Document 6wEx2bmqe4qa93z7GzEO6N8zg

The ScieneNof the Total Environment Llscvior Publishing Company, Amsterdam -- Primed in Belgium I POTENTIAL ENVIRONMENTAL CHEMICAL HAZARDS PART III. INDUSTRIAL AND MISCELLANEOUS AGENTS L. I ISIIBIilN wild W. Ci. I'LA M M National Institute of Environmental Health Seienees, National Institutes of Health, TithUc Health Senlev anti He/tariinenl of Health, Et/ttcalioit and Welfare, Research Triangle I'ark, North Carolina 277UV (U.S.A.) (Received May 19th, 1971) INTRODUCTION Iii the previous paper, die potential environmental chemical hazards related to drugs' and feed mcdicanls 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 and com monality of hazards present in 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, and their inertness and/or safety is far from being established. Polychtorobiphenyls. Polychlorinated biphenyls (PCB's) are produced by various manufactures and are represented as "a series of inert, chemically resistant, fuc-reinrding 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"'3. The series of Aroclors (Monsanto) are marketed under various numbers and consist of mixtures of chlorinated biphenyls and terphcnyls. The 1200 series relates to the biphenyls, the 5400 series to the terphenyls, and the 4400 scries to a mixture of bi- and terphcnyls. The annual production of PCB's in the Western world till 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, viz., 5` 6' 23 Set. Total Eat iron., I (1972) 117 DSW 033673 C.W, I I I i STLCOPCB4017635 c.w/ r* For example, three monochlorobiphenyl isomers are 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'pcntachlorobi phenyl). The chemical properties that make polychlorobiphcnyls desirable industrial materials are 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 PCB's include impregnation of cotton and asbestos for braided insula tions of electrical wiring, plasticizers of vinyl chloride polymer freons, a plasticizer in wire and cable coatings and in ballasts for fluorescent fixtures. Because of their thermal stability and fire resistance, the PCB's also find application in high-pressure hydraulic fluids, heat transfer agents, machine tool cutting oils, specialized lubricants and gasket sealers. Miscellaneous uses include; formulation into epoxy paints, protective coatings for wood, metal and concretes; adhesives and in carbonless repro ducing paper; and as plasticizers in plants, resin and chlorinated rubber and have been recommended for improving lindane residues4; they have also been shown to increase the insecticidal properties of DDT. Polychlorinated biphenyls along with DDE [l,l-dichloro-2,2-bis (p-chlorophcnyl) ethane] are reported to be the most abundant of the chlorinated aromatic pollutants in the global ecosystem5. Extracts from tissues of sea eagles, pike and salmon5 as well as in various species of British wildlife6 contained PCB's and in the latter instance it was found that in birds' liver and eggs the PCB residues were greater than the organochlorine 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 samples6,9-n. Polychlorinated biphenyls have been found in human adipose tissue12, 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 organochlorine insecticides. The PCB's are extremely stable; chemically, fat soluble and hence persis tent in the environment. Polychlorinated biphenyls and polychlorinated triphenyls have been found to be cslrogcnically active15 -- 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 DDT5. 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 birds5 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 ScJ. Total Environ.% l (1972) DSW 033674 STLCOPCB4017636 found in chicks'618 and Japanese quail7 after ingestion of PCB of American (Aroclor) and French (Phenoclor) origin respectively. The occurrence of lesions resembling those of chick-edema in birds fed PCB18-1'7 has also been reported. In most recent work, Vos et al.2 described the identification and toxicological evaluation of chlorinated dibenzofuran 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 pcntachlordibenzofurans (I and 2, respectively) as toxic factors in the PCB's Clophcn A-60 and Phenoclor DP6. \2 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 used21. PCB can react with sodium hydroxide at elevated temperatures to yield phenolic compounds and