Message From : BLEEKE, MARIAN S [AG/1000] [/O=MONSANTO/OU=NA-1000-01/CN=RECIPIENTS/CN=198145] Sent : 5/31/2016 3:59:50 PM To: LEVINE, STEVEN L [AG/1000] [/O=MONSANTO/OU=NA-1000-01/cn=Recipients/cn=594761]; LEOPOLD, VINCENT A [AG/1000] [/O=MONSANTO/OU=NA-1000-01/cn=Recipients/cn=VALEOP] Subject : RE: Emailing: CPDA-2012-2013-Accomplishments.pdf Attachments : CLA Presentation Adjuvants_PMRA Nov 20 2012.pdf Steve, We worked extensively on this in the CLA residue expert work group. EPA was primarily looking at three types of adjuvants surfactants, spreader/stickers, and oils. Registrants collected lots of data from side-by-side trials with and without adjuvants. We analyzed the data, EPA also analyzed the data, there were lots of discussions. Bottom line was that there was a modest statistical increase in residues with adjuvants, conclusion was that it was not significant from a risk assessment perspective, and label restrictions weren't needed (or trials re-run). EPA did highly encourage running residue trials with adjuvants, which is now standard procedure. I've attached a ppt, presentation from 20:1.2 on the topic. Probably more detail than you want: - but the last three slides show the EPA memo and ChemSAC recommendations. Marian From : LEVINE, STEVEN L [AG/1000] Sent : Tuesday, May 31, 2016 10:11 AM To: LEOPOLD, VINCENT A [AG/1000]; BLEEKE, MARIAN S [AG/1000] Subject : RE: Emailing: CPDA-2012-2013-Accomplishments.pdf Thanks. I am working on a tank-mix issue for dicamba and wanted to know if we did any work on this front. From : LEOPOLD, VINCENT A [AG/1000] Sent : Tuesday, May 31, 2016 10:10 AM Confidential - Produced Subject to Protective Order MONGLY05272935
To: LEVINE, STEVEN L [AG/1000]; BLEEKE, MARIAN S [AG/1000] Subject : RE: Emailing: CPDA-2012-2013-Accomplishments.pdf No, don't believe so. From : LEVINE, STEVEN L [AG/1000] Sent : Tuesday, May 31, 2016 10:07 AM To: BLEEKE, MARIAN S [AG/1000]! LEOPOLD, VINCENT A [AG/1000] Subject : Emailing: CPDA-2012-2013-Accomplishments.pdf Marian and Vincent, Did you ever get involved with this issue? CPDA scored a decisive victory with EPA's decision that the use of tank-mix adjuvants does not increase pesticide active ingredient residues in plants to levels that would be of concern. As such, EPA will no longer require a label statement prohibiting the use of a tank-mix adjuvant that has not been tested in residue field trials with the registered active ingredient. This decision was articulated in an August 13, 2012 internal memorandum and followed a four year effort, led by CPDA, to alleviate EPA's concern that the use of tank mix adjuvants on plants grown under actual agricultural practices could result in as much as a two-fold increase in pesticide residue levels Confidential - Produced Subject to Protective Order MONGLY05272936
Potential Effect of Adjuvants on Residues in Relation to Routine 0 §1 Residue Trial Vari ability CLA Residue Expert Working Group in collaboration with CPDA Health Canada - PMRA Nov 20, 2012 Confidential - Produced Subject to Protective Order MONGLY05272937
Adjuvants i n agriculture M Use of adjuvants is common practice for farmers • Surfactants (non-ionic - N IS, ionic, blends) • Oils (modified seed oil - MSO, crop oil concentrate - COC) • Stickers (e.g. polymers) ommercial Applicatio Function: • penetration • dispersion • emulsifying agents • ... etc. aids Confidential - Produced Subject to Protective Order MONGLY05272938
Potential for adjuvants to affect resmidues Do adjuvants increase residue levels? Limited data submitted to EPA suggested this • might be the case EPA concerned that US tolerances could be set • too low if based on trial data w/o adjuvants Prompted EPA to require "Adjuvant Prohibition" • statements on registrants' product labels Confidential - Produced Subject to Protective Order MONGLY05272939
Compilation of Data for Adjuvant Investigation 437 side-by-side trials "with adjuvant.-Wi'thout adjuvant," were compared (excluding values < LOQ) Data included fungicides, insecticides, herbicides; 25 . were predominantly oils & surfactants ; NAFTA and European trials Confidential - Produced Subject to Protective Order MONGLY05272940
Independent statistical analyses of data -1.2 -1 -0.8 -0.6 -0.4 -0.2 0 0.2 0.4 0.6 0.8 1 1.2 1.4 1.6 (Residue with Adjuvant / Residue without Adjuvant) Log of Ratios Analysis to Determine Effects of Adjuvants on pesticide Residues Final Report George Cas el la, PhD Consulting Statistician Gainesville', FL* May 23, 2012 Confidential - Produced Subject to Protective Order MONGLY05272941
