attributed to '.he whole molecule of the "transport forms " or to their i 134 Set Total Entirun., 1 (IJ72) P-CKj-Xr N-CHj-R --------------------- -- P-CH,-N-N-CH,-P HONS 072148 I enzymatic activation. The detection of carcinogenic properties in diazomethnnc and diuzouccutc as well as in directly acting alkylating agents such as alkyl lulidcs, a/indincs. dialkyl sulfates and 1,3-propane sulfone gives considerable support to the alkylation theory141. _ __ A number of reported reactions of mono-nucleic acids with diazonium salts hi i iira are informative1,3-1 '*. For example, the arylation of guanine in the 8-position by diazonium salts has been demonstrated***. HO HO Typical compounds formed include iV/i-benzolsulfoguamne (13). Guanine reacts with diazonium salts to yield guanine 6-izo compounds which can further reduce to -amino guanine and arylamme111-1** while adenine does not undergo the analogous reaction. ' Kosscl111 described the reaction of mononucleotides with diazonium salts to proceed as shown: Hj^N^N n gf|ni4c $c>0 a Xantiudyiic acid M,0 The mononucleotides guanyl-, adenyl and cyndyhc acid react with diazouzed sulfanihe acid at pH 10-11 forming colored dyes (pigments) which absorb strongly at 370-440 m;i. Guanylic acid reacts more rapidly than adenylic or cyndyhc acid while uridyl- and thymidylic acids show no reacion with diazonium sails. 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 diazoannno compounds SrL Tvtai nnrvn.t l (1972) 135 mons 072149 i Reactions of diazontum salts with nucleic acids were investigated by Pochon and Michclson111. Diazor.ii.n salts obtained from 2-amino-/>-bcnzcnc disulphomc acid and 2-aminonaplitlialcne-1,5-dtsulphomc acid were found to be highly specific giving 8-substiuncd guanine residues This type of reagem has been employed to mark DNA for studies by electron microscopy1 Polyphem h Ccruin polypfcnyl 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 toxic.ty of polyphenyl mixtures have been reportedAi a daily dietary intake of 350mg/kn or more Snmowax OM, a mixture of tcrphenyls 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-ierphcnyl (M.1%), niicrphcnyl (15.1%) and p-tcrphenyl (6.1%); while OMRE High Boilers consists of high boilers>98%, biphenyl (<0l%), o-lerphenyl (0.1%), m-terphenyl (<0.1%. p-terphenyi (<0.7) and inorganic (<0.1%). At a daily dietary intake of 33 mg/kg or more an OMRE High Boiler Sample (consisting of terphcnyl and radiolync and pyrolync 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 Acres1*1. The acute toxicity in rabbits of poly phenyl compounds used as atomic reactor moderator coolants was described by Haley el a/.133 Onho- and meta tcrphenyls were the only polyphcnyls that caused death after inhalation. Dusoc} a/tatts and po!)