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Page 11: 02800509
6. The MAFF report noted the similarity of target organ effects and biochemical changes with these substances, principally liver and peroxisomal proliferation, and the requirement for additional data in support of continued use of several compounds. 7. It is not established whether cigarette applications could contribute to human intake. At a total of 4 mg adhesive per cigarette from filter elements, a level of 10% of DDP in adhesive would provide 0.4 mg per cigarette. There is some possibility that a fraction of this might migrate on storage to the tobacco rod and hence provide a source for transfer to smoke. 8. It is increasingly desirable that we can claim conformity to key legislation in several markets, and the West German regulations are the most important element. 9. In view of some of the uncertainties attached to long term use of phthalates, it would be prudent to avoid or reduce their presence on the product wherever possible. 10. Subject to this proposal being agreed, the main adhesive suppliers will be advised of the intention and asked for help in achieving it. 11. Other sources of phthalates may need to be considered in the future e.g. inks and wrapping materials. / BATCo document for Legal Services • Health Canada 21 October 1999
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,, 4° °0 GS/JP/AGP i . 81.11 September 1989 ! = -- ! T * 13 WEEK INHALATION TOXICITY STUDY OF TOBACCO CONTAINING METHOPRENE A meeting was held at Microbiological Associates (MBA), Bethesda, on 24th August 1989 to discuss the draft report of the Kabat inhalation study. Present: Ray David Lucas Brenne:ke Bob Weir Graham Smith MBA - Study Director Pathology Associates Inc (PAl) ° - Study Pathologist Consultant - Zoecon BAT (UK&E) R&D • PAl - an independent organisalion responsible for the tissue Irom necropsy to full histopathology. The issues raised were those of BAT, Philip Morris, R.J. Reynolds, Brotherton & Associates (Consultants to Zoecon) and Zoecon Corporation. The majority of the comments were points of clarification or correction of minor errors. Copies are attached. The points raised were gone through on a company by company basis and the majority satisfactorily answered with no dilliculty. From the questions raised it is clear that, of the tobacco companies who made comments, BAT was alone in not accepting the study conclusions based on information presented in the draft report. Pldlip l~lorris I R.J. Reynolds Position Both Philip Morris and R.J. Reynolds were happy to accept the conclusions of the report. R JR - "We all agree with the conclusion of the study that rnethoprene in smoke has no independent etlects in rats'. PM - "My criticisms or] the draft report are minor in nature and ! do not feel there are any difficulties with the conclusion of this report'. ".... t feel confident that the quality of the data will go a long way in expanding methoprene's usefulness'. BAT Position Whilst the majority of comments by BAT may be regarded as minor, one or two issues raised were recognised as being of greater significance such that the conclusions of the report cannot be accepted until they are satisfactorily resolved. A list of the questions raised by BAT and the response by MBA is attached. C) c..3 L,,J Co BATCo document for Legal Services • Health Canada 21 October 1999
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Conclusions (BAT) 1. From the i nformation provided by (a) Weekly monitoring reports (b) The draft report (cl Discussions with MBA I am confident that the study protocol was met in that all smoke-exposed animals were exposed to cigarette smoke at the same concentration for the same length of time. The absence of diluting air control early in the study produced only a minor variation which was the same for all groups. 2. From our own discussions, plus those with MBA and company consultants, the observed group differences in electrolyte ~evel and adrenal organ weight were not due to the addition of methoprene. 3. Independent evaluation of the adrenal sec~'ons confirms the view expressed in the draft report that there were no structural changes attributable to the addition of methoprene. A separate report is being prc--pared. 5. I have no reason to think that all the issues raised with MBA witl not be satisfactorily resolved, although a final view must wait urn1 the corrected pathology report has been completed. 4. The significance of the inaccuracy of the ~ryngeal sections must remain unknown until they have been re-evaluated. I have asked to see all respiratory tract sections including those that have to be re-cuL The final report is expected by the end of Septe.,nber. c~ C3) co C~ BATCo document for Legal Services • Health Canada 21 October 1999
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POINTS RAISED BY BAT Page 11 In the table, the animal numbers do not cover 20 animals/sex. This will be corrected. Page 11 Is the laboratory happy that using only one smoking engine presented no problems in terms of methoprene residues? We assume not, but it should be stated. It was concluded that the laboratory could not make any supportable statement in answer to this quesEon. Page 13 (2nd para.) What is the acceptable range for a position 2 TPM? It should be defined. This will be defined. Page 17 Terminal sacrifice. It is not clear what smoking regime was followed on the last few days of the study. Were animals smoked on the Saturday if necropsy was on the Sunday? If so, would this influence the results? If they were not, again how would this influence the results? More detail is needed to define procedures. All autopsies were carried out on a Thursday or Friday, animals