tri n butyl phosphate

8/13/2019 Tri n Butyl Phosphate

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This report contains the collective views of an in-ternational group of experts and does not necessarilyrepresent the decisions or the stated policy of theUnited Nations Environment Programme, the Interna-

tional Labour Organisation, or the World HealthOrganization.

Environmental Health Cnteria ll2

TRI.n.BUTYL PHOSPHATE

Published under the joint sponsorship ofthe United Nations Environment Programme,the International Labour Organisation,and the World Health Organization

First draft prepared by Dr A. Nakamura,National Institute for Hygienic Sciences, Japan

World Health OrganizationGeneva, 1991


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The International Progranne on Chemical Safety (IPCS) is a jointventure of the United Nations Environment Programme, the InternationalLabour Organisation, and the World Health Organization. The main objec-tive of the IPCS is to carry out and disseminate evaluations of theeffects of chemicals on human health and the quality of the environ-

ment. Supporting activities include the development of epidemiological,experimental laboratory, and risk-assessment methods that could produceinternationally comparable results, and the development of manpower inthe field of toxicology. Other activities carried out by the IPCSinclude the development of know-how for coping with chemical accidents,coordination of laboratory testing and epidemiological studies, andpromotion of research on the mechanisms of the biological action ofchemicals.

WHO Library Cataloguing in Publication Data

Tri-n-butyl phosphate.

(Environmental health criteria ; l12)

l. Phosphoric acid esters - adverse effects2. Phosphoric acid esters - toxicityI. Series

rsBN 92 4 r57rr2 8rssN 0250-863X (NLM Classification: QV 627)

@World Health Organization l99l

Publications of the \ilorld Health Organization enjoy copyright pro-tection in accordance with the provisions of Protocol 2 of the Univer-sal Copyright Convention. For rights of reproduction or translation ofWHO publications, in part or in toto, application should be made to theOffice of Publications, World Health Orgariization, Geneva, Switzerland.

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The mention of specific companies or I 9f sanluin manufacturers'products does not imply that they are endorsbd or recommended by theWorld Health Organization in preference to others of a similar naturethat are not mentioned. Errors and omissions excepted, the names ofproprietary products are distinguished by initial Capital letters.

Printed in FinlandD H S S - Va m m a l a - 5 0 0 0


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l .

EHC 112: Tti-wWI Pmpnate

GONTENTS

EI.IVIRONIV{ENTAL HEALTH CRITERIA FORTRI-r-BUTYL PHOSPHATE

SUMMARY

l.l ldentity, physical and chemical properties,analytical methods

1.2 Sources of human and environmental exposure

1.3 Environmental transport, distribution, andtransformation1.4 Environmental levels and human exposure1.5 Effects on organisms n the environment1.6 Kinetics and metabolism1.7 Effects on experimental animals and

in vitro test systems1.8 Effects on humans

IDENTITY, PHYSICAL AND CHEMICAL PROPERTIES,ANALYTICAL METHODS

2.1 Identity2.2 Physical and chemical properties2.3 Conversion factor2.4 Analytical methods

2.4.1 Extraction and concentration2.4.2 Clean-up procedure2.4.3 Gas chromatography and mass spectrometry2.4.4 Contamination of analytical reagents2.4.5 Other analytical methods

SOURCES OF HUMAN AND ENYIRONMENTALEXPOSURE

l l

l ll l

l lt 2t 2t 2

2.

l 3l 3

z )

Z J

24

J .

4.

3 . 1

3.2

Production and processes

Uses

ENVIRONMENTAL TRANSPORT, DISTRIBUTION,AND TRANSFORMATION

4.1 Transport and transformation in the environment4.1.1 Release o the environment4.1.2 Fate in water and sediment

t 4

l 4l 5l 6r6r6l 9l 92020

22

22

22

23


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4.1.3 Biodegradation 244.1.4 Water reatment 25

4.2 Bioaccumulation nd biomagnification 26

5. ENYIRONMENTAL LEYELS AND HUMAN EXPOSURE 27

5.1 Environmental evels5 .1 .1 Ai r5.1.2 Water5.1.3 Sediment

5.1.4Fish, shbllfish,and birds

5.2 General population exposure5.2.1 Food5.2.2 Drinking-water5,2.3 Human issues

5.3 Occupational xposure

6. EFFECTS ON ORGANISMS N THE ENYIRONMENT

Unicellular algae, protozoa, and bacteriaAquatic organismsPlantsArachnids

6.16.26.36.4

J J

J J

3333333434353535

36

36364040

7 .

8 .

KINETICS AND METABOLISM

7.1 Absorption7.2 Distribution7.3 Metabolism7.4 Excretion

EFFECTS ON EXPERIMENTAL ANIMALS ANDIN VITRO TEST SYSTEMS

8.1 Single exposure8.2 Short-term exposure

8.3 Skin and eye irritation; skinsensitization

8.4 Teratogenicity8.5 Mutagenicity and carcinogenicity8.6 Neurotoxicity

EFFECTS ON HUMANS

4 l

4 l4 l4243

44

444547474749

50.


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IO. EVALUATION OF HUMAN HEALTH RISKS ANDEFFECTS ON THE ENVTF.ONMENT

l0.l Evaluation f human health isksl0.l.l Exposure evols10.1.2 Toxic effects

10.2 Evaluation f effectslon he environment10.2.1 Exposure evdls10.2.2 Toxic effects

I I. RECOMMENDATIONS

ll.l Recommendations of further research

REFERENCES

RESUME

RESUMEN

EN EL MEDIO AMBIENTE

RECOMENDACIONES

5 l

5 l5 l5r525253

5454

55

65

69

72

t 5

77

80


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WHO TASK GROUP ON ENYIRONMENTAL HEALTHCRITERIA FOR TRI-N-BUTYL PHOSPHATE

Members

Dr S. Dobson, Institute of Terrestrial Ecology, Monks WoodExperimental S tation, Abbots Ripton, Huntingdon,Cambridgeshire, England (Chairman)

Dr S. Fairhurst, Medical Division, Health and SafetyExecutive, Bootle, Merseyside, England ( JointRapporteur

MsN. Kanoh, Division of Information on Chemical Safety,National Institute of Hygienic Sciences, Setagaya-ku,Tokyo, Japan

Dr A. Nakamura, Division of Medical Devices, National

Institute of Hygienic Sciences, Setagaya-ku, Tokyo,Japan

Dr M. Tasheva, Department of Toxicology, Institute ofHygiene and Occupational Health, Sofia, Bulgaria

Dr B. Veronesi, Neurotoxicology Division, US EnvironmentalProtection Agency, Research Triangle Park, NorthCarolina, USA

MrW.D. Wagner, Division of Standards Development andTechnology Transfer, National Institute for Occu-pational Safety and Health, Cincinnati, Ohio, USA

Dr R. Wallentowicz, Exposure Assessment ApplicationBranch, US Environmental Protection Agency, Washington,DC, USA (Joint Rapporteur)

Dr Shen-Zhi Zhang, Beijing Municipal Centre for Hygieneand Epidemic Control, Beijing, China

Observers

Dr M. Beth, Berufsgenossenschaft er Chemischen ndustrie(BG Chemie), Heidelberg, Federal Republic of Germany

6


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Dr R. Kleinstiick, Bayerof Germany

Secretariat

Dr M. Gilbert, InternaDivision of Enation, Switzerland ( ary)

EHC 112: Tti-rvb@, Phosptnb

Leverkusen, Federal Republic

I Programme on Chemical Safety,tal Health, World Health Organiz-


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NOTE TO READERS OF THE CRITERIA DOCUMENTS

Every effort has been made to present information inthe criteria documents as accurately as possible withoutunduly delaying their publication. In the interest of allusers of the environmental health criteria documents,readers are kindly requested to communicate any errorsthat may have occurred to the Manager of the InternationalProgramme on Chemical Safety, World Health Organization,

Geneva, Switzerland, in order that they may be included incorrigenda, which will appear in subsequent volumes.

* *

A detailed data profile and a legal file can beobtained from the International Register of PotentiallyToxic Chemicals, Palais des Nations, l2ll Geneva 10,Switzerland (Telephone No. 7988400 or 7985850).


