organotin compounds: industrial - semantic scholar · however, as the chemistry of organotin...

Environmental Health Perspectives

Organotin Compounds: Industrial

Applications and Biological

Investigation

by Warren T. Piver*

Industial Uses of Organobn Compounds

According to Ross (1), there are threemain areas in which organotin compoundshave product and process utility: (1) heatstabilizers; (2) catalytic agents; (3) biocidalcompounds. Organotin derivatives account forthe fourth largest production of organo-metallics amounting to about 3-4 millionpounds per year as compared with about 485million pounds per year for organolead com-

pounds. Originally, organotin compoundswere developed as thermal stabilizers forchlorinated hydrocarbons which would beused in those applications for which there wasa strong possibility of thermal degradation.However, as the chemistry of organotin com-

pounds became better understood, theirapplication expanded to catalytic and bio-logically active agents.

Heat Stabilizers

Organotin stabilizers prevent the thermaldegradation of many chlorinated compoundssuch as certain types of transformer oils, PVC,poly(vinylidene chloride), chlorinated rub-bers, paraffins, and modified plastics. Theorganotins have also been used to stabilize

* National Institute of Environmental HealthSciences, P.O. Box 12233, Research Triangle Park,North Carolina 27709.

other nonhalogenated compounds of indus-trial and commercial important such as somelubricating oils, hydrogen peroxide, celluloseacetate, polyamides (nylon), polycarbonates,polyethylene, and polypropylene.

Chlorinated Transformer Oils: The useof organotin compounds as stabilizers forchlorinated transformer oils dates back to1932. At that time, the transformer insulationconsisted of paper and mineral oil. Largetemperature gradients across the oil generatedby power fluctuations in the transformer,caused decomposition of the mineral oil to asludge. This oxidative decomposition wasprevented by the addition of tetraalkyl ortetraaryl tin. In 1957 General Electricdeveloped replacements for mineral oils whichwere trichlorobenzene, pentachlorodiphenyl,and pentachlorodiphenyl oxide. Thechlorinated aromatic transformer oils hadmore accurately defined heat transfercharacteristics than did mineral oil. However,when arcing occurred in transformeroperation, these compounds decomposed andliberated HCl which corroded the interior ofthe transformer. Tetraalkyl and tetraaryl tincompounds were added to react with theliberated HCl to form organotin chlorides(and alkanes or benzene). The motivation forusing tetraorganotin compounds was thedesirable volume to efficiency factor forcorrosion prevention: one mole of organotin

June 1973 61

removed four moles of HCl. For example,tetraphenyltin stabilized chlorinated trans-former oil as shown in eqs. (1) and (2).

Chlorinated aromatic transformer oil HCl (1)

(C6H5)4Sn + HCI e+ (C6H5)3Sn C1 + C6H6 (2)

PVC Stabilizers: By far the largestproportion of organotin stabilizer productionis for the stabilization of PVC. PVC resin is awhite powder produced by free-radical, ionic,and emulsion polymerization. In order tomold the resin into finished products, theresin is softened by heating. For unplasticizedPVC, this softening temperature approachesthe thermal decomposition temperature ofthe resin. PVC polymers are particularlysusceptible to thermal degradation duringprocessing and use. Thermal stabilizers aretherefore an essential additive for both rigidand flexible PVC products.

PVC polymers are usually not linearmolecules; therefore, several mechanisms arerequired to explain the thermal decom-position of PVC (1,2). For the general poly-mer structure, which may be linear orbranched, degradation begins at a site. on themolecule either containing or adjacent to atertiary or allylic chlorine atom. These twokinds of sites can act as activating groups toinitiate degradation. Once the first moleculeof HCl is liberated, the reaction is propagateddown the chain, forming eventually a long-chain, colored, conjugated polyene. Beginningwith the linear molecular model of PVC, thisdegradation reaction is as shown in eq. (3),where X denotes the activating group.

CH2-CHC1-CH2-CHCl-CH2-CHC1-X

Initiation

(-HCI)

CH2-CHCI-CH2-CHCI-CH = CH - X

(-HCI)

* CH =CH-CH= CH-CH= CH~(propagation)

Also, for a linear molecule, an allylicchlorine is a weak point for degradativeattack. An allylic chlorine is formed generallyfrom disproportionation chain terminationmechanisms. An example of this kind ofstructure is' I: Cl

CH2-CHC1-CH2-CH-CH = CHC1I

Branching creates a tertiary chlorine on themain chain which is vulnerable to degradativeattach. An example of this type of structure isII: C1

CH2-CHC1-CH2-C-CH2-CHC1 -

ICH2ICHCI

IIIn both the allylic and branched PVC

structures, heating results in the liberation ofHCl, which initiates the reaction. The reactionis then propagated down the polymer chainproducing colored conjugated polyenes.

The organotin stabilizers probably comeclosest to being the ideal compounds forpreventing the thermal degradation of PVC.Particularly in unplasticized PVC productssuch as water and sewer pipe, organotinstabilizers make it possible to heat PVC resinto the high temperatures required formolding.

The concentration range of organotin com-pounds required to heat stabilize PVC duringprocessing is between 0.5 to 3.0 parts perhundred parts of resin (phr). Organotin com-pounds are compatible with PVC resins andplasticizers and give clear products. Theorganotins also stabilize for long periods oftime. This is important, since- the scrapgenerated during processing can be recycled.The major drawback to the widespread use oforganotin compounds is their cost whichranges from $1.50 to $2.50 per pound.Organotin stabilizers are four times asexpensive as barium-cadmium compounds,and approximately six times more costly thanlead stabilizers on a weight basis.

Environmental Health Perspectives62

There are approximately 1000 patents fororganotin stabilizer formulations, but onlyabout 11 basic compounds are of commercialvalue. The dibutyl and dioctyltin derivativesare the most important. In general the dibutyland dioctyl derivatives are synthesized byreacting the dibutyl or dioctyltin oxides witha fatty acid, anhydfride, or mercaptide to formthe respective stabilizer (and water). The mainorganotin stabilizers are given in Table 1,which has been compiled from Nass (2).

The most effective organotin stabilizers forPVC are the dibutyl derivatives. Their solu-bility in the resin and in almost all plasticizersimparts a clarity to the finished productwhich is unmatched by any other group ofstabilizers currently in use. Most dibutylderivatives are used in rigid PVC productssuch as pipes, bottles, insulation, siding, etc.Each particular dibutyl derivative has specialproperties for each method of processing.Therefore, the finished product usually con-tains a mixture of several stabilizers whichwas designed for a specific product, itsprocessing scheme, and its environmentalexposure. Because of this, the stabilizermanufacturer works very closely with theplastic manufacturer and custom blends hisadditives for the processing and end productuse.The dioctyltin derivatives were developed

specifically for PVC items which come incontact with food. The FDA regulates thesestabilizers in the CFR, Title 21, Part 121,Subpart F, 121.2602. The dioctyltinstabilizers must not be contaminated with themono- and tri-n-octyltin derivatives and foodin contact with these stabilized plastic con-tainers shall contain no more than 1 ppm ofthe organotin stabilizer. The analyticalprocedure (3) prescribed by this regulationdetermines total tin content extracted by thefoodstuff in contact with the dioctyltinstabilized container or wrapping.

Because of the complex nature of PVCmolecules, there are four highly probablepaths of thermal decomposition. It is for thisreason that a blend of several stabilizers isrequired to accomplish the stabilization ofPVC polymers. Corresponding to the four

mechanisms of thermal decomposition, thefour mechanisms of stabilization of PVC areas follows.

1. Scavenging of HCI to form dibutyl ordioctylmonochlorides and dichlorides:

PVC ZHCI

Bu2Sn(X)2 + HCI -e Bu2SnXC1 + XH

where X represents fatty acid, anhydride ormercaptide ligand.

