P.1 

OAR Box 1131 

Prepped by Ollie Stewart 

Document Number: 

138)11-1-18 

Docket Number: 

A-83-22 

Printed 4/21/2008 2:34:12 PM Sheet 138 of 162 
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CAH('IN(MJK.\I( ACTION OF .MOTOK KXUIXK OIL ADDITIVES 

\\. \\. BALDWIN . C.l . n'NXINCHA. M AN D I). I'HATT 

From tin- ('itncir l.'i'xitinh Liilmriitnri/. I'nirrrxili/ nf Siitliinjliii in., nml llir 

I >!• purl nn-nt nf I'liltmliMji/. Huijnl ('iillrijr af Suri/ttiii.s. Lanihiu 

KI'I'I-JVIM I I'i ir |Hll.li.-at LH, .In k -.1 . Mifil 

PKKVK M si.v it was reported that a proprietar y engine nil additiv e was carciiTiit'ciii'- following ri'|M-atril skin paint ini: in in in- ( I la Id w in. ('unninghain and I'rat I. 

Iiiili). Th is additiv e which is utilized as a high pressure. high temperature 

lulirii-aiit. contains a formulatio n consisting mainlv nl'lead naphthenate together 

with siiii'll ainiiunt s cl chlorinated hydrocarlions such as earhon tetraehloride or 

\ | : I -triehlnret h.-ine dispersed in a inineral oil hase. The various eoinponents 

,iv themselves highl y helerngeiieiuis mixtures without any well defined eharaci.-ri.-ties. Thus the lead naphthenate fraction is a sulisiiliary oil product 

..i.iaiiieil durin g the 11:; 111111".-1 < -1 ure of hyilrocarhoi i distillates. Thi s fraction . 

,T :;:<•11 is ol varying com pos it ion depending upon the source of crude oil. contains 

•.-tti salts of a complex mixtur e of aromati c and aliphati c carhoxyli c acids 

Kiiniiici'iis. I!i"i7). '!car! y therefore isolation and chemieal characterization of 

;:;r carcinogenic eon, j.niieni (s ! in the proprietar y oil addi I i\ es. alt hough desirahle. 

. n.it practical at this time. However it was considered essential to ascertain 

•,i-i.-llier i iie carcinogenic act ivi l v was associated wit h anv one of the crude pro-

-„•:.-. part ici i lar I v in view o| t he variet v ol uses. e.g. paint driers, w ood preservatives 

• ;,| u i-t 1 ing agents, of I he na phi heme acids. Accordingly . \ alio us components of 

•• •• nil add it ive. supplied hv the ma nu la d urcr. ha \ e heen assessed lor carcinogenic 

•

:

\il v following skin paint IIIL' in mice. In addition , a second proprietar v 

:.|jtjvi• utilized inainiv a- an upper cylinder luhricant has heen tested for 

• I. iiingenii- ac l i\ il V . 

M VIT.UI.VI.s \ M> ,\| KTHoli S 

.. ' ,/././,'/»'/v .< 

_\'lililin I. ('uiilpoiieii l fractions of the additiv e previoiislv shown to lie 

.T.-iimgciiic for mouse skin (|!al,lw in. ('uuningha m and I'ratt. I !Mil) were supplied 

'• 4 ihe manufacturer. 

• !• Hase oil into which the additiv e is dispersed. 

• ii) Additive formulatio n • 'flu - proprietar y additiv e contains |u per cent oi' 

• • . formulation in hase oil. fo r carcinogenic assay, the formulatio n was skin 

...:i,icil as a -

11

 per cent v v solution in doiilile distilled Al ! Iienzene. 

• jii) Lead naphthenate. Thi s material, supplied as a dark drown oilv liipiid . 

..!,.• nl t he major eoinponents ol the additiv e formulation . Lor carcinogenic 

..,-,. the material was skin painted as a i'n percent v v solution in Iienzene. 

.\ii'lili''' II - A proprietar y additiv e agent used mainl y as an upper cylinder 

.'Mi-ant. This was ohtained commerciall y in sealed cans. 