can for example yield polychlorohydroxybiphcnyls 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 et al. 23 who showed that many of the PCB's were toxic to Drosophila melanogastcr Meigen and houseflies Mttsca dontestica L. (but to a lesser extent than dicldrin or DDT: their toxicity increased with a decrease in their chlorine contents). Moreover, sublelhal 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 tests. DOO Cl Cl DOE Philialate ester plasticizers. Phthalate esters are among the most widely used compounds as plasticizers in a variety of lacquers, varnishes, paints, co-polymers and plastics. Sr/. Total Environ., 1 (1972) 1 )9 / W. DSW 033675 STLCOPCB4017637 I I I C.W. z1 < > In. general, pluhiilalc cslcrs have been reported to have a lower order of toxicity for experimental animals35 *'*' and thus have been approved for use in packaging materials for food intended for human consumption. However, Guess and cowerkers37"'0 have demonstrated the subtle toxicitics (tissue culture cell death or enhanced growth, changes in antibody reactivity and irritation its evidenced by dye extra vasation) of plasticizers and stabilizers used in the manufacture of polyvinyl plastics. Citrate and phth.ilatc ester plasticizers such as bis (2-elhylhexyl)phlhalaic and ncetylated tri-butyl citrate were found to be leached from plasticized polyvinyl chloride (PVC)3'. The significance of exposure time on the leaching of these plastici zers from PVC is important since the plastic is commonly used in in-dwelling surgical devices, e.(j. catheters, and itt pharmaceutical containers. Callcy cl al.i0 described the toxicology of a series of piuhalate 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 {e.t7. triethyl, acetyl tricthyltributyl- and acetyl tribulyl citrate) have well defined and marked pharmacological activity when administered parentcrally (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. Phthalatc ester plasticizers were found to be extracted by blood from plastic tubing and from plastic bags used for blood storage. Bulylglycolbulyl phthalale (BGBP) was found to be metabolized by isolated perfused rat liver to glycolyl pluhalatc. A second phthalale ester plasticizer di(2-elhylhexyl)phlhalatc (DEHP) which is commonly used in plastics in biological and medical practice w'as 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 bags35. C-0-C4H5 Ho o.. -OCH0*1,1C- 86BP a.COOH Co11 -OCH,`COOH Glycolyl phthalale COOCHjCHtCjHsMCHjPjCHj ^jj-COOCH,CH(C,Hs)(CHj JjCH, DEHP ' The isolation of plasticizers such as DEHP from the anticoagulant citric acid-dextrose solutions stored in disposable polyvinyl chloride blood bag assemblies has also been documented30-37. In addition to evidence of phthalatc ester plasticizers in certain foodstuffs such as milk38, there has been evidence concerning the presence of these plasticizers in animal tissues such as beef pineal gland30 and heart40. : The teratogenic effects in the chick embryo caused by esters of phthalic acid was described by Bower et /.41. Dibutoxyethyl phthalale caused teratogenesis in the 120 Sci. Tola! Environ., t (1972) QSW 033676 STLCOPCB4017638 developing chick embryo and also di-2-mcthoxyclhyl- and octa-isodccyl phihnlalc were capable of causing damage to the central nervous system of the developing chick embryo. Toxigenic effects in different mammals caused by several esters of phthalic acid have been well documented2''-47 4S. The cITect of chemical sterilization of plastic items and their contents with prim arily alkylating agents such as ethylene- and propylene oxide adds yet another dimen sion to the toxieilics and potential hazards that might 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-(2hydroxyclhyl-mcrcapto)benzo!hiazolc] of the vulcanization accelerator 2-mcrcaptobenzolhiazole was found to be more toxic than the precursor using cells in culture mice and rabbits46. O'Leary and Guess47 demonstrated the homoiyzing 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 tin compounds. Organo tins are compounds which contain at feast one tin-carbon bond and if all radicals attached to tin through carbon are designated R, and all other substituents X, the following series are obtained: RaSn, 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 pestlcidal utility are the derivatives of quadrivalent tin. Organo tin 