.2. Radical inhibition (chain transfermechanism):

R ±+ Bu2Sn(X)2 -+ RX + Bu2SnX.

In this particular application, the mercap-tide ligand is a very effective radical scavengerand inhibitor.

3. Carbalkoxylation:

Bu2SnX2 + (- CH2 - CHCI -C = CH-:)

Bu2SnC12 + 2 (- CH2 - CHX- C= CH-)

4. Diels - Alder addition:0'I

Bu2Sn/ XCH + (- CH2-CHCI-CH

8CH-CH = CH-CH2-CHCI-)

1! /ACHCI-CH2-

° CH, C gH / 3H

0 ~ CH2- CHCI1-

June 1973 63

Table 1. Commercially important butyltin and n-octyltin stabilizers.

Name and structure Trade names Suppliers Description and uses

Dibutyltin dilaurate

C4H9 OOCC11H23Sn

C4H9/ OOCC11H23

Dibutyltin maleate

[(C4H9)2SnOOCCH=CHCOO]Dibutyltin laurate-maleateMay be solution of dilaurateand maleate or

(C4H9)2-Sn-OOCC1 1H23OOCCCH4I

(C4H9 )2-Sn-OOCCHN OOCC1 1H23

Dibutyltin bis (lauryl mercaptide)

(C4H9 )2 -Sn-(SC1 2 H25 )2

Thermolite 12Advastab DBTLNiax D-22Clear 1

Thermolite 13Advastab T-340

Thermolite 17

Thermolite 20Advastab TM-918Mark A

Dibutyltin bis(monoalkyl Thermolite 25, 26maleate) (alkyl usually is C4or Advastab T-52N,T-C8) 150

(C4 H9 )2-Sn-(OOCCH=CHCOOR)2 Mark 275

Dibutyltin S,S-bis (isooctylthioglycolate)

(C4H9 )2 -Sn-(SCH2COOC8H1l7 )2

Dibutyltin ( - mercapto-propionate

[(C4H9)2-SnSCH2CH2coo-]Di-n-octyltin maleate

n-C8 .7-Sn-OOCCH=CHCHOO-

n 8CH17L _ ~~~~~n

Di-n-octyltin S,S'bis(isooctyl thioglycolate)(n-CBH17)2-Sn(C8H17 -OOCCH2S)2

Thermolite 31Advastab TM-180Mark 292Synpron 1001

Thermolite 35Advastab T-360Mark 488

Thermolite 813Mark OTS

Thermolite 831Advastab TM-188Mark OTM

M & T ChemicalsAdv.Div.,Carbide Chem.Union Carbide Chem.Cardinal Chem. Corp.

M & T ChemicalsAdv.Div.,Carbide Chem.

M & T Chemicals

M & T ChemicalsAdv.Div.,Carbide Chem.Argus

M & T ChemicalsAdv. Div., Carbide Chem.Argus

M & T ChemicalsAdv. Div., Carbide Chem.ArgusSynthetic Prod. Co.


M & T ChemicalsArgus


Excellent lubricatingproperties for easy pro-cessing; usually combinedwith other stabilizers;for film and sheet

Good stabilizer; poorlubricating ability; forfilm and sheet.

Outstanding heat and lightstability for film andsheet with good lubricatingproperties for processing.

Good lubricating properties;used with dibutyl tinS,S-bis (isooctylthio-glycolates)

Light and heat stabllityto tubing; and PVC andPVC copolymer sheet andfilm.

Stabilizer for rigid PVCpipe; control of meltvisosity; permanence;good for pigmented rigidapplications.

Used for bottles, filmand sheet.

Used in bottles, film andsheet for food contactaccording to CFR, FDA,Title 21, Part 121, Sub-part F, 121.2602.

Maximum heat stability andprocessability. FDAsanctioned for bottles,films and sheets forfood contact.


Table 1. Commercially important butyltin and n-octyltin stabilizers. (Continued)

Name and structure Trade names Suppliers Description and uses

Di-n-octyltin,-mercapto- Advastab T-270 Adv. Div., Carbide Chem.I propionate Mark 492 Argus

n-C5H1 7 S - CH2Sn CH2

n-C8 -H17 0o-cgg0

n-C8H17or -Sn-SCH2CH2COO-

n-C8H17 n

Di-n-octyltin S,S'-bis (2-ethyl Mark OTM Argus FDA sanctioned for bottles,hexyl mercaptoacetate) films and sheets for foodn-C8H17 contact.

ISn- (S-CH2COOCH2CHC4H9 )2

n-CC8H17 C2H5

Catalytic Agents

Urethane Catalysts: In the production ofpolyurethane foams, organotin catalysts allow

n[O=C=N - (CH2)6-N=C=O]

the foam to be made directly from hexa-methylene diisocyanate and 1,4-butanediol.The overall reaction mechanism is as shownin eq. (4).

+ n[HO-(CH2)4-OH±Addition

r-- ---H

N=C °O- (CH2)4- OH11 n0

-C -NH-(CH2)6-NH-C-O-(CH2)4 -O-

11 11O O0 n

June 1973

(4)

65

There are three main steps to this mech-anism. They are: chain extension [eq. (4a)],

gas reaction [eq. (4b)], and crosslinking[eq. (4c)].

[O=C=N -(CH2)6-N=C=O + HO-(CH2) -OH]

-OC -N (CH2)6-N-C-O-11 11O H H 0-n

R -N=C=O + H20 - R-N-C-OH-+ R NH2 + C0211

H o

R- N=C=O +R- NH2 - R- N-C-N- R'11

H O H

In urethane foam production, the rate ofgeneration of CO2 is extremely important forthe properties of the final product. On theother hand, the chain extension reaction hasto proceed at a sufficient rate so that the gelwill have sufficient strength to retain the CO2gas bubbles which produce the foam. Theorganotins appear to be most effective incatalyzing the chain extension reaction so

that the optimum rates of both the chainextension and gas formation reactions areachieved. The organotin catalysts mostcommonly used are dibutyltin diacetate,dibutyltin dilaurate, dibutyltin dichloride,dibutyltin dilaurylmercaptide, and di-methyltin dichloride. Several stannous com-

pounds have been discovered to be particu-larly effective in flexible urethane foamapplications. In particular, stannous octoatehas been used very successfully in this appli-cation.

Other Applications: Dibutyltin dioctoateand dibutyltin dilaurate are commonly used

to catalyze the room temperature curing ofsilicone rubbers used in making dental im-pressions and encapsulating electronic parts.The usual technique of curing silicone rubbersis with peroxide catalysts at elevated tempera-tures. Curing is a crosslinking reaction, andthe influence of organotin catalysts on thisreaction is shown in eq. (5).

OH3

-Si -OH

CH3

CH3 CH3

+ RO-Si -OR+HO-Si -0-

ICH3 CH3

Bu2Sn(OOCR)2

CH3 CH3 CH3

,-Si -0-Si -o-si -0-

1.CH3 CH3 CH3

(5)

Environmental Health Perspectives

(4a)

(4b)

(4c)

66

Organotin compounds have distinct ad-vantages as catalysts for esterification reac-tions. They are: (1) high catalytic efficiency;(2) low tendency to eliminate water fromsecondary alcohols to form olefins; (3) abilityto produce colorless esters; (4) absence ofacidic or basic residues in the esters; (5)ability to impart heat stabilization to con-densation type polymers (i.e., polyesters); (6)ability to improve physical and electricalproperties of the product.

Plasticizers, polyesters, lactones, pyrroli-dones, and glycolic acid have been poly-merized with organotin catalysts.