<urrthaes. The dnsocyaoates such as toluene-2,4dnsocyanate (TD1) and melhylenediphenyldiisocyanate (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 polyureethane type. Polyurethanes are used as paints and varnishes, surface coatings, flexible and rigid foams, wire covenngs and in thermal and sound insulation. CH, SCO TOl " NCO NCO MOl TDI IS usually prepared from toluene-2,4-diamine and phosgene in a solvent such as o-dichlorobenzene 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 {*$ blowing agents such as azodicarbonamidc). 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 liJ 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 effecls,,4"1,^ 136 Stl Total nnro* . \ (1912) #0NS 073150 -i Crude MDI used in rigid urethane foam formulations u prepared by treating the condensation product of amline and formaldehyde with phosgene Any uncondcnsed aniline initially present util be com cried in phenjl isocyanate, which because of its volatility, is more to\ic thatijhe dn>ocyanaics. The hazards involved in the decomposition of polyurethanes lute been suggested by Paisley110 l-'or example the decomposition of polyurethanes used in wire insulanon occurs at 220'C-275"C. producing iso-cyanatcs and A-oudes. (The temperature of a soldering iron in norma) soldering operations is approximately 300"C.) The possibility of a serious incipient ha7ard m eombatting fires involving buildings and refrigerated eompartments, etc , where large quantities of polyurethane foams are used was also raised by Paisley110 The effects of physiologically active media on polyurethanes were studied by Lipatova and Verclovskit111 to determine the potential use of polyurethanes as substitutes for tissues 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 HCI) The degradation of polyurethane m the model solution occurred as a result of cleavage of CO-bonds in the urethane group affording RNCOOH and R'OH. The degradation rate was inversely proportional to the number of intermolccular bonds in the polyurethane. SUMMARY We have examined but a small number of selected chemical agents from a spectra of environmental areas, nz., drugs1; feed medicants and pesticides1; polymer and plasne ingredients, rubber additives, brightening agents and industrial chemicals with a view toward elaborating their potential hazard via a primary consecration of their structural analogies to known carcinogens, mutagens and/or teratogens. Efforts were made to cue 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 ihetr known biological and toxicological effects. Recognition was also made wherever feasible 10 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 loxicities, but they may also interact in mro and in r/io 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 lop of an already staggering number of present and potential hazards, but the time may also be short m eliciting the hazards of these agents to man. Set Total Em-Iron., t (1971) 137 MGNS 072151 v------------ REFERENCES t L. Fislthein and W, C Fumm. Sri. Tmnl Em iron., I (1912) IJ 2 L. Fishbein and \t C. I lantm, Si l. T.u.tl Cm Iran, I t1972) 31. 3 Monsanto Tech Bull. C P L 1(X\ rtrurhlor /'fcijrirteen, I90S. 4 I Hornsliln and W. N. Sullitan. J from Enivinol. 