Joint FAO/WHO Expert Committee on Food Additives (JECFA) Guidance document for WHO monographers and reviewers evaluating food additives

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1 Jint FAO/WHO Expert Cmmittee n Fd Additives (JECFA) Guidance dcument fr WHO mngraphers and reviewers evaluating fd additives (excluding enzyme preparatins and flavuring agents) eneva i

2 Jint FAO/WHO Expert Cmmittee n Fd Additives (JECFA) Guidance dcument fr WHO mngraphers and reviewers evaluating fd additives (excluding enzyme preparatins and flavuring agents) Versin 1.0 February 2016 Geneva ii

3 WHO Library Catalguing-in-Publicatin Data Guidance dcument fr WHO mngraphers and reviewers evaluating fd additives (excluding enzyme preparatins and flavuring agents), versin Fd Additives. 2.Risk Assessment. 3.Meta-Analysis as Tpic. 4.Review. I.Jint FAO/WHO Expert Cmmittee n Fd Additives (JECFA). II.Wrld Health Organizatin. ISBN (NLM classificatin: WA 712) Wrld Health Organizatin 2016 All rights reserved. Publicatins f the Wrld Health Organizatin are available n the WHO website ( r can be purchased frm WHO Press, Wrld Health Organizatin, 20 Avenue Appia, 1211 Geneva 27, Switzerland (tel.: ; fax: ; bkrders@wh.int). Requests fr permissin t reprduce r translate WHO publicatins whether fr sale r fr nncmmercial distributin shuld be addressed t WHO Press thrugh the WHO website ( The designatins emplyed and the presentatin f the material in this publicatin d nt imply the expressin f any pinin whatsever n the part f the Wrld Health Organizatin cncerning the legal status f any cuntry, territry, city r area r f its authrities, r cncerning the delimitatin f its frntiers r bundaries. Dtted and dashed lines n maps represent apprximate brder lines fr which there may nt yet be full agreement. The mentin f specific cmpanies r f certain manufacturers prducts des nt imply that they are endrsed r recmmended by the Wrld Health Organizatin in preference t thers f a similar nature that are nt mentined. Errrs and missins excepted, the names f prprietary prducts are distinguished by initial capital letters. All reasnable precautins have been taken by the Wrld Health Organizatin t verify the infrmatin cntained in this publicatin. Hwever, the published material is being distributed withut warranty f any kind, either expressed r implied. The respnsibility fr the interpretatin and use f the material lies with the reader. In n event shall the Wrld Health Organizatin be liable fr damages arising frm its use. iii

4 Table f cntents List f abbreviatins... v Preface... vi Chapter 1: Rles and respnsibilities Selectin f cmpunds n the agenda and issuing the call fr data Identificatin f mngraphers and reviewers and assignment f cmpunds and tasks Dealing with the data submissin Handling cntacts with the spnsr Perfrming literature searches Evaluating the data Preparing the draft mngraph befre the meeting Preparing the reprt item and finalizing the mngraph at the meeting... 5 Chapter 2: Preparing the mngraph Intrductin General aspects Frmatting Units f measurement Presentatin f dses Presentatin f pint f departure Tables Histrical cntrl data In-text references Miscellaneus Detailed cntent f the mngraph Explanatin Bilgical data Dietary expsure Cmments Evaluatin References Chapter 3: Preparing the reprt item Chapter 4: Additinal cnsideratins Re-evaluatin f fd additives by JECFA Cmmentary n the use f NOEL/NOAEL and LOEL/LOAEL Overall NOAEL Health-based guidance values fr fd additives Acceptable daily intake (ADI) ADI nt specified Temprary ADI and ADI nt specified Grup ADIs Substances that are gentxic and carcingenic Acute reference dse (ARfD) Extensin f an existing ADI t substances btained frm different surces and/r by different manufacturing prcesses The use f the margin f expsure (MOE) fr the evaluatin f additives used in infant frmulas References Annex 1: Template fr mngraph Annex 2: Examples f table frmats Annex 3: Template fr reprt item Annex 4: Example f reprt item iv

5 List f abbreviatins ADI ARfD BMDL x bw CCFA CD-ROM DVD EHC FAO GLP JECFA JMPR LC 50 LD 50 LOAEL LOEL NHANES NOAEL NOEL OCR OECD PDF POD ppm QA SI URL USA USB WHO acceptable daily intake acute reference dse lwer 95% cnfidence limit n the benchmark dse fr an x% respnse bdy weight Cdex Cmmittee n Fd Additives cmpact disc read-nly memry digital vide disc Envirnmental Health Criteria Fd and Agriculture Organizatin f the United Natins gd labratry practice Jint FAO/WHO Expert Cmmittee n Fd Additives Jint FAO/WHO Meeting n Pesticide Residues median lethal cncentratin median lethal dse lwest-bserved-adverse-effect level lwest-bserved-effect level Natinal Health and Nutritin Examinatin Survey (USA) n-bserved-adverse-effect level n-bserved-effect level ptical character recgnitin Organisatin fr Ecnmic C-peratin and Develpment prtable dcument frmat pint f departure part per millin quality assurance Le Système internatinal d unités (Internatinal System f Units) unifrm resurce lcatr United States f America universal serial bus Wrld Health Organizatin v

6 Preface This guidance dcument replaces the previus guidance fr the safety evaluatin f fd additives by Jint FAO/WHO Expert Cmmittee n Fd Additives (JECFA) mngraphers and reviewers, issued by WHO in It is intended primarily fr WHO Experts (mngraphers) wh prepare mngraphs fr JECFA and fr Members (reviewers) wh have been assigned t peer review them. The guidance will als be useful t manufacturers wh submit dssiers t WHO and ther parties interested in understanding the prcess fllwed in the evaluatin f fd additives by JECFA. Detailed scientific guidance n the interpretatin f txiclgical and epidemilgical data may be fund in the mngraph Envirnmental Health Criteria 240 ( In this guidance dcument, reference t JECFA is t JECFA (fd additives and cntaminants). With the aim f harmnizing the wrk f JECFA with that f the Jint FAO/WHO Meeting n Pesticide Residues (JMPR), this guidance dcument takes int accunt the dcument entitled Guidance dcument fr WHO mngraphers and reviewers, prepared by JMPR in 2015 ( fdsafety/publicatins/jmpr_guidance_dcument_1.pdf?ua=1). The authrs f the JMPR guidance dcument as well as the authrs f this guidance dcument fr the evaluatin f fd additives are gratefully acknwledged. It is envisined that this guidance dcument will be mdified based upn cmments received and experience gained in using it. Cmments n this guidance dcument and suggestins fr future editins will be gladly accepted by the WHO Jint Secretary, Jint FAO/WHO Expert Cmmittee n Fd Additives, Wrld Health Organizatin, 1211 Geneva 27, Switzerland, at jecfa@wh.int. Separate guidance dcuments fr the evaluatin f enzyme preparatins and flavuring agents and fr the assessment f dietary expsure t fd additives are als available n the WHO website ( vi

7 Chapter 1: Rles and respnsibilities The rles and respnsibilities f the JECFA Secretariat and f bth mngraphers ( Experts 1 ) and reviewers ( Members ), frm the time they are assigned t their cmpunds thrugh t the pstmeeting finalizatin f their mngraphs, are utlined belw. 1.1 Selectin f cmpunds n the agenda and issuing the call fr data The cmpunds n the agenda fr the next JECFA meeting n fd additives are selected n the basis f a pririty list established by the Cdex Cmmittee n Fd Additives, requests by FAO and WHO and their Member States, and recmmendatins f earlier meetings f JECFA. The WHO and FAO Jint Secretaries pst a call fr data n the cmpunds n the agenda mnths in advance f the meeting n the Internet, utilizing as brad a distributin as pssible. The deadline fr submissin f data is rdinarily 6 7 mnths befre the meeting. 1.2 Identificatin f mngraphers and reviewers and assignment f cmpunds and tasks The WHO Jint Secretary will cntact ptential mngraphers and reviewers within the existing rster f experts abut their interest and availability t serve as experts fr the next meeting f JECFA n fd additives. Participants are invited as independent experts in their respective areas, and they d nt represent any rganizatin r gvernment. Participatin is nt cmpensated, althugh WHO is respnsible fr return airfare and prvides a daily subsistence allwance t cver accmmdatin, meals and ther miscellaneus expenses. In accrdance with WHO rules and prcedures fr declaratins f interest, 2 any ptential r perceived interests will be evaluated befre any tasks are assigned. In the interest f transparency and t avid ptential cnflicts, participants are encuraged t be inclusive in the declaratin f interests. It is imprtant t nte that the fcus shuld be n a cmprehensive declaratin f all interests, nt just thse perceived by the participant as ptentially psing cnflicts. In accrdance with WHO prcedures, declaratins f interest are nt published, but ptential cnflicts f interest that preclude participatin in discussins n particular cmpunds are nted in the meeting reprt. The WHO Jint Secretary will take int accunt whether mngraphers have been invlved with a particular cmpund, which may be perceived as a cnflict r bias. Interests t be cnsidered include the fllwing examples: Mngraphers have wrked fr r have an interest in the spnsring cmpany. Mngraphers have perfrmed sme f the studies t be evaluated. Mngraphers have recently been clsely invlved with preparing an evaluatin f a cmpund fr a natinal r supranatinal bdy. The last pint is imprtant as, althugh familiarity with a cmpund and the supprting data can make preparatin f the mngraph easier, there might be the perceptin that the JECFA evaluatin is nt entirely independent f the previus evaluatin. Accrding t WHO rules and prcedures, 3 expert meetings are private in nature, and participatin is by invitatin nly. The data used and discussins held befre, during and after the meeting n the subject matter f the meeting are t be held in strict cnfidence. Discussins held subsequent t the meeting with nn-participants shuld be limited t the public infrmatin made available in the mngraphs and meeting reprt. 1.3 Dealing with the data submissin After a cmpund has been assigned t a mngrapher and a reviewer, the Secretariat will ensure that the spnsring cmpany arranges submissin f the dssier, which cntains the riginal study reprts, relevant papers frm the literature and the cmpany verview (summary f the submitted 1 Previusly Temprary Advisers

8 data). As a gd practice, the spnsring cmpany is asked t alert the mngrapher, the reviewer and the WHO Jint Secretary when the data have been sent. Nrmally, the data are submitted as searchable PDF files n a suitably indexed CD-ROM, DVD r USB stick. A table f cntents using fully descriptive file names needs t be submitted with each electrnic submissin; fr example, a title f xyz is nt ging t help the mngrapher lcate a 90-day dg study by Jnes et al. (2001). Spnsring cmpanies shuld submit editable PDFs whenever pssible; when dcuments are scanned, these shuld be cnverted using OCR t editable frmat, if at all pssible. This facilitates the accurate transfer f infrmatin t the mngraph. Cmpanies shuld be aware that, wing t the wrklad f experts reviewing the dssiers, delay f a submissin may cause the cmpund t be remved frm the JECFA agenda. When the data are received, it is imprtant fr the mngrapher t cnfirm receipt t the spnsr and the WHO Jint Secretary. If the data submissin has nt arrived in a reasnable length f time, the mngrapher shuld cntact the spnsr and the WHO Jint Secretary, as it is nt unknwn fr items t g missing in transit. On pening the package, it is recmmended that the mngrapher perfrm sme basic checks n the quality and usability f the dcumentatin: Fr electrnic submissins D the dcument files pen prperly? Are a table f cntents and an apprpriate index prvided? Are the files searchable? Are the pages legible, especially lder study reprts that have been scanned? Are the titles f the files helpful? Check the cmpany verview Is it in the JECFA style and in a suitable frmat (PDF and/r Micrsft Wrd) t permit the use f text r tables fr the mngraph? Des it cntain a reference list in the JECFA style (see sectin 2.3.5)? If the mngrapher identifies any issues with the data submissin where it is believed that the spnsr culd prvide an imprved submissin, then the mngrapher shuld infrm the WHO Jint Secretary, wh will cntact the spnsr with a detailed request fr what is needed. It is in the spnsr s interest t prvide a usable submissin. If the mngrapher cannt read data in a key study reprt, this might prevent the establishment f a health-based guidance value. Unpublished cnfidential studies that are submitted will be safeguarded and will be used nly fr evaluatin purpses by JECFA. Summaries f the cnfidential studies will be published by FAO and WHO after the meetings in the frm f specificatins and txiclgical mngraphs. Submitted cnfidential data can be either returned t submitters at their expense r destryed after the evaluatins have been cmpleted. Key material can be stred by WHO fr up t five years and then destryed. 1.4 Handling cntacts with the spnsr T ensure transparency, it is imprtant that all cntacts between the mngrapher and the spnsr are dcumented and cpied t the WHO Jint Secretary. With respect t cntact with the spnsr: It is preferable t use rather than telephne. s need t be cc ed t the WHO Jint Secretary. If the spnsr telephnes t discuss an issue, the mngrapher shuld cnsider whether the discussins can be perfrmed by . If the mngrapher chses t prceed with the call, the mngrapher shuld ntify the WHO Jint Secretary abut the cntact, with a brief utline f the details. If a telecnference is requested r cnsidered useful, the mngrapher shuld invlve the WHO Jint Secretary, wh will set up the call. The spnsr shuld assist the mngrapher by prviding infrmatin required t perfrm a thrugh and independent evaluatin. The mngrapher may send questins t the spnsr, cpied t the WHO Jint Secretary, well in advance f the meeting, as well as, n ccasin, during the meeting itself. 2

9 The spnsr must nt cntact a mngrapher with repeated requests fr prgress updates r fr infrmatin that is nt apprpriate t be shared, such as the health-based guidance value; if this ccurs, the mngrapher shuld ntify the WHO Jint Secretary. 1.5 Perfrming literature searches 4 In additin t the unpublished study reprts and ther material submitted by the spnsr, a search f the public literature is required t ensure that all available infrmatin is being cnsidered in the evaluatin. The mngrapher is requested t perfrm a detailed search f the public literature. The literature search shuld be dcumented in detail, listing the exact search terms used, the databases that were searched, the number f references retrieved and the number f relevant references selected, as well as the criteria (bth inclusin and exclusin) fr the selectin f relevant references. The WHO JECFA Secretariat can assist in develping search strategies and in retrieving the full text f relevant publicatins. 1.6 Evaluating the data The basic principles n hw t evaluate txiclgical and epidemilgical data are utlined in Envirnmental Health Criteria 240 (IPCS, 2009). A JECFA mngrapher will already be an experienced assessr f txiclgical and epidemilgical data and will have his r her wn ways f wrking thrugh the txiclgical and epidemilgical database n a cmpund, including submitted data and publicly available infrmatin. Based n the mngrapher s experience and n a detailed search f the JECFA database, 5 the mngrapher shuld in particular identify previus evaluatins f the cmpund r f its metablites by JECFA, even if such an assessment was based n a different denminatin r chemical name. The JECFA prcess shuld nt require any significant changes t the mngrapher s and reviewer s usual way f wrking thrugh the data, prvided that each study is described and the relevance (including any ptential bias r prblems with study design r reprting f results) is dcumented in a clear and transparent manner. One imprtant difference fr mngraphers frm a regulatry agency backgrund is that stp the clck and demand fr new studies are nt freseen; even when majr deficiencies are identified, a mngraph summarizing available data and clearly identifying the deficiencies may need t be prepared. When the mngraph is being prepared, all data are evaluated in a thrugh and independent manner, taking int accunt specific guidance prepared fr JECFA mngraphers n the interpretatin f txiclgical and epidemilgical data (i.e. EHC 240 [IPCS, 2009] and subsequently published guidance). The depth f investigatin will clearly vary with the study type, the results and the impact n the verall cnclusin. Fr example, it can be valuable t g dwn t individual animal-level data fr a dg study with a small grup size and a marginal respnse, but this is nt nrmally required fr a rdent study with a larger grup size and clear effects (e.g. 8/10 animals with grade 3 versus 3/10 cntrls with grade 1). In general, the mngrapher shuld always check at least the results in the main study reprt, and nt just the spnsr s r study reprt authrs summary. If the study reprt authrs have discunted particular findings as nt being treatment related r adverse, the mngrapher shuld pay particular attentin t these t see if he r she agrees with the study reprt authrs cnclusins. If the mngrapher disagrees with the cnclusins f the study reprt authrs, this shuld be highlighted in the mngraph. In presenting findings where descriptive terms are used, it is imprtant t use the precise terms as given in the study reprt (e.g. in the histpathlgy tables r descriptins f anmalies in develpmental txicity studies). If fr any reasn a revised term is used, there shuld be sme cmmentary abut this, as it can prduce cnfusin fr smene cmparing reviews with the study reprt. If the term is an unfamiliar r unusual ne that is nt clarified in the study reprt, then there is the ptin t ask the spnsr t clarify and/r prvide pictures. Standard texts and websites are available that prvide descriptins f pathlgical and develpmental txicity terminlgy (e.g. 4 The JECFA Secretariat is currently investigating the applicability f systematic review methdlgy t the wrk f JECFA, with the ultimate aim f develping a wrkable apprach that is manageable and fllws the basic principles n transparency, minimizing risk f bias and reprducibility

