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sa~J/Jp/1. 4.6. LITERATURE SURVEY ON TIIE NITROSAHINES ASSOCIATED WITH TIlE COOI~TS PROJECT r ~" ~ - " U qq,]i , !3th February', I97~. U ¢ The following sources were consulted for the literature survey:- (i) Chemical Abstracts, 1934-1972, i.e. Vols. 28-77, (2) Organi c Synthesis, Collective Yols. 1-48. No evidence was found for the existence of either the imine nitrosamine (3) (for structures, see Note S~/JP/I.4.6, dated the Sth February, 1975) or any associated chemical studies, and it is therefore extremely unlikely that this is a stable compound. Only one referencs to N-t-butylnitrosamine (4) was found, this having been report~fl by PasternakI in connection with a study of the mutagenic activity of both carcinogenic and non-carcinogenic nitrosamines. Before including (4) in the group of nitrosamines to be studied, it is necessary to await arrival of the complete reference. IC was considered that, in addition to N,N-tuhutyl-methyl nitrosamine (6) it would be equally possible for lqSl4 to give rise to N,N-iso-propyt-methyl nitrosamine [7) and therefore the literature search was extended to cover this compo~md. CI!3 \ H-C --N --N ~O / t CH3 CH3 C7) A direct method for preparing (6), which can readily be applied to the pr~paratlon of (7), is reported by lleath and ~attocks2, although a reference3'4 to the p~paration Of (7), together with its physical data, has been found. SaxbyS has reported the mass spectral analysis Of both [6) and (7], and a paper bF Pensabene6 may contain some C~D 0 CXD t J7 BATCo document for Legal Services : Health Canada 27 November 2000

- 2- additionzl information. Heath7'8'9 has also reported sever~l investi- gations on the toxicology of [6) and references by other authorslO'll may give information which could be of use at s later stage. In view of the above information, it is proposed that the smoke from cigarettes treated with ~514 should be analysed for the presence of (6) and (7), and possibly (4). In addition, the presence of dimethyl-, methyl-ethyl-, and diethyl-nitrosamlnes, already known to be present in cigarette smoke12, will be determined. Analys~s for these simpler nitrosamines will require very little extra work and it is possible that the presence of ~$14 may enhance their production. Gaulolsc cigarettes will be used in this study and, since these simpler nitros~mines have already been determined in the smoke of untreated Cauloise cigarettes, re-analysis will serve as an internal standard for the whole experiment. References 2. 3. 41 5. 6. 7= 8. 9. 10. iI. 12. L. Pas~ernak, ~ech. ~lutnt. Inducing Factors, tree. Sy~p. 1965, (Pub. 1966), pp.285-g. D.F. Heath ~ A.R. Hattocks, J. Chem. Soc., 1961, 4226. A.~. Campbell CCo~nercial Solvents Corp.). U.S. Pat. 2,9SI,7S2, 25th April, 1961. B.V. doffe, Zu~ Obshehe~. Khim., 1958) 28, 1296. M.J. Saxby, J. Assoc. O£flc. Analyt. Chemists, 1972, 5S (i), 9. J.W. Pensabene, W. Fiddler, C.J. Dooley, R.C. D~err ~ A.E. ~Yasserman, J. Agr. Food Chem., 1972, 20 (2), 274. D.F. Heath, Nattrrv, 1961, 142, 170. D.F. Heath, Biochem. J., 1962, 85, 72. D.F. Heath, Brit. J. Ind. Med., Ig62, 19, 276. P. ~larquardt, Arznelm.-Forsch., 1971, 21 [Ii), 17S2. G. Osske, Ar~. Geschwu!stforsch., 1972, 39 (I), 62. B-A.T. Report No. RD.g39-R, lOth October, 1972. CSD CDO F~D BATCo document for Legal Services • Health Canada 27 November 2000

