Phlorizin 60-82-1 Cov Tshuaj Tswj Ntshav Qab Zib

Phlorizin(CAS Tsis yog. 60-82-1) yog dihydrochalcone flavonoid compound ib txwm tshwm sim hauv cov cag ntoo thiab txiv hmab txiv ntoo tev ntawm txiv apples (Malus domestica). Nws tau txais kev saib xyuas tseem ceeb hauv xyoo tas los no raws li cov nroj tsuag - muab cov khoom muaj txiaj ntsig hauv kev tshawb fawb txog kev tswj ntshav qabzib thiab carbohydrate metabolism. Raws li cov khoom siv ua haujlwm nrog lub qhov dej zoo -txhais tau hais tias cov txheej txheem ntawm kev ua, Phlorizin ua kom pom qhov muaj peev xwm loj heev rau cov ntawv thov hauv kev tsim cov phiaj xwm kev noj qab haus huv thiab cov ntshav qabzib sib npaug.

Feem ntau muab los ua cov dawb-rau- daj ntseg- cov hmoov daj, Phlorizin nthuav tawm cov qauv zoo sib xws thiab tsim nyog rau cov tshuaj ntsiav, ntsiav tshuaj, granules, thiab cov khoom sib xyaw metabolic. Hauv kev siv cov tswv yim, cov khoom xyaw no feem ntau muab tso rau hauv cov txheej txheem tswj cov ntshav qabzib, tswj kev nqus cov carbohydrates, thiab kev sib npaug ntawm cov metabolism. Nws kuj tseem tuaj yeem ua ke nrog cov khoom xyaw ua haujlwm xws li mulberry nplooj extract, iab melon extract, cinnamon extract, los yog alpha-lipoic acid los tsim ib tug multi-mechanism plant-raws li ntshav qabzib txhawb system.

PS: Nplooj ntawv no tsom mus rau lubcov ntaub ntawv thov cov khoom.

Rau qhovProduct Technical Data Sheet, thov nias90% Phlorizin Powder HPLC Test Cov ntaub ntawv.

Rau Sample & Supply Chain Solutions, thov niasKua Extract Phlorizin Hoobkas Qauv.

Phlorizin qhov chaw nyob hauv thaj chaw ntawm kev tswj glycemic tuaj yeem raug suav hais tias yog: "Qhov kev pioneering thiab benchmark ntuj SGLT inhibitor rau kev tswj ntshav qabzib." Qhov kev tso npe no yog hauv paus hauv kev ntsuam xyuas thoob plaws peb qhov loj:

Thawj Dimension: Pioneering Scientific Discovery

Phlorizin sawv ua thawj qhov sib xyaw ua ke hauv keeb kwm tau txheeb xyuas kom muaj sodium -glucose cotransporter (SGLT) inhibitory kev ua haujlwm. Los ntawm kev xav txog kev tsim kho tshuaj, Phlorizin sawv ua "cov hmoov txhuas" rau tag nrho SGLT inhibitor tshuaj tsev neeg. Cov qauv tsim molecular ntawm tam sim no tau siv dav siv SGLT2 inhibitors, xws li dapagliflozin, empagliflozin, thiab canagliflozin, txhua tus tau txais kev tshoov siab los ntawm kev kho kom zoo ntawm Phlorizin tus qauv.

Thib Ob Dimension: Qhov Zoo Tshaj Plaws hauv Mechanism of Action

Phlorizin tus nqi tseem ceeb hauv kev tswj glycemic yog nyob hauv nws ob lub hom phiaj - cov khoom inhibitory. Cov ntaub ntawv tshawb fawb qhia tias cov hauv paus bark glycoside nthuav tawm kwv yees li ib nrab ntawm -qhov siab tshaj plaws inhibitory concentration (IC₅₀) ntawm 65 nM rau tib neeg SGLT2 thiab 400 nM rau SGLT1, ua qauv qhia kwv yees li rau qhov kev xaiv rau SGLT2 tshaj SGLT1. Cov tshuaj siv tshuaj no ua rau phlorizin ib txhij lub hom phiaj ntawm SGLT2 transporter hauv lub raum proximal tubules thiab SGLT1 transporter nyob rau hauv plab hnyuv mucosa, exerting synergistic hypoglycemic teebmeem los ntawm inhibiting ob qho tib si qabzib absorption thiab reabsorption txoj kev. Piv rau hluavtaws SGLT2 inhibitors, phlorizin, raws li cov nroj tsuag ntuj extract, muaj cov hauv qab no sib txawv kev sib tw zoo:

• Ua ntej, ntau -cov ntsiab lus sib xyaw ua ke. Cov nroj tsuag rho tawm feem ntau muaj ntau yam zoo sib xws cov khoom siv, uas tuaj yeem ua rau muaj kev sib koom ua ke, ua rau muaj txiaj ntsig zoo rau kev noj qab haus huv ntau dua li ib leeg ib leeg. Phlorizin extracts feem ntau kuj muaj cov kab ntawm cov derivatives xws li phloretin, uas zoo ib yam muaj qee yam kev ua ub no.
• Thib ob, siab txais neeg siv khoom. Nyob rau hauv ib lub sijhawm ntawm kev nco qab txog kev noj qab haus huv, "natural origin" tau dhau los ua qhov tseem ceeb cuam tshuam rau cov neeg siv khoom kev txiav txim siab. Phlorizin, muab rho tawm los ntawm cov chaw cog qoob loo xws li cov txiv ntoo tawv ntoo, ua raws li cov neeg siv khoom xav tau rau "natural" thiab "cog-raws li" cov khoom.

Thib 3 Dimension: Kev Lag Luam Kev Lag Luam thiab Kev Txhim Kho Kev Lag Luam

Kev lag luam thoob ntiaj teb kev tswj cov ntshav qabzib txuas ntxiv nthuav dav, tau tsav los ntawm cov xwm txheej suav nrog: kev pheej hmoo ntawm kev mob ntshav qab zib thoob ntiaj teb, kev ua ntej - cov neeg mob ntshav qab zib, thiab kev paub txog kev noj qab haus huv ntau ntxiv ua rau muaj kev xav tau kev tiv thaiv kev noj qab haus huv. Raws li International Diabetes Federation (IDF), kwv yees li 537 lab tus neeg laus thoob ntiaj teb tau mob ntshav qab zib xyoo 2021, kwv yees tias yuav nce mus rau 643 lab los ntawm 2030. Cov pej xeem lub hom phiaj tseem ceeb no ua rau muaj peev xwm ua lag luam tseem ceeb rau cov khoom noj khoom haus tsom rau kev tswj ntshav qabzib.

Kev piav qhia ntxaws ntawm SGLT Inhibition Mechanism

Lub tshuab molecular uas phlorizin exerts nws cov ntshav qabzib - tswj cov teebmeem feem ntau muaj kev sib tw inhibition ntawm sodium -glucose cotransporter (SGLT). SGLTs yog ib chav kawm ntawm daim nyias nyias- cov neeg thauj khoom khi lub luag haujlwm rau kev tsav cov piam thaj hauv cov cell membranes, siv cov sodium ion concentration gradient. Ob SGLT subtypes ze ze nrog kev tswj cov piam thaj tau raug txheeb xyuas hauv tib neeg lub cev:

• SGLT1: Feem ntau faib nyob rau hauv txhuam ciam teb ntawm lub plab hnyuv mucosa, nws yog lub luag haujlwm rau kev nqus cov piam thaj hauv kev noj haus. Nws kuj tau qhia nyob rau hauv S3 ntu ntawm lub raum proximal tubule, qhov twg nws koom nrog hauv qabzib reabsorption. SGLT1 pom muaj kev sib raug zoo rau cov piam thaj tab sis muaj peev xwm thauj khoom tsawg.
• SGLT2: Feem ntau faib nyob rau hauv S1 ntu ntawm lub raum proximal tubule, nws suav txog kwv yees li 90% ntawm cov kua qab zib reabsorption thiab yog lub hom phiaj tseem ceeb rau kev tswj cov ntshav qabzib homeostasis. SGLT2 nthuav tawm cov affinity qis rau cov piam thaj tab sis muaj peev xwm thauj tau ntau heev.

Phlorizin sib tw khi rau cov piam thaj- khi qhov chaw ntawm SGLT cov proteins, yog li thaiv kev thauj mus los ntawm cov piam thaj hauv transmembrane. Nws cov qauv molecular muaj cov piam thaj moiety uas zoo sib xws rau lub hnab ntim substrate lees paub ntawm SGLT, ua kom muaj kev sib tw zoo heev.