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HIC 112: Tri-nfinyl ntryme

ENYIRONMENTAL TH CRITERIA FOR

TRI-n-BUTYLTE

A WHO Task Groupteria for Tri-n-butylIndustrial Biological

ng on Environmental Health Cri-was held at the British

Research Association (BIBRA),Carshalton, United Ki , from 9 to 13 october 1989. DrS.D. Gangolli, Director, BIBRA, welcomed the participants

titution and Dr M. Gilbert openedn behalf of the host

the meeting on behalf of the three cooperating organiz-ations of the IPcs (reviewed and revisedan evaluation of theenvironment from exposu

The first draft of thNakamura. National IDr M. Gilbert and Dr

IPCS Central Unit,

, UNEP, WHO). The Task Groupdraft criteria document and made

isks for human health and theto tri-n-butyl phosphate.

document was prepared bytute for Hygienic Sciences,.G. Jenkins. both members

responsible for the

Dr A.Japan.of the

overallscientific content and edi , resPectively.


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BCF

BUN

EC

FPD

GC

GPC

HPLC

LC

LD

MS

NADPH

NPD

OPIDN

TAP

TBP

TCP

TLC

TPP

ABBREYIATIONS

bioconcentration factor

blood urea nitrogen

effective concentration

flame photometric detector

gas chromatography

gel permeation chromatography

high performance liquid chromatography

lethal concentration

lethal dose

mass spectrometry

reduced nicotinamide adenine dinucleotidephosphate

nitrogen-phosphorus sensitive detector

organophosphate-induced elayed neuropathy

trialkyl/aryl phosphate

tri-n-butyl phosphate

tricresyl phosphate

thin-layer chromatography

triphenyl phosphate


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EHC 112: Tn-n-buty, Ptlns@e

1. SUMMARY

1.1 ldentity, physical and chemical properties, analyticalmethods

Tri-n-butyl phosphate (TBP) is a non-flammable, non-explosive, colourless, odourless liquid. However, it isthermally unstable and begins to decompose at temperaturesbelow its boiling point. By analogy with the known chemi-

cal properties of trimethyl phosphate, TBP is thought tohydrolyse readily in either acidic, neutral, or alkalinesolutions. It behaves as a weak alkylating agent. Thepartition coefficient between octanol and water (logPo*) is 3.99-4.01.

The analytical method of choice is gas-liquid chroma-tography with a nitrogen-phosphorus sensitive or flamephotometric detector. The detection limit in water is

about 50 ng/litre. Contamination of analytical reagentswith TBP has been frequently reported; therefore, caremust be taken in order to obtain reliable data in traceanalysis of TBP.

1.2 Sources fhuman and environmentalexposure

TBP is manufactured by the reaction of n-butanol withphosphorus oxychloride. It is used as a solvent for cellu-

lose esters, lacquers, and natural gums, as a primaryplasticizer in the manufacture of plastics and vinylresins, as a metal extractant, as a base stock in theformulation of fire-resistant aircraft hydraulic fluids,and as an antifoaming agent. During the past few years,the utilization of TBP as an extractant in the dissol-ution process in conventional nuclear fuel reprocessinghas increased considerably.

Exposure of the general population through normal usecan be regarded as minimal.

1.3 Environmental ansport, distribution, nd ransformation

When used as an extraction reagent, solvent, or anti-foaming agent, TBP is continuously lost to the air and


12/78

Sunmary

aquatic environment. The biodegradation of TBP is moderateor slow depending on the ratio of TBP to active biomass.It involves stepwise enzymatic hydrolysis to orthophos-phate and n-butanol, which undergoes further degradation.The concentration of TBP in water is not decreased bvstandard techniques or drinking-water treatment.

Bioconcentration factors (BCF) measured for twospecies of fish (killifish and goldfish) range from 6 to49. The depuration half-life was 1.25 h.

1.4 Erwironmentallevels nd human exposureTBP has been found frequently in air, water, sediment,

and aquatic organisms, but levels in environment samplesare low. Higher concentrations of TBP have been detectedin air, water, and fish samples collected near paper manu-facturing plants in Japan: 13.4 nglm3 in air; 25 200 ngper litre in river water; I l1 nglg in fish organs. Totaldiet-studies in the United Kingdom and the USA indicateaverage daily TBP intakes of approximately 0.02-0.08 t g perkg body weight per day.

1.5 Effectson organisms n the environment

The inhibitory concentrations (ECo, ECb', EC100) of TBPfor the multiplication of unicellular algae, protozoa, andbacteria have been estimated to lie within the range of

3.2-100 mgllitre. The acute toxicity fish (LCso) rangesfrom 4.2 to l l.8 mg/litre. TBP increases the drying rateof plant leaves, which results in rapid and complete inhi-bition of leaf respiration.

l-G Kineticsand metabolism

In experimental animals, oral or intraperitoneally in-jected TBP is readily transformed by the liver, and pre-sumably by the kidney, to yield hydroxylated products asbutyl moieties. TBP is excreted mainly as dibutyl hydrogenphosphate, butyl dihydrogen phosphate, and butyl bis-(3-hydroxybutyl) phosphate. Alkyl moieties hydroxylated asalkyl chains are removed and excreted partly as N-acetylalkylcysteine and partly as carbon dioxide.


13/78

EHC 112: ni-rvbdyl Pnarylnte

1-7 Effects on experimental nimals and n vito test systems

Oral LDuo values for TBP in mice andreported to range from about I to 3 glkg,tively low acute oxicity.

rats have beenindicating rela-

In subchronic toxicity studies with TBP, dose-depend-ent depression of body weight gain and increases in liver,kidney, and testis weights were reported. The results ofthe subchronic studies indicafe that the kidney may be atarget organ of TBP.

Primary skin irritation caused by TBP in albino rab-bits may be as serious as that caused by morpholine.

TBP is reported to be slightly teratogenic at highdose levels. The mutagenicity of TBP has been inadequatelyinvestigated. Negative results have been reported in bac-terial tests and in a recessive lethal mutation test withDroso phi a mel anog aster.

There are no adequate data to assess the carcino-genicity of TBP, and the effects on reproduction have notbeen nvestigated.

The ability of TBP to produce delayed neuropathy hasbeen inadequately investigated. Effects seen followingoral administration of a high dose (0.42 ml/kg per day for14 days) suggested delayed neuropathy, but no axonal de-generation was seen and no definite conclusions could be

drawn. This same high dose (0.42 ml/ke per day for 14days) caused a significant reduction in conduction vet-ocity of the caudal nerve and morphological alteration ofunmyelinated fibres in rats. These results indicate thatTBP has a neurotoxic effect on the peripheral nerve.

1-8 Effects on humans

In an in ritro study, TBP has been reported to have aslight inhibitory effect on human plasma cholinesterase.

There are no case reports of delayed neurotoxicity, ashas been observed in cases of tri-o-cresyl phosphatepoisoning.


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lderw, P@cal and Chsfical Proryrlies, AnalyticalMe./inods

2. IDENTffY,PHYSICALNDCHEMICAL ROPERTIES,ANALYTICAL ETHODS

2.1 ldernity

Chemical Structure:

o

t lHsC -(CHz)r - O- P - O- (CHr)s - CHs

Io

(CH2)s

CHs

Molecular formula: C .",H*TA P

Relative molecular mass: 266.3

CAS chemical name: Phosphoric acid, tributyl ester

CAS registry number: 126-73-8

RTECS registry number: TC7700000

Synonyms: TBP; tri-n-butyl phosphate; phosphoric acid,tri-n-butyl ester

Trade name: Phosflex 4Q Skydrol t O-4@; Celluphos 4QDisphamol I TBP@

Manufacturers and suppliers (Modern Plastics Encyclopedia,1975; Parker, 1980; Laham et al. , 1984):Albright & Wilson Ltd.;A & K Petroleum nd. Ltd. (Laham et al. , 1984);Ashland Chemical Co.; Bayer AG;Commercial Solvent Corp.; East Coast Chemicals Co.;FMC Corporation; McKesson Chemical Co.;


15/78

EHC 112: Tn-*buUI Pharyhate

Mobay Chemical Co.; Mobil Chemical Co.;Monsanto Chemical Co.; Rhone-Poulenc Co.;Protex (SA) Stauffer Chemical Co.; TennecoOrganics Daihachi Chemical Ind. Co.; NipponChemical Ind. Co. Ltd.