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fi.14 H. W. KAI.IlUTN . <:. .I'. (TN'XIMiHA M AN U l». I'KAI' l 

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KNI'KKIMKNT.VI. I'Ki H'Tflifl'K 

Youn g adul t mal e 

The y wer e maintaine d ii 

libitum. 

alhin o mic e (Seholiel d strain ) wer e employe d in al l tes' 

i group s of J u o n a standar d ciihe d die t wit h water ' 

Dorsa l hai r wa s remove d wit h electri c clipper s at th e lieginnin g o f each 

tes t an d the n subsequen t Iv w h el l lleeessa r y . < h i sample s wer e applie d dm ) ivvise t' 

t h e ski n fro m all-glas s tuhereiili n syringe s an d wher e necessar y sprea d wit h gla.--

rods . Mic e wer e t rea te d onc e o r t wie e weekl v fo r period s o f u p t o I '2 mou t hs an1' 

t h e tota l dos e iipplie d is show n i n Tabl e I. Mic e wer e examine d fo r tumou r 

-kl v interval s unti l th e test s •re terminate d (I s montlis ) an d killcu 

whe n the v we r e il l o r wi n n tumour s wer e considere d malignant . Al l tumour s wen 

take n fo r histologica l examinatio n an d tumou r incidence s wer e assessed fro m tin 

numbe r o f n lice survivin g (at ri.-k) whe n tumour s wer e first observe ' 

'I" 

KKSI'I.'I'S 

ie base oi l fractio n used i n t he addi t iv e prev ioiis l v show n t o be carcinogciii 1' 

(additiv e I) prove d t o be highl y toxi c causin g marke d inllaminator v changes in 

ski n simila r t o t hose uliserv ed wit h t he whol e addi t i Durin g th e first (1 mmi'l e 

i f treatmen t wit h thi s fraction , mi , ; m painte d t wie e w i II owevrl'. 

surviva l wa s poo r r. Mi u l tin - origina l mic e (i n per cent ) dvui g o r bein g ki l 

( fig . I ) an d t here lor e mic e w ere I rea le d I herea Ite r on b onc e w eekl y mi l il ski n pain 

t in g wa s terminate d (I _' mon i h-.). Nei l he r o f i he o i he r i w o trac t ion... o f l he additiv e 

showe d an v toxi c propertie s 1 

(fig . I) despit e i h 

ow a n 

ac l tha i th e 

Is sk in am i surviva l o f treate d m i ce wa.- gem 

l b.-t; vv ere a | ipln-i l I w ice w, •l:h •'' 

itration s doubl e thos e in th e whol e addiiiv i 

T h e I iase oi l Ira el ion prov ed t o he carcinogeni c follow in g repeale d ski n pa ni l ic 

inducin g ski n tumour s in M i pe r cent o l mic e at risk (Tabl e |) . Althoug h tl i 

t i n tumou r incidenc e i> coi n par; l o tha i iiid u wit h t ie w liole a Mnr . 

((iii pe r cent) . t he m a jori t v o f t unio n i s wer e benig n pa pi I Ioni a l a an d squamou s cd : 

carcinom a ta ( f I g . -) vi ere observe i Ill onl y .i mic e I I , pe r cel l 1 I . T l ns contra-' 

wit h th e hig h incidenc e o f ski n earcinomat a induce d b v th e whol e additiv e l-d 

p e r cent) . 