Inhibition Activity Data

Ntau qhov kev tshawb fawb tau ntsuas qhov inhibitory kev ua ntawm Phlorizin tiv thaiv SGLT1 thiab SGLT2:

Multidimensional Mechanisms ntawm Hypoglycemic Effects

Phlorizin cov kev tswj ntshav qabzib txuas ntxiv dhau SGLT inhibition kom koom nrog cov txheej txheem hauv qab no:

• Txhim kho lub raum qabzib tso tawm: Los ntawm inhibiting tubular SGLT2, phlorizin txo qis lub raum qabzib reabsorption pib, ua kom yooj yim rau cov zis tawm ntawm cov kua nplaum uas lim dej. Qhov kev txiav txim no ua haujlwm ntawm nws tus kheej ntawm kev tso cov tshuaj insulin, yog li khaws cov nyhuv hypoglycemic txawm tias nyob rau hauv insulin- tiv taus cov yam ntxwv ntawm hom 2 mob ntshav qab zib.
• Kev nqus cov piam thaj hauv plab qeeb: Los ntawm inhibiting plab hnyuv SGLT1, Phlorizin qeeb qhov nqus ntawm cov piam thaj hauv cov ntshav, txo cov ntshav qabzib tom qab peaks thiab ameliorating postprandial hyperglycemia.
• Txhim kho cov tshuaj insulin rhiab heev: Tsiaj cov kev tshawb fawb qhia tias kev kho phlorizin kho hyperglycemia hauv cov nas mob ntshav qab zib thiab kho cov ntaub so ntswg peripheral insulin rhiab heev. Cov nyhuv no yuav cuam tshuam nrog ntau lub tswv yim, suav nrog txo qis glucotoxicity thiab txhim kho lipid metabolism.
• -Kev Tiv Thaiv Cell: Ntev ntev hyperglycemia ua rau muaj kev phom sij rau pancreatic -cells. Los ntawm kev txo qis cov piam thaj hauv cov ntshav, Phlorizin tsis ncaj qha txo qis qabzib toxicity-induced -cell puas, yog li txhawb nqa ntev - lub sijhawm ua haujlwm ntawm pancreatic tu.

Daim ntawv thov cheeb tsam ntawm kev noj zaub mov ntxiv

Daim ntawv thov ntawm geniposide hauv kev noj zaub mov ntxiv feem ntau tsom rau cov hauv qab no:

1. Cov khoom siv tswj ntshav qabzib

Raws li cov ntshav qabzib- tswj cov khoom xyaw, Phlorizin tuaj yeem siv rau hauv cov pawg hauv qab no:

• Ntshav Glucose Balancing Formula: Ua ke nrog lwm cov ntshav qabzib - tswj cov khoom xws li chromium, alpha-lipoic acid, thiab cinnamon extract los tsim ntau cov khoom siv tshuaj tswj ntshav qabzib.
• Cov Khoom Pab Txhawb Ntshav Qab Zib: Ua cov khoom noj khoom haus rau kev ua neej nyob ntawm cov neeg mob ntshav qab zib.
• Ua ntej-Cov Khoom Siv Kho Mob Ntshav Qab Zib: Muab kev tiv thaiv kev noj zaub mov zoo rau sub- cov neeg noj qab haus huv uas pom cov piam thaj hauv cov ntshav txawv txav tab sis tsis ua raws li cov txheej txheem kuaj ntshav qab zib.

2. Cov khoom tswj qhov hnyav

Los ntawm kev txhawb nqa urinary glucose excretion, phlorizin theoretically pab tswj qhov hnyav los ntawm kev siv zog ntxiv. Tsis pub dhau kev noj zaub mov ntxiv rau kev tswj qhov hnyav, Phlorizin tuaj yeem ua haujlwm ua cov khoom sib xyaw ua ke nrog cov khoom xws li tshuaj yej ntsuab extract, garcinia cambogia, thiab conjugated linoleic acid.

3. Antioxidant thiab Anti-Cov khoom muaj hnub nyoog

Raws li polyphenolic compound, Phlorizin nthuav tawm cov haujlwm antioxidant. Hauv cov tshuaj pleev ib ce thiab qhov ncauj kev zoo nkauj, Phlorizin tab tom tshawb nrhiav rau kev suav nrog hauv kev tiv thaiv- cov khoom tsim tawm hnub nyoog.