Industry's Analysis Result .......... ........ ................. ......... ................ .......... ................ ......... ...... ....... . . . . . . . . . . . . . . . ............ . . . . . . . . . . . . . . . .......... . . . . . . . . . . . . . . . .......... . . . . . . . . . . . . . . . .. 0 d 75% of the ratios are below 1.4 (the log of the ratios are below 0.16).. m 87 % of the ratios are below (corresponding to log .8). 0. -1.2 -1 -0.8 -0.6 -0.4 -0.2 0 0.2 0.4 0.6 0.8 1 1.2 1.4 1.6 Log of Ratios (Residue with Adjuvant / Residue without Adjuvant) Confidential - Produced Subject to Protective Order MONGLY05272942
Industry's Analysis Conclusion • Range of variability seen is typical of residue data : sometimes residues are less with adjuvants , sometimes more . Were a few unusually high values (plums) • Existing labels in the market which are "silent" with respect to use of adjuvants are not a concern. Existing tolerances and dietary risk assessments are adequate Confidential - Produced Subject to Protective Order MONGLY05272943
A bt's A nalys i s for E PA ample, rcr t LL._F T non- en : ohs ce I o bs 1 : I I I I Ln a 0 Ln va Log Residue Pct €I t -A m r cu i; n Ii, st - m I I . n o Mean Confidential - Produced Subject to Protective Order MONGLY05272944
AN's Analysis Conclusion D ,ample. rcrol: MALL UT non-cans o: b s 11 c n: obs ln'wa - - r - 1 04 '. ', 654 VFM w a = -2,.1:09:+ 0.96 9.1 lnR The average percent differences between pesticide residues wi a nd without adjuvant were positive (im ply in g that adjuvant increases residue), ranging from 12% %. The average percent difference for the FRUIT category was approximately 6 0% , while the average percent difference for this category when we e l imin at ed all experiments with plums was only approximately 28 % . r :0 Me a n Confidential - Produced Subject to Protective Order MONGLY05272945
EPA ' s Bootstrapp h ig Analys i s r a Sample: n observations with r pl r rw i ent from the: na:1 e:: :re n is V data, w: :n fa f ate the MIRL e i .u i highest a Mean O) with appropriate r u in, It pl each: observation of the. sample co:: step ow M : ire : denotes the ppe:rcent increase d : ue to adjuva nt. : eca l c ul ate the R L o f : th is new s am pl e s it . appropriate rou nd i ng s D enote t: e MR: o f t h is r f r ed I' sample as M RL . Define an: I n d i ca t o r v a ri ab le , Z . If MR .... _ r use Z Repeat steps I and:' 4 many, B, times. Confidential - Produced Subject to Protective Order MONGLY05272946
EPA's Bootstrapping Conclusion " The previous finding by mathematical derivation. The result of the simulation implies that there is difference in MRL estimate with adjuvant and without ad j uvant. " MONGLY05272947
Question we should like to answer: Is the routine variation seen in residue trials greater than the observed variation found in the comparison of side-by-side trials with adjuvant vs without adjuvant? Field Res i due • Conduct controlled stud i es side - by - s i de t ri als range of data set s i zes us i ng vs no adjuvant - very expensive Confidential - Produced Subject to Protective Order MONGLY05272948
Dr, Davold Miller's suggestion. A m ore appea li ng a ltern a tive to this w oul d b e to te fiel d tri a ls t ha t we r e a lr ead y com pl eted ( sa y 1 6 fi e l d tri a ls for p ot a to) in to tw o ( equa l si zed ) g roups (r andom ly) of 8 and d ivi de esti ma te t h e toler a nce for ea c h g ro up . Th is coul d b e ea c h r epea t ed h u nd r e ds of ti me s (by co mp u te r), ea ch ti me r and o m ly g r ou ps. If it d r aw i ng e i gh t fi e l d tr a il v a l ue s fo r ea c h o f t he dem onstr a t ed t ha t the re su lti ng toler a nce d i ff ere d b y, coul d coul d t he n sa y t ha t t he a dj u v a nt vs. non- say, 75-100%, ea ch ot he r in ad ju va nt tri a l s exam i ned d i ffe r ed a manne r si m il a r t o wha t o ne w oul d fin d in r epea t ed fiel d tr a ils." Confidential - Produced Subject to Protective Order MONGLY05272949
Question we should like to answer: Is the routine variation seen in residue trials greater than the observed variation found in the comparison of side-by-side trials with adjuvant vs without adjuvant? Use OECD MRL Calculato r • Sub - sample ex i st i ng , actual res i due determine variability estimations data set s i zes - a more reasonable approach Confidential - Produced Subject to Protective Order MONGLY05272950
T est i ng of O EC D Calculator subsampling of real data sets 51 parent residue data sets from JMPR and EFSA Each parent set had at least 20 residue values (incl <LOQ values) Subsampling without replacement - 10 times for each parent set 3 subsample sizes (4, 8, and 16) MRL calculated for each subsample set (510 MRLs for each subsample size) 22 parent residue data sets with at residue values for subsample size of 20 Confidential - Produced Subject to Protective Order MONGLY05272951
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