.Neithe r th e whol e additiv e formulatio n no r th e lead naphthenat e bactiei i 

produce d an y significan t carcinogeni c respons e in mous e skin . Henc e skin 

TAKKK I.—-SLin T 

Aihlit 

ir I'nriilfiiri-s 

in s nr ( 'nmIIOIII n 

Min- Tn nlni irith Oil 

I Fnicti 

Skin tiiriM oil' iiM-iilcM, 

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I'Yiirtiuii 

Adiliti v 1 

A.lilitiv.- 11 

A.lililiv c I 

Cllln|l'illT'lll S 

(i) Has,' nil 

(ii) Aililitivc 

conci-iit rutt-

(iii) I.i-ml 

ilithi-iuil i 

'I'onil Iliu m imi 

ilnst- T'X| n-riirieii 

(ml.) (iln.vs) 

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t nli: 

NinnliT Tut.-iI u SU i l l l-Ill't-IIlT TlllMS 

,i ,,r 

(ilnvsl nt risk Nuiiilicr \\ 

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I n.'t 

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Ti-citta^ ' 

till 

Xiniili'T I'l'i-c-i-nlii 

IS "il 

III 

|-'.i|lli\'itlT-llt In the un,'i,int cniitiiiiM'it in Iili ml . <it' whole iiilitilivt 

'.-£&-' 
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I'AKCINOCENI C KNCINK Oil. ADDITIVKS ;i0:> 

ohillmiiata were observed in only 2 mice (4 percent) follow ing skin painting wit h 

Vjid inphthciiat c whilst onl y a single papilloma developed in mice treated wit h 

tin- whole additive forniulation (additive concentrate). However, skin painting 

• ii- lead naphthenate fraction induced marked kidney damage and tubula r 

,.icii<iinata were observed in 4 mice whilst one.had a renal carcinoma. 

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lilK,- Hi t 

I enc.-Ill l-ilti' 

l.cn. i II.'I|T|,I lu'iiul i 

A.l.litiv, - 11 

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Additive II . unlike the lirst preparation tested, did not induce skin ulceration 

.ii-l mi.'.- tolerated twice weeklv treatment . Thus when tumour s were lirst 

,,-•..nied ii'4 weeks) only li mice (I n per cent) had died or been killed (fig . I). 

!Vi-. additive also was carcinogenic inducing skin tumour s in L".I (i s per cent) of 

ii,in- at risk (Table I). These tumour s were mainl y benign papillomata but 

,|ii.un.nis cell carcinomata were observed in In mice (111 per cent). 

DiscrssiiiN 

The present findings clearly demonstrate that the base oil component ofthe . 

.,i! additive previouslv tested (Baldwin . Cunningha m and IVatt . liMil) is the onl v 

ji.nii. u wit h any significant carcinogenic activity . Whilst the act ivi l ies of the 

',..:-.,• oil ami w hole addit iv e were almost ident ical w hen assessed from t he incidences 

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"ilMi K. \\ . UAI.DWIN. r.. .1. CI'NMNCH.WI AM ' I". CHAI"I 

of total skin tumours , the incidence of skin caieinoniala was signilieant Iv |.,m •' 

in mice treated wit h base oil (Table I). This difference may si mpl v be due i,, 11,. 

poor surviv al of miee I reated wil h base oil (fig . I i. although the po.-.-ihilii v ' * ..i 

other components in the additive , e.g. halogenated hydrocarbon-., pus-,-..- pi<,u • 

ing properties cannot be e\cluded . Ilowevei-. the finding that the whole ; 11! • 11 > i \ • • 

forni uiat ion excluding the base oil and I he lead naphl henat<- I r.n t ion wen- uia<-' i\ • 

implies that component-, in ihe base oil are niainlv re-pon-il,!e for the ear. iu.> • • 

icity of t he aihlit iv e. 

I'rev ion-I v . t he ba-e oil w a-, cia s-i lied a- a \ eieziielan crude nil which h.e I 

undergone I hernial reform ing. I n v iew ol l he pre - -ni I ind nig-- luri le r . h.u i. i"' 

ist ies of t he base oil have been prov ided bv I In- ma 11 ula et nivr« and I le- e i:,.!;, ' :• 

thai it is a spindle oil .Moreover, it- phv-i'-al properties -u^' 1. -I that it !•' -

withi n tin- ,|a — o| ml - which Irom pn-v ion- -Hide - iTwoi t and I.v i C I''.':.. 