2.2 Physical nd chemical roperties

The physical properties of tri-n-butyl phosphate(TBP) are listed in Table l.

Table 1. Physical roperties f tri{t-buv phosphate

Physical stateMeltingpoint ('C)Boiling oint ("C)

Flash point "C)Relative enstyRelractive ndexViscosity cst)Surface ensionVapour pressure

Solubilltyn organic solventsSolubilityn water mg/litre)

Octanol-water artition coefficient0og Po*)

colourless, dourless iquid04289 (withdecomp.)b'd;177-178 3.6 kPQo'a;150 1.33 Pa)D193b: 66P: 46d0.973{.983 25 'go; 0.978 20 'ga1.4226(25'C)b; .4215 25 C)d

3.5-12.2Di.742gdynes/cm 20 'C)66.7 kPa 200 C)a:973 Pa (150 C)a133Pa 100 C)c;9Pa (25 C)misclblewithorganic solvents1012 4'C\e ; 9.422 125 67e'2.85x 10.4 50 .c)e

4.Od;9.99s; .01n

a laham et al. (1984)D ModernPlastics Encyclopedia 1975)c Parker 1980)o Windholz 1983)6 Hlggins t al. (1959)r Saegeretal. 1979)s Sasaki t al. (1981)t Kenmotsu t al. (1980b)

TBP is non-flammable and non-explosive. However, itis thermally unstable and begins to decompose at temper-atures below its boiling point (Paciorex et &1., 1978;Bruneau et al., I98l). The weak bond of the molecule isthe C-O bond, and its primary splitting leads to buteneand phosphoric acid (Bruneau et al., l98l). With anexcess of oxygen, complete combustion to carbon dioxideand water occurs at about 700 'C (Bruneau et al., l98l).


16/78

HerloTy, Physi@l aN Chsial Prqertie.s, Amlylial Metlds

Despite a lack of data, TBP is thought to hydrolysereadily in either acidic, neutral, or alkaline solution,based on the known chemical properties of trimethylphosphate Barnard et al., 196l).

2.3 Gowersionfactor

Tributyl phosphate I ppm = 10.89 mglms

2.4 Anatyticalmeffiods

Analytical methods for determining TBP in air, water,sediment, fish, and biological tissues are summarized inTable 2. The methods of choice are gas chromatography (GC)equipped with a nitrogen-phosphorus sensitive detector(GC/NPD) or flame photometric detector (GCIFPD), and gaschromatography plus mass spectrometry (GC/MS). The detec-tion limit in water by GC/NPD or GCIFPD is approximately50 ngllitre. TBP and other trialkyl/aryl phosphates

(TAPs), .8., triphenyl phosphate (TPP), trioctyl phos-phate, and tricresyl phosphate (TCP), can be simul-taneously determined by GC. Thin-layer chromatography(TLC) is sometimes used for determining TBP but is notwidely applicable.

2-4-t E

TBP is easily extracted from aqueous solution withmethylene chloride or benzene (Kenmotsu et &1., 1980a;Kurosaki et al., 1983; Ishikawa et al., 1985). Low levelsof TBP in water are successfully concentrated on AmberlitexAD-2 resin (Lebel et al. , 1979, l98l), xAD-4 resin(Hutchins et al., 1983), or a mixed resin of XAD-4 andXAD-8 (Rossum & Webb, 1978). The purge-trap method withcharcoal filter for ng/litre levels of TBP was reported byGrob & Grob (1974), but the percentage recovery was notcalculated.

TBP may be extracted from sediment with polar solventssuch as acetonitrile (Kenmotsu et al., 1980a) or acetone(Ishikawa et al., 1985).

Acetonitrile and methylene chloride (Kenmotsu et al.,1980a) or acetone-hexane Lebel & Williams, 1983; EAJ,1984) have been used for extracting TBP from fish or


17/78

EHC 112: Tri-rYAtV Pharylm,te

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18/78

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19/78

EHC 112: Tti-*Wttyt Prps@e

adipose tissues. Gas-phase and particulate TBP in theatmosphere have been simultaneously collected on glycerol-

coated Florisil@ columns (Yasuda, 1980).An octadecyl column has been used for extracting and

concentrating TBP in blood plasma preparations (Pfeiffer,1988). The sample was passed hrough the column from whichTBP was eluted with chloroform. The recovery of 50 FE perlitre was more than 900/o f the TBP added to the column.

2.4-2 CieelrFrygdure

Florisil column chromatography has been used forclean-up (Kenmotsu, et al., 1980a; Lebel & Williams, 1983;EAJ, 1984). This method allows the separation of TBP fromother phosphate esters, 0.9., TPP, and from organophos-phorus pesticides, .8., parathion.. Sulfur-containing com-pounds, which often exist in sediment samples and inter-fere with the analysis of TBP by GC/FPD, are easily separ-ated by elution with hexane from the Florisil column. Re-extraction with sulfuric acid from the hexane layer is auseful technique to avoid interference by sulfur-contain-ing compounds (Kenmotsu et al., 1980a). However, it isdifficult to separate TBP from lipids by Florisil columnchromatography because of their similar polarities(Kenmotsu et al., 1980a). In such cases, gel permeationchromatography (GPC) is useful (where the elution volumevaries depending on the type of phosphate ester, i.e.

trialkyl, triaryl, or tri(haloalkyl) phosphates) (Lebel &Williams, 1983). Partitioning between acetonitrile andpetroleum ether is an effective way of separating TBP fromadipose tissue (Kenmotsu et al., 1980a; EAJ, 1984). Actirvated charcoal column chromatography has also been used toseparate TBP from co-extractives of sediment samples(Kenmotsu et al. , 1980a)

2.4.3 Gas chron atograptry and rms spxtotnety

To identify TBP in environmental samples by packedcolumn GLC, a comparison of each retention time using twotypes of liquid phase of different polarity is desirable.As a low polarity liquid phase,3o/o or 100/oOV-l (Kenmotsuet ol., 1980a; Ramsey & Lee, 1980), 2o/o or 3o/o SE-30(Ramsey & Lee, 1980; EAJ, 1984),2o/o r 30/o OV-17 (Lebel et

19


20/78

Idqtfu, PWel aN Ctlenlcrtl PtWfies,Amlyricrll MMs

ol., l98l; EAJ, 1984), 3% or 7Vo OY-l0l (Sasaki et al. ,l98t; Lebel et al. , l98l), SP-2100 (Rossum & Webb, 1978.),2Vo OY-225 (Yasuda, 1980), 2% DC-200 (EAJ, 1984), aind 296OV-17 plus 2% PZ-179 (Ishikawa et al., 1985) have beenused. For the higher polarity liquid phase, l% or 2% QF-l(Bloom, 1973; Kurosaki et al., 1983), 5% FFAP, and 5%Thermon-3000 (Kenmotsu et al., 1980a, 1982) have beenused. When a non-polar liquid phase is used in packedcolumn GC, the reproducibility of the phosphate esterchromatogram is often poor. High loading of the liquidphase generally gives

agood reproducibility (Kenmotsu

etal., 1980q Nakamura et al., 1980).

Capillary column GC has also been used for theidentification and determination of TBP in environmentalsamples. Lebel et al. (1981) and Hutchins et al. (1983)used SP-2100 fused silica capillary column (25 m long;0.22 mm internal diameter) for the determination of TBP inwater samples. A wide-bore capillary glass column (25 mlong) coated with OV-l0l was used by Rogers & Mahood( 1 9 8 2 ) .

Lebel & Williams (1983) used GC-MS for identifyingTBP. The selected ion monitoring (SIM) technique is alsouseful for the quantification of low TBP levels (Lebel etol., l98l; Lebel & Williams, 1983; Ishikawa et al.,1985) .