Cov Khoom Siv Khoom Siv

Cov ntaub ntawv ntau npaum li cas rau cov khoom noj muaj xws li ntsiav tshuaj, tshuaj ntsiav, hmoov, thiab kua. Xav txog qhov physicochemical thaj chaw ntawm Phlorizin, qhov tsim nyog ntawm txhua daim ntawv raug tshuaj xyuas raws li hauv qab no:

1. Capsules

Capsules yog daim ntawv ntau npaum li cas rau Phlorizin raw khoom, rau cov laj thawj hauv qab no:

• Taste Masking: Phlorizin muaj qee yam iab; lub plhaub capsule zoo tiv thaiv tsis kaj siab saj.
• Cov khoom tiv thaiv: Capsule shells tiv thaiv cov khoom siv los ntawm lub teeb thiab huab cua, txhim khu kev ruaj ntseg.
• Dose precision: yooj yim rau kev xa khoom noj.
• Kev txais neeg tau txais txiaj ntsig siab: Capsules sawv cev rau ib qho ntawm cov ntaub ntawv siv ntau tshaj plaws hauv kev noj zaub mov ntxiv.
• Cov lus pom zoo: Txhua lub tshuaj ntsiav uas muaj 50-200mg ntawm Phlorizin, nrog kev hloov pauv hloov tau raws li lub hom phiaj pej xeem thiab kev tsim qauv.

2. Cov ntsiav tshuaj

Cov ntsiav tshuaj muaj qhov sib npaug haum rau Phlorizin, muab cov nqi qis dua thiab ua haujlwm ntau dua.

Txawm li cas los xij, nco ntsoov: Cov txheej txheem compression tuaj yeem tsim kom muaj cua sov, xav tau kev ntsuas ntawm nws qhov cuam tshuam rau cov khoom ruaj khov. Zaj duab xis txheej yuav raug txiav txim siab los txhim kho kev ruaj ntseg thiab txhim kho cov tsos.

3. hmoov

Powder formulations pab txhawb kev hloov pauv hloov pauv thiab tuaj yeem sib xyaw nrog lwm cov khoom xyaw hmoov los tsim cov hnab ntim khoom lossis dej haus. Txawm li cas los xij, nco ntsoov: Phlorizin iab yuav cuam tshuam rau palatability; flavoring agents los yog masking compounds yuav tsum tau ntxiv. Cov hmoov yog rhiab heev rau cov av noo thiab lub teeb raug, yuav tsum tau ntau dua cov qauv ntim.

Formulation Design Recommendations

Xav txog Phlorizin cov txheej txheem ntawm kev ua thiab cov yam ntxwv ntawm bioavailability, cov hauv qab no yuav tsum tau hais hauv kev tsim qauv:

Tam sim no, kev lag luam daim ntawv thov ntawm phlorizin nyob rau hauv kev noj haus ntxiv sector tseem nyob rau hauv nws nascent theem. Kev tshawb fawb kev lag luam qhia tias phlorizin, raws li "cov khoom tsim nyog thiab ruaj khov", tam sim no raug kev txom nyem los ntawm "kev ua tsis zoo hauv kev ua lag luam" thiab "kev lees paub tsis txaus". Qhov xwm txheej no qhia txog kev ua lag luam tsis txaus ntawm ib sab, thaum tib lub sijhawm qhia txog kev lag luam loj hlob tsis muaj peev xwm ntawm lwm qhov.

Qhov tseem ceeb Competitor Comparative Analysis

1. Physicochemical stability

Raws li polyphenolic glycoside compound, phlorizin kev ruaj ntseg yog cuam tshuam los ntawm ntau yam:

• Lub teeb ruaj khov

Phlorizin qhia rhiab heev rau lub teeb raug. Kev raug ultraviolet ntev los yog pom lub teeb tuaj yeem ua rau cov duab degradation, ua rau txo cov ntsiab lus thiab xim hloov. Yog li ntawd, lub teeb - tiv thaiv kev ntsuas yuav tsum tau siv rau ob qho tib si raw khoom thiab ntim khoom tiav.