The catalytic activity of the organotincompounds has been attributed to low-energy5d orbitals of the tin atom which can formhexa- and pentacoordinate bonds. In thistype of bond, the tin coordinates with eitheran oxygen or nitrogen. This coordinationbond causes polarization of the carbon atombonded to an oxygen or nitrogen atom, andmakes the carbon atom more susceptible toattack by an electrophilic reagent, such as analcohol, as in the urethane and esterificationreactions.

Biocidal Compounds

Organotin compounds, because they havebeen found to be effective in the control ofmany fungi and bacteria, have been used aspreservatives for wood, textiles, cordagefibers, paper, leather, electrical and electronicequipment, and glass. Most biologically activeorganotin compounds are trialkyl or triaryltincompounds. Bis(tributyltin) oxide, TBTO(M & T Chemicals, Inc.), gives antibacterial,antifungal, and mothproofing properties totreated fabrics. In this application, the tincompounds must compete with such com-pounds as copper 8-quinolinolate, copper andzinc naphthenates, zinc dimethyldithio-carbamate, pentachlorophenol, and quater-nary ammonium compounds. Their maindisadvantage is cost, but their major advan-tage is their lack of color and staining.TBTO is extremely effective in controlling

bacteria in hospitals, such as Staphylococcusaureus. TBTO has also been used to preventodors in garbage pails, control athlete's foot,

control molds in bathrooms, control mildewon leather goods, textiles, and plastics, andmothproof stored garments.

Industrial applications of organotinbiocides include their use for slime control inpaper pulp mills and cooling towers. Their usein processes involving food-grade papers, how-ever, has been curtailed. In the control ofslime in cooling towers, the tin compoundsmust compete with less costly, highly effec-tive, but hazardous compounds such as tri-chlorophenol and organomercurials.TBTO and tributyltin linoleate are active

ingredients in marine lumber preservation.Paint formulations containing TBTO havecontrolled marine fouling for as long ascuprous oxide paints. Concentrations between10 and 20% weight TBTO usually givesenough protection for the entire boatingseason. In this application, the organotinscompete with organomercurials and organo-lead antifouling paints.

Dibutyltin dilaurate is effective for thecontrol of Raillietina cesticillus in chickens,and the control of other poultry tapeworms.Dialkyltin compounds have also been used inthe control of other parasitic diseases ofpoultry, sheep, and swine.

Tributyltin chloride is an effective rodentrepellent.

Triphenyltin acetate and triphenyltin chlo-ride are effective molluscicides for the controlof snails which serve as vectors for schist-osome infections in man.

Tributyl- and isopropyltin compounds areeffective fungicides. Triphenyltin acetate andhydroxide control the fungus causing lateblight of potatoes, control sigatoka inbananas, and control 11 other fungal diseasesof important crops.

As insecticides, organotin compounds havebeen very effective. Trialkyltin compoundssuch as triphenyltin acetate and hydroxide,tributyltin chloride, and dibutyltin dilauratewhen applied to foliage generally repelinsects.

Figure 1 gives an overview of organotinproduct use patterns. It is interesting to notethat the dialkyltin derivatives are used as heatstabilizers and catalysts, and the trialkyl- and

June 1973 67

PRESERVATIVES FOR WOOD, TEXTILES,PAPER, LEATHER, AND GLASS

bis (tributyltin) oxide; TBTO;tributyltin linoleate

Figure 1. Organotin product distribution chart.

triaryltin derivatives are used mainly in bio-cidal applications.

Biological lnvssigauons on OrganOdn CompoundsMigration of Organotin Stabilizers from

Plastic Devices and Biological Reactions tothese Compounds

The ability of biological fluids to extractorganotin heat stabilizers from plasticizedPVC medical devices has been well docu-mented (4-11). The migration of organotinstabilizers from PVC bottles into liquid foodshas been studied by Carr (12), Woggon et al.(13-15), and Koch and Figge (16).

Guess and Haberman (4) have studied thebiological reactions to PVC resins obtainedfrom different manufacturers, and to a largevariety of PVC additives which include thecommercially important plasticizers and heatstabilizers. This is probably the most com-

prehensive toxicological evaluation of thesecompounds in the literature (and for thisreason will be discussed in some detail). As a

comparison, biological reactions to Teflon,nylon, polypropylene, polycarbonate, ABS,poly(phenylene oxide), cellulose triacetate,

and polyethylene plastics were also reported.This class of plastics usually does not requireplasticizers during processing, whereas PVCplastics do. However, all plastic formulationsto some degree require stabilizers as essentialadditives to prevent degradation during pro-duct use.

Several biological tests were employed toevaluate the toxicity of the PVC plasticformulation, the PVC resin, and the additives.In one test, slivers of the plastic were im-planted into rabbit tissue. After one week therabbits were sacrificed. Tissues surroundingthe implant were excised, transferred tobuffered formalin, sectioned and stained withhematoxylin and eosin for histopathologicevaluation. Cell culture reactions for PVCresins and for the additive compounds wereobtained for mouse fibroblasts (L-929) and10-day chick embryo cells which were bothallowed to form monolayers in petri dishes.The liquid nutrient medium was aspirated andreplaced with a 1% agar suspension in nutrientmedia. After gelation the sample was placedon the agar overlay and cells were incubatedfor 24 hr. A toxic sample produced a zone ofdead cells. Additional tissue culture tests

68lEnvironmental Health Perspectives

PVC STABILIZERS

dibutyltin dilaurate; dibutyltin maleatedibutyltin laurate-maleate; dibutyltinbis (lauryl mercaptide); dibutyltin S, S-bis (isooctyl thioglycolate); dibutyltina - mercaptopropionate; di-n-octyltin maleate;di-n-octyltin S,S-bis (isooctyl thioglycolate);di-n-octyltin a - mercaptopropionate

CURING AGENTS FOR SILICONE RUBBERSdibutyltin dioctoatedibutyltin dilaurate

URETHANE AND ESTERIFICATION CATALYSTSdibutyltin diacetatediethyltin dioctoatedibutyltin dilauratedibutyltin dichloridedibutyltin dilauryl mercaptidedimethyltin dichloridedibutyl tin dioctoatestannous octoateRODENT REPELLANTS, MOLLUSICIDES,

FUNGICIDES, AND INSECTICIDES

tributyltin chloridetri phenyl tin acetatetriphenyltin chloridetri phenyl tin hydroxidedibutyltin dilaurate

68

included human amnion and nasopharyngealcancer cells. In general these tests were donewith the undiluted chemical additives and theobservations were for whether or not theadditive enhanced cell growth or resulted indeath of the cell culture. These biologicaltests were common to many of the toxi-cologic studies of plastic medical devices.

The results of these studies by Guess andHaberman (4) showed that the organotinstabilizers, not the primary plasticizers inwhich they were dissolved, were the primarycause of toxicity. This was an importantobservation because the stabilizer was solublein the plasticizer, and the plasticizer wasreadily extracted by lipid materials. In boththe mouse fibroblast and chick embryo tissueculture tests, the organotin stabilizers gavepositive results. Cell necrosis was the observedresult which was considered a positive test.The organotins tested included all of thecommercially important dibutyl derivativesand one dioctyl derivatives which has notbeen approved by the FDA for food packageuse. The structures and use pattern for thesecompounds are shown in Table 1 and Figure1.

Guess and Haberman (4) also studied thetoxicologic reactions to unplasticized PVCresins. Samples of the compacted resin fromthree different manufacturers were evaluatedby the rabbit implantation and cell culturemethods described previously. Two differentbrands of PVC resin revealed an extremedegree of eosinophilia, while a third brand ofPVC and the polyethylene control did notshow this reaction. These results suggested thatthe two brands which produced the eosino-philic reaction must be contaminated with aleachable material which was extremely toxic.Alcohol extraction of these two resins yielded3.5% leachable material. The purified PVCresin was then implanted and showed only theusual foreign body reaction. The compositionof the alcohol extract was not determined,but when examined by the tissue culture testsalso gave very toxic reactions.