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 Aims; preserve the trans parency of polyvinyl chloride. Compounds used for this purpose are of the type R2SnX (e.g. dioclyl tin and dibulyl tin dilaurales, malealcs, 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 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-octylmercaptoacelalc) and di-octyl tin indicate 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 arc employed in a host of other applications that include: (a) fn rubber products and paints: as antioxidants and anticracking 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 11 Cl formed if a short circuit occurred in transformers, etc., using pyranols or chlorinated diphenyls (tetraphcnyl tin is usefully employed for this purpose); (c) Tn lubricants and textile oils: as acute oxidants and corrosion-reducing adjuvants for lubricants; as anti-oxidants for textile oils; (d) As activators and catalysts: in oxida te/, Tvml Etwiron., 1 (1972) 121 DSW 033677 **V lion, polymerization (polyesters and silicone elastomers) as 7ieeler-Nalla type catalysts for polymerization of olefins; (e) Tin-containing polymers: numerous tincontaining polymers and macromolcculcs 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 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: (n) agricultural fungicides: Iriphcnyl tin acetate (Brcstan; I'eniin acetate) and triphenyl tin hydroxide (Du-ter; fentin hydroxide) and bis(lri-n-bulyl tin) oxide (TBTO); K^ & Sn-O-COM -CH.J UQ Du-ter CjOo ! C,, h9- Sn-O-Sn -- C.H. TBTO (/>) General fungicidal action (e.g. Iriphcnyl 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 preservative, slimicide; paper production process paper; (c) Bactericides and biostats: disinfectant (triantyl tin), bactericides for seeds; (d) Anthelmintics: against worms in poultry (dibulyl tin laurate, tin oleate, lelraisobuiyl tin); _(e) Nemalocide: p-bromophenoxy Iricthyl tin; (/) Herbicides: vinyl tin compounds (trivinyl tin chloride); (g) Rodent repcllants: protecting food in treated bags (tributyl tin chloride, triphenyl tin chloride and acetate); (/t) Molluscidcs: iriphcnyl tins; (/) Ovicides: trialkyl and triaryl tin chlorides (e.g. R3SnCl, R being methyl, ethyl or propyl) as insecticides and ovicides in combination with DDT or pyrclhrum. 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 toxicilics50 of (he (rialkyl tins are in the order: triethyl>trimethyl> lriisopvopyl>lri-n-bufyl. (The decrease of toxicity with increasing length of alkyl chain is analogous to that observed with di- and telraalkyl tins). The conversion of telraalkyl tins to trialkyl tins51-53 in vivo (as demonstrated for tetraethyl tin) accounts for the latent toxicity of the telraalkyl tins, with the site of the conversion being the liver48,53. From the toxicological point of view, the tetraal- kyl tins can thus be considered to behave in a manner analogous to their trialkyl tin counterparts54. (This conversion of a telraalkyl to a trialkyl metal has also been shown for tetraethyl lead48-55-56, and may be a general phenomena). Once tetraethyl tin 122 Scl. Total Environ., 1 (1972) c.w. DSW 033678 STLCOPCB4017640 lias been converted to triethyl tin. it appears to persist in the body in that form without apparent further reaction to the dialkyl derivative. The trialkyl tin ion is a stable entity which is toxic per sc and persists for some time in the tissues*2. Long-term feeding experiments with tricthyl tin have disclosed some testicular atrophy in addition to lesions confined to the central nervous system49. Tricthyl tins and diethyl tins ionize in aqueous solution*7'*8 with production of the univalent (C2ll5)Sn* and divalent (C2fl})2Sn+ + cations, respectively. It is reasonable to assume that trialkyl and triaryl tins exert their biological action as RjSn+ ions or as the undissociated hydroxide RjSnOH formed on dissociation. The dealkylation of diethyl tin by the rat has been reported*9, with diethylation occurring in both (he gut and tissues. The induction of biliary and hepatic lesions by dibutyl tin salts in rats has also been described00. Triphcnyl tins, (CoHj^SnX, (where X was halide, hydroxide, alkyl or alkenyl, aryl or alicyclic radicals and ester groups or organic acids) have been found to be chcmosterilanls61-62 when fed to adult houseflies. Many of the triphcnyl tins were found to