10 see als the guidance belw under specific systems and effects). Where JECFA has its wn criteria fr the interpretatin f txiclgical end-pints (i.e. EHC 240 [IPCS, 2009] and subsequently published guidance), these shuld always be used in the preparatin f mngraphs in preference t thse frm natinal r ther supranatinal bdies. Where JECFA des nt have its wn criteria, then general guidance n the evaluatin and interpretatin f txiclgical data available in the WHO EHC mngraphs and elsewhere may be used. It is expected that standard appraches will be applied (e.g. statistical significance, clear dse respnse relatinship, change utside the nrmal bilgical range). If a cnclusin in a mngraph is based n a nnstandard apprach (e.g. the use f a specific cut-ff), then the basis fr this apprach shuld be prvided (r a publicly available supprting guidance dcument shuld be cited). It is imprtant t nte that fr fd additives, JECFA usually cnsiders nly the establishment f a chrnic health-based guidance value (i.e. acceptable daily intake [ADI]) r the safety f use fr a specified purpse. Acute txicity is rarely f relevance fr fd additives; hwever, shuld the txiclgical database prvide an indicatin f acute txicity in the range f dses relevant fr human expsures, the need t perfrm an acute risk assessment has t be cnsidered (see als sectin 4.4.6). 1.7 Preparing the draft mngraph befre the meeting The mngrapher prduces a first draft f the mngraph, based n the submitted dssier as well as a critical review f the published literature. Each mngraph includes a main bdy f text as well as an Explanatin sectin, a Cmments sectin and an Evaluatin sectin; these three sectins will be used as the basis fr the meeting reprt item fr the fd additive (see Chapter 3). Detailed guidance n preparatin f the mngraph is prvided in Chapter 2. Examples f recent mngraphs n fd additives can be accessed thrugh the WHO JECFA searchable database: In cases where new r additinal data are prvided t cmplete an evaluatin r t re-evaluate a fd additive previusly cnsidered by JECFA, an addendum t the riginal mngraph shuld be prepared with the summaries f the new studies. A shrt mngraph addendum is usually prepared even when the number f studies submitted is lw. Hwever, in specific instances, this may be cnsidered unnecessary fr example, where the additinal infrmatin is restricted t a narrw aspect f the evaluatin and des nt have any impact n the previusly established health-based guidance value. In such cases, nly the meeting reprt item is prepared. The first draft f the mngraph, which is cmplete except fr thse sectins prepared by ther experts (i.e. Chemical and technical cnsideratins and Dietary expsure), is distributed first t the reviewer. Under ideal circumstances, the reviewer shuld receive the first draft f the mngraph three mnths befre the meeting, althugh it is recgnized that this may nt ccur in practice. The mngrapher and reviewer are encuraged t wrk tgether and discuss critical aspects r studies thrughut the preparatin f the mngraph. It is the respnsibility f the reviewer t crss-check critical studies, suggest amendments in bth text and tables, and finalize the Cmments and Evaluatin sectins. The reviewer returns the mngraph t the mngrapher, wh incrprates agreed changes int the dcument and then sends the revised draft mngraph t the WHO Jint Secretary. During the preparatry phase, usually 4 6 weeks befre the meeting, the WHO Jint Secretary rganizes telecnferences fr each cmpund, invlving at least the mngrapher, the reviewer, ther JECFA experts, including FAO experts assigned t the same cmpund, and the WHO Jint Secretary. The purpse f these telecnferences is t clarify issues, crdinate the wrk between the WHO and FAO experts and identify additinal infrmatin r clarificatins required frm the spnsr. A list f any utstanding questins is established fr each fd additive and sent by the Secretariat t each crrespnding spnsr. The mngrapher is als respnsible fr making any additinal revisins suggested by telecnference participants. After the final revisins have been made t the draft mngraph, the mngrapher sends a cpy f the mngraph, withut the Evaluatin sectin (cntaining the prpsed health-based guidance value), t the spnsr fr an accuracy check f study descriptins, t be cmpleted within tw weeks. Any cmments received have t be cnsidered by the mngrapher in discussin with the reviewer. 4

11 The final mngraph is then submitted t the WHO Jint Secretary, wh is respnsible fr sending the draft mngraph t all meeting participants at least 10 days prir t the meeting. During the preparatin f the mngraph, the WHO mngrapher shuld be in cntact with his r her FAO cunterpart regarding the status f the preparatin f the Chemical and technical cnsideratins sectin, as well as with the WHO/FAO expsure experts regarding the Dietary expsure sectin. If thse sectins have been drafted befre the final mngraph is submitted t the WHO Jint Secretary, the WHO mngrapher can insert them int the mngraph befre the WHO Jint Secretary distributes it t all meeting participants. If they are nt ready at that time, then these sectins will be inserted int the mngraph at the end f the meeting (see sectin 1.8). 1.8 Preparing the reprt item and finalizing the mngraph at the meeting The physical meeting is rganized jintly by FAO and WHO and generally alternates between Rme and Geneva. During the meeting, the mngraphers lead the discussins n their particular cmpunds and prepare the meeting reprt item fr each cmpund under their respnsibility. The reprt item is prepared frm the Explanatin, Cmments and Evaluatin sectins f the mngraph (see Chapter 3) and is mdified during the meeting t incrprate the results f the meeting discussins. In parallel, during the meeting, the mngrapher updates the draft mngraph t ensure that the final versin is cnsistent with the meeting reprt item, t reflect decisins taken during the meeting (e.g. decisins n the NOAELs) and t include any extra details fund t be useful in supprting the cnclusins f the Cmmittee. It is the JECFA Members wh have the final respnsibility fr adpting the reprt. Hwever, during the meeting, cnclusins and decisins are reached by cnsensus frm all participants. Therefre, all mngraphers (and reviewers) shuld cntribute t discussins n all the cmpunds and general cnsideratins. This is particularly the case if the mngraphers have expertise in a specific area f txiclgy (e.g. histpathlgy, gentxicity, develpmental txicity), such that they can bring additinal insights and views t the discussins. It is als imprtant that mngraphers ask questins when they are unclear abut the basis fr a decisin r if the text relating t a tpic is nt well presented. Hwever, mngraphers need t be aware that their reprt items must be cmpleted prir t the cnclusin f the meeting and s must carefully balance the requirement fr the timely preparatin f drafts f their reprt items fr discussin at the meeting and cntributing t discussins n ther cmpunds. During the meeting, the rapprteur is respnsible fr ensuring that all necessary revisins resulting frm discussins have been made t each draft reprt item befre the item is again discussed by the Cmmittee. The editr is respnsible fr technical and language editing f each draft reprt item nce the Chair is satisfied that it is in near-final frm. The mngrapher is respnsible fr respnding t any queries raised by the editr during the editing prcess. After the meeting reprt item has been edited, subsequent changes, as suggested by meeting participants during discussins, will be tracked nscreen by the editr, until the Chair is satisfied that the meeting reprt item is in final draft frm. At that time, the editr passes the reprt item n t the FAO rapprteur fr FAO review and incrprates any changes suggested by FAO. Additinal editing may be perfrmed by the editr after the meeting has cncluded (see belw). On the last day f the meeting, all meeting participants (FAO and WHO) review the final versin f the meeting reprt in plenary sessin and suggest any necessary revisins, which are made nscreen by the editr r by the WHO Jint Secretary, and the JECFA Members frmally adpt the reprt befre the meeting is adjurned. The mngrapher needs t prvide an electrnic versin f the final draft f the mngraph t the editr and the WHO Jint Secretary befre the end f the meeting n the final day. The WHO mngrapher will need t insert the final Dietary expsure sectin frm the WHO/FAO expsure experts int the mngraph. There is n need fr the mngrapher t update the Explanatin (including the Chemical and technical cnsideratins sectin frm FAO), Cmments and Evaluatin sectins f the mngraph during the final sessin, as the editr will insert the final versins f thse sectins frm the meeting reprt int the mngraph during the editing prcess. In the weeks fllwing the meeting, a summary reprt is published and psted n the FAO and WHO websites. It includes the main cnclusins and the health-based guidance values (e.g. ADIs) r ther safety recmmendatins fr all fd additives evaluated at the meeting. 5

12 In the mnths fllwing the meeting, the editr edits the mngraphs. The mngraphers are respnsible fr answering any queries raised during the editing prcess in a timely fashin (generally within 1 2 mnths after receiving the mngraph back frm the editr). The meeting reprt is nt published until the mngraphs have been edited, s any errrs in the meeting reprt fund during the editing prcess can be crrected befre its publicatin. The meeting reprt is published by WHO in the Technical Reprt Series, and the mngraphs are published by WHO in the Fd Additives Series (bth available n the WHO website at The meeting reprt is intended fr nn-experts (bth plicy-makers and risk managers) and cntains the descriptin, cncise evaluatin and interpretatin f the key data relevant fr the verall assessment f each substance reviewed by JECFA in terms f its txiclgical, epidemilgical, chemical and analytical aspects, as well as infrmatin n the dietary expsure assessment. Reprts reflect the agreed view f the Cmmittee as a whle and describe the basis fr its cnclusins. Any Members wh d nt agree with the cnclusins can express a minrity pinin, which shuld be nted and described in detail in the meeting reprt, in accrdance with WHO rules and prcedures fr expert cmmittees. The txiclgical mngraphs are intended fr experts and cntain detailed descriptins f the full database n bichemical, txiclgical and epidemilgical data cnsidered in the evaluatin, as well as the dietary expsure assessment, in sufficient detail t enable the basis f the cnclusins reached by the Cmmittee t be independently verified. The Cmments and Evaluatin sectins f the mngraphs are in principle identical t the reprt item (with the inclusin f the Explanatin sectin). In exceptinal cases, these sectins culd cntain mre detail than in the reprt. 6

13 Chapter 2: Preparing the mngraph 2.1 Intrductin The mngraph summarizes the data that are used t assess the safety f fd additives. As such, it cntains the detailed study descriptins and numerical data used t underpin the meeting reprt item, referred t belw as the reprt item (see Chapter 3). The mngraph must therefre cntain all the elements identified in the reprt item, tgether with sufficient additinal details t permit an independent evaluatin f the cnclusins made. The guidance prvided in this dcument pertains t all fd additives except fr enzyme preparatins and flavuring agents, which are discussed in separate guidance dcuments ( fdsafety/chem/jecfa/guidelines/en/). A table f cntents r template fr the mngraph (fr the JECFA current year) will be prvided t mngraphers when they are assigned t a fd additive. An example is included in Annex 1. The layut and sequence f the template shuld generally be fllwed, althugh nt all sectins will necessarily be included in all mngraphs, depending n the infrmatin available and the type f fd additive being evaluated. The template fr the current year shuld always be used, as mdificatins may have been intrduced fllwing the previus meeting. 2.2 General aspects General aspects t be cnsidered while preparing the mngraph are utlined belw Frmatting The mngraph (r mngraph addendum) shuld be prepared using Micrsft Wrd r a cmpatible wrd prcessing package. Details f the frmatting requirements (e.g. fnt size, line spacing, line numbering, margins) shuld be btained frm the mngraph template (see Annex 1). Details f the frmatting requirements fr preparing tables are prvided in sectin Units f measurement Le Système internatinal d unités (SI units) shuld be used thrughut. This includes the use f milligrams per kilgram f feed (mg/kg feed) instead f parts per millin (ppm) fr dietary expsure levels and the use f becquerels (Bq) instead f curies (Ci) fr radiactivity. One exceptin is millimetres f mercury (mmhg) fr pressure (the equivalent in kilpascals [kpa] shuld be given in parentheses). When expressing dietary expsure levels in milligrams per kilgram, the wrd feed shuld always be included (i.e. mg/kg feed), t avid cnfusin with the actual dse t the animals (in mg/kg bw, where bw is bdy weight). There are n hyphens between numbers and units, but there is a space. Fr example, 0.5 kg rat (nt 0.5-kg rat r 0.5kg rat) is used. There shuld be n wrds between units and the slidus (/). Fr example, 3 µg pectin/kg bw is nt crrect. Instead, the sentence shuld be rewritten mre clearly as, fr example, a pectin dse f 3 µg/kg bw. It is recgnized that there may need t be ccasinal exceptins t this rule in rder t avid extremely awkward wrding. Only ne slidus shuld be used. Fr example, 3 mg/kg bw per day, nt 3 mg/kg bw/day, is used. Figures with mre than fur digits use a space (nt a cmma) t separate grups f three digits n either side f the decimal pint (e.g ; ). Nte that the WHO rule is that in tables, figures with mre than three digits use a space t separate grups f three digits n either side f the decimal pint. The WHO rule is t be fllwed, even thugh the 7

14 guide fr the use f SI units (Thmpsn & Taylr, 2008) states that the practice f inserting spaces in numbers having nly fur digits n either side f the decimal marker is nt usually fllwed except when unifrmity in a table is desired Presentatin f dses Parentheses, rather than cmmas, are used when presenting dse cnversins: X and Y mg/kg feed (equal [r equivalent] t x and y mg/kg bw per day fr males and a and b mg/kg bw per day fr females, respectively). Equal t is used when the cnversins have been calculated using feed r drinking-water cnsumptin and bdy weight data generated fr the animals that have been dsed in a particular study, and equivalent t is used when dse cnversin factrs (i.e. default values) have been used t calculate the dses. Where accurate dses cannt be calculated n the basis f measured bdy weights and feed r drinking-water cnsumptin, apprximate dses can be estimated using the dse cnversin factrs shwn in Table 1, adapted frm EHC 240 (IPCS, 2009). When dses are cnverted frm ppm, mg/kg feed, mg/l drinking-water, mg/animal per day r percentage f the substance in the diet (ften given when the lwest dse is 1000 mg/kg feed r mre; e.g mg/kg feed = 1%) t mg/kg bw per day, up t tw additinal significant figures can be used fr the cnverted dse, where necessary, t avid intrducing additinal uncertainty in the calculatin f the final runded health-based guidance value. As lng as the dse cnversins have been presented at the beginning f a study descriptin, the riginal dses (e.g. in mg/kg feed, mg/l drinking-water r percentage in the diet, but nt in ppm, which must be changed t mg/kg feed r mg/l drinking-water) can be used thrughut the study descriptin until the n-bserved-adverse-effect level (NOAEL) is identified at the end f the study descriptin. Equivalent dses shuld be crrected fr the purity f the cmpund, but nly when this is less than 90%. Dses shuld be crrected fr nn-cntinuus dsing (e.g. 5 days/week dsing) Presentatin f pint f departure Health-based guidance values (e.g. the ADI) are ften established using a pint f departure (POD) frm a txicity study in experimental animals. The mst frequently used POD is the NOAEL. Hwever, if the data are adequate t permit dse respnse mdelling, a lwer 95% cnfidence limit n the benchmark dse fr an x% respnse (BMDL x ) r similar POD can (and shuld) be used. In such cases, the basis fr the derivatin f the POD shuld be prvided (fr details, see EHC 240 [IPCS, 2009]). Past tense shuld be used when presenting the POD: The NOAEL/BMDL x was 10 mg/kg bw per day. The POD used in risk assessment by the Cmmittee shuld be that identified by the mngrapher/cmmittee. When this differs frm the POD identified by the study authrs, the latter shuld als be reprted, with an explanatin fr the difference. When dses have been derived frm a dietary r drinking-water cncentratin using the feed r drinking-water cnsumptin and bdy weight data frm the study, the POD shuld be expressed as equal t x mg/kg bw per day. If predefined dse cnversin factrs (see Table 1) need t be used, the POD shuld be expressed as equivalent t x mg/kg bw per day. The POD, as either equal t r equivalent t dses, can be (but des nt have t be) prvided fr bth males and females in the main text, but nly the lwer value f the tw (usually the value fr males) is given in the Cmments sectin. An exceptin t this rule is where the effect is sex specific, in which case the apprpriate POD fr the sex in which the effect is bserved is prvided. 8