2.4-4 Cm@ntndion d amlytial reglgnts

The widespread use of TBP in the plastics and paperindustries may cause contamination of analytical reagents.Traces of TBP have been found in cyclohexane (Bowers et81., l98l; Karasek et ol., l98l), methylene chloride(Lebel et 81., l98l), activated charcoal, and Avicel(crystalline cellulose) (Kenmotsu et Bl., 1980a). There-fore, care must be taken in order to obtain reliable datain

trace analysis of TBP.2.4.5 Other analytical m&tods

TLC has been used for determining TBP. Bloom (1973)reported good separation of Ttsp by coupling TLC with GC.Komlev et al. (1979) described an analytical method forTBP in waste water and air using TLC. Tittarelli &

20


21/78

EHC 112: Tri-tlbuyt P@we

Mascherpa (1981) described a highly specific HPLC detectorfor TAPs using a graphite furnace atomic absorptionspectrometer. In general, TLC and HPLC have not been aswidely used as GC. Parker (1980) described the automaticmonitoring of air using a flame photometric detector.

2 1


22/78

futces d Hmran and Eruironrnenal ryosure

3. SOURCES F HUMAN NDENVIRONMENTAL(FOSURE

3.1 Productions nd prooesses

TBP does not occur naturally in the environment. Fig-ures concerning total world production are not available.In Japan, 230 tonnes were produced in 19844, and 45tonnes were produced in the USA in 1982 (Schultz et al.,

1984). The estimated 1985 worldwide production capacitywas 2720-4080 tonnes per year (US EPA, 1987a).

TBP is prepared by the reaction of phosphorus oxy*chloride with n-butanol (Windholz, 1983).

3-2 Uses

TBP is used as a solvent for cellulose esters,

lacquers, and natural gums, as a primary plasticizer inthe manufacture of plastics and vinyl resins, and as anantifoam agent (Sandmeyer & Kirwin, l98l; Windholz, 1983).In recent years, there has been a considerable increase inthe use of TBP as an extractant in the dissolution processin conventional nuclear fuel processing (Parker, 1980;Laham et al., 1984; schultz et al., 1984) and in thepreparation of purified phosphoric acid (wet phosphoricacid method) (Davister & Peeterbroeck, 1982). Some 400/o

to 60% of all TBP consumed (probably in the USA) is usedas a base stock in the formulation of fire-resistantaircraft hydraulic fluids (US EPA, 1985). In Japan, 140tonnes was used in 1984 as an antifoaming agent (mainly inpaper manufacturing plants), 40 tonnes as a metal extract-ant, and 50 tonnes for miscellaneous purposesa. TBP isalso used as a constituent of cotton defoliants, which actby producing ieaf scorching (Harris & May-Brown, 1976).

a Personal ommunication o IPCS rom he Association f the Plasticizer ndustryot Japan 1985)


23/78

EHC 112: Tti-tvtrtilyl Phoqphafe

4. E]WIRONMENTAL TRANSPORT, DISTRIBUTION,

AND TRANSFORMATION

Surnntary

TBP has been found widely in environmental mqdia (air,water, sediment, and biological tissues) but usually at lowconcentrations. Sources of TBP in the environment includeleakage from sftes of production and use (e.g., aircrafttrydraulic fluids) and release rom plastics or other products.No figures on the amounts released nto the environment areavailable.

Once in the environment, t appears that the majority ofTBP finds its way to sediments. Biodegradation n water isdependent on water quality (1 mg/itre was degraded in 7 daysin River Mr.ssisslppi water). Lifle or no degradation occursin sterile river water or natural sea water. The degradation

pathway mostprobably nvolves stepwise enzryatic frydrolysis.tn drinking-water treatment, TBP levels do not decrease

unless powdered activated carbon is used, when very effectiveadsorption ccurs (9F100o/o t a TBP concentration f 0.1 g perlitre).

The bioaccumulation potential for TBP in killffish andgoldfish is low, the bioconcentration actor ranging from 6 to49. Depuration s rapid (half-lite,1.25h).

There is no information on the fate of TBP in air, but thisdoes not appear to be an area of concern. ln addition, thereare no data on transport o ground water.

4.1 Transport and transformation in the environment

4.1.1 Relegise o lhe erwironmerfi

A major potential pathway of entry of TBP into theenvironment s by leakage rom sites of production or use,and leaching from plastics disposed n landfill sites oraquatic environments. TBP has been foqnd widely in air,water, sediment, fish, and several biota, but usually atlow concentrations.


24/78

Envirwnwtul 7anWt Disribtfron, and Tran$ffiim

Extraction reagents and solvents are continuously lostfrom solverit extraction processes and may be transferredto aquatic environments. Ashbrook (1973), Ritcey et al.(1974), and Ashbrook et al. (1979) estimated the lossesfrom solvent extraction plants. When recycled acid isused in the dissolution process in a conventional nuclearfuel reprocessing plant, TBP and its phosphate derivativesbuild up to a level where low concentrations of organo-phosphate vapour are released to the off-gas stream(Parker, 1980). However, no data on TBP levels in air at

these plants are available.TBP used in antifoaming agents may be lost from manu-

facturing plants into the environment, but the resultantamounts in the environment have not been measured. Highconcentrations of TBP have been detected in river water(7 61-25.2 1tg/litre), fish (4.2-ll1.0 nglg), and air overthe sea (13.4 nglm3) sampled near Kawanoe City, Japan,where there are many paper manufacturing sites (Yasuda,

1980: Tatsukawa et al., 1975) (Table 5).

4-1-2 Fate n watq aN sd,imert

The solubility of TBP in water is considerably lessthan I g/litre at ambient temperatures (Table l). Monitor-ing studies have shown that it is widely present in waterand sediment (Suffet et ol., 1980; Hattori et &1., l98l;Williams & Lebel, l98l; Shinohara et al., l98l; Williamset &1., 1982; Ellis et rl., 1982; Kurosaki et &1., 1983).The difference in TBP concentrations between water andsediment was estimated to be about 3 orders of magnitude(river water, 20-l l0 ng/litre; river sediment, 8-130 nglg;sea water, 6-150 ngllitre; sea sediment, 2-24Q ng/g) (EAJ,l978a,b). The concentration factor of TBP on marine sedi-ment was reported to be 4.3 (Kenmotsu et al., 1980b).

4.1-3 Elidqrdatiott

The biodegradation of TBP in river water is slowerthan that of triphenyl phosphate and may depend to a con-siderable extent on water quality. Hattori et al. (1981)reported that I mg/litre completely disappeared in 6 daysin Oh River water, Osaka, Japan, after a two-day lagperiod. Howevere at an initial TBP concentration of 20 mg

24


25/78

EHC 112: Tthll'Ouyt Ptnffie

per litre, only 21.9% was biodegraded in Oh.River waterafter 14 days (Hattori et al., l98l). In Neya River water,

Osaka, Japan, degradation started at 6 days and was com-plete after 9 days. In River Mississippi water (St. Louiswaterfront, USA), degradation of TBP (l mgllitre) startedafter 2 days and was complete within 7 days (Saeger etal., 1979). No degradation was observed in sterile riverwater (Saeger et dl., 1979; Hattori et Bl., l98l) or inclear non-sterile sea water after l5 days (Hattori et al.,l98l). Primary biodegradation rates from semicontinuousactivated sludge studies (US $ap and Detergent Assoc.,1965; Mausner et ?1., 1969) generally showed the sametrend in degradation rates as river die-away studies. TBPdegradation was 96% complete at a 3-mg per litre, 24-hfeed level, but only 56% (x 2lo/o) at a l3-mg/litre, 24-hfeed level (Saeger et al., 1979). The ultimate biodegrad-ability of the phosphate esters was measured by Saeger etal. (1979) using the apparatus and procedure developed byThompson & Duthie (1968) and modified by Sturm (19731.

Two widely different results were obtained for the degra-dation TBP (20 mgllitre): 3.3% and 90.8% of the theoreti-cal carbon dioxide evolution were measured in two exper-iments. Such differences are probably due to variations inthe composite seed used in the two tests. A difference inthe ratio of TBP to active biomass may have resulted ininhibition in the first case but not in the second(Saeger, t al. , 1979).

The degradation pathway for TBP most likely involvesstepwise enzymatic hydrolysis to orthophosphate and al-cohol moieties (Pickard, et a l., 1975). The alcohol wouldthen be expected to undergo further degradation.