be superior as chemoslerilants, to the aziridincs, if both groups were administered orally. The highest chcmostcrilizing activity was shown by triphcnyl tins in which X is mobile and the triphcnyl 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 state in which triphcnyl tins are applied to plants, they are susceptible to light and oxygen53. Phenyl 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 ntonophenyl tins64, viz., (C&HjljSn - -------- > (C6M,)jSn/; -------- [C6H5Sn/( J -------->- --SI n-- \ \I Pate and Hays6* described several degenerative changes in 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 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 Iumina. Tricyclohexyl tin hydroxide is used as a miticide (Plictran, miticide) for apples, pears and citrus fruits. Exposure of tricyclohexyl 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 lime. 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 litteirutt., 1 (1972) 123 DSW 033679 STLCOPCB4017641 *' * Bisphcnol. Bisphcnol A[(2.2-bis(p-hydroxyphcny|) propane] as a copolymer is an important monomer in several resins used as I'ood packaging materials for industrial processing and consumer use. C Hj Bispftenot A The mouiholic hue and properties of bisphcnol A are of importance since some unrcaclcd monomer does migrate to food. The metabolism of bisphcnol A in the rat following oral administration"7 indicates that less than 1% of the material present in urine was free bisphcnol A while the feces contained 35% free bisphcnol A and an additional 35% was identified as a hydroxylaled product of bisphcnol A. It is important to also note the marked exlrogenic activity of bisphcnol AIS (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. Gcnerically, however, the organic additives could be grouped into a dozen or so chemical classifications. Among these arc the thiurams, dithiocarbamates, thinzoles, sulfonamides, thioureas, guanidines, amines, amides, quinolines and phenols. The categories of utility include accelerators, activators, antioxidants, blowing agents, vulcanizers, retarders, reinforcing agents, plasticizers, dusting or dipping agents and inert fillers. Table 1 illustrates the structures of a number of classes of common rubber additives. It is of interest to note that ethyl selcnac (selenium diethyldilhiocarbamalc) which is used both as rubber accelerator and fungicide is carcinogenic in the mouse68, while the rubber additive polymerized A'-nitroso-2,2,4-trimethyl-l,2-dihydroquinolinc has recently been found carcinogenic in the rat69,70. The dithiocarbamates and their metal salts have also wide utility as fungicides and their decomposition products include: alkyl thiourea, ethylene thiuram monosullidc, carbon disulfide, carbonyl .sulfide, hydrogen sulfide, metal sulfide salts and elemental sulfur. Both thiuram71 and thiourea are carcinogenic for the thyroid72, and 4,4'-mcthylenc bis (2-mcthylanilinc) and 4,4'-methylcne bis (2-chloroanilinc) 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 varying 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 arc deposited in minute amounts on fabrics during laundering and emit a bluish fluorescence when exposed to ultraviolet radiation, thus improving the appearance of whiteness or brighteners in the fabrics. 124 Sci. Total Environ., 1 (1972; DSW 033680 STLCOPCB4017642 TAI1LC I COMMON RUHUCR ADDITIVES Category Accelerators Tetramclhylthiurum disulfide Tel ra methyl thiuram monosulfidc Dipontamclhylcncthiuram hcxasulfidc Structure 3 CH, CH. 'n-Cri -S-S-Cn -N VCH, CH3\ CH ' 3 N-CII S ,CH, S -- CII -n' CH, CHj-CHJv /Hj-CH^ HojeC.. N-C-(S).-C-N' " `'CH, NCH2-CH/ M n ^CHj-CH/ * Melallodimelhyl- and dicthyldilhiocarbumatcs l"H3''N_c_s _M _ - _c _ CH 3/ ii S M Cu. Pb, Zn VCH, CjHj H,N - C - S - Ci-!HhS S n.2; Cd n : Se, Tc Hciuolhiazyl disulfide N, ,N. , 'c-S-S-c' ^ s' Ss^ 2-Mcrcap(oben/.othiazolc i y\-sH A'-Oxydicihylencbenzothiazolc-2-sulfenamide A'-Cyclohexyl-2-bcnzothiazolcsulfcnamidc Trimethyl thiourea Diphenyl guanidine CHj-CHj^ CHj-CHj N. ,CH,CH, L II C-S-N-c( CHj ^^'S ^ ch,ch/ CH, CH, />-CII ch, $ -N.NH. c6h5n-cnhc6h4 H NH Scl. Total Environ., I (1972) 125 c.w. DSW 033681 STLCOPCB4017643 TABLE I (continued) Category A ntioxiflanls Plienyl'/i-ruiplithylaminc Oiphcnyl-p-phenylencdiaminc p-lsopropoxy diphenylaminc llydroquinonc monobcnzyl ctlier