46 (19<1) 9)7, i R W, Rucbmugli, P, Rciclte, H B PcaLult, S. C. Herman and M. N. Kirven, Nature, 220 (19*8) 1098 6 D, C Holmes. J II Simmom and 1 O. C. Tattoo. Suture, 2IA (19*7) 127. 7 J H. Kocman. M C. DcUrau* and R H de Vo>, Suture, 22) (1969) 1126. * S Jtnvcn. A G JnhiKls. M Oliwn and G. OtteranJ, Nature, 224 (1969) 1126. 9 S Jensen. Sen Sri., 32 11966)612. 10 G E H.t;)c>, W, L Rctchel and E Cromantie, J, Alt, Ofhe Ami. Chrm., J3 (1970) 2M. 11 A. V Holden and F. Mjrsden. Nature, 2i6 (1967) 227. 1? F J lliros, A C. Waller and A. Medbury, Bull. Enrireu. Cuntam. Toxteot., S (1970) J)7, I 3 R Riscbrough and V. Drodine, Cmiranmeul, 12 (19701 16 14 G. Wc*ioo. K. Noren and M Anderson, Vat Fordo, 2-3 (1970) 10, 15 J Bitman and H C. Cecil, J Am' Food Chrm , It (1970) I !0t. 16 D. F Flick. R. G O'D.ll ard V A. Childs. Pouttrx Set., 44 (1965) 1460. (7 E- L. McCune, J E. Sasuge and B. L O'Dell, Pauliri Sri 41 (1962) 295, II J. G. Vos and J K. Kocman, To\irol. Appt. Fharutorol., 17 (1970) 656. 19 A. Huang, D Firestone and A. D. Campbell, J. An, "Offir Anal. Chrm., 50 (I967| 16. 20 J G. Vos. 1. II Kocman, II. L Vandermaas, M. C. Ten Noeverde Braun and R. H. de Vos, Food Cato,rt. Taunt., I (1970) 625 21 J W. J Fa) and J. M Richards. Office Tech. Scrv. PB Rep). 75159, Biot Final Rcpl (1947)19) 22 S. A. Progil. Bril Pal. 779,221, July 17, 1957. 2) E- P. Licltlensicin, K. R. Schutx, T. W. Fuhremann and T, T Liang, J. Eton. EatomoL, 62 (1969) 76), 24 Anon, Enriron. Artmu Bull, April 25, 1970. 25 H. C Hodpc, Peer. Sue Exp. Biol. Med., 5) (1943) 26. 26 C- P. Carpenter, C. S Weil and H. F. Smylh, Artk. tnd Hig. Oreup. Med., I (1953) 219. 27 W, L, Guess and S. Habcrman, J. Brnmed. Muter. Bet, 2 (1966) 313. 28 3 Nemaiollahl, W, L. Guess and J Aultan, J. Fharm. Sri., 56 (1967) 1446. 29 D. Cal Icy. J. Aultan and W. L. Guess, J. Pkarm. Sri , 55 (1966) I5t. 30 D B. Myers,). AuUan and W. L Guess, J. Fharm. Set., 5) (1964) 774 31 O. Schciuno and M I. Larolondo, Bull Soe. hat Biot. Spur., 45 (1969) 13)7. 32 W, H. Laurence, J. L. Mitchell, W L. Guess and J. Aultan, J. Fharm.Sri., 52 (1963) 951. 33 W. L. Guess and J. Autian, Ami. J. Hote. Fhtirm., 21 (1964) 261. 34 S. A Roscnbluth. G. R. Weddtngion, W. L. Guess and J. Auttan, J. Fharm. Sri, 54 (196 5) 156. 35 R J Jaeger and R. J. Rubin, Sciratt, 170 (1970) 460. 36 W. L. Guess, J. Jacob and J. Aultan, Drug Imrlt,, I (1967) 121. 37 Y. L. Msr.-ell and S. P. Noel, Lautrt, I (1970) 35 38 J Cerbults and J S. Ard, J An OJTte. Aual. Chrm., 50 (1967) 646. 39 R J. Tahortky, J. Agr. Food Chem, (J (1967) 1073. 40 D J. Naur, M. Beroza and P. P Nai, Fret. Fror., 26 (1967) 411. 41 R K Bo,er, S Habcrman and P D Minton. J Fharm Exp. 73mm,171 (1970) 3)4 42 C- B. Shafer, C. P. Carpcnier and H F Sntyth, J. Ind. Hyg ToxiroL, 27 (1945) 130-135. 43 H F. Smyth, Jr, C. P Carpenter, C S Weil and U. C. Pouam, Arth. Ind. Hit Oreup. Med., 10 (1954) 61-66. 44 R. S. Harris, H. C. Hodge, E. A. Maynard and H. T. Blinchet, Jr., Arth. Ind. Health, I) (1956) 259. 45 S. Habcrman, Sot. Finn Eng J., 34 (1961) 62-69. 46 W. L. Guess and R. K. O'Leary, Toxicol Appl. Pkormotol., 14 (1969) 22). 