15 Table 1 Apprximate relatinship f mg/kg (ppm) in the diet r mg/l (ppm) in drinking-water t mg/kg bw per day Species Bdy weight (kg) Feed cnsumptin (g/day) a Type f diet 1 mg/kg in feed is equivalent t x mg/kg bw per day Water cnsumptin (L/day) 1 mg/l in water is equivalent t x mg/kg bw per day Muse Dry b 4 b labratry 0.13 b b 0.20 b,c chw Rat (yung) diets Rat d 0.06 (multigeneratin 0.40 d (average: studies) (average: 15) 0.25) Rat (ld) b 18 b 0.05 b 0.05 b 0.14 b,e Hamster 0.14 b 12 b 0.09 b 0.03 b 0.21 b Chick Guinea-pig b 34 b 0.04 b 0.20 b 0.24 b Rabbit b 186 b 0.05 b 0.41 b 0.11 b Dg b 300 b 0.03 b 0.61 b 0.05 b Cat Mist, b 168 b semislid diets 0.11 b 0.15 b 0.10 b Mnkey (e.g rhesus, cynmlgus) Rhesus mnkey 8.0 b 320 b 0.04 b 0.53 b 0.07 b Dg Human Pig r sheep Relatively Pig 80 b b dry grain 0.03 b 5.5 b 0.07 b frage Cw mixtures (maintenance) Cw (fattening) Hrse bw: bdy weight; ppm: parts per millin a Liquids mitted. b Frm Health Canada (1994). Nte that the type f diet has nt been specified in this reference. c EFSA (2012) uses cnversin factrs f 0.18, 0.15 and 0.09 fr mice fr subacute, subchrnic and chrnic studies. The first tw types f studies are assumed t start with mice 5 7 weeks f age. d Bdy weight and feed cnsumptin values vary ver the stages and generatins f the studies. The average values are used in calculating the dse cnversin factr. e EFSA (2012) uses cnversin factrs f 0.12, 0.09 and 0.05 fr rats fr subacute, subchrnic and chrnic studies. The first tw types f studies are assumed t start with rats 5 7 weeks f age. 9

16 The general statement will read as fllws: When the POD is the NOAEL: The NOAEL was x mg/kg feed (equal t y mg/kg bw per day), based n [effects] bserved at z mg/kg feed (equal t a mg/kg bw per day) [where z mg/kg feed is, f curse, the lwest-bserved-adverse-effect level (LOAEL), but this des nt need t be stated explicitly in the text]. When the POD is the BMDL x r similar: The BMDL x [r similar] was y mg/kg bw per day, based n [the effects that serve as the basis f the benchmark respnse x]. When n effects are bserved up t the highest dse tested, it is nt pssible t determine a BMDL x. In such cases, the highest dse tested is the NOAEL, which serves as the POD fr this study. Cnsistent language shuld be used when expressing the NOAEL in such circumstances: The NOAEL was x mg/kg bw per day, the highest dse tested. OR The NOAEL was x mg/kg feed (equal t y mg/kg bw per day), the highest dietary cncentratin tested. When effects are bserved at all dses, it is nt pssible t identify a NOAEL. In such cases, it might be pssible t determine a BMDL x r similar POD. Otherwise, the POD fr the study is the LOAEL. Cnsistent language shuld be used in such circumstances: N NOAEL culd be identified, as effects were bserved at all dses. The LOAEL was x mg/kg bw per day, the lwest dse tested. OR The LOAEL was x mg/kg diet (equal t y mg/kg bw per day), the lwest dietary cncentratin tested. If an effect has been cnsidered nt relevant fr determining the POD fr a study, a statement shuld always be made n the reasn fr this fr example, the effect was cnsidered nt t be txiclgically relevant r the effect was cnsidered nt t be substance related (with an explanatin as t why, if pssible), t make the basis fr POD determinatin clear t the reader. Determinatin f verall NOAELs (see sectin 4.3) is nrmally reserved fr the Cmments sectin Tables It is ften preferable t present numerical infrmatin in the frm f a table rather than in the text (e.g. t illustrate the results f acute txicity and gentxicity studies). It is the chice f the mngrapher as t whether data are presented in tables r text, as lng as it is pssible fr readers f the mngraph t perfrm an independent evaluatin f the data and reach their wn cnclusins. Pasting tables frm PDF dcuments int the mngraph is nt recmmended and shuld be dne nly if there is n realistic alternative (in which case the editr will need t re-enter the tables in Micrsft Wrd frmat in rder t edit them accrding t WHO style). If the spnsring cmpany has nt prvided tables in Wrd frmat, it shuld be requested t d s by the mngrapher. Tabs shuld nt be used t create the table clumns. All tables must be cited in the text, in cnsecutive numerical rder frm 1 t x. Tables shuld be placed in the text immediately fllwing the paragraph in which they are first cited, r as near t this as is practical. Repeating header rws can be used where the table extends ver mre than ne page. The cntents f a table shuld be restricted t the data relevant t decisin-making. If a 200- rw table cntains 16 rws f data that shw n changes with dsing, it is difficult t identify the data that are imprtant. There shuld be n blank cells in the table (unless the cells are in a heading rw). If a cell des nt cntain text r figures, then a 0, dash, NA (fr nt applicable r nt available) r ND (fr nt determined r n data), r smething alng these lines, is needed, depending n the table, with a clear definitin f the terms used included belw the table, if necessary. Data in tables shuld be quted t an apprpriate number f significant figures (e.g. quting rgan weights relative t bdy weight t six significant figures is nt apprpriate, as it implies spurius accuracy six significant figures implies that a change f % culd be determined with cnfidence and is bilgically significant). The apprpriate number f 10

17 significant figures t be used may vary with the situatin but shuld be sufficient t shw differences in utcme while being prprtinate t the variance (r standard deviatin). In sme instances, it may be useful t include the standard deviatin (r ranges) in additin t mean values. An indicatin f statistical significance shuld be included wherever apprpriate. Bldface type t indicate a statistically significant treatment-related effect can be used, but must be explained in a ftnte. Alternatively, superscripts such as * and ** may be used t indicate statistical significance, with definitins included belw the table (see next bullet pint). A listing f all abbreviatins used in the table is included belw the table, in alphabetical rder (e.g. BUN: bld urea nitrgen; Hb: haemglbin), immediately fllwed, n the same line, by a descriptin f any P-values used (e.g. *: P < 0.05; **: P < 0.01), tgether with a descriptin f the statistical test used in parentheses (e.g. Fisher exact test). Table ntes (given with lwercase superscripted letters: a, b, c ) appear immediately belw the listing f abbreviatins. Table ntes shuld be inserted manually, nt using the Wrd ftnte functin. Within the table itself, lettered table ntes are t appear sequentially in alphabetical rder, reading acrss and then dwn the table (i.e. rw by rw). The table surce (Surce: Smith & Jnes (1999)) is given belw the abbreviatins and any table ntes (superscript a, b, c). Nte that permissins t reprint (t be requested by the WHO Jint Secretary) are required fr any tables (r figures) that are taken directly frm published surces. Given this requirement, it is preferable t avid the direct cpying f illustrative material (tables and figures) frm published surces wherever pssible. Additinal miscellaneus pints relating t table frmats fllw: Clumns f figures are aligned t the decimal pint, where pssible. Clumns f text are aligned at the left-hand side. The alignment f clumns f figures and text cmbined shuld be decided n a case-by-case basis. Clumn headings may be set left r centred ver the clumns as apprpriate (usually centred when the clumns cntain figures and aligned at the left-hand side when the clumns cntain text). The first clumn heading is nrmally aligned at the left-hand side. Clumn headings shuld increase in number frm the tp t the bttm (e.g. ne clumn heading ver three subheadings, each f which is itself ver tw sub-subheadings). All clumn headings are aligned at the bttm f the header rws. Clumn headings are in bldface type. Figures with mre than three digits n either side f the decimal pint shuld have a space inserted after each grup f three digits (e.g ; ). This rule applies t tables nly (in the text, figures with mre than fur digits have a space after each grup f three digits). As nted abve, this is nt an SI requirement, but a WHO ne. Each table entry shuld ccupy its wn rw t ensure that alignment remains crrect when the table is edited. It is preferable t have nly ne r tw rw heading levels, in which case the first rw heading is flush left and the subheading is indented belw it. Where several different rw heading levels are needed in the first clumn, the general rder f heading is (1) bld, (2) rman and (3) indented rman (where three levels are needed), (1) bld, (2) italics, (3) rman and (4) indented rman (where fur levels are needed) and (1) bld, (2) italics, (3) rman, (4) indented rman and (5) rman fllwing a dash (where five levels are needed). The bld heading rw may be shaded fr emphasis. Sme examples f table frmats are prvided in Annex 2. Additinal examples may be fund in published JECFA mngraphs ( Histrical cntrl data Histrical cntrl data shuld be reprted if cnsidered useful and apprpriate fr interpreting study findings. 11

18 Histrical cntrl data are ften presented fr tumurs and develpmental effects, but can be used in an attempt t determine whether the bserved results fr any end-pint in test animals fall within the nrmal bilgical range. Histrical cntrl data are mst useful when they are frm the same strain f animal, cme frm the same labratry and are reasnably cntemprary t the study with which they are being cmpared (ideally frm tw years befre the start f the study t tw years after the end f the in-life phase). If they d nt match these criteria, this shuld be identified in the text. If pssible, the histrical cntrl data shuld have been submitted such that the results in each study in the database can be seen separately. As an abslute minimum, the number f studies must be given tgether with the mean and range (just the upper range is nt acceptable, as this culd be skewed by ne atypical study). The mngrapher shuld seek cnfirmatin frm the spnsr that there were n changes in interpretative r investigative techniques between the histrical cntrl studies and the ne n the test cmpund. If the submitted histrical cntrl data d nt match these criteria, the spnsr shuld be asked t clearly describe the differences In-text references References are cited by ne (Brwn, 1999), tw (Brwn & Jnes, 1999) r three authrs (Brwn, Smith & Jnes, 1999), r first authr plus et al. fr fur r mre authrs (Brwn et al., 2000). Nte the use f an ampersand instead f the wrd and and the use f a cmma befre the year. If the same authr(s) published mre than ne reference in the same year, a, b, etc. shuld be used t differentiate between the references (Jnes & Brwn, 1999a,b; Smith, 2000b). This rule als applies t et al. references, even if the ther authrs are nt the same in each reference (Brwn et al., 1999a,b). In the rare case where different authrs with the same surname have published a paper in the same year, initials are used t differentiate between the references (Y. Li et al., 2000; R. Li et al., 2000). These references must nt be cited as Li et al. (2000a,b). References are cited in the text in increasing chrnlgical rder (but all references by the same authr(s) are given tgether) and alphabetically when published in the same year (Brwn, 1988, 2003; Brwn & Smith, 1989; Smith & Brwn, 1989, 1991; Brwn, Smith & Jnes, 1990; Brwn et al., 1991; Jnes, 1999a,b). Reprts and mngraphs frm previus JECFA meetings are cited in the text as (Annex 1, reference xxx) and are nt included in the reference list. Annex 1 refers t the list f previus JECFA publicatins that is included at the back f bth the meeting reprt and the publicatin cntaining all f the mngraphs frm the meeting. Persnal cmmunicatins and ther unpublished infrmatin are cited in the text nly, nt in the reference list. They shuld be cited as fllws: [name f authrity cited], [name f institutin], unpublished data r unpublished bservatins r persnal cmmunicatin, [date]). Fr infrmatin n the frmatting f references fr the reference list at the end f the mngraph, see sectin Miscellaneus Mngraphs shuld be cncise dcuments, with nly as much detail as is necessary t be able t understand and reprduce the evaluatin; t much detailed descriptin f irrelevant studies and t many nn-critical tables shuld be avided. Mngraphers need t make every effrt t reduce the length f their mngraphs withut eliminating essential infrmatin. The physical meeting is referred t as the meeting (e.g. the meeting was held in April); the grup f meeting participants is referred t as the Cmmittee (e.g. the Cmmittee established an ADI f mg/kg bw). 12

19 JECFA is referred t, rather than the JECFA. Reference t previus Cmmittees shuld be made by number (e.g. the thirty-sixth meeting f the Cmmittee) rather than by year, because in many cases reprts were nt published in the same year as the meeting and in sme years mre than ne meeting was held, which creates cnfusin. It is cnventinal t list cuntries alphabetically, and cuntry names must crrespnd t the mst current listing f Member States and Assciate Members f WHO, as given in the current versin f the WHO style guide r an interim updated list f Member States and Assciated Members f WHO. Where the POD is a NOAEL, this is identified, as it is ne f the dse grups used fr example, 0.5 mg/kg bw per day was identified as the NOAEL. Health-based guidance values (e,g. ADIs) are established fr example, the Cmmittee established an ADI f mg/kg bw. Each study summary shuld prvide a shrt descriptin f the methdlgy used in the study. Mst studies will cmply with an Organisatin fr Ecnmic C-peratin and Develpment (OECD) test guideline r equivalent natinal guideline, and in such cases there is n need t prvide lengthy descriptins f the methdlgy. Attentin shuld be drawn t any deviatins frm the test guideline, either missins r significant additins. If in-life examinatins such as phthalmscpy and bld sampling are perfrmed at multiple time pints, these time pints shuld be identified. Studies perfrmed befre the implementatin f gd labratry practice (GLP) will be cnsidered n a case-by-case basis, with careful cnsideratin f the quality and apprpriateness f the study. JECFA style is t use free-flwing text rather than large numbers f subheadings fr each particular level f investigatin. Overall cnclusins f the Cmmittee regarding, fr example, the carcingenicity and gentxicity f a cmpund shuld generally be reserved fr the Cmments sectin. Cnclusins f the Cmmittee regarding specific studies (e.g. when the Cmmittee disagrees with the study authrs cnclusins) are given in the bdy f the mngraph. WHO huse style uses a mix f British and Nrth American spellings. Examples f spellings f sme cmmnly used wrds in JECFA mngraphs are as fllws: anaesthetize, analyse, antimicrbial, caesarean, centre, cenzyme, clur, cperate, criticize, decisin-making, diarrhea, end-pint, estrgen, et al., etilgy, faeces, feed (fr animals, nt fd), fetus, haemglbin, hmepage, hypcalcaemia, in vitr, in viv, leukcyte, litre (L, nt l), metaanalysis, metablize, mdelled, neurbehaviural, edema, esphagus, xidize, paralyse, pharmacpeia, pstmrtem, pstnatal, pstpartum, pretreatment, prgramme, re-examine, repen, side-effect, subgrup, sublethal, sulfur, tumur, webpage, website, wrldwide, X-ray. Abbreviatins are defined the first time they are used in the text; thereafter, nly the abbreviatin is used. A list f abbreviatins shuld be prepared fr each mngraph. This list will be incrprated by the editr int an verall list f abbreviatins fr all mngraphs published after the meeting. Mngraphs will be edited accrding t the mst recent versin f the WHO style guide. Mngraphers can request a cpy f the WHO style guide frm the WHO Jint Secretary. 2.3 Detailed cntent f the mngraph The guidance in this sectin appraches the cntent f the mngraph frm the viewpint f the end result f the meeting that is, the prductin f the reprt item. As mentined abve, the mngraph shuld cntain sufficient infrmatin t permit all the details required fr the reprt item t be identified and independently cnfirmed. If a mngrapher is in dubt abut whether t include extra detail, it shuld be added t the mngraph s that it is available fr thers t see; it can always be deleted fllwing discussin at the meeting. Until the final changes are made by the mngrapher at the end f the meeting, the mngraph is a draft dcument t supprt the discussin. It is therefre ften helpful t include cmment bxes r 13