Several possibilities as to the nature ofthese toxic substances in PVC resins dependon the production scheme involved. The two

main schemes involve free-radical initiationwith benzoyl peroxide in monomer solutionor in an emulsion. Impurities may be in thevinyl monomer, free-radical initiator, or thesolvents used. However, it seems possible,because of the amount of material extracted,that the alcohol-extractable material is un-reacted vinyl chloride monomer, which is verysoluble in methanol and is also extremelytoxic and even carcinogenic (17).

Cell culture and rabbit implantation testsfor other commercial plastics which usuallyare unplasticized but contain stabilizers,either caused a very low degree of celldestruction in the tissue culture tests, orproduced no destruction at all. Alcohol ex-tracts of these plastics produced measurablequantities of material which gave positivetoxic reactions for Teflon, polycarbonate,ABS, poly(phenylene oxide), and cellulosetriacetate. The volume of the extract in allbut the Teflon and polycarbonate samplesagain suggested that this was unreacted mono-mer or low molecular weight dimers andtrimers. Another interesting aspect of thiscomprehensive study was that the toxicreaction for a particular plastic formulationdiminished with the absence of plasticizer.This observation reinforced the earlier con-clusion that the plasticizer was the vehicle forthe transport of the more toxic stabilizer intolipid materials, i.e., the diffusion of thestabilizer into the lipid material was enhancedby the presence of the plasticizer. Thoseplastics which did not require plasticizationappeared to produce less toxic reactions inbiological applications than did plasticizedplastics.

In a related study, Haberman et al. (5)studied the effects of commercially availablePVC plastics and resins on human serumprotein, antibodies, and developing chickembryos. In all, 56 heat stabilizers, 45 plas-ticizers, 5 PVC resins, and 120 finishedplastics prepared from these components weretested. Of the organotin thermal stabilizerstested, only bisdibutyltin monolauryl maleateand dibutyltin di(lauryl mercaptide) had noeffect on complement. Dibutyltin diisooctylthioglycolate and monobutyltin carboxylate

June 1973 69

improved the biological activity of the pro-teins in the blood serum tests. Other testresults showed that bisdibutyltin monolaurylmaleate caused no change in blood groupingantiserum, but did cause red blood cellagglutination. Dibutyltin diisooctyl maleatewas destructive to antibodies and causedblood grouping reagents to lose their abilityto selectively agglutinate human blood cells.This compound also caused human blood cellsto lyse within 24 hr. Dibutyltin dilaurate,which affected the delicate serum proteincomplex of guinea pig complement, had noobserved effect on human red blood cells andblood grouping antisera.

Guess and Stetson (6) found that intuba-tion devices made from PVC demonstratedtoxicity to cells in culture and to rabbitmuscle tissue. The PVC device was plasticizedwith tributylacetyl citrate and used amercapto ester of an organotin heat stabilizer.The toxicity was manifested as necrosis of cellcultures and rabbit muscle tissue.

Other reports dealing with toxicologicalreactions to medical devices were by Dukeand Vane (18), PVC tubing used in extra-corporeal circulation; Autian (7), evaluationof dental materials; Guess (8), plastic trachealtubes; Stetson (19), biological reactions toprolonged tracheal intubation; O'Leary et al.(20), evaluation of organotin stabilizers forrigid PVC using differential thermal analysis;Guess et al. (11 ), characteristics of subtletoxicity of certain plastic components used inmanufacturing PVC; Little and Parkhouse(21), tissue reactions to polymers; and, Nimni(22), biological tests for medical grade plasticsand the toxicity of organotin stabilizers.

The migration of stabilizers from PVC foodcontainers into liquid foods has been studiedby Woggon et al. (13-15), Carr (12), and Kochand Figge (16). Woggon et al. investigated themigration of di-n-octyltin bis(2-ethyl hexylthioglycolate) (or isooctyl thioglycolate) intosunflower oil. The concentration of theorganotin stabilizer was less than 2 ppm after6 months' storage. The daily tolerance levelset by the West German government forhumans has been established at 0.0065 mg/kg.For the daily consumption of 50 g of sun-

flower oil, the migration of the dioctyltinstabilizer into the oil did not exceed the dailytolerance level. The oral LD5 0 for di-n-octyltin bis(2-ethyl hexyl thioglycolate) was2100 mg/kg in rats.

Carr (12), in a study with 10 liquid foods,attempted to distinguish between the tincontent of these foods due to processing andabsorption of tin from the environment, theso-called "natural tin," and the tin whichdiffuses into the food from the food con-tainer. In this study food was analyzed fortotal tin before packaging in PVC containersand after storage in these containers for twomonths at 300C. The tin was in the form ofdioctyltin stabilizers which have been sanc-tioned for food packaging by the FDA. Theresults of this investigation are shown in Table 2.

It is interesting to note that the FDAregulations provide that the allowable levelsof octyltin stabilizers in food shall not exceed1 ppm. This regulation is given in CFR, Title21, Subpart F, 121.2602, 1971. The organo-tin stabilizers identified in this regulation aredi-n-octyltin S,S'-bis(isooctyl mercapto-acetate) and di-n-octyltin maleate polymer.The analytical technique prescribed for de-termining tin content is given by Farnsworthand Percola (3).

Koch and Figge (16) studied the migrationof an organotin stabilizer from PVC beerbottles into beer. The organotin stabilizer wasdi-n-octyltin bis(2-ethyl hexyl thioglycolate),and its concentration in the PVC bottle was1.13% by weight. Beer was stored in thesebottles at 200C for 8 weeks. At the end ofthis 8-week period, the concentration of theorganotin stabilizer in the beer was 0.01 ppm.

Toxicity of Organotin CompoundsTrisubstituted Organotin Derivatives: Be-

sides the toxicity evaluation of commerciallyimportant organotin stabilizers found-in PVCmedical devices, there have been manyinvestigations concerned with the toxicity ofall types of organotin compounds. The toxi-city of alkyl- and aryltin derivatives has beenrecognized for a long time and is primarilydue to the solubility of these organotinderivatives in body fluids. Many of the investi-


Table 2. Results of tin extraction tests compared with tin extractions of natural foods.a

Tin content Tin extracted Organotin stabilizerNatural tin, after aging in PVC from bottle, extracted from PVC

Food product ppm/b bottle, ppm ppm bottle, ppmc

Blended whiskey 0.01 0.02 0.01 0.063Mineral water 0.76 0.088 0.01 0.063Tomato juice 0.03 0.03 0 0Peanut oil 0.05 0.06 0.01 0.063Vegetable oil 0.08 0.09 0.01 0.063Apple juice 0 0.02 0.02 0.126Cherry soda 0 0.07 0.07 0.443Beer 0 0.01 0.01 0.063Milkd 0.2 0.04 0.02 0.126Redwine 0 0 0 0

aData of Carr (12).bNatural tin defined as tin in food as a result of processing and absorption from environment.cConcentration of octyltin in ppm was obtained by multiplying the tin extracted from the bottle by 6.3.

The organotin stabilizer was di-n-octyltin S,S -bis(isooctyl mercaptoacetate), Argus Chemical, Mark OTM.dMilk sample in PVC bottle was aged for 2 weeks at 650C.

gations have been conducted in trialkyl-,triaryl-, and tetraalkyltin derivatives whichfind their main use in biocidal applications.