4-'l-4 Watert&nent

Fukushima and Kawai (1986) reported that 0.105-21.2 tgTBP/litre (geometric mean: 0.543 pg/litre) in untreated waterwas reduced to 0.018-3.80 1tg/litre (geometric mean:0.156 p,g/litre) by conventional waste water treatment.

Piet et al. (1981) investigated the behaviour of or-ganic compounds in dune infiltration: no change of concen-tration of TBP was observed. Sheldon & Hites (1979) re-ported that a TBP level of 400 ngllitre was not decreasedby standard techniques for drinking-water treatment.


26/78

Erruironmenhl TranWG Disffbutiol, and Truts/ionnaitiot

However, TBP is effectively adsorbed to powdered activatedcarbon (90-100% at a TBP concentration of 0.1 g/litre).

The adsorption coefficient (Freundlich equation) obtainedfrom an experiment using 0.01 to l0 mg TBP/litre at 25 "Cwas 190 (Ishikawa et al., 1985).

4.2 Bioaccumulation nd biomagniftcation

Data reported on the bioaccumulation and depuration ofTBP in killifish and goldfish are given in Table 3. Nodata for other fish species are available. Calculationsof bioconcentration factors (BCF) for other species havebeen made on the basis of physico-chemical properties(Sasaki et al. , 1981, 1982). However, these must be con-sidered less reliable than the low values actuallymeasured n killifish and goldfish.

TaUs 3. Bioaccumulation rd dearanco of TBP by fish

Specles Temp.fc)

no{/$at

Bloconcen- E)eosure Oopurationtratlon oonc. halllile Referencetactort (r/itrd (h)

Killifish(Oryzlas,atipes)

Goldtish(Caiassrlrsauftltrrs)

25 etatf,ow

25 slat

25 stat

11-4916-2730-35

e l t

0.2{.060.84{.1

3'{

34

Sasakl t al. (1982)

Sasakl t al. (1981)

Sasakl st al. (1982)

a Determlned yGGFPD


27/78

EHC 112: Tti-tubuty, Pt'Alpl'E,te

5. ENVIRONMENTAL LEVELS AND HUMAN D(POSURE

Summary

TBP has been found frequently in environmental sarnp/es(air, water, sediment, and fish) but usually at low levels.Measured ambient air concentratlons ange trom non-detectableto 41.4 ng/m3; the higher levels occurring near manutacturingsifes. Sudace water levels up to 25 200 ng/itre have been

reported, but no groundwater sampling data are available.Levels n sediment ange rom 1 o 350 ng/g.TBP /evels in biological samples, including fish and

shellfish, of up to 111 ng/g have been measured. t has a/sobeen detected n blrd populations.

Human adipose tissues obtained from the autopsy ofindividuals with no known occupational exposure o TBP showedone positive ample 9.0 ng TBP/g) out of 16.

Exposure of the general population can occur by severalroutes, including the ingestion of contaminated drinking-water(levels up to 29.5 ng/litre), fish and shellfish, and otherfoodstu,Ts. US FDA total-diet studies have fourtd averageintake levels of 38.9, 27.7, and 2.7-6.2 ng/kg body weight perday or lntants, oddlers, nd adults, espectively.

Occupational exposure an occur in several ndustries, ndespeclally where aircraft malntenance workers handle trydraulicfluids. Exposure during the synthesris of TBP and in plasticsproduction is unlikely if protective measures are taken aNbecause the various processes have been automated to aconsiderable esient.

Although production amounts are lower than for othertriaryl/alkyl phosphates, BP has been found frequently inenvironmental amples water, sediment, and fish), whereas

other triaryl/alkyl phosphates ccur more rarely. However,the measured concentrations are usuallv low. These arelisted n Tables 4-6.

27


28/78

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EHC 112: Tri-*butyl Phos$nte

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33/78

EHC 112: Tti-rlr@t Phosptnte

5-1 Environmental enrels

5-1-l Nr

Yasuda (1980) investigated the distribution of variousorganic phosphorus compounds in the atmosphere above theDogo Plain and Ozu Basin agricultural areas of WesternShikoku and above the Eastern Seto Inland Sea, Japan(Table 4). TBP concentrations were usually less than l0 ngper ms, but higher concentrations (13.4-41.4 ng/ms) were oc-casionally found. These higher atmospheric concentrationsof TBP are probably due to fumes liberated from papermanufacturing plants located around Kawanoe City. However,the source of these higher concentrations has not beenclearly identified. TBP has also been detected in theatmosphere in Okayama City, Japan, but the levels wereless han I nglm3 (Kenmotsu et al. , l98l).

5.1.2 WaW

TBP has been widely detected in river, lake, and seawater in Europe, Japan, Canada, and the USA (Tables 4 and5) .

Tatsukawa et al. (t975) measured ttre distribution offive phosphate esters in river water in the Seto InlandSea area of Japan and' found l0 to several hundred ng perlitre. Higher TBP concentrations (7600 to 25 200 ngllitre)

were detected in Kinsei River, Kawanoe City, Japan. Theauthors suggested that these high concentrations were theresult of effluent from paper manufacturing plants.

5.1.3 Sd,ime't

Despite low sediment adsorption coefficients, TBP hasfrequently been detected in sediment samples in Japan(EAJ, l978a,b; Wakabayashi, 1980; Rogers & Mahood, 1982;Ishikawa et al., 1985). The concentrations ranged from Ito 350 nglg.

5.1.4 Fistt, sfiell/iM, and birds

Although bioconcentration factors are low (section4.2), significant concentrations of TBP (ranging from I to


34/78

Ewiromnqbl Levds and Hwwt fryure

30 nglg) have been found frequently in fish and shellfish(Tables 4-6). Tatsukawa et al. (1975) reported a high

concentration (l I I nglg) in the organs of goby caught inKawanoe harbour at the entrance to the Kinsei River, Japan(Table 4). Although no clear evidence was available, thismay have been due to pollution by paper manufacturingplants located around Kawanoe City. Rogers & Mahood (1982)also found TBP in fish caught downstream from pulp millsand a sewage plant outfall, but the concentrations werenot reported.

Reports of wildlife monitoring by the EnvironmentalAgency of Japan (EAJ, 1982, 1983, 1984) indicated TBPlevels of 20-250 nglg in birds (Gray starlings).

5.2 General opulation xposure

5-2-1 Fod

The presence of TBP in infant and toddler total-dietsamples and in adult diet samples was studied by Gartrellet al. (1986a,b). These samples were collected betweenOctober 1980 and March 1982 during a survey made for theUS Food and Drug Administration (FDA). Gunderson (1988)also investigated the presence of TBP in samples collectedbetween April 1982 and April 1984 during FDA total dietstudies. TBP was only found in approximately 2o/o of thesamples, corresponding to average daily intakes of 38.9,

27.7, and 2.7-6.2 nglkg bodyweight per day for infants,

toddlers, and adults, respectively.

Gilbert et al. (1936) analysed composite total-dietsamples (representative of l5 different commodity foodtypes encompassing an average adult diet for each of eightregions in the United Kingdom) for the presence of trial-kyl and triaryl phosphates. Of the food groups, offal,other animal products, and nuts consistently contained thehighest levels, but the proportion of individual compoundsin the different food groups varied. Trioctyl phosphatewas the major component in the carcass meat, offal, andpoultry groups, and there were significant amounts of TBPand TPP. Total phosphate intake was estimated to bebetween 0.08 and 0.16 mg per person per day.


35/78

EHC 112: fri-ftb$ Plrmpffi

5.2-2 Dd*ing+raw

TBP has been monitored in drinking-water in. Canada(Suffet et 81., 1980; Lebel et &1., l98l; Williams &Lebel, l98l; Williams et ol., 1982), and the concen-trations ranged from 0.2 to 29.5 ngllitre.

Hurmn 0bs{res

Lebel & Williams (1983) analysed phosphate esters inhuman adipose tissue and detected TBP (9.0 nglg) in one of16 autopsy samples from humans with no known occupationalexposure to TBP. In a similar study carried out by the USEPA (1986), a trace amount of TBP was detected in one of46 samples.