l,2-Dihydro-2,2.4-trimclhyl quinoline Aldol-a-napluhylaminc Structure M 2,2-Mclliylcnc-bis-(4-nicthyl-6-/<'/'/-butyl phenol) Anti-ozontmts A',/V'-Di(2-ociyl)-p-phenylcnc diamine HH HH c6hu-c-n-^^n-c-csh,, CHj CHj A'-(l,3-Dimolhylbutyl)-N'-phenyl-p-phenylcncdiamine Mowing agents Azodicar bonamidc H,N-C- oII N-C. NH, oII Dinitrosopeniamclhylcnc tetraminc (3,7-Diiiitroso-l,3,5,7-lctraazabicyc]o[3,3,l}nonane) HjC-N --CH, III ON-NI CI H*-NI -NO HjC--N--CHj, 126 Scl. Total Em'iron., 1 (1972) DSW 033682 STLCOPCB4017644 TABLE I (continued) Category Retarders /V-Nilrosodiplutnylaminc Salicylic acid I'iusiictzcrs Dibulylphthalatc Structure NO COOH tr COOC,,h9 [roc'H> DioctylphIhulale Ibis(2-cthylhcxyl)phlhalalc] COOCHaCH(CaH5)(CHa)3CH3 jL COOCWjCH-(CH2)3CH3 Vulcanizing agents 2,5-Bis(r<w-bulyl pcroxy)-2,J-dimcthyl hexane CHJ CH3 CHJ-C-CH3 CH3-C -CH3 11 oo , 0i - . 0T ^ CH^-C -CH5-CH5*-C-CH3 CH3 CH3 Fungicides /V-Trichloromcthyhhio-4-cyclohcxcne-1,2- dicarboxiniidc (Captan) Miscellaneous additives Polymerized A'-nitroso^,2,4-trimethyl-1,2- dihydroquinolinc o li Cx>s-"" II 0 CH, 13 ^'n-c'-chj NO 4,4-Dianiinodiphcnylmcthanc Set. Total Environ., 1 (1972) C.W.' 127 DSW 033683 STLCOPCB4017645 table i (commuoti) Cuh'xory *4,4 ' Methylene bis(2chloro;milmc) 4,4Methylene bis-(2-moihyl;milinc) Structure Cl ci The most commonly used cotton brighlcners, shown in Fig. 1A arc bis tria/inyl derivatives of 4,4'-diaminoslilbcnc-2,2'-disulfonic acid. These so-called CC/DAS brighlcners arc prepared from 2 moles of cyanuric chloride (CC) and I mole of the disodium salt of diaminostilbcnc disulfonic acid (DAS). With the exception of briglitener DMDDEA all arc reaction products of I mole of CC/DAS with 2 moles of aniline. Brighlcner DMDDEA is the reaction product of 1 mole of CC/DAS and 2 moles of sulfanilic or mclanillic acid. A number of typical structures of brighteners that are stable to chlorine bleach in the wash liquor are shown in Fig. IB. These are benzidine sulfonc disul fonic acid (brighiencr BS), naphthotriazoylstilbene sulfonic acid (brighlcner NTS, R = I I) and bcnximidnzolyl (brightener BBI) derivatives. The general structures of typical nylon and wool brighteners arc shown in Fig. 1 C and include the derivatives of amino coumarin (brighlcner 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. I D and include bisbcnzoxazolyl (brightener BBO), naphthoxazolyl (brightener NOS) and naphlhotriazolyl (brightener NTSA) derivatives. The (CC/DAS) brighteners behave like direct, dyestuffs on cotton74 Brighte ning of hydrophobic fibers such ns 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 the liquor. It is claimed that the total concentration of brightener in the liquor of the modern American home laundry would be only 3-10 mg/liicr, even if ail the brightener were in solution at one time75. Of all laundering aids commonly added to the wash liquor apparently only active chlorine products affect the stability of some brighteners. The extent of attack on the so-called bleach unstable brighteners depends on their chemical structure, temperature, amount of bleach used, etc. Differences in stability to hypochlorite and dichloroisocyanurate bleaches I2S Sci. Total Environ,, 1 (1972) DSW 033684 STLCOPCB4017646 r-.v exist also among the CC/DAS brighicncrs. 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. X H H Brightener designation TA DM B H DMCA H ODEA SOjNa DMDDEA Brigntener DP Brightener BBO XR Brightener N05 Brightener NTSA l:ig. 1. Structures of optical brighicncrs. A, Bis triazinyl derivatives of 4,4'-diaminoslilbene-2,2'disulfonic acid (CC/DAS cotton briglilcners). B, Blcacli-stablc brighicncrs. 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), disodiunv4,4'-bis (2,4-dimelhoxybenzamido)-2,2'-slilbenedisulfonatc (4), diso dium-4,4'-bis (4,6-dianilino-S-triazin-2-yl)-amino-2,2'-stilbenedisulfonate (5). An. Total T.iwiron., I (1972) 129 I i DSW 033685 STLCOPCB4017647 *' * ,, 0 5 Tumors were not found in any mice receiving topical application of the optical brightcner in DMSO alone, but with addition of ultraviolet light (6 h/day on 5 days/wcek to a germicidal lamp having 60% of its energy at 254 m/t) a high incidence of tumors developed that resembled grossly the tumors (squamous cell carcinomas) arising from repealed application of carcinogenic polycyclid aromatic hydrocarbons. Since the use of optical