TO DR. S.J. GREEN, RESEARCH & DEVELOPMENT, M~LLBANK. ~EF DJW/JP/1.4~ 6. i F ROM 1 OATC f, rou# . ~.:,,,-,. tt*.!-''" ~,TrliP4'~-lopment~r.,nlre / D.J. WOOD. ~' 7th February, 1973. COOLANTS -..:..,~ You will remember that I spoke to you last week about certain safeguards which I felt we should take prior to consumer testing. I new enclose notes on a meeting which was held to discuss this subject, from which you will see that we have decided on a course of action. J £1..~r.....=~ Encs. 1 o CD C~ ~Jq CO ~D tJq t~4 BATCo document for Legal Services • Health Canada 27 November 2000

s~,~iJ~l],. 4.6. 5th February, 1973. ~EETING H~D ON THE 2nd FEBRUARY, 1973, TO DISCUSS ~{E POSSIBLE PYROLYTIC FOPI,!ATION OF NZTF, OSfd-IINES BY W.S. COt.'/~OL~DS Present: Dr. C.I. Ayres M.A. Baylis, Esq. Dr. S.R. ~:assey D.J. Wood, E:{q. Dr. J.G° Underwood ~.to of thd coolant compounds that are of, inte,:est to us, WSl4 (]) and WSIO (2), are chemically similar amides ~d it is possible that~ under the pyrolytic conditions of a burning cigarette, they may degrade to give nit~. The WSI4 compo~d %:as discussed in detail since this material is the stronger candidate for c~n.~=umer te~ting. %~wo methods of determining the possible degradation of wsld have been considered, these being:- (a) Transfer studies using specially syntb~,~sised ~'adio- labelled s~.ple of ?~S14, (b) Direct aualysis of cigarette condensate :o detezmine the presence of certain nitr~sa,,~ines u:~ing GLC,/accura~e mass measurements (P.C.M.U.). It was decided th0t the second app'2oach is to be ado r'ted as being of mo~e i~nediate relev~:ce. Discussicn revealed that ['IS14 could give rise to four possible nitros~,mines, these being illustrated in Structures 3-6. Ther~- was some doubt as to whether the nitrosamines (3) and (5) exist and, thel'eforc, a literature snatch for these compounds will be ca~:yied out (by S.R.M.) before considering any onalytical work. O O t/] tTn BATCo document for Legal Services • Health Canada 27 November 2000

- 2 - Because the possible amide nitros~mine (5) is a novel compound, some development work to determine its chemistry a-nd recovery from smoke condensate will be necessary before any analysis can be carried out. Thus it was decided that an investigation to deterr~ine the presence of (5} would be held in abeyance, most probably until some estimate of the commercial potential of WS14 has been obEained from the results of consumer testing. The meeting considered that the most likely nitrcs~]ine to be formed would be N,N-t-butyl-methyl nitros~ine (6), ~%d it was decided that experiments to determine its pl-esence should be carried out as soon as possible. The existing method to dotemnine the prc~cnce of N-dialkylnitrcsamines in cigarette smokei will be used add it was thought that this work will take about two monnhs. The Alde~aston official list of mass spectra does not yet include data on (C) , although its analysis has been reported by Saxby2. Dr. A. McCo~nick of P.C.M.U. has no sampl~ or mass spectral d~ta on (6], althou<jh he did i:'~forv. S.R.M. that Dr. T. Bryce of Unilever may be able to help us. In any event, the availability of (6} and also the parent amine (N,N-t-butyl-methy!amin,~ will be investigated (S.R.M./M.A.B.). Structures C lJ C< \N--C~ N-~CH ) OH3 CH3 (i) (2) / CH3 -\ CH3 c 13 CH3~" CH3 / C E{3 H (3) [4) Q OlD <2q ~O BATCo document for Legal Services : Health Canada 27 November 2000

- 3- structures (Continued) N CH3 O CH3- C--N -- N z O t CH3 CH3 C6) References i= B-A.T. Report No. RD.939-R, 10.10.72. 2. Saxby, M.J., Jo Assoc. Offic. ~nalyt. Chernistsr 1972~ 55 (i), 9° C q> CO CrD ~O BATCo document for Legal Services • Health Canada 27 November 2000