Cook. I'arrut hel- and W Illoll-e I • • -~»— 1 mav be expected lo lie e.,re|| I,|, 

Detail-, of ihe n>iii|i,i-ii ion of I he second addiliv e (additive II) which !,.• I i, 

sho w II t o li e e.l ni l lo g elli e (T a bl e I ) ;ll e Ho t ;l V;l i I.I I li e . I lo w CV e r 1 hi.- addi ' 'V e , d .. 

contain- a Iormulal ion di-per-ed in a muicr.d oil ba-.e and lie po-alah l , I*..I 

I he carcinogenic -i 11 • -1.1111 , ~ o i • • c n it a ined in I hi- It act ion : ds lo lie , . a,-id- ; c l 

Clearly, a larger -ere - n\' oil addiiives and iheir component- i-eipiu-'- l " '•• 

eva lua I cil in ni del |„;|..,.. , I I n • | T, .- -. j I ii, pot en I ial heal I ii ha/.-ird ot t le- e -id,- i.u,, • • 

Moreov er. although I le- e experiment a 1 iii id ing.- arc noi din-el Iv applicable i n ma:. 

in con-idcrmg ti c i-llr, l- ol oil additive - and ai.-o lubricating oil- in general li " v 

need to In- eoii-idered a- po —iblc atmospheric pollulan!-•. resulting Irom en,i--ii 

as oil particle- in vehicle rsh.-iu-l fume-. Whil.-I li e amount ,,(' oilv mati-ii 1' 

emitted mav onlv be -mai l compare,! to that ol the petroleum ,, o, 11 o; -: i..:. 

product.-, although ihi - wil l depend upon the el'ieieiey of' the engine, ti c hi_ " 

eareinogenicit v of additive I and iis base oil ,u,_.e,.s|.- that ,-ueh materia! HM V 

represent a -igiiilic.ini carcinogenic factor. Wynde r and I lotVin inn il'.a'il': C v 

deinoii.-l rated that i -11 •_ no e\hau-t condeii.-ale.-. prepared so ihal much o| t h. ..i.v 

material via- excluded and - " presumably containing mainl y petioleiini eomlmtion product-, were carcinogenic |,,r mouse -kin . Whilst direct compaii-on ••! 

these si ud ies w it h t In • present finding.- i.- complicated bv v.-iriat ion.- in i-.x periiueiii.il 

procedure, tin- carcinogenic re.-ponse elicited bv additiv e I approximate - |,, that 

of the most potent condeii.-ale traction. 

That air pollutant- represent a signilieant factor in environmenta l i-an-ino 

genesis is now w ell esi.ililished (11 neper . / nl.. I'.MiJ. fal k and Ixotiu. IIHlL'. Koiii . 

and falk . I'.Mi!!) and several polvcvelic h v diocaiboi i carcinogens have IM-I-II 

detected in urban polluted atmosphere.-. (Ixotiu and falk . I'.Hi!!). As vet howevei 

the significance of mineral oils as environmenta l carcinogens has not received 

sufficient consideration although numerous .-Indies have demon-l rated can li e 

genie activit v in a variet y of lubricating and cuttin g oil- (Shubik and S.illeii. 

Iil.il ; Cihna n and Vcs-clinov il ch. I'.Cili; Kckardl . I'.CiT: Cook .('arru t In i - ami 

Woodhousc. I!I."IS; llueperan d I'avne. I'.MiU). I n considering t he cai einogeneit v 

of petroleum derivatives . Hueper and I'avne il'.Hiii) have also enipha-i/ed ti e 

potent ial hea It h hazard of res pi ral or v expo-ure to eon I ing and lubrie.it ing oil nn-i -

KXI'I.ANATluN <'!•' I'I. \ ll-! 

Ke. L'. Aililiim I Im- I in,In.cI -.|ii; is ,-T-ll .•in..in..iii.-i with I.T.-.-II IIIMK II v I-! 