brighleners is widespread in laundry products such as detergents, starches, fabric softeners, in fabrics and paper and in miscellaneous products such as toilet soap and all-purpose cleaners, questions relating to the poten tial hazard of dermal contact and/or penetration of the above brighteners as well as those listed in Fig. 1 A-D, are 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-methyl coumarin) (7) that is used as a whilener in laundry detergents as well as 6 a brightcner in dentrifrices. It 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 cepa78,79. Miscellaneous agents Trichloroethylene and tetrachloroethylene. Both trichloroethylene and tetrachlorocthyicne (perchloroethylene) 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 phenol-formaldehyde, urea-formal|30 SW. Total Environ., I (1972) DSW 033686 STLCOPCB4017648 dchydc and epoxides in the production of special fiber glasses. Tclrachlorocthylene is used in small amounts as a commodity fumigant. Both trichloro- and tetracldorocthyicnc have been shown to be neurotoxic80~8\ but tclrachlorocthylene is believed to be more hcpatoxic than the irichtoro derivative. The metabolism of''6C-labeled trichloro- and tetrachlorocthylcnc was studied by Daniel8'' who found that both compounds arc largely excreted through the lungs. It is well known that trichloroethylene is excreted in the urine as trichloroacetic acid and trichloroclhanol in all species of experimental animals studies. In addition to these compounds, monochloroaeetic acid is also a urinary metabolite of man. A point of major importance is the nature of the rearrangement which results in the formation of 2,2,2-trichlorocthnnol and trichloroacetic acid from 1,1,2-trichloroclhylcne. This has been shown to be an intra-molecular rearrangement of trichloro ethylene and no exchange of chloride with the body chloride pool. Fig. 2 illustrates the metabolic pathways of trichloroethylene and tetrachloroethylene. Cl2C = CHCl Epoxiaation --------------------- Trichloroethylene CljC------ CHCl Intramolecular rearrangement CCl, Reduction. CHO \pxidation CCi3CHjOH Trichloroethanol CCljCOOH Trichloroacetic acid CljC =CCtj Eooxidation --------------------- - CI2C------CCIj Tetracniorocthyiene Intramolecular rearrangement CCIjCOCI --Hy-d---r-o--l-y1-s--i-s--- _ CCljCOOH Trichioroac etyl Trichloroacetic chloride acid Fig. 2. Metabolic pathways of trichloroethylene and tetrachloroethylene in the rat. 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 aclinic radiation. Rearrangement of the oxide yields trichloroacctaldchyde (chloral). The formation of chloral in men exposed to trichloroethylene vapor has been reported88. 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 tetrachloroethylene may also involve the intermediate oxidation formation. For example, following exposure of tetrachloroethylene vapor for 2h in mice, the urinary metabolites included 52% trichloroacetic acid, 11% oxalic acid and traces of dichloroacelic acid. An epoxide intermediate was postulated to account for these products88 as shown in Fig. 2. ScL Total Environ.* I (1972) 131 /*V 1 lie acid chloride would be rapidly hydrolyzed to trichloroacetic acid and neither trichlorocihanol or oxalic acid would be formed. In till of the above discussion of the metabolism of trichloro- and letra- chlorocthylcnc it is important to note the mutagenicity of the intermediate chloral hydrate81'1'0 as well as the potential mutagenicity and carcinogenicity of epoxides in general with sped lie reference to tell achloroethylene 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- trinuoro-2-bromo-2-ehIorocthanc) (9) and lluoroxcnc (2,2,2-trifluoroethyl vinyl ether) (10). H CFj-C-CI I Br 9 CFjCHiOCH^CH, 10 Trifluorocihanol. triOuoroacetaldehyde hydrate and trifluoroacetic acid arc the metab olites of both anesthetics and their formation may proceed via an intermediate epoxidaiion and intramolecular rearrangement as described for trichloro- and tetrachloroethylcnc in Fig. 2. Little is known of the chronic toxicilies of the above fluoro-mctabolitcs. Triazenes. Certain triazenes have technical importance as intermediates in the "Rapidogen" dyeing process'1 and aryl dialkyl triazenes have been patented for use as rodent repcllants and herbicides'1"94. Other triazenes have been evaluated as carcinoslatic agents95-98. 