20 highlighted text that draws attentin t ptentially imprtant r cntentius aspects f the evaluatin, as lng as these are subsequently deleted. It is imprtant fr the mngrapher t recgnize that the final mngraph is the prduct f the Cmmittee and nt f the mngrapher. If n studies were available fr ne f the main headings in the template, this shuld be nted in the mngraph. Fr mngraph addenda, it may nt always be sufficient just t cnsider new data, especially if there have been changes in evaluatin criteria since the last evaluatin. An apprpriate descriptin f any such studies that were cnsidered in the present evaluatin shuld be included in the mngraph addendum. Smetimes, it may be sufficient t cpy and paste relevant sectins frm the previus mngraph, in which case they shuld be s indicated (e.g. indented, italics r smaller fnt). Details that shuld appear in each sectin f the mngraph are described in the fllwing sectins. Nte that the sectin numbering used fr the headings (shwn in red) is that used in the actual mngraph (see als Annex 1). A table f cntents generated frm the final headings used in the mngraph shuld be included n the first page f the mngraph, belw the title, authrs and authrs affiliatins. All individuals cntributing t the preparatin f the draft mngraph fr the meeting shuld be listed as authrs. As the end prduct reflects the discussin f the Cmmittee at the meeting, the listing f authrs is preceded by the phrase First draft prepared by. Authrs may refer t recently published mngraphs n fd additives fr examples f frmatting and cntent (e.g. mngraphs frm the seventy-ninth meeting: /3/ _eng.pdf?ua=1) Explanatin 1. Explanatin This part f the mngraph will frm the basis fr the first few paragraphs f the reprt item. The editr will insert the final versin f the Explanatin sectin (fllwing the adptin f the meeting reprt) int the final draft f the mngraph. The mngrapher can indicate whether any detailed infrmatin that was deleted frm the Explanatin sectin during the preparatin f the reprt item shuld be retained in the final mngraph. The first paragraph shuld prvide a brief descriptin f the fd additive and its primary uses in fd. If the Cmmittee has evaluated the fd additive previusly, previus evaluatins shuld be referenced by number using the standardized reference list f JECFA publicatins, which may be fund in Annex 1 f recent JECFA reprts (WHO Technical Reprt Series) and txiclgical evaluatins (WHO Fd Additives Series). Thus, the reprt f the seventyseventh meeting n certain fd additives and cntaminants wuld be referenced as (Annex 1, reference 214), and the mngraphs prepared after the seventy-seventh meeting wuld be referenced as (Annex 1, reference 215). Reasns fr the present re-evaluatin shuld be given and, if a full mngraph n a fd additive that has been evaluated previusly is being prepared, a statement shuld be made t the effect that the previusly published mngraph has been expanded and is reprduced in its entirety belw. If the Cmmittee has nt previusly evaluated the fd additive, the reasn fr it being placed n the agenda shuld be given. Fr example, [Cmpund X] has nt previusly been evaluated by the Jint FAO/WHO Expert Cmmittee n Fd Additives (JECFA). The Cmmittee evaluated [cmpund X] at the present meeting at the request f the [Xth] Sessin f the Cdex Cmmittee n Fd Additives (FAO/WHO, 20xx). The final paragraph f the Explanatin shuld describe the data that were prvided by the spnsr and whether the critical studies were cnducted in cmpliance with GLP, unless therwise specified. In additin, whether a literature search was cnducted, the keywrds used and the number f references btained shuld be prvided. The structure f the fd additive shuld nrmally be included in a full mngraph. The FAO expert assigned t the fd additive prepares ne subsectin fr the Explanatin sectin in the mngraph: Chemical and technical cnsideratins. This 14

21 subsectin heading shuld be included in the draft mngraph, with [t be prepared by FAO] inserted belw it (unless the FAO expert is able t prvide this sectin t the WHO mngrapher befre the mngraph is distributed t meeting participants). The editr will insert the final FAO subsectin int the mngraph after the meeting (in ther wrds, the Chemical and technical cnsideratins sectin in the meeting reprt is identical t the Chemical and technical cnsideratins sectin in the mngraph) Bilgical data 2. Bilgical data This sectin cntains summarized descriptins f studies that are imprtant fr assessing the safety f the fd additive. Studies that prvide the basis fr the safety evaluatin shuld be summarized in greater detail than ther studies. Single paragraphs cmpsed f very brief summaries may be sufficient fr reprting the results f studies f limited design r minr relevance fr the evaluatin. Bilgical data shuld be gruped under three headings: Bichemical aspects, Txiclgical studies and Observatins in humans. In a full mngraph, but nt in a mngraph addendum, if n data are available under any f these headings r under subheadings under Txiclgical studies, except fr Special studies, the heading shuld be included in the mngraph tgether with the statement N infrmatin was available. Fr fd additives, the substance tested shuld be the (intended) article f cmmerce. If the article f cmmerce is nt the test substance, its relatinship t the test substance must be accurately described. Species infrmatin is prvided in rder frm smallest t largest species (this differs frm many ther rganizatins, where the rat is presented befre the muse). Headings fr each species shuld be included when mre than ne species is discussed ((a) Mice, (b) Rats, (c) Hamsters, (d) Rabbits, (e) Dgs, (f) Pigs, (g) Mnkeys), but n species heading is necessary (althugh it can be inserted if desired) if nly ne species is discussed. It shuld be nted that mnkeys cmprise a higher phylgenetic gruping than species, and the individual species (e.g. cynmlgus, rhesus) shuld be specified. 2.1 Bichemical aspects Fr all fd additives, this sectin describes studies designed t measure the cncentratin time prfiles f the ingested substance and its metablites in the varius tissues and rgans f the bdy as well as studies f effects n enzymes and ther bichemical parameters designed t elucidate the mde f actin and txicdynamics f the fd additive. The Cmmittee uses the results f these studies in interpreting the txiclgical studies, including the elucidatin f the mechanism f txicity, and the results may facilitate the establishment f the health-based guidance value. Cmparisns f bichemical data between different experimental animal species and humans helps t determine the relevance f the txicity bserved in experimental animals; such cmparisns shuld be summarized at the end f this sectin. The types f bichemical studies that shuld be summarized under each heading are given belw. Human bichemical studies that fall under these categries shuld be included in this sectin. Other human studies shuld be included under Observatins in humans Absrptin, distributin and excretin Infrmatin in this sectin shuld be drawn primarily frm studies n experimental animals, such as mice, rats, rabbits and dgs. Infrmatin n pharmackinetics in animals such as pigs, cws, gats, hrses and pultry can be included where relevant. 15

22 Infrmatin n metablism fllwing absrptin shuld nt be included in this sectin. Rather, it is included in sectin n bitransfrmatin. Fr each study, details n the psitin and type f radilabel used, test species, sex and number f animals, dse levels used (in terms f bth the drug [mg/kg bw] and radiactivity [MBq/kg bw], as apprpriate) and rute f expsure shuld be prvided. Infrmatin in this sectin includes, where pssible: hydrlysis/metablism f the parent cmpund and its prducts in the mammalian gastrintestinal tract (including prducts f metablism by the gut micrflra) (distinguish between hydrlysis/metablism befre absrptin and f biliary excretin prducts); rate and extent f absrptin f the unchanged cmpund and its hydrlysis prducts/intestinal metablites, with time t maximum cncentratin (T max ) and the cncentratin achieved (C max ); biavailability f the parent cmpund; pattern and rate f distributin f absrbed substances t tissues and rgans within the animal; mde, rate and extent f excretin r eliminatin f the parent cmpund and/r radilabel and its identified intestinal metablites frm bld and tissues, with percentage recvery in majr excreta (urine, faeces, bile) ver a given time interval (e.g. 35% in urine frm 0 t 48 hurs); pharmackinetic parameters, such as vlume f distributin, terminal eliminatin half-life frm plasma and ttal bdy clearance. It shuld be made clear as t whether the findings relate t the radilabelled material r t the parent cmpund. Differences between sexes, dse sizes and single versus repeated dsing shuld be nted, tgether with any ther relevant findings Bitransfrmatin Infrmatin in this sectin shuld be drawn primarily frm studies n experimental animals, such as mice, rats, rabbits and dgs. Infrmatin n metablism in animals such as pigs, cws, gats, hrses and pultry can be included where relevant. Where infrmatin n metablism fllwing absrptin has been btained frm studies previusly described in sectin 2.1.1, a brief study descriptin and crss-reference t that sectin can be made, rather than repeating full study details. This sectin describes the metablism f the parent cmpund, if absrbed as such, and f its prducts if they are nt nrmal dietary r bdy cnstituents. Infrmatin n the main rutes f metablism, the metablite prfile and the mde, rate and extent f excretin r eliminatin f identified metablites is included here. If the bitransfrmatin pathway is knwn, a figure depicting the main metablic reactins shuld be included alng with an identificatin f the species t which it applies. Such schemes are usually prvided by the spnsr and can be scanned fr inclusin in the mngraph. If the data spnsr des nt prvide a metablic scheme, a scheme shuld be requested Effects n enzymes and ther bichemical parameters This sectin describes the effects f the absrbed substance and/r its metablites n cellular and tissue enzyme prductin and mrphlgy, chemical cnstitutin, enzyme activity r physicchemical state. If there is n relevant infrmatin t be included in this sectin, the heading can be deleted. 16

23 2.2 Txiclgical studies This sectin cntains summarized descriptins f txiclgical studies that are imprtant fr assessing the safety f the fd additive. These summaries generally cmprise the bulk f the mngraph. Infrmatin frm five main categries f studies n fd additives shuld be rutinely included: Acute txicity, Shrt-term studies f txicity, Lng-term studies f txicity and carcingenicity, Gentxicity and Reprductive and develpmental txicity. Smetimes these rutine studies pint twards the need t lk at particular target rgans r tissues r end-pints; such studies are classified as Special studies. Studies that prvide the basis fr the evaluatin shuld be summarized in greater detail than ther studies. Single paragraphs cmpsed f very brief summaries may be sufficient fr reprting the results f studies f limited design r minr relevance fr the evaluatin. The study cnclusins shuld be summarized in this sectin. If the persn wh arrived at the cnclusin is nt identified, it is assumed that it is the authr(s) f the study and that the mngrapher agrees with the cnclusins. When the mngrapher disagrees with the cnclusins f the study authr(s), he r she shuld discuss the cntentius issues and present his r her wn cnclusins as a separate paragraph, t flag the issue fr discussin by the Cmmittee. In the final mngraph, the paragraph cncludes with the Cmmittee s cnclusin and identificatin f the NOAEL and the study reference. When adjacent paragraphs summarize different studies under the same heading, an extra space shuld be left between them. Hwever, an extra space shuld nt be left between paragraphs when they bth describe the same study. The GLP status f the study, alng with the relevant authrity, shuld be indicated. If there is n GLP certificatin, the mngrapher shuld at least nte whether the study was inspected by a quality assurance (QA) unit, as nted by the presence f a signed QA statement, and make sme cmment n the apparent quality f the prtcl and adequacy f the methds used. In additin, whenever the study authr prvides infrmatin n the test guideline r prtcl that was fllwed, it shuld be s indicated. General study details that shuld be prvided fr each txiclgical study described in the mngraph include the fllwing: purpse r bjective f the study; identity, specificatin and purity f the test material and its batch and/r lt number; species and strain f animal used; the methd f dsing (e.g. gavage, capsule, variable dietary cncentratin); vehicles used fr gavage studies (and if there appear t be any findings that change with different vehicles); if the vehicle is nt prvided, it will be assumed t be water; sex and number f animals in each grup (if there are satellite grups, numbers fr the main grup and satellites are given separately); whether a study is nn-guideline r a range-finding study with limited investigatins. In such cases, a cnclusin n the value f the study in evaluating the txiclgical prfile f the cmpund (e.g. prvides useful infrmatin n repeated-dse effects; end-pints studied t limited t prvide useful infrmatin) can be prvided; any additins t the standard test prtcl, such as measurement f specified hrmne levels r evaluatin f txickinetics during the dsing perid; all the administered dse levels, including 0 fr cntrls; fr dietary studies, this shuld include bth mg/kg feed values (even if riginally given as parts per millin r percentage f cntaminant in the diet) and the equal (if measured) r equivalent (if based n default cnversin factrs) mg/kg bw per day dse fr bth males and females; fr drinking-water studies, this shuld include bth mg/l drinking-water values (even if riginally given as parts per millin) and the equal (if measured) r equivalent (if based n dse cnversin factrs) mg/kg bw per day dse fr bth males and females. If the authr f a study presents administratin levels in terms f mg/animal per day, these values shuld be cnverted t mg/kg bw per day using animal weights if they are included in the reprt; whether the study used dse patterns that did nt invlve dsing every day (e.g. 5 days/week rather than 7 days/week). If s, it shuld be checked whether the stated dse 17

24 levels are given nly fr the days f dsing r averaged ver the whle duratin f the study. JECFA gives dse levels averaged ver the entire study duratin; whether there were any cmplicatins assciated with dsing, such as slubility, stability and palatability; duratin f the study; details f any recvery grup (e.g. numbers, duratin f dsing, interval between last dse and terminatin, extent f investigatin f animals in this grup); any mrtalities seen during the study, bth in treated and in cntrl grups, and infrmatin n the causes f mrtality, if knwn (e.g. dsing errrs in gavage studies, which are nt cmpund related); descriptin f cmpund-related findings, if any, identifying the effect, its severity r magnitude and, fr dichtmus data, an indicatin f the number f animals affected. This infrmatin is ften presented in tabular frm. If n significant effects were seen at a particular dse level, a simple statement t that effect shuld be made; whether there is dse-dependency f the findings and if nt, whether there is any explanatin fr this; relevant infrmatin n histrical cntrl data, if available, where this may help in the interpretatin f the findings (e.g. marginal effects at highest dse, incidence in cntrls is particularly high r lw); statistical significance f an effect if the effect is bilgically r txiclgically relevant; any findings that are statistically significant but are discunted as nt adverse r nt relevant t a human risk assessment; any in-life findings early in the study that might be relevant t establishing an acute reference dse (ARfD) (e.g. bdy weight changes r behaviural effects after ne r a few days f dsing); anything else f nte in the study (e.g. high mrbidity in cntrls); the POD, such as the NOAEL (if ne was identified), and the critical findings n which the POD was based (e.g. at the LOAEL), given at the end f the study descriptin; study authrs cnclusins and cnclusins f the mngrapher, if different; the authr(s) and date f preparatin f the study reprt, given at the very end f the study descriptin (even if already cited at the beginning f the study descriptin). Any relevant infrmatin that is identified in the peer-reviewed literature that prvides insight int the txicity f the cmpund additinal t that prvided by the studies submitted by the spnsr shuld be summarized under the apprpriate heading belw. In general, the same frmat shuld be fllwed as fr a submitted study, highlighting any imprtant details that are missing (e.g. details f dsing regimen) and als any bservatins additinal t thse that might be fund in a typical guideline study, which may be f value in evaluating the cmpund. As nted abve, if studies n mre than ne animal species are summarized under ne heading, then the studies shuld be gruped in such a way that studies in smaller rdent species are listed first, with larger species and species mre clsely related t humans last. The fllwing is an example f a typical summary f a study f txicity fr a fd additive: Lng-term studies f txicity and carcingenicity (a) Rats Grups f 45 male and 45 female inbred Wistar rats were given diets cntaining steviside (purity 85%) at 0, 2000, 6000 r mg/kg feed (equivalent t 0, 100, 300 and 600 mg/kg bw per day, respectively) fr 2 years. After 6, 12 and 24 mnths, bld was btained frm the tail vein f five male and five female rats in each dse grup fr haematlgical and clinical bichemical tests. One week later, these rats were hused in metablism cages fr urine cllectin and were then killed fr further bichemical, pathlgical and histpathlgical examinatin. All surviving animals were killed at 2 years. Grwth, feed use and cnsumptin, general appearance and mrtality were similar in treated and cntrl grups. The mean lifespan f rats given steviside was nt significantly different frm that f the cntrls. N treatment-related changes were bserved in haematlgical, urinary r clinical bichemical values at any stage f the study. The incidence 18

25 and severity f nn-neplastic and neplastic changes were unrelated t the cncentratin f steviside in the diet. The NOAEL was mg/kg feed (equivalent t 600 mg/kg bw per day), the highest dietary cncentratin tested (Xili et al., 1992) Acute txicity Acute txicity studies can prvide useful infrmatin regarding target tissues and species and sex differences. The results f acute txicity studies that are expressed in terms f the median lethal dse (LD 50 ) (used fr ral, intramuscular, intraperitneal r dermal administratin) and/r median lethal cncentratin (LC 50 ) (used fr administratin by inhalatin) shuld be presented in tabular frm, as illustrated in Annex 2. When three r mre LD 50 r LC 50 determinatins by the same rute in the same species are available, the results may be expressed as a range in which the lwest t the highest values are recrded. Other acute txicity data imprtant t the evaluatin, such as the nature f txicity, clinical signs and target tissues, may be presented in summary frm as text r in table ntes belw the table Shrt-term studies f txicity Txiclgical studies in which fd additives are administered in regularly repeated dses in feed r drinking-water ver perids ranging up t, but nt including, ne year fr mst small animal species and up t, but nt including, tw years fr dgs and primates shuld be summarized in this sectin. These studies, when prperly perfrmed, prvide imprtant infrmatin regarding the majr txic effect(s) f the test substance and its dse respnse relatinships. Shrt-term studies f txicity are ften perfrmed t help in dse selectin fr lng-term studies f txicity, and they can give sme indicatin f target tissues and rgans. In sme cases, shrt-term studies f txicity can help clarify lwest-effect dse levels fr effects bserved in lng-term studies f txicity, and they can prvide infrmatin that is useful fr the interpretatin f lng-term studies f txicity and carcingenicity (e.g. early signs f txicity in the kidney r liver when tumurs appear in these rgans after lng-term expsure t the test substance). It can be useful t cmment n findings that were nt seen in a study if they were seen in anther similar study. Fr example, if a certain effect was seen in a 28-day rat study, it wuld be expected that it wuld als be present in the 90-day study at similar, r lwer, dse levels. Any findings that were cnsidered nt relevant t humans and the reasns why (e.g. kidney findings in male rats nly, supprted by investigatins f α 2u -micrglbulin) shuld be indicated Lng-term studies f txicity and carcingenicity Txiclgical studies in which fd additives are administered in regularly repeated dses r cntinuusly in feed r drinking-water ver the greater part f the nrmal lifespan f the animal species (i.e. ne year r lnger fr mst small animal species, in line with OECD test guidelines, and tw years r mre fr dgs and primates) are summarized in this sectin. These studies are used fr detecting chrnic effects that are nt bserved in shrter-term studies r that shw prgressin with duratin f dsing. Lng-term studies that are designed t investigate specific effects, such as carcingenicity, shuld be included in this sectin. Often lng-term studies, particularly in rats, are designed t assess bth chrnic txicity and carcingenicity. Because certain animal strains have high backgrund levels r susceptibilities t develping certain tumur types, it is imprtant t give the strain details (but nte that the strain is nt given in the meeting reprt unless the effect is strain specific). 19