Renewed interest in the toxicology oforganotin compounds occurred as a result ofthe Stalinon affair, which happened in Francein 1954 and resulted in the death of about100 people. Stalinon was a proprietary pre-paration sold in capsules throughout Francefor the treatment of furuncles and otherstaphylococcal skin infections, osteomyelitis,anthrax, and acne. The main active com-ponents of this preparation were diethyltindiiodide (15 mg/capsule) and Vitamin F(linoleic acid, 100 mg/capsule). The mainimpurities were monoethyltin and triethyltiniodides. The concentration of the triethyltinderivatives was found to be approximately10% by weight of the diethyltin component.It was concluded that people so treatedreceived a total dose of 3 g over a period ofsix to eight weeks. Triethyltin derivativeswere found to be 10 times more toxic thandiethyltin derivatives to rats when adminis-tered orally. The most constant complaints ofpatients were of severe, persistent headaches.Other common symptoms were vomiting,retention of urine, vertigo, abdominal pain,photophobia, loss of weight, psychic distur-bances, and several cases of hypothermia(350C). At autopsy, marked interstitial edema

of the white matter of the brain was seen.There was no degeneration of the fat tissue ofthe nerve fiber which had been severed fromits nutritive centers (Wallerian degeneration),and the only other lesion of possible signifi-cance was some endothelial proliferation inthe smaller veins accompanied in some casesby thrombosis and small perivenous hemor-rhages. Immediately following the Stalinonaffair, there was a proliferation of articlesconcerned with the toxicology of trialkyltinderivatives and their influence on biochemicalreactions.

Because the triethyltin derivative wasidentified as the toxic contaminant inStalinon which resulted in neurologicalsymptoms in many of the afflicted patients,the toxicity of this compound has beenwidely studied. In one of the earliest toxicitystudies on organotin compounds followingthe Stalinon affair, Stoner et al. (23) studiedthe acute and chronic effects of a series oftetra-, tri-, di-, and monoalkyltin compoundsand some inorganic tin salts in rats, rabbits,and guinea pigs. In acute studies with rabbits,triethyltin appeared to be the most active,producing muscular weakness followed bysome recovery, but progressing in turn tomuscular tremors, convulsions, and death. Inother animal species the compounds used inthese acute studies produced similar response

June 1973 71

patterns. The results of the acute studies aregiven in Table 3.On discounting the unexpected acute oral

toxicity for the rat for the trimethylderivative on a comparative basis, the toxicityof trialkyltin derivatives decreases as the sizeand stability of the ligand increases.Generally, the toxicity of the dialkylderivatives was less than the toxicity of the tri-alkyl and triaryl derivatives.

The chronic studies in this investigation byStoner et al. (23) were conducted on rats,rabbits, and chickens, and the only organotincompound used was triethyltin hydroxide. Inrats, the daily dose was 20 ppm, in rabbits 20ppm and 40 ppm, and in domestic fowls 160ppm of triethyltin hydroxide. The out-standing feature of chronic poisoning wasmuscular weakness. Although there was noevidence of concentration of tin in any organ,these alkyltin derivatives appeared to havetheir main effect on the central nervoussystem.

Further work by Magee et al. (24) made itclear that triethyltin derivatives exerted apowerful toxic action on the central nervoussystems of rats. Both acute and chronicstudies were performed; acute studies used

triethyltin sulfate; chronic studies usedtriethyltin hydroxide. In the acute studies, adose of 10 mg/kg body weight (approxi-mately 2LD50 doses) was injected intraperi-toneally and produced a generalized pro-gressive -weakness which ended in death aftera maximum of 5 days. An intraperitonealdose of diethyltin dichloride of 20 mg/kg ofbody weight did not produce the charac-teristic paresis, but still caused death within24 hr. In chronic studies, the daily dose was20 ppm of triethyltin hydroxide in rats. Theonly noteworthy lesion in these animals wasan interstitial edema confined to the whitematter of the brain. It seemed clear fromthese studies that the first reaction in the ratto poisoning was the accumulation of fluid inthe white matter of the central nervoussystem. Furthermore, this accumulation offluid persisted for as long as these organotincompounds were administered. When feedingof the triethyltin compound was stopped, thelesion was reversible. It was interesting tonote that the symptoms exhibited by theanimals used in this chronic study withtriethyltin compounds were similar to thesymptoms of the victims involved in theStalinon affair.

Table 3. Acute toxicities of organotin compounds.a

Lethal dose, mg/kg body weight

GuineaCompound Rabbit Rat pig,

Oral IP Oral IP oral

Trimethyltin sulfate - - 30 16Triethyltin sulfate 10 10 10 10(LD50-5.7) 5 - 10Tri-n-propyltin acetate - - >40Triisopropyltin acetate - - 80 - -

Tri-n-butyltin acetate 60 - 50-100 10 20Tri-n-hexyltin acetate - - >100Triphenyltin acetate >40 - >150 10Diethylphenyltin acetate - - 50-100 -

Diethyltin dichloride - - >40 15Diethyltin diiodide - - 100 26Dibutyltin dichloride - - 100Dibutyltin dilaurate - - - 85Monoethyltin trichloride - - - 200

aData of Stoner et al. (23).


In the discussion of these results, Magee etal. (24) noted that the lesion produced by thetriethyltin derivatives was very different fromthe lesions caused by alkyl derivatives of lead,antimony, bismuth, and mercury, which causedamage to the nerve cells. It was suggestedthat the explanation for the lesions producedby the triethyltin compounds must incor-porate the general tissue effects of thesecompounds on the inhibition of oxidativephosphorylation. There was no explanation ofwhy the brain tissue should be more sensitiveto these compounds, but it was suggested thatthe transport of free fluid and overallmetabolic processes should be studied in moredetail in order to find out more about theexact biochemical changes in the centralnervous system of rats as a result of triethyltinpoisoning.More recently, Pelikan and Cerny (25)

studied the acute toxicity of tri-n-butyltinderivatives in white mice. The tributyltinderivatives were the acetate, benzoate,chloride, laurate, and oleate. These com-pounds were given per gavage in a single doseof each compound at 500 mg/kg body weight.After 8 hr autopsy findings showed signs ofdamage to the digestive tract, liver, andspleen. The histological findings includedsteatosis of the liver cells in all animals, but tovarying degrees, traces of lipids were found inrenal tubule cells of animals receiving thelaurate and oleate compounds, and hemor-rhages were found in the digestive tract andkidneys. The LD50 results for these com-pounds in white mice are shown in Table 4.A large amount of acute toxicity data has

been obtained for trisubstituted organotincompounds; the results of these and several

Table 4. LD50 Results for tributyltin derivatives inwhite mice.a

LD50,, mg/kg LD50body weight range, mg/kg

Tributyltin oleate 230 175-301Tributyltin laurate 180 136-237Tributyltin chloride 117 80-170Tributyltin benzoate 108 74-156Tributyltin acetate 46 24.8-85.16

aData of Pelikan and Cerny (25).other important studies are summarized inTable 5.

Suzuki (28) performed acute and chronicstudies with triethyltin sulfate on newbomrats. In the acute studies, 5 mg/kg bodyweight of the triethyltin sulfate was injecteddaily intraperitoneally. The rats in this studydied after 3 days. The brains of the testanimals showed diffuse hemorrhagic encepha-lopathy. In the chronic studies, 5 mg/l. indrinking water was taken each day. The testanimals showed no clinical symptoms ofcerebral involvement, but severe, diffusestatus spongiosus was evident throughout thewhite matter of the central nervous system.

Pelikan (29) studied the effects of bis-(tri-n-butyltin) oxide, an important preser-vative for wood, textile paper, leather, andglass, on the eyes of rabbits. Both male andfemale albino rabbits, ratio 1:1, were used inthis study, and were divided into four groups.The actual concentrations of the organotincompound administered to each group were:6.1 mg/kg; 4.6 mg/kg; 0.61 mg/kg; and 0.46mg/kg. A single dose of 0.03 ml per rabbitwas administered to the conjunctival sac ofthe left eye. The largest concentration ap-proximated the highest accidentally adminis-

Table 5. Acute toxicity data for trisubstituted organotin compounds.