5-2.3

5.3 Ocqrpational exposure

In its 198l-1983 National Occupational Exposure Survey

(NOES), the National Institute for Occupational Safety andHealth (NIOSH), USA, estimated that 12 lll workers in 6industries and l3 occupations were potentially exposed toTBP. Not included in this survey were workers involved inaircraft maintenance. Due to manipulation of hydraulicfluids containing TBP, these workers represent the largestpopulation occupationally exposed. In 1988, the TributylPhosphate Task Force (TBPTF) of the Synthetic OrganicChemical Manufacturers Association (SOCMA) estimated thatapproximately 45 000 aircraft workers, the greatest numberof workers potentially exposed to TBP, are exposed onceper week for 30 min to 2 h to hydraulic fluids containingTBP (US EPA, I9g7b, 1989).


36/78

E/fects ut Organisrts in tte Erwironmsft

6. EFFECTS ON ORGANISMS IN THE ENVIRONMENT

Sunnary

TBP ts moderately adc to aquatic organismq the 9&hLCro being 2.2 ng/itre for Daphnia and 4.2.11.4 mg/itre forfish in strfic fests. No data on non-target plants are avall'able, but srnce the compound is used in desiccant defoliants,some damage to plants adiacent o treated areas could be ex'

pected.6.1 Unicellular lgae, protozoa, and bacteria

Toxicity data of TBP for protozoa, algae, and bacteriaare given in Table 7. The inhibitory concentrations(ECo, EC56, EC166) of TBP for the multiplication ofunicellular algae, protozoa, and bacteria have been esti-mated to lie within the range of 3.2-100 mgllitre.

6.2 Aquaticorganisms

Data on the toxicity of TBP for aquatic organisms aregiven in Table 8.

There is little difference in sensitivity between thefew species of fish that have been studied; 96-h LCuo valuesrange from 4.2 to ll.8 mg/litre. It seems that embryo-

larval stages are less sensitive than post-natal stages ofthe fish life-cycle" but since the test conditions usedwere not identical this has not been fully confirmed. Aseries of tests carried out at different temperatures withrainbow trout suggested that toxicity increases withincreasing temperature (Dave et al., 1979).

In studies by Dave & Lidman (1978), rainbow trout didnot show any obvious effects at water concentrations below

5.6 mg TBP/litre but behaved very calmly when trapped in ahand-net at a concentration of I mg/litre (all concen-trations are nominal value). At l0 mgllitre, the fishstarted showing severe balance disturbances, which in-cluded highly atypical movements like darting, coilingswimming, and backward somersaults, but they recoveredafter 24-72 h at this concentration. On the other hand,


37/78

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40/78

Etrects n Arganivns n tlre Emirqwwrt

the balance disturbances persisted until the end of theexperiment at a concentration of ll.5 mg/litre. At I3.5 mgper litre, the fish were immobilized, lying on their sidesat the bottom of the water, and some of them died.

6.3 Plants

TBP is used as a constituent of cotton defoliants,producing leaf scorching, and is associated with anincrease in the rate of leaf drying (Harris & May-Brown,1976). Kennedy

et al.(1955)

reported thatTBP

increasesthe drying rate of lucerne, resulting in excessive leafloss.

TBP applied by spraying as an emulsion (at a rateequivalent to 0.25% of freshly harvested leaflweight)doubled the drying rate of ryegrass leaves. Leaf respir-ation stopped and did not resume in the subsequent 4 days(Harris & May-Brown, 1976). TBP has been shown to damagethe leaf surface and help herbicides penetrate bean lbaves(Babiker & Dancan, 1975; Turner,1972).

There is no information on the effects of TBP on non-target plants, even at conceittrations designed to producedesiccation of crop plants.

6.4 Arachnids

No mortality was observed among two-spotted spidermites (Tetranychus urticae) fed TBP at a concentrationof 2 g/kg (Penman & Osborne, I976).


41/78

EHC 112: Tfi-n-bw Phophate

7. KINET|GSAND METABOLISM

Sunrnary

IBP is readlly absorbed (> 50%) from the gastrointestinaltract in rats. Some absorption of TBP through the skin alsoocc rs, although the extent of dermal absorption is difficultto quant$ trom the data available. No information is avail-able on the absorption of TBP following inhalation, and thereis no satisfactory nformation on the distribution of TBP or

its metabolites ollowing absorption. The metabolism of TBP ischaracterized by oxidation af the butyl moieties. Oxidizedbutyl groups are removed as glutathione conjugates and sub-sequently excreted as N-acetyl cysteine derivatives. TBP metab-olites are excreted predominantly in the Ltrine, althoughsmaller amounts /so appear n the faeces and expired air.

7.1 Absorption

No information is available on the absorption of TBPfollowing inhalation. Substantial absorption from thegastrointestinal tract occurred in rats given a singleoral dose of TBP (Suzuki et 81., l984a,b; Khalturin &Andryushkeeva, 1986). Suzuki et al. (1984b) reported thatmore than 50% of an orally administered dose of TBP wasabsorbed within 24 h. Dermal absorption of TBP has beendemonstrated in pigs, and there was little difference in

therate of skin penetration between regions with or

without hair follicles (Schanker, 1971). In vitroinvestigations on isolated human skin showed that TBP hasa high penetrating capacity. The average maximum steady-state rate of penetration through isolated human skin is6.7 x l}-a pmol/cmz per min (Marzulli et al., 1965).

In a study by Sasaki et al. (1985), TBP was poorlyabsorbed n goldfish but readily absorbed n killifish.

7.2 DistributionLittle information is available on the distribution of

TBP and its metabolites. Following single or repeated oraldosing in rats, TBP was detected in the gastrointestinaltract, blood, and liver (Khalturin & Andryushkeeva, 1986).


42/78

Knelicsad M&irllistn

7-3 Metabolism

The metabolic transformation of TBP has been studiedin male rats following oral or intraperitoneal adminis-tration of raC-labelled TBp (Suzuki et ol., l9g4a,b).The first stage in the metabolic process appeared to beoxidation, catalysed by cytochrome P-45O-dependent mono-oxygenase, at the u or u-I position on the butyl chains.The hydroxy groups generated at the r,r and u- I positionswere further oxidized to produce carboxylic acids and

ketones, respectively (Suzuki et ol., 1984b). Followingthese oxidations, the oxidized alkyl moieties were removedas glutathione conjugates, which were then excreted as N-acetyl cysteine derivatives (Suzuki et ol., 1984a). It hasbeen reported that TBP is also metabolized in rodents tobutyl-n-cysteine (Jones, 1970). However, the presence ofbutyl-n-cysteine was refuted by Suzuki et al. (1984a).In the urine, the major phosphorus-containing metabolitesare dibutyl hydrogen phosphate, butyl dihydrogen phos-phate, and butyl bis(3-hydroxybutyl) phosphate as well assmall amounts of the following phosphates: dibutyl 3-hyroxy-butyl, butyl 2-hydroxybutyl hydrogen, butyl 3-hydroxybutylhydrogen, butyl 3-carboxypropyl hydrogen, 3-carboxypropyldibutyl, butyl 3-carboxypropyl 3-hydroxybutyl, butyl bis (3-carboxypropyl), and 3-hydroxybutyl dihydrogen (Suzuki et al.,1984b)

The rate of metabolism of TBP and the nature of the

metabolites produced were determined in in vitro tests onrat liver homogenate. It was found that rat liver micro-somal enzymes rapidly metabolized TBP in the presence ofNADPH (within 30 min), but only slight metabolic breakdown(ll0/o) occurred in the absence of added NADPH. Dibutyl(3-hydroxybutyl) phosphate was obtained as a metabolite inthe first stage of the test. The extended incubation timein the second stage of the test yielded two further metab-olites, butyl di(3-hydroxybutyl) phosphate and dibutylhydrogen phosphate, which were produced from the primarymetabolite dibutyl(3-hydroxybutyl) phosphate (Sasaki etal., 1984). The degradation of TBP to these three metab-olites has also been observed in in vitro studies on gold-fish and killifish (Sasaki et al., 1985).