26 If the nature f the dse respnse relatinship is nt clear (e.g. respnse is marginal and is nt mntnic) r there is cncern abut the incidence level in the cntrls, histrical cntrl data shuld be prvided. These shuld be requested frm the spnsr, if necessary. It shuld be indicated whether the survival rate is adequate in the tp-dse animals (there shuld nrmally be a minimum f 25 animals [50% f a standard grup size f 50] in each grup surviving t terminatin). If survival did nt meet this level, it shuld be indicated whether the deaths were mainly twards the last few weeks f the study and whether survival was adequate t enable the varius end-pints in the study t be assessed. It shuld be nted whether there is any indicatin f findings ccurring earlier in treated animals. This can be imprtant fr lesins that have a high backgrund incidence and in interpreting sme lng-term effects. General study details that shuld be prvided fr each txiclgical study are given abve. In additin, the types f bservatins made (e.g. mrtality, feed and water cnsumptin, bdy weight, haematlgy, clinical chemistry, urine analysis, phthalmscpy examinatins, physical/neurlgical examinatins, functinal bservatinal batteries, clinical signs, rgan weights, grss pathlgy and histpathlgy) and any ther infrmatin abut the design f the study cnsidered t be ntewrthy shuld be prvided. When histpathlgical examinatins were perfrmed, the tissues that were examined shuld be indicated, alng with the identificatin f tissues that were f particular interest t the evaluatin and whether nly certain dse grups were investigated. Negative findings shuld be limited t general statements n survival, grwth, rgan weights, tumur incidence, rgan functin tests, and grss and micrscpic appearance f tissues. In particular, if there were n increases in cmpund-related tumur incidences, a clear statement shuld be made Gentxicity Data frm an apprpriate range f in vitr and in viv gentxicity tests can be useful in elucidating the mechanism f txicity f certain cmpunds. The results f these studies are als cnsidered when evaluating the results f rdent carcingenicity biassays and when determining whether an in viv carcingenicity biassay was necessary t enable adequate assessment f the carcingenic ptential f a cmpund. T present the data in a mre understandable frm and t cnserve space, the results f gentxicity tests shuld be tabulated. Annex 2 prvides examples f the tabular representatin f such data. Where the results f a particular gentxicity study were cnsidered psitive r equivcal (e.g. clny cunts, size f clny, survival rates r aberrant cell numbers), the study can be described in mre detail in textual frm r in table ntes belw the summary table Reprductive and develpmental txicity These studies are designed t evaluate effects n the sexuality and fertility f males and females and n the develping rganism. (a) Multigeneratin reprductive txicity Multigeneratin reprductive txicity studies prvide general infrmatin n the effects f the test substance n gnadal functin, estrus cycles, mating behaviur, cnceptin, parturitin, lactatin, and grwth and develpment f the ffspring until the age f weaning. With dietary expsures at cnstant milligram per kilgram feed cncentratins, the achieved intakes vary greatly with reprductive stage. Achieved intakes are nrmally determined fr varius stages f the study (e.g. premating, lactatin). When determining NOAELs, JECFA plicy is t use the lwest achieved intake f any f the measured stages, unless a critical stage and assciated intake can be determined. 20

27 Data shuld be presented fr each stage and generatin separately (e.g. parental generatin fr first generatin, first mating pups, parental generatin fr secnd generatin, etc.). Sme indicatin f whether findings were cnsistent acrss the generatins shuld be prvided subsequently. It shuld be indicated whether litters were standardized in size at arund day 4. If pup weights are different in treated grups, it shuld be determined if this relates t litter size and if there are effects n ttal litter weight. If pup mrtality is increased in treated grups, it shuld be determined if there were mre pups in the litters t start with (e.g. cntrl litter mean f 10.8 pups with 0.9 dying gives 9.9 alive; test grup mean f 12.1 pups with 2.1 dying might be statistically significant, but still gives 10.0 alive, mre than in cntrls). Fr develpmental end-pints (e.g. tth eruptin), it shuld be determined if there are effects n the time t achievement; the bdy weight at that time shuld als be checked. PODs, usually NOAELs, shuld be identified fr reprductive txicity (e.g. impairment f fertility, parturitin, lactatin), parental txicity (usually systemic txicity, such as effects n bdy weight r feed cnsumptin) and ffspring txicity (e.g. effects n pup bdy weight r pup viability). (b) Develpmental txicity Develpmental txicity studies are used fr assessing effects n the develping rganism, which may include death f the develping rganism, structural abnrmalities, altered grwth r functinal deficiencies. The days f dsing shuld be indicated (i.e. which days f gestatin). Details f the investigative techniques (e.g. dissectin, staining, X-ray) and the prprtin f fetuses being examined by each technique shuld be given. If a range-finding study has been submitted, it can be described separately if there are imprtant findings. If it adds nthing t the discussins, it can just be mentined in the intrductin t the main study. The unit fr statistical cmparisn in develpmental txicity studies is the litter, nt the individual fetus. Hence, when statistically significant differences are reprted in incidences relative t the ttal number f fetuses per dse grup, the mngrapher shuld check whether such differences are als apparent when the results are expressed per litter. If there are develpmental anmalies in the main test, it shuld be determined if they were seen in the range-finding study as well (if submitted). Range-finding studies nrmally include nly limited examinatins f maternal txicity, external malfrmatins and fetal viability. It shuld be indicated whether there were any increases in malfrmatins, even at maternally txic dses. Any effects that ccur within the first day (r first few days, if this was the first time f bservatin) after dsing shuld be nted, as they culd be used as the basis fr establishing an ARfD. PODs, usually NOAELs, shuld be identified fr maternal txicity (usually systemic txicity, such as effects n bdy weight r feed cnsumptin) and fr embry and fetal txicity (e.g. effects n fetal weight, fetal mrtality, incidence f skeletal and visceral anmalies r variants) Special studies Special studies, when relevant and submitted by the spnsr in supprt f the safety evaluatin f the fd additive r identified frm a literature search, shuld be reviewed. It is imprtant fr the mngrapher t be aware that special studies d nt typically fllw specific well-established prtcls, but rather are designed t reslve particular scientific 21

28 issues and cncerns, and prtcls may vary frm study t study; hence, n specific guidance is included here. General study details reviewed and described by the mngrapher might include the bjective f the special study, number, species and strain f animals, any details specific t the unique special study, the study utcme and its relevance t the end-pint being investigated. Examples f the types f special studies that might be included are neurtxicity, carditxicity and immuntxicity studies (see als Annex 1). Special studies designed t elucidate qualitative interspecies differences in the manifestatins f txicity (e.g. different target rgans in different species) shuld als be included in this sectin. Special studies shuld be listed alphabetically. 2.3 Observatins in humans Observatins in humans can be particularly useful fr establishing health-based guidance values, fr assessing the relevance f the results f studies in experimental animals and fr cnfirming health-based guidance values. All studies dealing with humans (except fr thse summarized under Bichemical aspects) shuld be included in this sectin, including epidemilgical surveys, clinical experience, anecdtal bservatins, health effect studies relating t ccupatinal expsure, reprts f abuse and vlunteer studies measuring intlerance. Details such as number f subjects, sex, age and general statements n physical cnditin shuld be given if imprtant t the evaluatin. JECFA will use human data in establishing health-based guidance values if the study is scientifically valid and perfrmed ethically, accrding t the principles f the Declaratin f Helsinki. Dcumentary evidence f this shuld be prvided by the spnsr, r, where the results are frm a published study, a statement t this effect shuld be included in the paper Dietary expsure 3. Dietary expsure This sectin is prepared by expsure experts. If it is at all pssible, this sectin shuld be incrprated by the WHO mngrapher int the draft mngraph befre it is distributed t meeting participants. At the end f the meeting, befre the final mngraph is prvided t the editr and the WHO Jint Secretary, the WHO mngrapher shuld ensure that the final Dietary expsure sectin has been incrprated int the mngraph. Fr mre infrmatin n what shuld be included in this sectin, readers shuld refer t the separate guidance dcument n preparing wrking papers n dietary expsure t (r intake f) fd additives (see Cmments 4. Cmments The bjective f the Cmments sectin is t prvide a cncise summary f the relevant bichemical/txiclgical/epidemilgical infrmatin and its interpretatin, while prviding sufficient explanatin that the bases fr the cnclusins f the Cmmittee are clear. This sectin shuld cntain shrt summaries f the bilgical findings in the studies f significance fr the evaluatin. The findings shuld be listed in the same general rder as they are summarized in the main bdy f the mngraph, under the headings Bichemical aspects, Txiclgical studies and Observatins in humans. 22

29 The sectin shuld begin with a statement as t whether the Cmmittee cnsidered the verall data package sufficient t derive a rbust health-based guidance value r cnclusin as t health cncern. All relevant NOAELs (r ther PODs) shuld be included. Only ne value fr each NOAEL in units f mg/kg bw per day (usually fr the sex with the lwer value, unless the effect is sex specific) shuld be given fr each study. Strains f animal species are nt prvided in this sectin unless critical effects are knwn t be strain specific. Details such as sex, age and general statements n physical cnditin shuld be given if imprtant t the evaluatin f bservatins in humans. The Cmments sectin will cmprise the bulk f the meeting reprt item (which als includes the Explanatin and Evaluatin sectins) (see Chapter 3). The Cmments sectin shuld be fully referenced. This is a change frm the usual practice, but it makes the Cmmittee s cnclusins mre pen, transparent and verifiable and enables the Cmments sectin t be mre readily used by ther interested grups. The editr will delete these references fr the final meeting reprt, except fr thse pertaining t the critical study r studies, but they will be retained fr the mngraph. Annex 3 cntains a template fr the reprt item, and Annex 4 prvides an example f a reprt item. Bth shuld serve as a mdel fr the preparatin f the Explanatin (see sectin 2.3.1), Cmments and Evaluatin sectins (see sectin 2.3.5) Evaluatin 5. Evaluatin A prpsal shuld be prvided by the mngrapher, in agreement with the reviewer, as t whether the Cmmittee shuld establish a health-based guidance value (usually an ADI) and, if s, n what basis. The NOAEL frm the critical study shuld be given with the units mg/kg bw per day. Only ne value shuld be reprted, which is derived frm the sex that gives the lwer value based n feed intake (r drinking-water cnsumptin) and bdy weight data, unless the critical effect is sex specific. The basis fr the uncertainty (r safety) factr applied shuld be explained. EHC 240 (IPCS, 2009) and previus JECFA meeting reprts n fd additives shuld be cnsulted fr guidance n selectin f uncertainty factrs in establishing ADIs. The ADI is expressed as a range frm 0 t x mg/kg bw, and it shuld be runded t ne significant figure (see sectin 4.4.1). The ARfD, if established, is given as a single number (x mg/kg bw). An ADI nt specified may be prpsed when the estimated dietary expsure t the fd additive is expected t be well belw any numerical value that wuld rdinarily be assigned t it (see sectin 4.4.2). Fr example, if the margin f expsure between the NOAEL frm the critical study and the dietary expsure estimate is cnsidered adequate (>100), the Cmmittee may establish an ADI nt specified fr a fd additive used in the applicatins specified and in accrdance with gd manufacturing practice. It shuld be nted that fr fd additives prpsed fr use in infant frmula, lwer margins f expsure (<100) culd be interpreted as indicating lw risk fr the health f infants 0 12 weeks f age when uncertainties r cnservatisms that may exist in the txiclgical pint f departure r in the expsure estimates are taken int cnsideratin (see sectin 4.6). It shuld als be nted that where n effects have been bserved at the highest dse tested in all available studies, the calculatin f a margin f expsure may nt be meaningful. 23

30 A grup ADI (see sectin 4.4.4) may als be prpsed if several substances that prduce similar txic effects are being cnsidered fr use as fd additives, in rder t limit their verall dietary expsure. If a temprary numerical ADI r ADI nt specified is prpsed (see sectin 4.4.3), infrmatin required t reslve the utstanding issues t permit the establishment f an ADI fr the substance shuld be listed, alng with a date by which time the results f the indicated studies shuld be submitted t WHO fr evaluatin. If n ADI can be established because there were critical data gaps r because f appreciable bilgical uncertainty in the assessment, the infrmatin that the Cmmittee wuld wish t have befre reviewing the cmpund again shuld be listed. Where a numerical ADI is established, high-percentile dietary expsure t the fd additive is cmpared with the upper limit f the ADI range, and the Cmmittee cncludes as t whether there is likely t be a health cncern. The Evaluatin sectin ften ends with a statement abut the chemical specificatins prepared by FAO, which is taken frm the meeting reprt item. (The statement n the preparatin f a txiclgical mngraph that appears in the meeting reprt item is deleted frm the mngraph itself.) References 6. References References shuld be presented at the end f the mngraph; the spnsr shuld be asked t prvide the references in the JECFA style. Persnal cmmunicatins and ther unpublished infrmatin are included in the text, nt in the reference list (see sectin 2.2.7). In the reference list itself, all authrs shuld be given if there are six r fewer; if there are mre than six authrs, the first six authrs are given, fllwed by et al. Order f references in reference list: single authr by increasing year, tw authrs alphabetically by secnd authr, three authrs alphabetically by secnd r third authr, mre than three authrs by increasing year: Brwn J (1999a). Brwn J (1999b). Brwn J (2000). Brwn J, Jnes F (2001). Brwn J, Smith M (1988). Brwn J, Jnes F, Smith M (2012). Brwn J, Smith M, Jnes F (2010). Brwn J, Jnes F, Smith M, Kennedy B, Lewis M (1999). Brwn J, Smith M, Kennedy B, Lewis M, Clark T, Jnes F et al. (2010). Abbreviated jurnal names as given by the United States Natinal Library f Medicine (e.g. Am J Txicl) are used. Nte that the abbreviated jurnal name ends with a perid, befre the vlume number. Page ranges use en dashes and are abbreviated (nly thse digits that change in the higher page number are given): e.g ; ; Examples f references in reference list: 24