47 R, K. O'Leary and W L. Guess, J. Fharm. Sei, 57 (1961) i2. 41 H. B. Stoner, J M Barnes and J I DufT, Brit. J. Fharmaral., 10(1935) 16. 49 P. N. Magee, H. B Sioncr and J. M. Barnet, J. Pathol. Bacterial., 73 (1957) 107. 30 J M. Barnes and H B. Stoner, Bnt J. Ind. Med., J3(|93l) IJ. 51 J. E Crcmer, Bioehem. J , 61 (1931) 615. 138 Set. Totol Ennrou., I (1972) HONS 072152 c.w. i 52 J E Cremer, Bwrhem. 47 (1937) 17. 3* J. E. Crcrntr. Bwrhrm. J . 67 (1937) ISP. 54 R. Ltcop. C. ft. Arad. Sri Farit. 239 11934) 67|. 33 1 E. Cremer, Srii J M \lrd. 16 11959). 36 W. Zeman. E. Gadcrman and k HjrJcb.'cS, Oral. Arch Klin. Mrd, 191 (19311 71 J. 37 J. G. A Luijicn und G J M van dir )v.-k, Aturrrj of the ehrmittry and apphcatruns of organa tin compound!, Trn Research InalJUik, 1932. 31 J G A Luijtcn and G. J M. van Jt. .,irk, Ini etugoilont In Ihr firId of organa nn ehemhtry. Tin Research Institute. 1931. 39 J. W, linden. DS Davies and R. D Williams, Bloehrni. J., 91 (1966) |4F. 60 J. M names and P. S Magee, J Pmhol. BJCtenoi, 73 (1951) 267. ' 61 E. L. teenage, Oirin. II erf, 93 [1964)66, 62 E. E kentiga, 12th Ini Congr. Enlomol., London, July 1-16, [964. 63 A. K Sijpeticlin, Airdtd Landhuur hvgrtrh Oprorkingma. Stool Ornr, 24 (1939) >30. 64 E Kroller, Oral Lehrimn Bamltrh., 36 (I960) 190 63 P. D Pale and R. L. Hays, / Eton. Emonnd, 61 (1966) 32. 66 G N Smith, F. S. Fisher and R. J Axelrod, cited in H. O. Corbin, J. Ait. Ofte Anal, Chem., 33 (1970) 140. 67 J B Knaak and L. i Sullivan, Tnxieal Appl. Pharmarol., t 0966) 173. 64 J R M Innes, B. M LllamJ. M G. Valerio, L. Peirucelh, L, Frsltbcm. t. R Hart, A. J, Pullotia R R. Bates, H. L. Falk, 1. S. Gan, M. Klein, 1. Mitchell and 3. Peters, J. Sot. Contrt Inti. 42 (1969)1101. . 69 R. L. Carter and F. 3 C. Roe, Food Cotmri. Toxicol6 (1964) 123. 70 E Bovland. R L, Carter. J. W Gorrod and F. J. C. Roc, Ear, J. Canerr, 4 (1964) 233. 7) F. Gnepentrog, Briir Fuihvf Anal. Allg., 126(1962)243. 72 A Rosrn and H. Ungar, Conrrr Bn , 17 (1937) 302. 73 E. F. Stulla, H Sherman and J. A. Zapp, Jr., |0th Ann. Meet. Sex Toxicol, Washington, D C . March 7-1t, f 971. 74 P. S, Stensby, Soap Chrm. Spec., 43 (1967) 41. 73 P. S. Stensby, J. Am. Oil Chrm. Sat., 43 (1961) 497. 76 E. Bingham and H. L. Falk, Food Cotmri. Toxicol., I (1970) 173. 77 E. Arrhenius, personal communication. 71 S. Avanzr. Coryologio, 6 (1954) 134. 79 S Avanrr. Cor) aingm, 6 (1954) 160 40 R D Stewart, J. Am. Med Alt., 201 (1969) 1490. 11 R 1. Vernon and R. K Ferguson, Arch. Enrlron. Health, II (1969)194. 12 A. Frtborski, Brtt. J. lad. Mrd., 26 (1969) 1490. I' P H Gchring, Toxicol. Appl Fhormacol., 13 (1961) 217. 14 J. W, Daniel. Biothrm. Fhormacol, 12 (1963) 793. 13 J F. Powell, Bril J. lad Mrd., 2 (1943) 141 16 G. G. Scansetti, G. F. Rubino and G. Trompeo, Med. Loo., 30 (1939) 743. 17 J. R. Cooper and P. J. Friedman, Btoehtm. Fhormacol., 1 (1931) 76. It S. Yllner, A.-iarr, 191 (1961)120. 19 A, Banhelmess. Arznrmt .fern*, 6 (1936) 137. 