Compound LD50, mg/kg Animal used Reference

Triethyltin chloride 5 (IP) Female rats (26)Tributyltin oxide 7 (IP) Female rats (26)Trioctyltin dilaurate >800 (IP) Female rats (26)Tributyltin acetate 133 (oral) Male rats (27)Tributyltin salicylate 137 (oral) Male rats (27)Bis(tributyltin) oxide 122 (oral) Male rats (27)Tri-n-octyltin chloride >10,000 (oral) Male rats (27)

June 1973 73

tered dose. The lower two concentrationsproduced very profound changes in therabbits' eyes. Within 3 hr after administration,erythema and mild edema of the eyelids wasobserved. In addition, there were numerouslarge necrotic areas, petechial hemorrhages,early chemosis of the bulbar and polpebralconjunctivae, and distinct pericorneal injec-tion and dullness of the shine of the corneawith decreased transparency. 'l'hese effectspersisted so- that 2-5 days after administrationof the organotin compound, eschars andulcerations, some 10-15 mm in size, formedon the eyelids partly covered with pus.Between these eschars were numerouspapules, pustules, hemorrhages, and smallnecroses. In the rabbits given the largerconcentrations, these effects were more pro-nounced and produced in two of the animalsa clinical situation which showed markeddeterioration after 3-4 days. These twoanimals (after 3-4 days) showed extremeweakness, kept their eyes closed, and let theirheads hang down. On day 11 and 12 therabbits died. (Microscopic examinations oftissue in and around the eye were performed,and results are given in the paper.) Thiscommercially important biocidal agent, whenadministered in low concentration doses, hasa very pronounced and irreversible effect onnormal eye functions in rabbits.

Di- and Monosubstituted OrganotinDerivatives: From this work on the tri-ethyltin derivatives, interest in other organotincompounds of commercially importance wasgenerated. Barnes and Magee (30) studied thetoxicity of the salts of dibutyltin hydroxidebecause these stabilizers were used for plasticswhich were made into flexible tubing forblood-transfusion sets and the transport ofliquids such as beer and milk. In acute studieswith rats a single oral dose of dibutyltindichloride of 50 mg/kg body weight producedbile-duct lesions. It was shown that the flowof bile was a prerequisite for the developmentof bile duct lesion. It was, therefore, con-ceivable that the dibutyltin salt was present inthe bile in sufficient concentration to produceinjury. As a result of this initial damage, bileescaped into the adjoining parts of the

pancreas and a yellow-stained edemadeveloped locally. Liver damage was alsonoted in the rats.

Chronic toxicity studies on di-n-butyltindichloride in rats were conducted by Gaunt etal. (31). The compound was fed to rats for 90days at dietary levels of 0 (control), 10, 20,40, and 80 ppm. At 80 ppm, there was aslight reduction of growth and food intake,and instances of mild anemia. The no-effectlevel in rats was established at 40 ppm for 90days. This level corresponded to an intake ofapproximately 2 mg/kg-day. Di-n-butyltindichloride is the final product of thestabilization reaction of PVC resins, and is acatalyst for the formation of polyurethanefoam. Other important acute toxicity studieswith di- and monosubstituted organotinderivatives are summarized in Table 6.

Biochemical Studies on Organotin Compounds

Trisubstituted Organo tin Deriva-tives: Most of the biochemical research onorganotin compounds has been confined totriethyltin compounds and how they inhibitoxidative phosphorylation. Oxidative phos-phorylation is a complex heterogeneous,catalytic, electro-chemical process occurringon the mitochondrial membrane. Althoughthe exact mechanism of conversion of ADP toATP has not been determined completely,studies by Aldridge and Street (35,36) indi-cate that part of this process involves bindingof the reactants to sites on the mitochondrialmembrane. Mechanisms for catalytic reactionsinvolve adsorption-desorption steps and there-fore the determination of an equilibriumconstant which can be related thermo-dynamically to the binding energy involved inadsorption-desorption processes. The exactnature of the equilibrium constant is afunction of the number of binding sitesinvolved in the reaction mechanisms.

Triethyltin derivatives and trimethyltinderivatives have been shown by Aldridge andStreet (35,36) to have very high affinityconstants (-1Gf5M-1) for the binding to ratliver mitochondria. It was shown for rat livermitochondria that the presence of these com-pounds could inhibit oxidative phosphory-


Table 6. Acute toxicity data for disubstituted organotin compounds.

Compound

Dibutyltin oxideDibutyltin oxideDibutyltin dichlorideDibutyltin dichlorideDibutyltin dichlorideDibutyltin di-2-ethylhexyl thioglycolateDibutyltin di(monobutyl) maleateDibutyltin di(monononyl) maleateDibutyltin dilaurateDi-n-octyltin thioglycolateDi-n-octyltin ,B-mercaptopropionateDi-n-octyltin 1,4-butanediol bismercapto-acetate

Di-n-octyltin ethyleneglycol dithioglycolateDi-n-octyltin maleateDi-n-octyltin di-(1,2-propyleneglycolmaleate)

Di-n-octyltin di-(monobutyl maleate)Di-n-octyltin bis(2-ethylhexylmaleateDi-n-octyltin dilaurateDi-n-octyltin bis(lauryl thioglycolate)Di-n-octyltin oxideDi-n-octyltin acetateDi-n-octyltin bis(2-ethylhexyl mercapto-acetate)

Di-n-octyltin bis(dodecyl mercaptide)Di-n-octyltin bis(butylmercaptoacetate)Mono-n-octyltin tris(2-ethylhexylmercaptoacetate)

Mono-n-octyltin trichloride

LD50, mg/kg520 (oral, oil solution)39.9 (IP)35 (oral)112 (oral)100 (oral, oil solution)510 (oral, oil solution)120 (oral, oil solution)170 (oral, oil solution)175 (oral, oil solution)945 (oral)1,850/2,050 (oral)2,950 (oral)

880 (oral)1,265 (oral)4775 (oral)/30 (IP)

2030/2750 (oral)2760/3500 (oral)6450 (oral), 95 (IP)3700 (IP)2500 (IP)>800 (IP)2010 (stomach tube)

4000 (stomach tube)1140 (stomach tube)1500 (stomach tube)

10000 (oral)

lation by binding with high affinity to sites onthe mitochondria which would be normallyused for phosphorylating oxidation. This iscomparable to catalyst poisoning experiencedin industrial catalytic processes. The concen-

tration of triethyltin required to effectively in-bit oxidative phosphorylation is 0.3 pM.

In related studies on the inhibition ofoxidative phosphorylation by trialkyltin com-

pounds, Stockdale, Dawson, and Selwyn (37)showed that the order of effectiveness ininhibiting coupled respiration was tributyltin> tripropyltin > triphenyltin > trimethyltin.It was concluded that with two exceptions, all

the effects of trialkyltin compounds on mito-chondria could be explained on the basis oftwo separate effects. These were the oligo-

mycinlike inhibition of coupled phosphory-lation exhibited in all media and the anion-hydroxide exchange across lipid membranes.In the latter effect, it was shown that mediacontaining certain anions could produceuncoupling, swelling, and the lowering ofintramitochondrial substrate and phosphateconcentrations together with structuraldamage following gross swelling. The twoexceptions are the detergentlike action at highconcentrations of chlorides of trialkyltin com-pounds and the potent inhibition of electrontransfer found at high trialkyltin concentra-tions with iodide and thiocyanate anions.