31 Jurnal reference Amara S, Patin A, Giuffrida F, Wster TJ, Thakkar S, Bénaruche A et al. (2014). In vitr digestin f citric acid esters f mn- and diglycerides (CITREM) and CITREM-cntaining infant frmula/emulsins. Fd Funct. 5: Magne F, Hachelaf W, Suau A, Budraa G, Buziane-Nedjadi K, Rigttier-Gis L et al. (2008). Effects n faecal micrbita f dietary and acidic ligsaccharides in children during partial frmula feeding. J Pediatr Gastrenterl Nutr. 46: Saenphet K, Aritajat S, Saenphet S, Mansri J, Mansri A (2006). Safety evaluatin f aqueus extracts frm Aegle marmels and Stevia rebaudiana n reprductin f female rats. Sutheast Asian J Trp Med Public Health. 37(Suppl. 3): Vandenplas Y, Hauser B, Blecker U, Suys B, Peeters S, Keymlen K et al. (1993). The nutritinal value f a whey hydrlysate frmula cmpared with a whey-predminant frmula in healthy infants. J Pediatr Gastrenterl Nutr. 17:92 6. Bk reference Barrw PC (2012). Use f the swine pediatric mdel. In: Hberman AM, Lewis EM, editrs. Pediatric nnclinical drug testing: principles, requirements, and practice. Hbken (NJ): Jhn Wiley & Sns; Chenweth WL, Leveille GA (1975). Metablism and physilgical effects f pectins. In: Jeanes A, Hdge J, editrs. Physilgical effects f fd carbhydrates. Washingtn (DC): American Chemical Sciety; Rthkötter HJ, Swa E, Pabst R (2005). The pig as a mdel fr develpmental immuntxiclgy. In: Hlladay SD, editr. Develpmental immuntxiclgy. Bca Ratn (FL): CRC Press; Wehle MJ, Segura JW (2002). Chapter 38: Pediatric urlithiasis. In: Belman AB, King LR, Kramer SA, editrs. Pediatric urlgy, furth editin. Bca Ratn (FL): Taylr and Francis; Unpublished study There is rm fr flexibility in the frmat f unpublished studies. The essential elements f unpublished studies that shuld be included, where available, are: the name f the authr(s) wh perfrmed the research wrk, if prvided; the year in which the experimental wrk was cmpleted; the title f the experimental study (if the title is in a language ther than English r French, translatin f the title int English is preferred); study number, if prvided; an indicatin that the study is unpublished; the name f the institutin at which the experimental study was perfrmed; the name f the institutin that submitted the reprt t WHO. Examples: Beck M, Rssi B (2005). Absrptin, distributin and excretin f tritium labelled lignsulfnate after single ral administratin t rats. Unpublished reprt submitted t WHO by DSM Nutritinal Prducts (RDR N ). EFEMA (2014). Submissin f data n citric acid esters f mn- and diglycerides f fatty acids (CITREM) (INS 472c) fr prpsed use in infant frmula and frmulas fr special medical purpses intended fr infants n behalf f EFEMA. Submitted t WHO by the Eurpean Fd Emulsifiers Manufacturers Assciatin, Brussels, Belgium, 12 February MPI (2013). Pectin: a dietary 3-week safety study in farm piglets. MPI Research Study N Unpublished study carried ut at MPI Research Inc., Mattawan, MI, USA. Submitted t WHO by Internatinal Special Dietary Fds Industries. 25

32 Thiel A, Köhl W, Sklwski A (2005). Salmnella typhimurium and Escherichia cli reverse mutatin assay with Ultrazine FG-R (fd grade lignsulfnate). Unpublished reprt n (RDR ) frm RCC-Cyttest Cell Research GmbH, Rssdrf, Germany. Thrsrud B (2013). Carrageenan: a 28-day infant frmula feeding safety and txickinetic study in preweaning Yrkshire-crssbred piglets. MPI Study (FMC Study ), MPI Research Inc., Mattawan, MI, USA. Dssier prepared by FMC Crpratin, Philadelphia, PA, USA, and the Internatinal Frmula Cuncil. Submitted t WHO by the Republic f the Philippines. Agency reprt EVM (2003). Safe upper levels fr vitamins and minerals. Lndn: Fd Standards Agency, Expert Grup n Vitamins and Minerals. FAO/WHO (2013). Reprt f the Frty-fifth Sessin f the Cdex Cmmittee n Fd Additives, Beijing, China, March Rme: Fd and Agriculture Organizatin f the United Natins and Wrld Health Organizatin, Jint FAO/WHO Fd Standards Prgramme, Cdex Alimentarius Cmmissin (REP13/FA; reprt/796/rep13_fae.pdf, accessed 30 July 2014). FAO/WHO/UNU (2004). Human energy requirements: Reprt f a Jint FAO/WHO/UNU Expert Cnsultatin, Rme, Octber Rme: Fd and Agriculture Organizatin f the United Natins, Wrld Health Organizatin, United Natins University ( accessed 27 August 2014). NTP (2004). Txiclgy & carcingenesis studies f Elmirn (CAS N ) in F344/rats and B6C3F1 mice (gavage studies). Research Triangle Park (NC): United States Department f Health and Human Services, Natinal Institutes f Health, Natinal Institute f Envirnmental Health Sciences, Natinal Txiclgy Prgram (NTP Technical Reprt Series, N. 512). Scientific Cmmittee n Fd (2002). Opinin f the Scientific Cmmittee n Fd n the tlerable upper intake level f prefrmed vitamin A (retinl and retinl esters), expressed n 26 September Brussels: Eurpean Cmmissin, Scientific Cmmittee n Fd (SCF/CS/NUT/UPPLEV/24 Final). USEPA (1994). A 90-day subchrnic ral txicity study with PDMS fluid in the muse. Washingtn (DC): United States Envirnmental Prtectin Agency, Office f Txic Substances (EPA/OTS Dcument N ). Cnference prceedings Atta-ur-Rahman, Le Quesne PW, editrs (1986). New trends in natural prducts chemistry. Prceedings f the Secnd Internatinal Sympsium and Pakistan U.S. Binatinal Wrkshp n Natural Prducts Chemistry, January 1986, Karachi, Pakistan. Amsterdam: Elsevier Science Publishing C. (Studies in Organic Chemistry, Vl. 26). Reference in a freign language (ther than French) Akashi H, Ykyama Y (1975). [Security f dried-leaves extracts f stevia reprt f txiclgical test.] Shkuhin Kgy. 18:34 43 (in Japanese). Secndary reference Add [cited in reference x] at the end f the reference. Examples: Buchanan RL, Gldstein S, Budre JD (1981). Examinatin f chili pepper and nutmeg leresins using the Salmnella/mammalian micrsme mutagenicity assay. J Fd Sci. 47:330 1 [cited in Jhnsn, 2007]. 26

33 de Grt AP, Fern VJ, Immel HR (1988). Inductin f hyperplasia in the bladder epithelium f rats by a dietary excess f acid r base: implicatins fr txicity/carcingenicity testing. Fd Chem Txicl. 26: [cited in Garthff et al., 2010]. Reference fund nline Give URLs, with access dates, fr as many references as pssible, particularly WHO prducts. Examples: Maher D, Frd N (2011). Actin n nncmmunicable diseases: balancing pririties fr preventin and care. Bull Wrld Health Organ. 89:547A ( vlumes/89/8/ pdf, accessed 3 August 2011). WHO (2009). Infant and yung child feeding: mdel chapter fr textbks fr medical students and allied health prfessinals. Geneva: Wrld Health Organizatin ( accessed 20 August 2014). Databases, electrnic publicatins and website references Derry S, Mre RA (2012). Tpical capsaicin (lw cncentratin) fr chrnic neurpathic pain in adults. Cchrane Database Syst Rev. 9:CD WHO Reginal Office fr Eurpe (2012). Eurpean health fr all database [nline database]. Cpenhagen: WHO Reginal Office fr Eurpe ( accessed 3 August 2012). HBSC Internatinal Crdinating Centre (2012). HBSC: Health behaviur in schl-aged children: Wrld Health Organizatin crss-natinal study [website]. St Andrews: Child & Adlescent Health Research Unit, University f St Andrews ( accessed 11 Octber 2012). Sectin f a website WHO Reginal Office fr Eurpe (2012). Twards a new Eurpean public health actin plan. In: WHO/Eurpe public health frum [website]. Cpenhagen: WHO Reginal Office fr Eurpe ( accessed 21 June 2012). Online jurnals Garrett L, Chwdhury AMR, Pabls-Mendez A (2009). All fr universal health cverage. Lancet. 374: di: /s (09) Piemntese P, Gianni ML, Braegger CP, Chiric G, Grüber C, Riedler J et al. (2011). Tlerance and safety evaluatin in a large chrt f healthy infants fed an innvative prebitic frmula: a randmized cntrlled trial. PLS One. 6(11):e di: / jurnal.pne

34 Chapter 3: Preparing the reprt item During the first few days f the meeting, the Cmmittee will discuss in detail each txiclgical mngraph, reslving any cntentius issues raised by the mngrapher and reaching agreement n the general apprach t be taken in evaluating the fd additive. Once agreement has been reached n a way frward, the mngrapher shuld prepare the first draft f the meeting reprt item. The mngrapher prepares the reprt item during the meeting by fllwing the template shwn in Annex 3 (the current template will be made available n the cmputers in the meeting rm). This invlves extracting the Explanatin, Cmments and Evaluatin sectins frm the mngraph int the meeting reprt template and mdifying them as suggested during initial discussins f the Cmmittee. During the preparatin f the first draft f the meeting reprt item, the WHO mngrapher shuld include headings fr the sectins being prepared by the FAO and expsure experts assigned t the fd additive. These include Chemical and technical cnsideratins after the Explanatin sectin and Assessment f dietary expsure after the Observatins in humans sectin. These sectins will be inserted by the editr after the meeting if they have nt already been inserted by the mngrapher r by FAO during its review f the WHO meeting reprt item. The Evaluatin sectin may include a statement prepared by FAO cncerning the chemical specificatins and the preparatin f a Chemical and Technical Assessment fr the fd additive. This statement is usually added by FAO during its review f the WHO meeting reprt item. The Evaluatin sectin in the reprt ends with a statement that a mngraph r mngraph addendum has been prepared. (This statement is deleted frm the mngraph.) References shuld be cited fr all f the studies in the reprt item. The editr will retain nly the references fr the key study r studies and will change them t italicized numbers (e.g. (1)) fr the final meeting reprt, unless n mngraph r mngraph addendum is being prepared, in which case all references in the reprt item will be retained fr the final meeting reprt. All f the references will be retained in the Explanatin, Cmments and Evaluatin sectins that are inserted int the final mngraph by the editr after the meeting. After the (usually) first draft f the reprt item has been apprved by the Cmmittee and any suggested revisins have been incrprated by the mngrapher, the WHO rapprteur checks the revisins and, when satisfied, passes the file t the editr. The editr edits the draft reprt item and sends it back t the mngrapher t check all changes made and t answer any questins raised during the editing prcess. During subsequent discussins n the reprt item, the editr is respnsible fr making all necessary revisins nscreen, until the Cmmittee is cmpletely satisfied with the reprt item (referred t as ging t final ). At this pint, the editr passes the final reprt item t FAO (usually the FAO rapprteur) fr its review and incrprates any changes resulting frm that review. It is the mngrapher s respnsibility t keep track f any changes made t the reprt item that will require crrespnding changes t the mngraph. By the end f the meeting, all such changes t the mngraph need t have been made s that the tw are cnsistent. The editr can prvide the mngrapher with the final edited versin f the meeting reprt item at the end f the meeting t facilitate this task. An electrnic versin f the final mngraph needs t be prvided t the editr and WHO Jint Secretary (by uplading it t the meeting cmputer in the Final mngraphs flder) befre the mngrapher leaves the meeting n the final day. 28

35 Chapter 4: Additinal cnsideratins The EHC mngraph entitled Principles and methds fr the risk assessment f chemicals in fd (EHC 240 [IPCS, 2009]) shuld be referred t fr detailed infrmatin n hazard identificatin and characterizatin, dse respnse assessment, derivatin f a health-based guidance value, dietary expsure assessment and risk characterizatin fr fd additives. This chapter includes general cnsideratins relevant t fd additives that were discussed at meetings f the Cmmittee subsequent t publicatin f the abve mngraph. It als highlights sme relevant definitins and ther infrmatin frm that mngraph that are critical in perfrming safety assessments f fd additives. 4.1 Re-evaluatin f fd additives by JECFA Since its establishment, JECFA has evaluated mre than 600 fd additives (excluding flavuring agents), and apprximately 30% f JECFA evaluatins are mre than 30 years ld. JECFA has repeatedly nted the imprtance f reviewing substances previusly evaluated when new data n thse substances becme available and in light f further develpments in science and risk assessment methdlgies. The Cmmittee has develped criteria that will trigger a review f substances, which were published in EHC 240 (IPCS, 2009). Peridic review f past decisins n safety may be made necessary by ne r mre f the fllwing develpments: a new manufacturing prcess fr the fd additive; a new specificatin; new data n the bilgical prperties f the cmpund; new data cncerning the nature and/r the bilgical prperties f the impurities present in a fd additive; advances in scientific knwledge relevant t the nature r mde f actin f fd additives; changes in cnsumptin patterns r level f use f a fd additive; and imprved requirements fr safety evaluatin, made pssible by new scientific knwledge and the quality and quantity f safety data cnsidered necessary in the case f fd additives. 4.2 Cmmentary n the use f NOEL/NOAEL and LOEL/LOAEL The sixty-eighth meeting f the Cmmittee (FAO/WHO, 2007) recnsidered the use f the terms nbserved-effect level (NOEL), n-bserved-adverse-effect level (NOAEL) and the related terms lwest-bserved-effect level (LOEL) and lwest-bserved-adverse-effect level (LOAEL) in evaluatins f the safety f fd additives and cntaminants. The Cmmittee decided t use the term NOAEL when the relevant effect at the next higher dse is cnsidered adverse. If such an effect is nt cnsidered adverse, then the term NOEL wuld be used. This included assessments where n effects were bserved at the highest dse tested, in which case the highest dse tested wuld be taken as the NOEL. The same apprach wuld be used by the Cmmittee with respect t the terms LOEL and LOAEL. When effects were bserved at all dses, the lwest dse wuld be identified as the LOEL if the effects at the lwest dse were nt cnsidered adverse r as the LOAEL if the effects at the lwest dse were cnsidered adverse. The Cmmittee emphasized that this decisin des nt entail any change in its evaluatin practice and has n impact n any f the previus evaluatins made by this Cmmittee. 4.3 Overall NOAEL JECFA generally uses the lwest NOAEL in the mst sensitive species, usually amng mice, rats and dgs, t establish the ADI; hwever, there might be situatins where there is mre than ne study in which the same end-pints have been addressed. In such situatins, the dse spacing may be different, resulting in different NOAELs and LOAELs. In such circumstances, it might be apprpriate t cnsider the studies tgether. When they are cmparable, including cnsideratin f study design, duratin, end-pints addressed, and species and strain f animal, an verall NOAEL is identified, 29

36 which is the highest NOAEL in the available studies, prvided that there is a reasnable margin ( 2) ver the lwest LOAEL (which becmes t the verall LOAEL ) and that due cnsideratin is given t the shape f the dse respnse curve. JECFA has applied this apprach in the evaluatin f, fr example, phytsterls, phytstanls and their esters (FAO/WHO, 2009). 4.4 Health-based guidance values fr fd additives Acceptable daily intake (ADI) JECFA generally sets the ADI n the basis f the lwest relevant NOAEL r ther POD in the mst sensitive species and applicatin f an uncertainty (safety) factr t accunt fr the inherent uncertainties in extraplating txicity data frm experimental animal studies t ptential effects in humans as well as variatin within the human species. The ADI is usually expressed in the units f milligrams r micrgrams per kilgram f bdy weight, as a range frm 0 t an upper limit. Given that there are assumptins and uncertainties in deriving the ADI, such as the use f uncertainty factrs, the use f a range f dses in txiclgical studies and nrmal bilgical variatin, it is mre meaningful t express the ADI t nly ne significant figure t avid any inference f inapprpriate precisin. If an ADI is calculated frm a POD that has mre than ne significant figure, the ADI wuld therefre be runded t ne significant figure, cnsistent with accepted runding prcedures. 6 JECFA has cnfirmed that the runding practices used in expressing the ADI are scientifically and mathematically sund ADI nt specified There are ccasins when JECFA cnsiders the setting f an ADI in numerical terms nt t be apprpriate. This situatin arises when the estimated dietary expsure t the fd additive is expected t be well belw any numerical value that wuld rdinarily be assigned t it. Under such circumstances, JECFA uses the term ADI nt specified. The Cmmittee defines this term t mean that, n the basis f available data (chemical, bichemical, txiclgical and ther), the ttal daily expsure t the substance arising frm its use at the levels necessary t achieve the desired effect and frm its acceptable backgrund in fd des nt, in the pinin f the Cmmittee, represent a hazard t health. Fr that reasn, and fr the reasns stated in the individual evaluatins, the establishment f an ADI in numerical frm is nt deemed necessary. An additive meeting this criterin must be used within the bunds f gd manufacturing practice that is, it shuld be technlgically efficacius and shuld be used at the lwest level necessary t achieve this effect, it shuld nt cnceal inferir fd quality r adulteratin, and it shuld nt create a nutritinal imbalance Temprary ADI and ADI nt specified JECFA has encuntered several situatins in which either the bdy f available data n a new fd additive had sme limitatins r the safety f a fd additive fr which the Cmmittee had previusly assigned an ADI was brught int questin by new data. When the Cmmittee feels cnfident that the use f the substance is safe ver the relatively shrt perid f time required t generate and evaluate further safety data, but is nt cnfident that its use is safe ver a lifetime, it ften establishes a temprary ADI, pending the submissin f apprpriate data t reslve the safety issue n a timetable established by JECFA. When establishing a temprary (numerical) ADI, the Cmmittee always uses a higher than usual uncertainty (safety) factr, usually increasing it by a factr f 2. The additinal bichemical r txiclgical data required fr the establishment f an ADI are clearly stated, and a review f these new data is cnducted befre expiry f the prvisinal perid. In many cases, lng-term studies are requested, but timetables are nt met, which means that JECFA has had t extend temprary ADIs fr further perids f time. In instances where data have nt been frthcming, JECFA has withdrawn temprary ADIs as a safety precautin. When establishing a temprary ADI nt specified, the additinal data (e.g. a nn-prprietary analytical methd) required fr the 6 The general runding rule fr mid-way values (x.5) is t rund up, in line with cmmn cnventin (e.g. Standards Australia Internatinal, 2003). Examples fr runding t ne significant figure are as fllws: 1.25 becmes 1, 0.73 becmes 0.7 and 1.5 becmes 2. 30