43/78

EI]C 112: Tti-t*utyl P'?,c p/7fle

7.4 Excretion

In studies by Suzuki et al. (1984b), male Wistar rats(weighing 180-210 g) were given a single oral or intra-peritoneal dose of 14 mg r4c-labelled TBP per kg bodyweight. Urine and faeces were collected separately.Within 24 h of oral administration, 50% of the radioac-tivity was eliminated in the urine, l0% in the exhaledair, and 690 in the faeces; the total elimination after 5days was 8290. Following intraperitoneal injection, 70o/o of

the radioactivity was eliminated in the urine,7o/o

byexhalation. and 4% in the faeces within 24 h; the totalelimination after 5 days was 900/0.

43


44/78

EM m EWinerllEal Anhmlsand ln Vkro est Slctams

8. EFFECTS ON E(PERIMENTALAT{IMAISAND''V Y'}AOTEST SYSTEMS

Suwwy

Acltte toxicity studies suggesf that the chicken js fhe/east sensfuye species to TBP, afs and mice being more sensi-tive. A single iniection of TBP produces clinicat symptoms ofmild anaesthesi4 weal


45/78

EIIC 112: Tti-nil$ f@e

TaUe 9. Acute ethality date for TBP

Species Route ofadministration LDso/LCsovaluesReference

Mouse

Rabbit

Cat

Chicken

oraloraloraloraloral6-h inhalationimraperitonealintravenous

oraloralintraperitonealsubcutaneous

dennal

4-5-h nhalation

oral

1,O0mg/kgr3g0{530 mg/kg1552mg/kg1m0200 mg/kg3000 mg/kgtsss mgTma

800-1600 g/kg100mg/kg

900-1240mg/kg40000 mg/kS100-200mg/kg3000 mg/kg

> 3100 mglkg

2500 mg/m3

1800mg/kg

Johannsen t al. (192)Mitomoet al. (1980)BayerAG 1986)Eastman Kodak (1986)Dave&Lidman 1978)Eller 1937)Eastman Kodak (1986)Vandekar 1954

Mftomo t al. (1980)Eastman odak 1986)Eastman Kodak (1986)Eller 1937)

Johannsen t al. {1977)

Eller 1937)

Johannsen t al. (1977)

Mitomo et al. (1980) reported acute toxicity studieson TBP. The oral LDro values for ddY mice and Wistar ratswere 1240 me/ke (male mice), 900 mglkg (female mice), 1390mC/kC (male rats), and 1530 me/ke (female rats).

8-2 Short-term xposureIn a short-term toxicity study with TCP and TBP,

Wistar rats were fed pelleted diet containing a mixture ofTBP and TCP at a concentration of 5000 mglkg for 9 weeks(Oishi et 81., 1982). The body weights of TBP-treatedrats were significantly lower than those of the controls.Oishi and his co-workers also reported a short-termtoxicity study with TBP in which Wistar male rats were feddiets containing 0, 5000 or l0 000 mg TBP/kg for l0 weeks(Oishi et al., 1980). The body weights and food consump-tion of the treated groups were significantly lower thanthose of the controls. The relative weights of the brainand kidneys in the high-dose group were significantlyhigher although the absolute weights were significantlylower than those of the control rats. Total protein and

45


46/78

Efrects n EWdmenAI Ani/mals N ln yrtro fesr qAfems

cholesterol in the high-dose group and blood urea nitrogen(BUN) in both TBP-treated groups were significantly higherthan those in the controls. Cholinesterase activities werenot inhibited. The blood coagulation time of the treatedgroups was significantly prolonged.

Laham et al. (1984) reported the results of a short-term toxicity study in which Sprague-Dawley rats were ad-ministered TBP by gavage at doses of 0.14 and 0.42 ml/kgfor 14 days. No overt signs of toxicity were observedthroughout the study. There were no significant differ-ences in body weight between the test groups and theirrespective controls, but absolute and relative liverweights were significantly increased in the high-dosegroup (both sexes). Histopathological examination revealeda low incidence of degenerative changes in the seminifer-ous tubules of the high-dose group.

In a follow-up l8-week study, Laham et al. (1985)administered TBP by gavage once a day (5 days/week) to

Sprague-Dawley rats (12 rats of each sex per group). Low-dose animals received 200 mg/kg per day throughout thestudy. High-dose animals received 300 mglkg per day forthe first 6 weeks and 350 mg/kg per day for the remainingl2 weeks. Histopathological examination of tissues re-vealed that all treated rats developed diffuse hyperplasiaof the urinary bladder epithelium. Similar changes werenot found in the control animals. No testicular changeswere observed n the high-dose rats.

When Sprague-Dawley rats were fed diets containing TBPat levels of 0, 8, 40, 2A0, 1000, or 5000 me/kg for 90days, clinical chemistry changes included increased serumgamma-glutamyl transpeptidase levels in both sexes given5000 me/kg (Cascieri et ol., 1985). Both absolute andrelative liver weights were increased in both sexes atthis dose. Histopathological studies indicated TBP-inducedtransitional cell hyperplasia in the urinary bladder ofmales given 1000 or 5000 mg/kg and females given 5000 mgper kg.

Mitomo et al. (1980) reported that seven consecutivedaily oral intubations of TBP at doses of 140 or 200 mgper kg in Wistar rats resulted in marked increases in therelative weights of the liver and kidneys, increased BUN


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EHC 112: Tri-wbuUl

values, and tubular degeneration. The daily ad ronof 130 or 460 mg TBP/kg to rats for one month caused amarked depression of body weight gain and mo20 and 4006, respectively. Three-month feedingTBP doses f 0, 500, 2000, or l0 000 mC/kg n ddYSD rats produced dose-dependent depression ofgain accompanied by increases in liver, kidney,weights and a decrease in uterine weight. Ivalues were found in the high-dose groups of botmice.

ities oftudies atmice and

weighttestesBUN

rats and

8.3 Skin and eye nitationand skin sensitization

primaryml appli n

A single dermal application of 500 mg TBPtact or abraded skin of six rabbits produced se

tation, inducing erythema and oedema in all tThe instillation of 100 mg TBP in the conjunctirabbits gave rise to mild irritation, which was

EPA, 1987b, 1989). Although results suggest hatnot elicit any sensitization reaction in humans,protocols sed prevent any pertinent assessment.

8.4 Teratogenlcity

Roger et al. (1969) reported that TBPteratogenic n chickens at high levels.

8.5 Mutragenicity nd carcinogenicrty

Smyth & Carpenter (1944) observedtation effects following a single 0.01TBP to the clipped belly of albino rabbits.

lrfl-

ofintio

the in-re irri-

animals.I sac of

2, 3, and 7 days following the application (ation, 1985a).

noted l,Corpor-

A test on the irritating and corrosive tial ofTBP, conducted according to the OECD Gu lines for

), showedesting of Chemicals, No. 404 and 405 (OECD, 198that TBP was slightly irritating to rabbitexposure) and to rabbit eyes (Bayer AG, 1986).

in (4-h

Skin sensitization testing in human is (USTBP doesthe poor

slightly

ot muta-anna & Dyer (1975) reported that TBP wasgenic in recessive lethal mutation tests using


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EfrecEd, EpinwtErl fuirmls and n \fifo Tesf qlsrems

melanogaster. Ilowever, Gafieva & Chudin (1986) reportedthat TBP was mutagenic in the Ames test with Salmonellatyphimurium TA 1535 and TA 1538 at concentrations of 500and 1000 pglplate both with and without metabolic acti-vation. No mutagenicity was noted at lower concentrations(< 100 lelnlate1.

The mutagenicity of TBP was also evaluated inS. typhimurium strains TA 98, TA 100, TA 1535 and TA 1538(Ames Test) both in the presence and absence of addedmetabolic activation by Aroclor-induced rat liver 59fraction. TBP, diluted with DMSO, was tested at concen-trations up to 100 pl/plate using the plate incorporationtechnique. TBP did not produce a positive response in anystrain with metabolic activation. Strains TA 1535, TA1537, and TA 1538, without metabolic activation, producedtwice the number of revertants per plate compared to thesolvent control (DMSO) for at least three of the five testconcentrations, but no dose-response relationship wasobserved US EPA, 1978).