Radioactive triethyltin (113 Sn) chloridewas used by Rose and Lock (38) to identifythe molecular groups of guinea-pig liver mito-

June 1973

Animal used

Male ratsFemale ratsWhite miceWhite miceMale ratsMale ratsMale ratsMale ratsMale ratsMale ratsMale ratsMale rats

Male ratsMale ratsMale rats

Male ratsMale ratsMale ratsMale ratsMale ratsFemale ratsWhite mice

White miceWhite miceWhite mice

Male rats

Reference

(27)(26)(31)(31)(27)(27)(27)(27)(27)(27)(27)(27)

(27)(27)(27)

(27)(27)(27)(27)(27)(26)

(33, 34)

(33, 34)(33, 34)(33, 34)

(27)

75

chondrial protein involved in binding trie-thyltin compounds. It was shown that thebinding sites consisted of a pair of histidineresidues. The type of coordination bindingproposed involved the formation of a systemof linear polymers with trialkyltin binding theimidazole portion of histidine. This kind oftrigonal bipyramidal coordination complex isshown as:

-N N

CH21.

R I

- Sn

IR

CH-NH2

COOH

R

N N-

CH2

CH-NH2ICOOH

In studies by Coleman and Palmer (39) itwas shown that pH influences the inhibitionof oxidative phosphorylation and electrontransport by triethyltin sulfate. With rat livermitochondria, in an assay medium containingCl- at an alkaline pH, above 7.1, triethyltininhibited both the ADP stimulated rate ofoxygen uptake and the dinitrophenol-inducedATPase, but had no effect on the dinitro-phenol-stimulated rate of oxygen uptake. Ifthe pH was reduced to below 6.9, the patternof inhibition changed and both the ADP anddinitrophenol-stimulated rates of oxygenuptake were inhibited by triethyltin. In theabsence of Cl- in the medium, trialkyltininhibited both the ADP-stimulated rate ofoxygen uptake and dinitrophenol-inducedATPase, and had no effect on the dinitro-phenol-stimulated rate of oxygen uptake ateither pH 7.4 or 6.6. In either the presence orabsence of Cl- the ability of triethyltin toinhibit ATP synthesis appeared to markedlydecrease as the pH was lowered from 7.4 to6.6.

In vivo studies were conducted by Cremer(40) on the selective inhibition of glucoseoxidation by triethyltin sulfate in rat brain.

14C tracers were used to study the meta-bolism of glucose and acetate after intraperi-toneal injection of triethyltin sulfate, 10 mg/kgbody weight. It was shown that incorporationof 14C from glucose into glutamate, gluta-mine, a-aminobutyrate and asparate wasgreatly decreased. The incorporation of 14Cfrom acetate into these amino acides wasunaffected. The experimental data indicatedthat the main action of triethyltin was todecrease the rate at which pyruvate wasoxidized. Glycolysis was not inhibited.Changes in glucose metabolism in the brainwere shown not to be directly due to hypo-thermia.

In a related study, Joo et al. (41) demon-strated that triethyltin poisoning in ratsresulted in increased permebility of theblood-brain barrier. It was shown that thepattem of soluble brain protein underwentmarked changes due to increased permeabilityof the barrier on the one hand, and/or tometabolic disturbances of the brain substanceon the other.Disubstitu ted Organotin Deriva-

tives: Unpublished results obtained bypersonal communication with Aldridge statedthat action of the whole series of homologsfrom dimethyl to dioctyltin on mitochondrialfractions of rat liver had been examined. Mostof these compounds inhibited mitochondrialrespiration by preventing the oxidation ofa-keto acids. Dihexyltin was an active homo-log, but the dioctyltin derivative appeared tobe inactive.

CodusinsIn this review, an attempt has been made to

bring together from technological andbiological literature information aboutorganotin compounds. There were severalreasons for a review article on this particulargroup of chemicals. Because of the uniquechemistry of these compounds, they havebeen developed as important thermal stabili-zers for plastics, as catalysts, and as biocides.Important questions asked at this point werewhether or not these chemicals in theirproduct and process use pattems constitutedeither an immediate or potential health


hazard to living organisms. In order to beginanswering these questions, current infor-mation was gathered on the toxicity of thesesubstances and about the methods of trans-port of these compounds through the environ-ment. With this background information,rational discussions about the potential ofthese substances as environmental healthhazards, and about the types of additionalinformation required to evaluate thispotential completely can continue in a non-crisis atmosphere.

Renewed biological interest in these com-pounds was a result of the disastrouspoisoning of over 100 Frenchmen in 1954 bya triethyltin contaminant in the drug calledStalion. The toxicity of these compounds wasshown to be associated with their organicligands which increased their solubility inbiological fluids.

Acute toxicity studies in rats showed thattrialkyltin and triaryltin compounds werevery toxic, with toxicity diminishing as thesite and stability of the organic ligandincreased. Chronic toxicity studies in ratsshowed that these compounds affected thefunction of the central nervous system, butthat these lesions were reversible whenadministration of these compounds ceased. Itwas also shown in in vitro studies that thesecompounds bind to mitochondria and inhibitoxidative phorphorylation. Trialkyltin andtriaryltin derivatives are commercially impor-tant biocides.

Acute and chronic toxicity studies in ratswith dialkyltin and triaryltin compounds,commercially important as thermal stabilizersand catalysts, showed them to be less toxicthan the trialkly- and triaryltin derivatives.The toxicity of these compounds againdiminished as the size and stability of theorganic ligand increased. However, it wasshown in in vitro studies that these com-pounds did have the ability to inhibit mito-chondrial respiration by preventing theoxidation of ax-keto acids.The transport mechanisms for these com-

pounds into biological systems have profoundimplications for environmental health. Twomethods of introduction of dialkyl- and

diaryltin derivatives into man are migrationfrom plasticized plastic containers into liquidfoods and migration from plasticized plasticmedical devices into biological fluids. Tissueculture tests with dialkyl- and diaryltinthermal stabilizers showed them to be moretoxic than the plasticizers in which they weredissolved. It was also shown that the presenceof the plasticizer enhanced the diffusion ofthe more toxic stabilizers into biologicalfluids. The FDA has specified that onlydioctyltin derivatives can be used to stabilizeplastic food containers. These compounds arenot the most effective stabilizers, but they aremuch less toxic than the dibutyltin deriva-tives. Medical devices use the more effectivedibutyltin stabilizers. Although this group ofproducts does not represent a significantpercentage of plasticized plastic products, theuse of dibutyltin stabilizers in these devices,offers a direct route of entry for the moretoxic group of compounds into biologicalfluids.

With the increasing information on thenumber of methods by which chemicals can.be transported throughout the environment,it is possible to apply these methods to theprediction of environmental distribution oforganotin compounds. The combined or-ganic-inorganic nature of these substancesallows them to be soluble in a very broadrange of fluids, so that liquid transportmechanisms by many types of fluids arepossible. On examining the use pattems forthese compounds, the dialkyl- and diaryltinderivatives are widely used in a variety ofcommercially important plastic products,because of their effectiveness in preventingthermal degradation of the polymer chains ofthese plastics. Marketing of plastics is a highvolume business because they are generallyinexpensive and can be fabricated intoproducts which can compete favorably withestablished market items. Plastics are alsoconsidered to be disposable. The percentageof solid waste as a result of the disposabilityof plastics is increasing yearly, from thepresent 3% to approximately 5% by 1980.The methods of solid waste disposal-landfll-ing, composting, and incineration-could offer

June 1973 77

an increased number of mechanisms for con-centration through the food chain, and anincreased number of possibilities for entryinto man's svstems.