1 -Phenyl-3,3-dimcthyltriazene is both a potent carcinogen99 and teratogen in rats100,101. Certain other 1 -aryl-3,3-dialkyl triazenes of the general formula: " ^alkyl ary!-N-N-N^ 1 2 3 \ulkyl arc also potent ncmotropic carcinogens in rats102. The potency increases in the order: phenyl, 3-pyridyl, pyridyl-tV-oxide, and methyl and ethyl, respectively. In acid medium, aryldialkyltriazcncs arc hydrolyzed to yield aryl diazonium salts and a secondary amine. (It is of importance to note that methyl phenylnitrosaminc and phcnylnitrosourea are both carcinogenic102-104 forming probably phcnyldiazoniumion as a reactive intermediate.) Preussmann vt al.l0i studied the enzymatic dealkylation by rat liver and lung microsomal fraction in vitro. l-Phcnyl-3,3-dimethyl triazene was found to be oxidat ively dcalkylaicd to form the corresponding aldehyde (formaldehyde) and aniline was also shown to be a metabolite. The results suggest that carcinogenic aryl dialkyl triazenes arc dcalkylated to form aryl-mono alkyl triazenes as proximate carcinogens. Aryl mono-alkyl triazenes are known alkylating agents and the carcinogenic activity of triazenes was explained by alkylation of biopolymers (nucleic acids). Fig. 3 illus trates a proposed activation mechanism of carcinogenic phenyl dimethyl triazene 132 Set. Total Environ., I (1972) DSW 033688 STLCOPCB4017650 to form phenyl monomethyl triazcnc as proximate carcinogen and carbonium ion as ultimate alkylating agent. The proposed reaction mechanism, however, docs not exclude that certain triazcncs may act by a purely chemical heterolysis to form aryl diazonium ions as reactive intermediates (for example, the very local sarcomas after subcutaneous injection of l-phcnyl-3,3-dimeihyl triazene may be explained on this basis). /CHj N=N-NV C K, Emymatic hyoroxyiattoft ch3 ' N = N-N CHj-OH + H^O Phervy>0`friethylirta2ene l-Pheryi-3-methyJ-3hydroxy methyl triazene N = N-n(CH:> + CHjO Formaidetiyde nd ^r~^-NH-N = N-CHJ r HjO Phenyimonorrtethyltriaxert* + CHO*-N = N-CH3] -OH* Aniline + Methyidiazohydroxide CH, " Carbonium ion as alKyiating agent t7ig. .t. Proposed activation mechanism of carcinogenic phcnyldimcthyltriazcnc to form phcnylniononicihyltriazone us proximate carcinogen, and carbonium ion as ultimate alkylating ageiu'0J. The in vitro alkylation of guanosinc, RNA and DNA with aryl-monoalkyltriazenes to form 7-alkyIguanine was demonstrated by Preussmann and von Hodenberg106. Aryl monoalkyltriazcncs are alkylating agents107-110 as shown: NH-N=N- CHj + H* + N2 + CH3* The alkylation of biopolymers was earlier proposed as the first step in carcino genesis by aryldialkyliriazcncs105. Reactions of l-phenyl-3-monomelhyl- and nionocihyl triazcncs, respectively, with guanosine, RHA and DNA resulted in the formation of 7-mclhyl and 7-ethyl guanine. It 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. Scl. Total Environ,, 1 (1972) 133 c.w/ OSW 033689 1 i i i i i i i STLCOPCB4017651 /* * v The first and decisive step in the activation of these groups in an enzymatic a-C-hydroxylation of an alky! 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 azoxyalkane cycasin (mcthylazoxymethanol glucuridc) (11) is transformed to its nicthylazoxymcthanol (12). + Cllj-N-N CII,0-($-0-CIil,0, CHj-N = N-CHjOH o- II o- 12 This proximate carcinogen is then easily hydrolyzed to formaldehyde and an alkylating agent, probably methyl diimine oxide, which is a tautomer of mcihyldiazohydroxidc. Azoalkancs could possibly be oxidized in vivo to yield azoxyalkancs, 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 Prcussmann et al.ul. R-CHj-NH-NH-CHj-f? R-CHj-N=N-CHj-R o R-CHj-NrN-CHj-R R-CWj-N=N-CH-R I OH O R-C H R-CHj--N=N-H a-C-hydroxylase O R-CH,-N 1 = N-CI H-R OH - R-C ^ H O H-CHrN=N-H CHj-R l-ig. 4. Proposed reaction 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 (viz., (a) nitroso compounds, (b) hydrazo, azo, and azoxyalkanes, and (c) 1-aryl-3,3-dialkyl triazenes) are the same, c.