• Thermal stability

Phlorizin nthuav tawm cov txheeb ze ruaj khov ntawm qhov kub thiab txias, tab sis tej zaum yuav raug degradation los yog kev hloov pauv ntawm cov qauv hauv qab kub siab. Ntev ntev -kev ua haujlwm kub yuav tsum zam thaum tsim khoom; Nws raug pom zoo kom tswj cov txheej txheem kub hauv qab 60 degree.

• pH stability

Phlorizin tseem nyob ruaj khov nyob rau hauv acidic rau nruab nrab ib puag ncig (pH 4-7). Txawm li cas los xij, nws tau nkag mus rau hydrolysis nyob rau hauv cov xwm txheej alkaline, yielding phloretin thiab qabzib. Yog li ntawd, kev tsim qauv tsim yuav tsum zam kev sib xyaw ua ke nrog cov khoom muaj zog alkaline.

• Oxidative stability

Phlorizin molecules muaj ntau pawg phenolic hydroxyl, nthuav tawm cov khoom txo qis uas yuav raug oxidation. Cia yuav tsum airtight sealing kom cais tawm ntawm cov pa oxygen; kev txiav txim siab yuav raug muab ntxiv rau cov tshuaj antioxidants rau kev tiv thaiv.

2. Cov lus pom zoo cia

Raws li cov kev qhia tshwj xeeb uas muab los ntawm cov khoom siv raw khoom, cov kev pom zoo cia rau Phlorizin yog raws li hauv qab no:

• Kub: Khaws rau hauv qhov chaw txias, qhuav. Rau qhov ntev - khaws cia, -20℃raug pom zoo.
• Humidity: Khaws cov av noo qis dua 60%.
• Teeb pom kev zoo: Khaws kom deb ntawm lub teeb uas siv cov ntim tsaus nti lossis ntim opaque.
• Ntim: Siv cov thawv ntim khoom kaw. Aluminium foil hnab los yog ob npaug - lub hnab ntim tau pom zoo.

3. Kev tsis sib haum xeeb

Cov hauv qab no muaj peev xwm incompatibilities xav tau kev saib xyuas thaum lub sij hawm tsim formulation:

• Alkaline Cheebtsam: Tsis txhob sib xyaw ua ke nrog cov tshuaj muaj zog alkaline xws li sodium bicarbonate lossis sodium carbonate
• Hlau ions: Polyphenolic tebchaw yuav tsim complexes nrog hlau ions, muaj feem xyuam rau kev nqus
• Enzymatic Cheebtsam: Phlorizin tej zaum yuav hydrolyzed los ntawm txoj hnyuv -glucosidase; formulation tsim yuav tsum suav rau qhov no.

Peb tsis yog tsuas yog ib tus neeg muab khoom zoo ntawm - zoo Phloretin raw cov ntaub ntawv, tab sis kuj yog ib tus neeg koom tes uas ntseeg siab ntawm koj cov khoom tsim kev taug kev. Nrog xyoo ntawm kev tshwj xeeb hauv kev cog qoob loo, peb muaj peev xwm loj thiab muaj lub koob npe zoo.

Tuam txhab Milestones

Tsim los ntawm 2006, peb lub tuam txhab tshwj xeeb hauv kev tshawb fawb, kev tsim kho, thiab tsim cov khoom xyaw ntuj. Nyob rau hauv 2007, peb tau nqis peev los tsim ib lub tuam txhab niaj hnub, ywj siab tshaj 6,900 square meters, integrating R & D, ntau lawm, thiab kev tswj kom zoo nyob rau hauv ib lub ru tsev. Hauv xyoo 2008, peb tau ua tiav peb thawj ISO 9001 Kev Tswj Xyuas Kev Tswj Xyuas Kev Tswj Xyuas Zoo, uas qhia txog qib tshiab ntawm kev tswj hwm zoo. Niaj hnub no, peb tuav lub npe ntawm "National High-Tech Enterprise", muaj ntau yam kev tsim patents, thiab pab ntau pua lub npe nrov thoob ntiaj teb cov tshuaj pleev ib ce.