The solution to these problems would bean example of responsible consideration ofthe total life cycle of a product for theconsumer market. Several possible suggestionsare therefore given as a beginning. The use ofunplasticized plastic food containers andmedical devices would decrease the diffusivityof organotion stabilizers in liquid foods andbiological fluids from approximately 10-icm2 /sec to approximately 10-1 2cm2 /sec.Recognition of what additives were present inplastic products would result in better wastemanagement procedures and would result inthe design of waste disposal equipment formore efficient reclamation of these tracematerials. The economic incentive wouldcertainly be there since the organotin com-pounds have a market value of approximately$2.00/lb. Recogniton of the health hazards ofthe more toxic trialkyl and triaryl biocidesshould result in their curtailment or use inclosed systems, which would prevent entry ofthese compounds into the environment.

REFERENCES

1. Ross, A. Industrial applications or organotincompounds. Ann. N. Y. Acad. Sci. 125: 107(1965).

2. Nass, L. I. Stabilization. In: Encyclopedia ofPolymer Science and Technology, H. F. Mark, N.G. Gaylord, and N. Bikales, Eds., Interscience,New York, 1967.

3. Farnsworth, M., and Percola, J. Determination oftin in inorganic and organic compounds and mix-tures. Anal. Chem. 31: 410 (1959).

4. Guess, W. L., and Haberman, S. Toxicity profilesof vinyl and polyolefinic plastics and theiradditives. J. Biomed. Mater. Res. 2: 313 (1968).

5. Haberman, S., et al. Effects of plastics and theiradditives on human serum proteins, antibodies,and developing chick embryos. In: TechnicalPapers Regional Technical Conference, SPE, N.Y. Section, Sept. 1967, pp. 22-43.

6. Guess, W. L., and Stetson, J. B. Tissue reactionto organotin stabilized PVC catheters. JAMA204: 580 (1968).

7. Autian, J. The use of rabbit implants and tissueculture tests for the evaluation of dentalmaterials. Int. Dent. J. 20: 481 (1970).

8. Guess, W. L. Plastics for tracheal tubes. Int.Anestresiol. Clin. Winter 8 (4): pp. 805 (1970).

9. Guess, W. L. Tissue testing of polymers. Int.Anesthesiol. Clin. Winter 8 (4): 787 (1970).

10. Guess, W. L., et al. Parenteral toxicity of a seriesof dioctyl and dibutyl tin stabilizers used in PVCformulations. Tech. Papers, SPE, Stanford,Conn., 12: 4 (1966).

11. Guess, W. L. et at. Characteristics of subtletoxicity of certain plastic components used inmanufacture of the polyvinyl. Amer. J. Hosp.Pharmacy. 24: 494 (1967).

12. Carr. H. G. Interaction between PVC bottles andliquid foods. SPE J. 25 (10): 72 (1969).

13. Woggon, H., Jehle, D., and Uhde, W. J. Testing ofplastic commodities. Migration of PVC stabilizersinto edible oil. Nahrung 13: 343 (1969).

14. Woggon, H. and Uhde, W. J. Plast. Kaut. Toxico-logical aspects in the migration of PVC stabilizersinto food. 16: 88 (1967).

15. Seidler, H., et al. Testing of plastic commodities:the migration of bis(2-ethylhexyl) [(di(octyl-1_14C,)stannylene] dithio] diacetate from rigidPVC into edible oil. Nahrung 13: 257 (1969).

16. Koch, J., and Figge, K. Migration of tin-stabi-lizers from PVC-bottles into beer. Zlufar. 147(9):(1971).

17. Viola, P. L. Carcinogenic effect of vinyl chloride.Paper presented at 10th International CancerCongress, Session 3, Chemical Carcinogenesis,Houston, Texas, 1970.

18. Duke, H. N., and Vane, J. R. An adverse effect ofPVC tubing used in extracorporeal circulationLancet 8 (716): 21 (1968).

i9. Stetson, J. B. Prolonged tracheal intubation forfacilitation of tracheobronchial toilet and thetreatment of alelectrois. Nahrung. 14: 969(1970)

20. O'Leary, R. K., Foy, J., and Guess, W. L.Quantitative evaluation of the heat-stabilizingproperties of orgonotin compounds in rigid PVC,using differential thermal analysis. J. Pharm. Sci.56: 494 (1967).

21. Little, K., and Parkhouse, J. Tissue reactions topolymers. Lancet 2: 857 (1962).

22. Nimni, M. 1964. Sensitive biological tests formedical grade plastics. 1. Toxicity of organotinstabilizers. J. Pharm. Sci. 53: 1263 (1964).

23. Stoner, H. B., Barnes, J. M., and Duff, J. I.Studies on the toxicity of alkyltin compounds.Brit. J. Pharmacol. 10: 16 (1955).

24. Magee, P. N., Stoner, H. B., and Barnes, J. M.The experimental production of edema in thecentral nervous system of the rat by triethyltincompounds. J. Path. Bact. 73: 107 (1957).

25. Pelikan, Z., and Cerny, E. The toxic effects oftri-n-butyltin compounds on white mice. Arch.Toxikol. 23: 283 (1968).

26. Robinson, I. M. Effects of some organotincompounds on tissue amine levels in rats. Food

78 Environmental Health Perspectives

Cosmet. Toxicol. 7: 47 (1969).27. Klimmer, 0. R. The application of organotin

compounds are viewed by the experimentaltoxicologist. Arztl.-Forsch. 19: 934 (1969).

28. Suzuki, K. 1971. Some new observation intriethyltin intoxication of rats. Exp. Neurol. 31:207 (1971).

29. Pelikan, Z., 1969. Effects of bis (tri-n-butyltin)oxide on the eyes of rabbits. Brit. J. Ind. Med.26: 165 (1969).

30. Barnes, J. M., and Magee, P. N. The biliary andhepatic lesion produced experimentally bydibutyltin salts. J. Path. Bact. 75: 267 (1958).

31. Gaunt, I. F., et al. Acute and short-term toxicitystudies on di-n-butyltin dichloride in rats. FoodCosmet. Toxicol. 6: 599 (1968).

32. Mazayev, V. T., Korolev, A. A., andSkhachkhova, I. N. Experimental investigation ofthe toxic effect of tetraethyltin and dichloro-dibutyl tin on the animal organism. J. Hyg.Epidemiol. Microbiol. Immunol. 15: 115 (1971).

33. Pelikan, Z., and Cerny, E. The toxic effects ofsome di- and mono-n-octyltin compounds onwhite mice. Arch. Toxikol. 26: 196 (1970).

34. Pelikan, Z., and Cerny, E. Toxic effects of some"mono-n-butyltin compounds" on white mice.Arch. Toxikol. 27: 79 (1970).

35. Aldridge, W. N., and Street, B. W. The relationbetween the specific binding of trimethyltin andtriethyltin to mitochondria and their effects onvarious mitochondrial functions. Biochem. J.124: 221 (1971).

36. Aldridge, W. N., and Street, B. W. The specificbinding of trimethyltin and triethyltin to rat livermitochondria. Biochem J. 118: 171 (1970).

37. Stockdale, M., Dawson, A. P., and Selwyn, M. J.Effects of trialkyltin and triphenyltin com-pounds on mitochondrial respiration. Europ. J.Biochem. 15: 342 (1970).

38. Rose, M. S. Evidence for histidine in the trie-thyltin-binding site of rat haemoglobin. Biochem.J. 111: 129 (1969).

39. Coleman, J. 0. D., and Palmer, J. M. Theinfluence of pH on the inhibition of oxidativephosphorylation and electron transport by trie-thyltin. Biochim. Biophys. Acta 245: 313(1971).

40. Cremer, J. E. Selective inhibition of glucoseoxidation by triethyltin in rat brain in vivo.Biochem. J. 119: 95 (1970).

41. Joo, F., et al. Collapse of the blood-brain barrierin lymphostatic cerabral hemangiopathy and intriethyltin poisoning. Med. Exp. 19: 342 (1969).

June 1973 79

organotin compounds: industrial - semantic scholar · however, as the chemistry of organotin...

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