Tests on Escherichia coli strains WP2, WP2uvrA, CM56l,CM57l, CM6ll, WP67, and WPl2 showed no m.utagenic ffectafter 48 or 72 h of incubation at 37'C (Hanna & Dyer,197 ).

TBP was tested for mutagenic effects in a Salmonella/microsome test, both with and without 59 mix (metabolizingsystem), at doses of up to 12.5 mg/plate using four S.

typhimurium LT2 mutants (histidine-auxotrophic strains TA1535, TA 100, TA 1537 and TA 98). Doses of up to120 pg/plate produced no bacteriotoxic effects.. Bacterialcounts remained unchanged. At high concentrations therewas marked strain-specific bacterial toxicity so that onlythe range up to 500 pg/plate could be evaluated. Therewere no indications that TBP had any mutagenic effect(Bayer AG, 1985).

The testing of TBP at doses of 97 to 97 000 pg perplate, both with and without a metabolizing system (S9mix), on S. typhimurium strains TA 98, TA 100, TA 1537,and TA 1538 confirmed the lack of mutagenic activity (FMCCorporation, 1985b).

No data are available on the carcinogenicity of TBP.


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8_6

EHC 112: Tri-wfi..ttyl

Neurotoxicity

Sabine & Hayes (1952) showed that bothreagent grades of TBP possess very weakactivity and that very large doses produce csymptoms in vivo. They concluded that althoughcapable of producing cholinergic symptoms,required were so large that the "risk ofabsorption of acutely toxic amounts is negligi

may be interpreted as an early response toinsult. No axonal degeneration was observed in t

overt signs of neurotoxicity (ataxia, convulsion,righting reflex, etc.).

Johannsen et al. (1977) administered TBPadult chickens at a cumulative dosage of 3680dysfunctional changes were noted during the periodto 42 days following exposure. Formalin-fixedatic nerve, and spinal cord samples examined 42

exposure showed no pathology.

dosages for rats are roughly applicable to hu , i t

would be necessary or the development of syhuman ingest a dose in the order of 100 mlseveral millilitres parenterally". Sabine & Hafound that TBP induced sleepiness and coma in maleSprague-Dawley rats when it was orally and terallyadministered.

Laham et al. (1983) reported the effects of TBperipheral nervous system of Sprague-Dawley rats.

rats fed TBP bygavage

for 14 consecutive days ml/kgnerveer day) a small but significant reduction ofconduction velocity, accompanied by morphological changes

roscopicn the sciatic nerve. was found. Electron miexamination of sciatic nerve sections showed a tionof Schwann cell processes in unmyelinated fi which

ical and

rgicP was

dosesidentalIf the

that areceive(1952)

on theIn male

loss of

ly to/kg. Nofrom 24

, sci-ys after

chemicalani-

mals. Laham et al. (I984) also investigated su ute oral

toxicity of TBP in Sprague-Dawley rats and no


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ffier;lsottHwtnns

9. EFFEGTSON HUMANS

Although there are no case reports of delayed neuro-toxicity resulting from TBP exposure, workers exposed to15 mg TBP/ps air have complained of nausea and headaches(ACGIH, 1986).

TBP has a high capacity for skin penetration(Marzulli et al., 1965) and has been shown to have anirritant effect on the skin and mucous membranes n humans(Stauffer, 1984). It also appears to have an irritanteffect on the eye and respiratory tract.

In an ir vitro study, Sabine & Hayes (1952) found thatTBP had a slight inhibitory effect on human plasmacholinesterase.


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EHC 112: Tri-wbutyl Phogp/7lte

10. B/ALUANON OF HUMANHEALTHRISKSAND EFFECTS ON THE ENVIRONMENT

1O-1 Evaluation of human health effects

There have been no reports that TBP has effects on oc-cupationally exposed humans other than headache, nausea,and symptoms of skin, eye, and mucous membrane irritation.No cases of poisoning among the general population havebeen reported.

There is no indication from animal studies of a neuro-toxic effect comparable to organophosphate-induced delayedneuropathy (OPIDN). Systemic toxicity in humans followingacute exposure s likely to be low.

From in vitro test results. TBP is not considered tobe mutagenic.

TBP is absorbed through the skin and so dermal ex-posure should be minimized.

The likelihood of long-term effects in occupationallyexposed humans is small.

10.1.1 Eryosurelqels

The general population may be exposed to TBP throughvarious environmental media, including drinking-water.However, the concentrations of TBP measured in drinking-water by the USA Environmental Protection Agency wereextremely low and similar low levels were found in Japan,Canada, and Switzerland. Analyses in the USA of humanadipose tissue revealed trace amounts of TBP in a smallnumber of samples. There are insufficient data to evalu-ate the significance of general population exposure toTBP.

Workers involved in aircraft maintenance are poten-tially the most highly exposed population because of ma-nipulation of hydraulic fluids containing TBP.

1O-1.2 Toxicelfects

Tributyl phosphate may enter the body by dermal pen-etration and by ingestion. However, the data available do

5 1


52/78

Ewluationd Human Hath Bisks ard Efiects ut the Erwironment

not permit a useful comparison of the dermal and oralpharmacokinetics.

The available information does not permit an assess-ment of the risk presented by TBP as a potential carcino-Betr, neurotoxic agent, or dermal sensitizer. Observationsrelating to hyperplasia of urinary bladder epithelium inrats, neurotoxicity signs (ataxia, incoordination, weak-ness, respiratory failure) in rats, and sensitization ofguinea-pigs are considered inadequate to evaluate thehazardous potential of TBP for human health. No tumourdevelopment has been observed in rats. TBP does not pro-duce delayed neurotoxic effects in hens. No adequate dataare available on the effects of TBP on reproduction (func-tion of gonads, fertility, parturition, growth and devel-opment of offspring).

10.2 Evaluation f effects on the environment

Although, on the basis of physico-chemical properties,TBP has a high potential for bioaccumulation, measurementsin laboratory experiments show that this is not realizedin practice. Residues in biota sampled from the environ-ment are generally low, though measurable residues inbirds suggest that some transfer in the food chain ispossible. Toxicity data are limited but suggest moderatetoxicity to aquatic organisms. This information tends tosupport the view that TBP presents little risk to organ-

isms in the environmont since measured concentrations insurface waters are generally low.

1O.2.1 F4oswe lanels

TBP has been found widely in surface water, sediment,and ground water, but normally only at low concentrations.The biodegradation of TBP in water is substantial underaerobic conditions but proceeds only at a slow rate belowcertain concentrations. It is possible that a low levelequilibrium is reached in the environment between continu-ous release and removal. The lack of data on the rate ofTBP hydrolysis does not permit a reliable assessment ofthe persistence of TBP in the environment. Consequently,the potential hazard of the substance cannot be evaluated.More data are required on the rate of TBP hydrolysis,


53/78

HIC 112: Tri-*buty| Pfioqphate

which, when used with the available information on thebiodegradability, will facilitate the assessment of itspersistence and consequently the environmental risk posedby its manufacture, use, and disposal.

lO-2-2 Toyicfi*E

The sensitivity of aquatic organisms to TBP has beendetermined in static tests. Itrowever, the biodegradabilityand relative hydrophobicity suggest that flow-through

testing would provide more reliable data because of moreconstant exposure. The available information indicatesmoderate toxicity of TBF to algae, daphnids, and rainbowtrout. TBP causes damage to terrestrial plants by increas-ing leaf drying rates, which results in excessive leafloss. No information is available on uptake and trans-location.

53


54/78

Recsnmedatiuls

11. RECOMMENDATIONS

11.1 Recommendations ior urther esearcfl

There is a need for further studies on skin sensitiz-ation, teratogenicity and reproductive toxicity, and o"nthe pharmacokinetics of different exposure routes.

Further testing for mutagenic potency is required.

Initial in vitro tests on mammalian cell cultures should,if necessary, be followed by in vivo testing. Dependingon the outcome of these mutagenicity tests, a carcino-genicity study may be required.


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EHC 112: Tti-ftW, Phmdrarc.

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EHC 112: Ttt-*W Plmlfiade

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EHC 112: Trt-*turty| Phephate

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