[Yog xav paub ntxiv txog peb txoj kev taug, thov nyem qhov no mus saib peb "Keeb kwm kev loj hlob"page]

 

 

 

 

Txiav - Ntug R&D thiab Chaw Tsim Khoom

Lub Chaw Tshawb Fawb: Peb Xi'an-raws li lub chaw ua haujlwm hauv tsev muaj cov chaw kuaj mob tshwj xeeb uas muaj cov cuab yeej tshuaj ntsuam xyuas thiab R&D, suav nrog High-Performance Liquid Chromatography (HPLC), Gas Chromatography (GC), Liquid Chromatography-Mass Spectrometry (LC-MS)), thiab F.

Kev tsim khoom ib puag ncig: Peb cov chaw tsim khoom tsim thiab tswj hwm nruj raws li GMP cov qauv, muaj plaub txoj kab ntau lawm los xyuas kom meej cov txheej txheem huv, tswj, thiab ua haujlwm zoo.

[Los tshawb nrhiav peb lub peev xwm tshiab, thov nyem qhov no mus saib peb 'R & D thiab Innovation' paj]

Stringent Quality Control System

Peb lav tias txhua pawg ntawm Phloretin tau dhau los ua qhov kev sim ua tiav.

Purity: Txiav txim siab los ntawm HPLC kev tshuaj xyuas, ua kom cov ntsiab lus Ntau dua lossis sib npaug li 90%.

Residual Solvents: Ua raws li cov lus qhia nruj me ntsis, cov kuab tshuaj residue khaws cia zoo hauv qab qhov kev nyab xeeb.

Cov Hlau Hnyav: Lead, arsenic, mercury, cadmium, thiab lwm yam hlau hnyav ua raws li cov qauv thoob ntiaj teb nruj tshaj plaws (tsawg dua lossis sib npaug li 10ppm). Cov kab mob: Tag nrho cov phaj suav tsawg dua lossis sib npaug li 1000cfu / g, poov xab thiab pwm Tsawg dua lossis sib npaug li 100cfu / g.

Daim ntawv pov thawj

Peb tuav ISO 9001 Kev Tswj Xyuas Kev Tswj Xyuas Kev Tswj Xyuas Zoo, kom ntseeg tau cov txheej txheem txheej txheem thiab cov neeg siv khoom txaus siab. Peb tuav ISO 22000, SC, Kosher, thiab Halal ntawv pov thawj, ua kom pom peb qhov chaw tsim khoom thiab cov qauv kev ua haujlwm raws li cov qauv ntsuas thoob ntiaj teb.

[Yog xav pom peb daim ntawv pov thawj tag nrho, nyem qhov no mus saib peb 'Daim ntawv pov thawj' paj]

Kev siv
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[3] A. Oku, K., Ueta et al. "T-1095, tus inhibitor ntawm lub raum Na+-glucose cotransporters, tuaj yeem muab txoj hauv kev tshiab los kho ntshav qab zib." Mob ntshav qab zib (1999).
[4] EM Wright, D. Loo et al. "Biology ntawm tib neeg sodium glucose transporters." Physiological tshuaj xyuas (2011).
[5] E. Makarova, P. Górnaś et al. "Kev mob hnyav los tiv thaiv-hyperglycemic cuam tshuam ntawm kev npaj cov txiv apples uas tsis muaj phlorizin hauv cov neeg ua haujlwm noj qab haus huv: kev tshawb fawb ua ntej." Phau ntawv Journal ntawm Science of Food and Agriculture (2015).
[6] P. Hilt, A. Schieber et al. "Kev kuaj pom phloridzin hauv strawberries (Fragaria x ananassa Duch.) los ntawm HPLC-PDA-MS/MS thiab NMR spectroscopy." Phau ntawv Journal of Agriculture thiab Food Chemistry (2003).
[7] C. Gosch, H. Halbwirth et al. "Phloridzin: biosynthesis, faib thiab physiological cuam tshuam hauv cov nroj tsuag." Phytochemistry (2010).
[8] M. Najafian, MZ Jahromi et al. "Phloridzin txo cov ntshav qabzib thiab txhim kho lipid metabolism hauv streptozotocin-induced ntshav qab zib nas." Molecular Biology Reports (2011).
[9] M. Anastassiadou, Alba Brancato et al. "Pesticide Residue Intake Model- EFSA PRIMo hloov kho 3.1." EFSA Txhawb Kev Tshaj Tawm (2019).
[10]Alba Brancato, D. Brocca et al. "Siv tus qauv EFSA Pesticide Residue Intake Model (EFSA PRIMo, hloov kho 3). EFSA Journal (2018).