Jul i. 
CAKCINOCKNIC KM : INK oil. AKMTIVK- 51 r, 

ietli in special occupational groups such as metallurgical workers and also in the 

i.emulation at large. However, evidence of the influence of occupational exposure 

•,i nil mists is still inconclusive (Hendricks. Collings. Donley. Carrett and Rather, 

;inij) and clearly there is a need also for a more comprehensive assessment, ofth e 

iia/.ai'ds of oil mist exposure. 

si jniAI;v 

1. Kxamiiiation of component fractions of a proprietary engine oil additive 

iirrv ioiislv' shown to be carcinogenic for mouse skin has denionsl rated that the 

.•;iiviiiogcnic substances are contained almost exclusively in the base oil. 

2. A further additive agent used mainly as an upper cylinder lubricant also 

in-lived to be carcinogenic for mouse skin. The significance of t he findings are discussed, particiilarlv with regard lo the possibility that these substances may be 

atmospheric pollutants. 

Thanks are due to Mrs. ,M. I'.. Marshall for skilled technical assistance. This 

Investigation was supported by a block grant from The Urilish Km pire Cancer 

Campaign for Uescaieh. 

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!', vi.livvix. It. \\'.. CCNNI son,v.M. C .1. ,vx I) I'll ATT. I >. ( llllil ) lirii. ./. I'lliirir. 15. \2'.\. 

I'.IUK -I W • < A III; i rn KITS. W. .vxn WooiHinrsi:. I). I.. \ I'.Cis) lirii. mnl. Hull.. 14. I!{:.'. 

Kek-.vlil'T. IV K. (I'.I.TT) Imlu-lr. .1/../ . >'</,;/.. 26. !.!Hi. 

|.'M.|T. II. I.. AM . KoTIN . |*. (I'.HiJ ) Sill. Cm,,; r Inst. .1/,«»/.;/. No . !». X I . 

OILMAN -I. I". W . AM I VK.-SKI.INO V mil . S . I'. (ItClCi) Air},, iii.lu.-lr. Illlll. 14 . HI I . 

Hr. xi >I;I i KS. N . V.. ('ot.I.I NOS. (1. II . I iooi.i:v . A. IV. (! vi;i: KIT. .1. T v M I I! vi u I:I: .1 I!. 

. I'.lti:'! Anii. • n ri nm. Illlh. 4. I!!u. 

p.i.iii : W. ('.. K<i-rix. I'.. Tvitni; IV C.. I'VVXK W.W . I'M . K II. v M I S A W KKI . IV 

: I'.tliJi Airli. I'nlh 74. s'.l. 

;./.;,.. >-.i. I' vv M. . W W. (I iiiio) //,,',/. 70. !!T-J. 

KMI-|M'.I-: I - . -I . (I'.CiT) ./ . In.il. /'./;•.-/. . 43. !io7. 

K-.TI . I', v.-.n IVvi K. II. I.. ll'.ll'.!!) .\,lr,ll,r. c,,„,;,- li..--.. 7. 47.".. 

Siiir.n. I', v \ n S vi l IOTTI. IV illLVIj /V.' 1. .Im./ . .1- - I'.IIH-O' /,',-.. 1. I;">. 

|.vid ' i . ' '. AM . I.v III. II . | !'.«!{| ././///;/.. r,i„,/,.. 33. Ii'.l. 

UV .iU..: K I.. AM. lbU i .MANX. I). I I '.Mil') Cm,; /'. 15 I O!! 

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THE BRITISH JOURNAL OF 

CANCER 

(The official journal of the British Empire Cancer Campaign 

for Research) 

KDITOR 

A. C. Thackray 

ASSISTANT KDITOR 

CJ. Fa mi-Brow n 

ADVISORY EDITORS 

Sir Samuel P. Bedson 

Sir Stanford Cade 

Sir Charles Dodds 

Malcolm Donaldson 

L. H. Gray 

Sir Brian Windevcr 

A. Haddow 

W. I). Newconib 

Sir Heneage Ogilvie 

F. .1. C. Hoe 

Percy Stocks 

VOL. EIGHTEEN 

1964 

DIRECTOR 

R. W. Scarff 

l.O.YDO.N 

H. tt. LI:!WIS & CO. LTD. 

136 COWER STUCKI, W.C. |.