receiving either3 or4 days" full smoke prior to sacrifice. The terminal sacrifice procedure will be cladfiedo Page22 Blood CO and nicotine values on their own are of vaiue; however, it is desirable to compare measured levels against chamber CO and nicotine levels present prior to taking the blood sample, i.e. it would be useful to plot individual blood CO and nicotines against the individual chamber CO, nicotine values. This point will be covere(l; a preliminary graph indicated a good correlation between blood and chamber CO. Page 23 The variability in handling the blood samples resulted in differences in measured nicotine levels. Reassurance that the values are meaningful would be oi use. Are they sure that the nicotine "found" in the sham group is not due to smoke from the engines in the same room? Suitable 'reassurance' will be provided. The level found in the sham group is within the resolution of the technique used and will be described as such. J~ BATCo document for Legal Services " Health Canada 21 October 1999
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Page 25 Page 26 Changes in electrolyte levels are described in terms of smoked v nonsmoked and also differences between smoke groups. A little more discussion in this area would be of value, bearing in mind organ weights of the adrenals, Could the two be linked, or is it due to, for example, alteration of kidney function? As the adrenals were considered a possible target organ before the study was carried out. consideration of the changes noted in relative organ weights would be of value. There is n~.,ed for an authoritative statement as to their significance. Any possible confusion relating to the significance of the adrenal weights and changes in the electrolyte levels will be resolved. Discussions with Ray David provided the reassurance that the observed changes were not treatment-related. A more authoritative statement on this part of the work is to be included in the final report. Page 27 In considering the histopathology, the pro-schedule deaths and scheduled deaths are grouped together. They should be separated and any observations based only on those animals that were exposed for the full 13 weeks. This will be carried out; data from the early deaths will be tabulated but not commented on. Page 28 If the rotameters were fully open, why a smoke concentration change assuming a reproducible posifion 2 and stable air supply? I am still not sure why chamber monitoring figures showed a 'dip" mid-study that was not reflected in position 2 values or level of dilution. MBA admitted to their shortcomings early on in the study with regard to monitoring and controlling the diluting air flow. Ray David is to tabulate the individual air flows on a daily basis and provide more detailed information regarding smoke dilution. Whilst this is a recognised shortcoming early on in the study, variations in chamber concentration were small and the same for all exposed groups. Page 29 No mention of male adrenal weights in group 4. Although the differences were not statistically significant on a % brain weight basis, they were still elevated compared to other groups. This witl be considered under the whole area relating to adrenal organ weights. Page3! How can there be week 15 in a 13 week study? Even with a staggered start it shc,uld only be 14 weeks. Week t4 for a t3 week study is due to a staggered start/finish. Week t5 is a calendar week. Le. the final "experiment week" was across two calendar weeks. This will be clarified in the report. Cb Cb Co (3o BATCo document for Legal Services • Health Canada 21 October 1999
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Page 63 This is all the animals, not only those exposed tor the full 13 weeks. It should also include the sham group and "no effect"incidence. Lung changes appear to be smaller than macroscopic. Why are the macrophage (pigmented) changes not tabulated? Regarding the histopathology group, comparisons are made on the severity of the individual lesions, not taking into account the extent of the changes. It is not clear if both elements should be considered. For example, which, if any, is the greater response - a grade 3 focal change or a grade 1 multifocai or diffuse change? Does just taking the severity score in isolation reflect the relative magnitude of the response? The points will be covered in the final report. Discussions with the pathologist suggested that the severity score was sufficient to distinguish between any variation in response, Le. grade 3 is a larger response than grade 1, irrespective of extent. Page 66-69 Bodyweight curves include days 100 and 101 for a 91 day study, The scale also changes from 7 day to 1 day valuesl Why the fall off in bodyweight after day 99? Bodyweight fall off after day 99 is due to starving the animals prior to autopsy. The values for days 100/101 are misleading and will be removed from the growth curves. The other issue raised was: Accuracy of larynx sections (see attached note) The apparent deviation from the protocol and laryngeal sections provided was outlined and concern expressed as to the accuracy of the histcpathoiogy report on this subject. Lucas Brennecke accepted the crifisicm and, fotlowing detailed discussions, agreedto re-evaluate all the laryngeal tissue from existing or re-cut sections. The significance of this re-evaluation will not be known until it has been completed. Reassurance is being sought regarding the quality, in terms of level of section, of the nasal cavity slides. This action was fully supported by Dr. Weir. Distribution Dr. R.E. Thornton Dr. R. Binns Dr. R.R. Baker Mr. T.G. Mitchell cb c~ c~ L~ 'q3 BATCo document for Legal Services - Health Canada 21 October 1999