90 A Goldstein, W. J. Schull (cd)., in Mmioiiont, Univ, of Michigan Press, Ann Arbor, Michigan, I960, p. 172. 91 H Zollinger. Datro and Ago Chemutrr, Iniertnenee, New York, 1961, p. 117. 92 Dm. Fat. 941, 4(9 (1939); C. A. 60(1962) P67IIA. 93 U. S. For. 3, 162, 371 (1962): C. A. 61 (1963) 63I2D. 94 V. S. Fat. 3, 131, 321 (1961). C. A 62 (1964) 14366F 93 C. S. Rondctlvcnt and S J David, J Org Chrm., 22 (1937) 200. 96 G. A. Usbeck, J. W. Jones and R. K. Robins, J. Am. Chtm. Sot., 13 (1961) 1113. 97 Z. B. Papanastasslow, R T Brum, E While and P. L Levins, J Med Chrm , 9 (1966) 723. 91 Y F. Shcalcy, C. A. Krauih, L. B Holum and W E. Fitzgibbon, J.Fhorm Sei., 37(1961) 13. 99 H. Druekrey, S, Ivankovie and R Prcutimann, Plaineritirnichafrea, 34(1967) |7|, 100 M L. Murphy, Clin Free Chddrru't Hvtp, 11 (1962)307. 101 H. Druekrey, S. Ivankovie and R. Preussmann, Experlenlio, 23 (1967) 1042. 102 H Druekrey, Anger. Chrm ,9 (1970) 742. Sei, Total Enrlron., 1 (1972) 139 WQNS 072153 I I 103 11. Drucfcrcy, X. Preussmann, 5. IvankOMe and D. Schmahl, Z. Krehtfuneh , 69 0967) 163. 104 R. Preusimann, H. Dru,*> .i.d J. Buctw'kf. Z- Krektfartrk., 7| (14^'t) r.l, 103 R. Preusimann, A. Von Hodenborj and H Hcnty, Bioehcm. Bharmartil., IS (1969) 1. 106 R Preusimann aod A. Von Hodcnbcrg, Btochem, fharmoto!., 19 (1970) 1303. 107 O. Oimroih, Bee., 36 (1903) 909. ~ * [OS O Dtmroih, Bet.. 31 11903) 670. (09 L, H. While and H. Seherrcr. Teitnhedron Lett. (1961) 7SJ. 110 R. I'wmmann, H. Schneider and F. Epplc, Arsoeim ~Forteh, 19 ((969) 1039. Ilf R. Preusimann, H. Druckrey, S. IvankOnc and A. Von Hodcnberg, Ann. N, Y, Acod. Set., 163 (1969)697. M3 If. Kmwl, Z. Mi'ifof Chew. 340 (1963) 210. M3 If. Fischer, Z. PAjiiof Cktm., 60 (1909) 69. 114 H. Koisc) and S- Doehnnj, Z. fhytiol. Chtm., 340 (1963) 221. 113 H. D. Hodman and W. Muller, Biochlm. Btophyt. Acta, 123(1964)421. 116 L, F. Cav alien and A. Bendieh, J. Am. Chem. Sof., 72 (1930) 2317. 117 F. Pochon and A M. Michelson, Btochim. Biophyt. Acta, 149 (1967) 99. 111 E. M. Moudnanakn and M. Beer, froe. Not. Acad. Scl., 33 (1963) 364. 119 A Pctk.iu and i. Hnogstraatcn, J Am. tod. Nyy. Am., 26(1966) 310. 120 G. Young. A. Pcikau and J. Hoogstraaten, J, Am. lad H)g. Asj., 30 (1969) 7. 121 ' E. Guiltric and O. E. Acre*, Bolt. Cariron. Camam. Toxicol., 3 (1970) )46. 122 T. J. Haley, L. E. Tcirick, N. Komctu, P. Williams, H. C. Upham and L. Bnormash, Toxicol Appl HmrmaCol., 1 (1939) 313. * 123 H. G. Parkes, ftor. Key. Soc. Med, 63 (1970) 10. 124 H. Elkins, G. W. McCart, H. G. Brugsh and 3. P. Fahy, J, Am. Ind. Hyf. Att., 23 (1962) 263. 123 A. Munn, Tram. Ate lad. Med. Off., 9 (I960) 134. 126 G. M. Hama, Arch, tod Health, 16 0937) 232. 127 A. Munn, Aon. Ocrup. Hyf., I (1963) 163. 121 K. S. Williamson, Ttant. At*, lad. Med. Off., IS (1963) 29. 129 3. M. Pcten, Croc. Bay. Sac Med., 63 0970) 14. 130 D. P. G. Paisley. Bert. J. lad. Med,, 26 (1969) 79. 131 T. E. Lipatova and R. A. Vcaclovakd, Vyiohomol. Soedm., Sec. A., 11 ((969) 1439; C. A., 71 (1969) 105131B. 140 Scl. Total CooIron., ) ()9T2) HONS Q?215^