37 establishment f an ADI nt specified are clearly stated as well as the time by which the data must be submitted Grup ADIs If several substances that prduce similar txic effects are t be cnsidered fr use as fd additives, it may be apprpriate in establishing an ADI t cnsider the grup f substances in rder t limit their verall dietary expsure. Fr this prcedure t be feasible, the substances shuld have a similar mde f actin and a similar range f txic ptency. Flexibility shuld be used in determining which NOAEL is t be used in calculating the ADI. In sme cases, the average NOAEL fr all the substances in the grup may be used fr calculating the grup ADI. A mre cnservative apprach is t base the grup ADI n the substance with the lwest NOAEL. The relative quality and length f studies n the varius substances shuld be cnsidered when setting the grup ADI. When the NOAEL fr ne f the substances is ut f line with the thers in the grup, it shuld be treated separately. When JECFA is cnsidering a substance fr which txiclgical infrmatin is limited but that substance is a member f a series f substances that are very clsely related chemically (e.g. fatty acids), it may be pssible fr JECFA t base its evaluatin n the grup ADI established fr the series f substances. This prcedure can be fllwed nly if a great deal f txiclgical infrmatin is available n at least ne member f the series and if the knwn txic prperties f the varius substances fall alng a well-defined cntinuum. Interplatin, but nt extraplatin, can be perfrmed. The use f this prcedure by JECFA represents ne f the few situatins in which the Cmmittee has used structure activity relatinships in its safety assessments. In sme instances, grup ADIs can be established primarily n the basis f metablic infrmatin. Fr example, the safety f esters used as fd flavuring agents culd be assessed n the basis f txiclgical infrmatin n their cnstituent acids and alchls, prvided that it is shwn that they are quantitatively hydrlysed in the gut. The calculatin f a grup ADI is als apprpriate fr substances that cause additive physilgical r txic effects, even if they are nt clsely related chemically. Fr example, it may be apprpriate t establish a grup ADI fr additives such as bulk sweeteners that are prly absrbed and cause a laxative effect Substances that are gentxic and carcingenic Substances that are bth gentxic and carcingenic wuld generally nt be cnsidered acceptable fr use as fd additives, and JECFA des nt establish health-based guidance values fr such substances Acute reference dse (ARfD) Fr mst fd additives, n acute txicity ccurs at the dses relevant fr human expsure. Therefre, n acute reference dses (ARfDs) are established, and n acute dietary expsure assessments are needed. Occasinally, acute intlerance reactins may be relevant, such as laxatin frm plyl sweeteners. Fr sme chemicals, allergic reactins may als smetimes be f cncern, but there are currently n accepted prcedures fr establishing safe expsure levels fr allergic reactins t use in evaluating the significance f acute expsures. Research is under way t allw the identificatin f threshlds fr allergenicity f a variety f fd allergens. 4.5 Extensin f an existing ADI t substances btained frm different surces and/r by different manufacturing prcesses A recurring questin facing the Cmmittee is whether an ADI allcated t an additive btained frm a specific surce material and/r by a specific manufacturing prcess can be applied t encmpass similar additives btained by ther means r frm ther surces. The Cmmittee at the sixty-eighth meeting (FAO/WHO, 2007) therefre cnsidered the pssibility f elabrating principles r guidelines fr evaluatins in this area. At previus meetings, the Cmmittee had evaluated several fd additives cntaining the same chemical entity as the functinal cmpnent in relatin t its fd additive use but btained frm 31

38 different surce materials and/r different manufacturing prcesses. One such example is clurs cntaining β-cartene, which may be btained by extractin frm vegetables, algae r a genetically mdified micrrganism r prduced by chemical synthesis. Depending n the substance in questin and infrmatin received, the Cmmittee has reached varius cnclusins in its evaluatins. A guiding principle in the safety evaluatin f fd additives has been that the material tested txiclgically is representative f the material f cmmerce. T this end, specificatins have been established primarily t reflect substances that have been txiclgically tested and secndarily t cver as far as pssible prducts cmmercially available in the market. When additives cntaining the same chemical entity r entities as the functinal cmpnent are prduced frm different surces r by different methds f manufacture, pssibly leading t substantial differences in cmpsitin, it has been fund necessary t prepare mre than ne specificatins mngraph, as was the case fr the abve-mentined β-cartene-cntaining additives. In rder t answer the questin f whether it is pssible t apply an existing ADI t an additive frm a new surce r nvel methd f manufacture (the new prduct ), the Cmmittee cnsidered that it is necessary t cmpare the surce, methd f manufacture and cmpsitin f the new prduct with thse f the prduct that was tested txiclgically and fr which the ADI was riginally allcated (the ld prduct ). In additin t the surce, the cmpsitin f a prduct is cmmnly related t the manufacturing prcess. Typical methds f manufacture are chemical synthesis, extractin frm natural surce materials and prductin by a micrrganism (with r withut genetic mdificatin). All f these may result in different residues and impurities that have t be taken int accunt. The cntent f the functinal cmpnent(s) is ften lw in prducts btained by extractin f natural surce materials, whereas the cntent is nrmally high in prducts btained by chemical synthesis. It is evident that a prduct with a lw cntent f the functinal cmpnent cntains significant amunts f ther substances (e.g. cmpnents resulting frm the surce material r frm an rganism used in its prductin). The Cmmittee recmmended that the fllwing stepwise prcedure be adpted t determine whether a new prduct might be included in a previusly allcated ADI: 1. Infrmatin n manufacture and cmpsitin f bth the new and the ld prducts shuld be cllated and cmpared, and any majr differences r significant lack f infrmatin identified. 2. Data frm the first step might be used t determine whether a) the new prduct is sufficiently similar t the ld prduct t be included in the ADI, b) it is impssible t include the new prduct in the ADI because f substantial cmpsitinal differences between the tw prducts, r c) it may be pssible t include the new prduct in the ADI prvided that additinal infrmatin is received by the Cmmittee. In all cases, bth the nature and amunt f any new by-prducts/slvent residues r ther cntaminants need t be cnsidered. If the cntent f the functinal cmpnent(s) f the additive is high and any new cntaminants wuld be present in nly minute amunts, cnsideratin f expsure t the additive and cnsequential expsure t the minr cntaminant may indicate whether the presence is f safety cncern. 3. The specificatins shuld include infrmatin n surce, manufacture and cmpsitin in rder t reflect materials cvered by the evaluatin. In particular, where indicated fr txiclgical reasns, criteria/limits fr specific cmpnents shuld be included in the specificatins. 4.6 The use f the margin f expsure (MOE) fr the evaluatin f additives used in infant frmulas The ADI cncept des nt apply t infants up t the age f 12 weeks because they might be at risk at lwer levels f expsure cmpared with lder age grups. This is due t special cnsideratins, such as their immature metablic capacities, the greater permeability f the immature gut, and their rapid grwth and develpment. Therefre, risk characterizatin fr very yung infants has t be cnsidered n a case-by-case basis. 32

39 Txiclgical testing strategies fr additives t be used in infant frmulas require appraches that differ frm thse generally adpted fr fd additives. Fr example, evaluatin f fd additives t be used in infant frmulas requires cnsideratin f safety studies invlving expsure f very yung animals. The reprductive and develpmental txicity studies cmmnly available fr evaluatins f chemicals in fd address the pssible impact n nenatal animals arising thrugh in uter and lactatinal expsure. Hwever, they frequently d nt incrprate direct ral administratin t nenatal animals, and such studies are required fr the evaluatin f fd additives in infant frmula. If the additive is prpsed fr use in infant frmula at relatively high levels (e.g. 0.1% r greater), then cnducting txiclgical studies in nenatal animals at dses tw r mre rders f magnitude greater than the anticipated human expsure, which is the apprach cmmnly taken fr fd additives, may nt be feasible. The Cmmittee at its seventy-ninth meeting (FAO/WHO, 2014) nted that fr several fd additives that are prpsed fr use in infant frmulas, the margins f expsure (MOEs) between the NOAEL and the estimated daily expsures t the fd additives were in the range f fr infants. Interpretatin f the MOE needs t take int accunt uncertainties r cnservatisms that may exist in the txiclgical pint f departure r in the expsure estimates. Cnsideratins related t the txiclgical pint f departure t be taken int accunt in interpreting the MOE include: absrptin, distributin, metablism and excretin fr example, whether r nt the additive is absrbed, cmparisn f ptential fr metablic activatin and detxicatin in the nenatal rganism cmpared with the adult; the verall txiclgical prfile f the substance, including identificatin f critical effects; the ptential effects f expsure during life stages in experimental animals f relevance t human infants; the relevance fr the human infant f the nenatal animal mdels used in txiclgical testing; whether adverse effects have been identified in the txiclgical studies in nenatal animals, r if the NOAELs are the highest dses tested; the design and utcme f any clinical studies cnducted with infants (e.g. ttal number and age f infants tested, grwth, tlerance, types f adverse reactin examined); and reprts f adverse reactins in pst-marketing surveillance, where the infant frmula is already in use in sme cuntries. Factrs related t the dietary expsure assessments that shuld be taken int accunt fr the interpretatin f an MOE include the fllwing assumptins and cnsideratins: Frmula is the nly surce f nutritin fr the first 12 weeks f life. The additive will be used at the maximum prpsed level. An energy density f 67 kcal/100 ml (280 kj/100 ml) is used t cnvert energy t the vlume f frmula ingested daily. High infant frmula cnsumptin is derived frm 95th percentile energy intakes. Variability f expsure amng infants is small. Duratin f expsure is fr a limited time, and expsure decreases n a bdy weight basis during the expsure perid. The Cmmittee cncluded that when the abve issues have been taken int accunt, an MOE in the regin f 1 10 culd be interpreted as indicating lw risk fr the health f infants aged 0 12 weeks cnsuming the fd additive in infant frmula (FAO/WHO, 2014). 33

40 References EFSA (2012). Guidance n selected default values t be used by the EFSA Scientific Cmmittee, Scientific Panels and Units in the absence f actual measured data. EFSA J. 10(3):2579 [32 pp.] di: /j.efsa FAO/WHO (2004). Pesticide residues in fd Reprt f the Jint Meeting f the FAO Panel f Experts n Pesticide Residues in Fd and the Envirnment and the WHO Cre Assessment Grup n Pesticide Residues. Rme: Fd and Agriculture Organizatin f the United Natins (FAO Plant Prductin and Prtectin Paper, 178; agphme/dcuments/pests_pesticides/jmpr/reprts_ /reprt2004jmpr.pdf, accessed 9 April 2015). FAO/WHO (2007). Evaluatin f certain fd additives and cntaminants. Sixty-eighth reprt f the Jint FAO/WHO Expert Cmmittee n Fd Additives. Geneva: Wrld Health Organizatin (WHO Technical Reprt Series, N. 947; _eng.pdf, accessed 9 April 2015). FAO/WHO (2009). Evaluatin f certain fd additives and cntaminants. Sixty-ninth reprt f the Jint FAO/WHO Expert Cmmittee n Fd Additives. Geneva: Wrld Health Organizatin (WHO Technical Reprt Series, N. 952; accessed 22 April 2015). FAO/WHO (2010). Evaluatin f certain fd additives. Seventy-first reprt f the Jint FAO/WHO Expert Cmmittee n Fd Additives. Geneva: Wrld Health Organizatin (WHO Technical Reprt Series, N. 956; accessed 21 April 2015). FAO/WHO (2014). Evaluatin f certain fd additives. Seventy-ninth reprt f the Jint FAO/WHO Expert Cmmittee n Fd Additives. Geneva: Wrld Health Organizatin (WHO Technical Reprt Series, N. 990; _eng.pdf?ua=1, accessed 8 February 2016). Health Canada (1994). Human health risk assessment fr pririty substances. Ottawa: Health Canada ( accessed 14 July 2015). IPCS (2009). Principles and methds fr the risk assessment f chemicals in fd. Geneva: Wrld Health Organizatin, Internatinal Prgramme n Chemical Safety (Envirnmental Health Criteria 240; accessed 9 April 2015). Standards Australia Internatinal (2003). Australian Standard AS : Numerical values runding and interpretatin f limiting values. Sydney: Standards Australia Internatinal. 34

41 Annex 1: Template fr mngraph A sample table f cntents fr the txiclgical and dietary expsure mngraphs fr fd additives is given belw. Nt all headings will be applicable in all cases; N infrmatin was available can be inserted under main headings (usually up t third level), r minr headings that are nt applicable can be deleted. It shuld be nted that the design f the mngraphs was changed in 2015, which has resulted in several frmatting changes. Text is 12 pt Times New Rman, headings are 14/12/10/9 pt Arial, paper size A4, 1 inch margins, single spaced, first line f first paragraph under each heading is flush left, first line f all subsequent paragraphs is indented 0.5 inch, n spacing between paragraphs, paragraphs are fully justified, extra line space is added between different study descriptins, line numbering is required fr the draft mngraph. Fd additive name (addendum, if applicable) First draft prepared by Authr 1, 1 Authr 2 2 and Authr x x 1 Affiliatin f authr 1 2 Affiliatin f authr 2 x Affiliatin f authr x (include names and affiliatins f all experts wh cntributed t the draft, including WHO and FAO authrs and reviewers; main WHO authr is given first, fllwed by rest f cntributrs in alphabetical rder) 1. Explanatin... x 1.1 Chemical and technical cnsideratins (FAO)... x 2. Bilgical data... x 2.1 Bichemical aspects... x Absrptin, distributin and excretin... x (a) Absrptin... x (b) Distributin... x (c) Excretin... x Bitransfrmatin... x Effects n enzymes and ther bichemical parameters... x 2.2 Txiclgical studies... x Acute txicity... x Shrt-term studies f txicity... x (a) Mice... x (b) Rats... x (c) Hamsters... x (d) Rabbits... x (e) Dgs... x (f) Pigs... x (g) Mnkeys... x Lng-term studies f txicity and carcingenicity... x (a) Mice... x (b) Rats... x (c) etc.... x 35

42 2.2.4 Gentxicity... x Reprductive and develpmental txicity... x (a) Multigeneratin reprductive txicity... x (b) Develpmental txicity... x Special studies (belw are examples nly; nte alphabetical rder)... x (a) Allergenicity... x (b) Cardivascular effects... x (c) Immune respnses... x (d) Macrmlecular binding... x (e) Metablites... x (f) Neurtxicity... x (g) N-hrmnal-effect levels... x (h) Ocular txicity... x (i) Phtismerizatin prducts... x (j) Thyrid functin... x 2.3 Observatins in humans... x 3. Dietary expsure (expsure experts)... x 4. Cmments (nte: includes reference citatins)... x 4.1 Bichemical aspects... x 4.2 Txiclgical studies... x 4.3 Observatins in humans... x 4.4 Assessment f dietary expsure... x 5. Evaluatin... x 5.1 Recmmendatins... x 6. References... x 36

43 Annex 2: Examples f table frmats Table 1 Pharmackinetic parameters fllwing a single ral (gavage) dse f ethyl lauryl arginate (prpylene glycl/water frmulatin) administered t male rats Dse level (mg/kg bw) Ethyl lauryl arginate C max (ng/ml) / T max (h) N α -Lauryl-Larginine Ethyl lauryl arginate AUC (ng h/ml) N α -Lauryl-Larginine ± 1.28 / ± 31.9 / 1 a 52.5 ± ± 0.29 / ± 2.5 / 0.75 a 103 ± ± 1.81 / ± 79.7 / ± ± 58 AUC: area under the plasma cncentratin time curve; bw: bdy weight; C max: maximum cncentratin in plasma; T max: time taken t reach C max a Culd nt be calculated wing t the small number f quantifiable samples. Table 2 Mean cumulative excretin f radiactive material fllwing administratin f single ral dses f 14 C-labelled PVA-PEG graft cplymer t male and female rats Dse (mg/kg bw) 48 h Mean cumulative excretin f radiactive material (% f administered dse) Faeces Urine Bile Exhaled air Males Females Males Females Males Females Males Females ND ND ND ND 168 h ND ND 0.15 ND ND ND 0.11 ND bw: bdy weight; ND: nt determined Table 3 Acute txicity f stevil glycsides and related substances Species Sex Test substance Rute Muse Male and female Muse Male Isstevil (purity nt supplied) Muse Male Isstevil (purity nt supplied) Muse Male Isstevil (purity nt supplied) Rat Male Isstevil (purity nt supplied) LD 50 (mg/kg bw) Reference 93 95% steviside Gavage > Akashi & Ykyama (1975) Oral >500 Baztte et al. (1986) Intraperitneal Baztte et al. (1986) Intravenus Baztte et al. (1986) Oral >500 Baztte et al. (1986) 37