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. Total Environ., I (1972) DSW 033690 STLCOPCB4017652 enzymatic activation. The detection of carcinogenic properties in diazomethane and diazoacctate as well as in directly .acting alkylating agents such as alkyl halides, aziridincs, dialkyl sulfates and 1,3-propane sulfone gives considerable support to the alkylation theory102. A number of reported reactions of mono-nucleic acids with diaz.onium salts in vitro arc informative112-1M. For example, the arylation of guanine in the 8-position by diaz.onium salts has been demonstrated115. Typical compounds formed include <5-p-benzolsulfoguanine (13). Guanine reacts with diaz.onium salts to yield guanine <5-azo compounds which can further reduce to <5-amino guanine and arylamine113,116 while adenine docs not undergo the analogous reaction. Kbsscl112 described the reaction of mononucleotides with diazonium salts to proceed ns shown: o h2n'k^n'1^-n/ R Guanylie acid diazotized suifanthc acid + MjO Xantnidyhc acid The mononucleotides guanyl-, adenyl and cylidylic acid react with diazotized sulfanilic acid at pH 10-11 forming colored dyes (pigments) which absorb strongly at 370-440 m/r. Guanylic 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 starling materials, The pigment formation is inhib ited in the presence of formaldehyde. The reaction products are suggested to be dia zoamino compounds. Set. Toiul Environ., 1 (1972) 135 DSW 033691 Reactions of diazonium sails with nucleic acids were investigated by Pochon and Micliclson117. Diazonium salts obtained from 2-amino-/>-bcnzcne disulphonic acid and 2-aniinonaphthalcnc-l,5-disulphonic acid were found to be highly specific giving 8-subsiiiutcd guanine residues. This type of reagent has been employed to mark DNA for studies by electron microscopy116. . Polyphcnyls. Certain polyphenyl 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 polypheny! mixtures have been reported1At a daily dietary intake of 350 mg/kg or more Sanlowax 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. Sanlowax OM consists of a mixture of biphenyl (4.7%), o-tcrphcnyl (64,1%), m- leiphenyl (25.1%) and /Merphenyi (6.1%); while OMR.E High Boilers consists of high boilers>98%. biphenyl (<0.1%), o-terphenyl (0.1%), /u-tcrphcnyl (<0.l%, /Merphenyi (<0.7) and inorganic (<0.1%). At a daily dietary intake of 33 mg/kg or more an OMRE High Boiler Sample (consisting of terphenyi and radiolytie 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 Acres121. The acute toxicity in rabbits of polyphenyl compounds used as atomic reactor moderator coolants was described by Haley et at}11. Ortho- and meta lerphenyls were the only polyphenyls that caused death after inhalation. Diisocyanates and polyurethanes. The diisocyanates such as toluene-2,4- diisocyanatc (TDI) and methylenediphenyldiisocyanate (MDI) are representative of chemically hghly reactive moieties that will combine with many organic compounds. The industrially useful reactions involve the combination with a resin, usually an organic polyhydric alcohol, to form a high molecular weight polymer of the polyure- eihanc type. Polyurethanes are used as paints and varnishes, surface coatings, flexible and rigid foams, wire coverings and in thermal and sound insulation. NCO TOl NCO NCO TDI is usually prepared from toluene-2,4-diamine and phosgene in a solvent such as o-dichlorobcnzenc 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 azodicarbonamide). 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.ni.123. 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 effects124-129. 136 Set* Tola! Environ., I (1972) DSW 033692 STLCOPCB4017654 i ** 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 diisocyanalcs. 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-cyanales and /V-oxidcs. (The temperature of a soldering iron in normal soldering operations is approximately 300*0 The possibility of a serious incipient hazard in combatting fucs involving buildings and refrigerated compartments, etc., where large quantities of polyurethane foams arc used was also raised by Paisley130. The effects of physiologically active media on polyurethanes were studied by Lipatova and Verclovskii131 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 in the model solution occurred as a result of cleavage of CO-bonds in the urethane group affording RNCOOII and R'OH. The degradation rate was inversely proportional to the number of intermolccular bonds in the polyurethane. SUMMARY Wc have examined but a small number of selected chemical agents from a spectra of environmental areas, viz., drugs1; feed medicanls and pesticides3; 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. 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