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Technical Memorandum @ {UJL and Export) Limited RESEARCH & DEVELOPMENT CENTRE SOUTHAMPTON ENGLAND No TM.89-08-004 Subject DIOXINS - A Review of Properties and Implications Authors T.G. Mitchell, G. Smith To Mr.N. Da~s Circulation Mr. A.L. Heard Dr. R. Binns Dr. R.E. Thornton Dr. T. Hirji File File AGP Date 25 August 1989 Key words Cigarette Paper, Paper, Dioxins, Furans, Carcinogens Teratogens, Mainstream Smoke, Smoke Condensate, Toxicity, Review, PVC J~ C~ c~ : C,',,:~ -" - :.._- NOT TO BE COPIED OR SHOWN TO UNAUTHORISED PERSONS (,..,q ,..o BATCo document for Legal Services - Health Canada 21 October 1999
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1 TGM/GS/MM/AGP 25 August 1989 DIOXINS - A REVIEW OF PROPERTIES AND IMPLICATIONS TECHNICAL MEMORANDUM NO. TM.89.08.004 Authors: T.G. Mitchell, G. Smith SUMMARY: Recommendations . 'Dioxins' is the collective common name for a group of compounds more properJy identified as polychlorinated dibenzodioxins (PCDO's). The common name is frequently assumed to include reference to related substances known as polychlorinated d~enzofurans (PCDF's), or more simply lurans'. = These substances have achieved notoriety as a result of studies on their toxic properties in animals which have demonstrated carcinogenic and teratogenic (birth defects) properties following extremely minute doses in some species. . Despite a number of claims of adverse effects in man following gross exposure from industrial and other incidents, there is little proof of any serious clinical effect apart from the skin condition chloracne, , Assessments by governments of their effects have led to a range of values being proposed for maximum regular intake by man. The guideline figure of 1 I:X3 per kiiogramme bodyweight per day set in the U.K. in 1989 has been used to examine the concerns arising from manufacture of consumer products - cigarettes. o The West German data on estimated current intake of dioxins of 1.3 pg per kg bodyweight has been used to compare the significance of smoke exposure and other related factors. ° For cigarette smoke, a number of assumptions have to be made regarding the very small amount of data so far available. The analysis indicates that cigarette smoke is probably of iittte significance in respect of gross discharges of dioxins into the atmosphere. © 1989 BATUKE. Do not copy or show to unau~odsed persons. C~ C3 L,-J ,,,£) BATCo document for Legal Services - Health Canada 2"1 October "1999
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o 9~ 10. 11. 12. 13. For a smoker of 60 cigarettes a day, it would constitute possibly 2.5% of the guideline ,figure for human daily intake and 2% of current estimated West German daiiy intake. Of rather greater importance is the observation that it would, at these figures, comprise a significant proportion of total inhaled dioxin intake. it is recommended that validation is obtained of the amount of dioxins in cigarette smoke in order to confirm or refute these conclusions. The possible sources of dioxins in cigarette smoke have been considered. Cigarette tissue is probably the most important potential direct contributor to dioxin s in the product. When sound information on products of specific composition is obtained, i'¢ will be possible to determine the relevance of specificatfons for dioxin content in ~ssue. Other sources have also been examined including residues of chlorinated chemicals from agriculture, chlorinated phenol preservatives and factory materials. The longstanding recommendation not to use chlorinated hydrocarbon herbicides and insecticides in tobacco growing should be re-emphasised, even though their contribution to dioxin levels in the product would be very small. In the same way, chlorinated phenols should not be used as preservatives in the direct tobacco environment. Any proposed use of chlorine compounds, including inorganic salts, as product additives, will require consideration of potential effects on dioxin production. The possible contribution of chlorinated compounds such as the plastic PVC emphasises the importance of strict control of waste streams in factories wherever recovery and reconstitution of tobacco is employed. There is adequate evidence to show that the production of bleached paper pulp leads to the formation of dioxins both in the product and in waste streams deriving from it. 14. Two approaches should be followed with bleached paper production: 15. 16. (a) To reduce and supplant as far as possible the use of chlorine as bleaching agent. (b) To increase the use of chlorine dioxide in place of chlorine Where black liquor recovery systems are employed, dioxin levels in gaseous emissions should be controlled indirectly by combustion temperature. In the case of liquid effluents, the main approaches to reduction of dioxins should be via attack of the pdmary process supported by monitoring of effluent streams for total organic chlorine content. © 1989 BATUKE. Do not copy or show to unautt~orised persons. o CC) "..O BATCo document for Legal Services - Health Canada 21 October 1999
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17. 18. Any re-use of fines recovered from liquid streams may require individual review. As a first step, analysis for total organic chlorine content is recommended. At present, there is no officially recommended occupational exposure limit. The proposed level of 0.2 ng m"3 from one group is recommended for use as a guideline ,'or determining workplace concerns should they arise. O 1989 BATUKF_ Do not copy or show to unauff'K~ised persons. C2~¸ BATCo document for Legal Services - Health Canada 21 October 1999

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