44 Species Sex Test substance Rute Rat Male Isstevil (purity nt supplied) Rat Male Isstevil (purity nt supplied) Dg Male and female Isstevil (purity nt supplied) bw: bdy weight; LD 50: median lethal dse LD 50 (mg/kg bw) Reference Intraperitneal Baztte et al. (1986) Intravenus Baztte et al. (1986) Oral >500 Baztte et al. (1986) Table 4 Bdy weight change and feed efficiency in a 3-week dietary txicity study f OSA-mdified starch in farm piglets OSA dse (mg/kg bw per day) Mean bdy weight, day 1 (kg) Mean bdy weight, day 21 (kg) Ttal bdy weight change (kg) Ttal feed cnsumptin (kg) Feed efficiency a Males Females bw: bdy weight; OSA: ctenyl succinic acid a Feed efficiency = bdy weight change/feed cnsumptin. Surce: Adapted frm MPI Research (2012) Table 5 Mean terminal bdy weight and relevant relative rgan weights in F 1 rats (10 f each sex per grup) after receiving paos via the diet fr 13 weeks Parameter Males Cntrl Relative rgan weight (g/kg bw) a Reference cntrl (10% sc-fos) Test grups 5% paos 10% paos Terminal bdy weight (g) 336 ± ± ± ± 23 Kidneys 5.37 ± ± ± ± 0.40* # Caecum full 11.0 ± ± 3.0* 13.9 ± 1.4* # 17.1 ± 2.2* # Caecum empty 2.4 ± ± 0.0* 2.8 ± 0.5 # 3.8 ± 0.5* 38

45 Parameter Females Cntrl Relative rgan weight (g/kg bw) a Reference cntrl (10% sc-fos) Test grups 5% paos 10% paos Terminal bdy weight (g) 200 ± ± ± ± 13 # Kidneys 5.98 ± ± ± ± 0.52 Caecum full 13.6 ± ± 2.5* 15.2 ± 2.5 # 17.4 ± 4.2* Caecum empty 3.2 ± ± 0.2* 3.4 ± 0.4 # 3.6 ± 0.3* # bw: bdy weight; paos: pectin acidic ligsaccharides; sc-fos: shrt-chain fruct-ligsaccharides *: P < 0.05, significantly different frm cntrls; # : P < 0.05, significantly different frm reference cntrls a Values are presented as means ± standard deviatin. Surce: Garthff et al. (2010) Table 6 Incidence and mean severity f main micrscpic findings in mesenteric lymph nde and kidneys Grup 1 Famy histicytsis Tubular vaculatin Incidence Mean severity Incidence Mean severity Male 0/20 0/20 Female 0/20 0/20 Grup 2 Male 4/ /20 Female 3/ /20 Grup 3 Male 17/ /20 Female 8/ / Grup 4 Male 20/ / Female 19/ / Recvery grup 1 Male 0/10 0/10 Female 0/10 0/10 Recvery grup 4 Male 10/ / Female 10/ / Surce: Brwn et al. (1998) 39

46 Table 7 Gentxicity f PVA-PEG graft cplymer in vitr and in viv End-pint In vitr Reverse mutatin Gene mutatin In viv Micrnucleus inductin Test system Salmnella typhimurium TA98, TA100, TA1535 and TA1537 and Escherichia cli WP2uvrA Muse lymphma L5178Y TK +/ cells Rute f administratin Cncentratin Result Reference µg/plate, ±S9 First experiment: µg/ml, ±S9 Secnd experiment: µg/ml, S µg/ml, +S9 Muse; male Intraperitneal 500, and mg/kg bw Negative a Negative b Negative c Engelhardt & Hffmann (2000) Engelhardt & Hildebrand (2000a) Engelhardt & Hildebrand (2000b) bw: bdy weight; PVA-PEG: plyvinyl alchl plyethylene glycl; S9: 9000 g supernatant fractin frm rat liver hmgenate a Tw independent experiments were perfrmed. The first experiment was perfrmed using the plate incrpratin methd, and the secnd experiment was perfrmed using the preincubatin methd. A slight decrease in the number f revertants and a slight reductin in bacterial grwth were ccasinally bserved frm 2500 µg/ml nwards. b Tw independent experiments were perfrmed. Cells were expsed fr 4 hurs in the absence and presence f S9 (except in the secnd experiment, in which cells were expsed fr 24 hurs in the absence f S9), fllwed by an expressin phase f hurs and a selectin perid f apprximately 10 days. After an expsure perid f 24 hurs, relative ttal grwth was decreased at 2500 µg/ml ( 55%) and 5000 µg/ml ( 37%). c Tw dses were administered intraperitneally at 0 and 24 hurs. Examinatins were 24 hurs after the last dsing (i.e. at 48 hurs). N increases in grup mean micrnuclei were bserved. The Cmmittee nted that intraperitneal administratin is nt a relevant rute fr human expsure t PVA-PEG graft cplymer. 40

47 Annex 3: Template fr reprt item A sample template fr the meeting reprt item is given belw. It shuld be nted that the design f the meeting reprt changed in 2015, resulting in several frmatting changes. Text is Times New Rman 12 pt, headings are Arial 11 pt, paper size A4, 1 inch margins, 1.5 line spacing, first line f first paragraph belw each heading is flush left, first line f all subsequent paragraphs is indented 0.5 inch, n spacing between paragraphs, paragraphs are fully justified. WHO template Reprt tpic: Authr(s): Date: Versin: 3.1.x Fd additive name Explanatin (general intrductin t the cmpund; whether it has been evaluated befre, including shrt descriptin f the cnclusins f previus evaluatins, and why it is n the agenda; als shrt intrductin t chemical nature f cmpund and primary uses in fd) Chemical and technical cnsideratins (FAO) Bichemical aspects (WHO) (brief descriptin f key infrmatin n absrptin, distributin, metablism and excretin) Txiclgical studies (shrt summary f the key txiclgical data relevant fr the evaluatin) Observatins in humans (brief summary f the mst relevant human data) Assessment f dietary expsure (expsure experts) 41

48 Dse respnse analysis (where apprpriate, brief descriptin f and justificatin fr data set selected, dse respnse mdels applied, benchmark dse results) Evaluatin (gives the Cmmittee s cnclusin re derivatin f health-based guideline value r margin f expsure between dietary expsure and critical effect level) Recmmendatins (gives recmmendatins fr research needed, infrmatin required t cmplete evaluatin, etc.) (reprt item ends with a shrt sentence t indicate whether a mngraph r mngraph addendum has been prepared (WHO) and a shrt sentence t indicate whether new specificatins and a Chemical and Technical Assessment were prepared (FAO)) 42

49 Annex 4: Example f reprt item Magnesium dihydrgen diphsphate Explanatin At the present meeting, the Cmmittee evaluated magnesium dihydrgen diphsphate fr use as an acidifier, stabilizer and raising agent. It is prpsed fr use as an alternative t sdiumbased acidifiers and raising agents, primarily in self-raising flur, ndles (riental style), batters and prcessed cereals. Magnesium dihydrgen diphsphate has nt been evaluated previusly by the Cmmittee. Phsphates, diphsphates and plyphsphates were evaluated by the Cmmittee at its sixth, seventh, eighth, ninth, thirteenth, furteenth, seventeenth, twenty-sixth and fiftyseventh meetings (Annex 1, references 6 8, 11, 19, 22, 32, 59 and 154). A maximum tlerable daily intake (MTDI) f 70 mg/kg f bdy weight (bw) was established at the twenty-sixth meeting n the basis f the lwest dietary cncentratin f phsphrus (1% in the diet) that caused nephrcalcinsis in rats. It was cnsidered inapprpriate t establish an acceptable daily intake (ADI), because phsphrus (primarily as phsphate) is an essential nutrient and an unavidable cnstituent f fd. The MTDI is expressed as phsphrus and applies t the sum f phsphates naturally present in fd and the phsphates derived frm use f these fd additives. At its seventy-first meeting, the Cmmittee evaluated ferrus ammnium phsphate and cncluded that cnsideratin f the txicity f phsphate did nt indicate a need t revise the Cmmittee s previus evaluatin f this in (Annex 1, reference 191). The MTDI was cnsidered t cver a number f phsphate salts, accrding t the principle established by the Cmmittee at its ninth, twenty-third and twenty-ninth meetings (Annex 1, references 11, 50 and 70) that the ADI (r MTDI) established fr inizable salts shuld be based n previusly accepted recmmendatins fr the cnstituent catins and anins. Magnesium-based salts previusly discussed by the Cmmittee and cvered by the MTDI fr phsphates included magnesium phsphate (mnbasic, dibasic and tribasic) and mnmagnesium phsphate. Hwever, certain specific phsphate salts were nt included, because specificatins were lacking and because infrmatin was nt available t indicate whether they were being used as fd-grade materials. The Cmmittee has previusly evaluated ther magnesium salts, allcating ADIs nt limited 7 r nt specified t magnesium carbnate, magnesium hydrxide, magnesium chlride, magnesium DL-lactate, magnesium hydrgen carbnate, magnesium glucnate, magnesium di-l-glutamate and magnesium sulfate (Annex 1, references 11, 50, 70, 77, 137 and 187). At its twenty-ninth meeting (Annex 1, reference 70), the Cmmittee highlighted that the use f magnesium salts as fd additives was acceptable, prvided that the fllwing were taken int cnsideratin: The minimum laxative effective dse is apprximately 1000 mg f magnesium miety frm a magnesium salt (bserved nly when the magnesium salt is administered as a single dse). Infants are particularly sensitive t the sedative effects f magnesium salts. Individuals with chrnic renal impairment retain 15 30% f administered magnesium. 7 At its eighteenth meeting (Annex 1, reference 35), the Cmmittee replaced the term ADI nt limited with ADI nt specified. 43

50 At its present meeting, the Cmmittee was asked t cnduct a safety assessment and set specificatins fr magnesium dihydrgen diphsphate by the Frty-third Sessin f the Cdex Cmmittee n Fd Additives (3). The Cmmittee received a submissin that included tests fr acute txicity, skin and eye irritatin and gentxicity f magnesium dihydrgen diphsphate and cnsidered ther infrmatin available in the literature f relevance t the magnesium and phsphate ins. Chemical and technical cnsideratins Magnesium dihydrgen diphsphate (chemical frmula: MgH 2 P 2 O 7 ; Chemical Abstracts Service registry number: ) is the acidic magnesium salt f diphsphric acid. It is manufactured by adding an aqueus dispersin f magnesium hydrxide slwly t phsphric acid until a magnesium t phsphrus rati f abut 1:2 is reached. The temperature is held under 60 C during the reactin. Abut 0.1% hydrgen perxide is added t the reactin mixture, and the slurry is then dried and milled. Txiclgical data Magnesium dihydrgen diphsphate inizes int its cmpnent ins: magnesium, hydrgen and diphsphate. Therefre, the safety assessment shuld be based n previusly accepted recmmendatins fr the cnstituent catins and anins. Magnesium and phsphrus (primarily as phsphate) are essential minerals that are naturally present in the human bdy and in fd. The Cmmittee received data shwing that magnesium dihydrgen diphsphate des nt exert acute txicity, skin r eye irritatin r gentxicity. At previus meetings, the Cmmittee nted that txicity can arise frm an imbalance f calcium, magnesium and phsphate. Excessive dietary phsphrus causes hypcalcaemia, which can result in bne lss and calcificatin f sft tissues. The MTDI f 70 mg/kg bw was derived frm studies demnstrating nephrcalcinsis in rats at dietary cncentratins f 1% phsphrus. Nephrcalcinsis has been defined as calcified depsits, mainly in the frm f calcium phsphate, in tubules lcated predminantly at the crticmedullary junctin f the kidney. The exact apprach taken in deriving the MTDI frm this end-pint is unclear. In additin, the Cmmittee nted that there is evidence that rats are particularly sensitive t mineralizatin in the kidneys resulting frm an imbalance f calcium and phsphate in the diet. Therefre, the relevance f mineralizatin in the rat kidney fr safety assessment is unclear. The available txiclgical infrmatin n phsphate salts did nt indicate that the MTDI is insufficiently health prtective. Assessment f dietary expsure Fr the evaluatin f magnesium dihydrgen diphsphate as a new fd additive intended t be used as an alternative t sdium-based acidifiers and raising agents, the Cmmittee evaluated an anticipated dietary expsure based n individual fd cnsumptin data frm the Eurpean Unin with the maximum prpsed use levels f magnesium dihydrgen diphsphate (0.1% up t 0.7% by weight in slid fd, as phsphrus) in the Cdex General Standard fr Fd Additives (GSFA) fd categries such as flurs, pasta, ndles and similar prducts, puffed prducts, bread and rlls and fine bakery wares. Based n this cnservative scenari, assuming that 100% f fd prducts wuld be manufactured and cnsumed at the maximum prpsed use levels, the Cmmittee cncluded that anticipated average dietary expsures t magnesium dihydrgen diphsphate wuld be up t apprximately 20 mg f phsphrus per kilgram f bdy weight per day fr an adult and up t 70 mg f phsphrus per kilgram f bdy weight per day fr a child. The 95th 44

51 percentiles f expsure are estimated t be up t 40 mg f phsphrus per kilgram f bdy weight per day fr an adult and up t 115 mg f phsphrus per kilgram f bdy weight per day fr a child. The main fd grups cntributing t these verall dietary expsures within all ppulatin grups were bread and rlls (7 86%), fine bakery wares (6 58%) and flurs and starches (5 98%). The dietary expsure t magnesium estimated frm the anticipated use f magnesium dihydrgen diphsphate wuld be 39% f the estimated expsure t phsphrus, based n the cntributin t mlecular weight. This crrespnds t an average dietary expsure f up t apprximately 8 mg f magnesium per kilgram f bdy weight per day fr an adult and up t 27 mg f magnesium per kilgram f bdy weight per day fr a child. The 95th percentiles f expsure are estimated t be up t 16 mg f magnesium per kilgram f bdy weight per day fr an adult and up t 45 mg f magnesium per kilgram f bdy weight per day fr a child. Evaluatin Althugh an ADI nt specified has been established fr a number f magnesium salts used as fd additives, the estimated chrnic dietary expsures t magnesium (960 mg/day fr a 60 kg adult at the 95th percentile) frm the prpsed uses f magnesium dihydrgen diphsphate are up t twice the backgrund expsures frm fd previusly nted by the Cmmittee ( mg/day) and in the regin f the minimum laxative effective dse f apprximately 1000 mg f magnesium when taken as a single dse. The estimates f dietary expsure t phsphrus frm the prpsed uses f magnesium dihydrgen diphsphate are in the regin f, r slightly exceed, the MTDI f 70 mg/kg bw fr phsphate salts, expressed as phsphrus, frm this surce alne. Thus, the MTDI is further exceeded when ther surces f phsphate in the diet are taken int accunt. The Cmmittee therefre cncluded that the prpsed use levels and fd categries result in an estimated dietary expsure t magnesium dihydrgen diphsphate that is a ptential cncern. The Cmmittee emphasized that in evaluating individual phsphate-cntaining fd additives, there is a need fr assessment f ttal dietary expsure t phsphrus. Recmmendatins The Cmmittee nted that an ADI nt specified has been allcated individually t a number f magnesium-cntaining fd additives and recmmended that ttal dietary expsure t magnesium frm fd additives and ther surces in the diet shuld be assessed. The infrmatin submitted t the Cmmittee and in the scientific literature did nt indicate that the MTDI f 70 mg/kg bw fr phsphate salts, expressed as phsphrus, is insufficiently health prtective. On the cntrary, because the basis fr its derivatin might nt be relevant t humans, it culd be verly cnservative. Therefre, there is a need t review the txiclgical basis f the MTDI fr phsphate salts expressed as phsphrus. A txiclgical mngraph was prepared. New specificatins and a Chemical and Technical Assessment fr magnesium dihydrgen diphsphate were prepared. 45

52 46 ISBN

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