Initially proposed chemical mixtures for in vivo BCF experiments (WP2)

Transcription

1 Initially proposed chemical mixtures for in vivo BCF experiments (WP2) Mixture 1 (at 2 different ph s) Primary alkyl amine Secondary alkyl amine Tertiary alkylamine Quaternary alkylamine Mixture 2 Mixture 3 Mixture 4 Primary alkyl amine (diff chain length) Secondary alkyl amine (diff chain length) Tertiary alkylamine (diff chain length) Quat (diff chain length) Sodium lauryl sulfate Sodium laureth sulfate Sodium dodecyl sulfonate C12-LAS Zwitterionic alkylsulfobetaine C12-Pyridinium C12-benalkonium dialkylamine Dicationic diamine (N-dodecyl-1,3- propanediamine) Footer Date Month

2 Revised proposal chemical mixtures for in vivo BCF experiments (WP2) Mixture 1 (at 2 different ph s) Primary alkyl amine (2 different chain lengths) Secondary alkyl amine (2 different chain lengths) Tertiary alkylamine (2 different chain lengths) Quaternary alkylamine (2 different chain lengths) Mixture 2 Mixture 3 Mixture 4 C8 EO4 Sodium lauryl sulfate C12-Pyridinium C12 EO4 Sodium laureth sulfate C12-benalkonium C12 EO8 Sodium dodecyl sulfonate dialkylamine C16 EO8 C12-LAS Dicationic diamine (N-dodecyl-1,3- propanediamine) Zwitterionic alkylsulfobetaine To cross check new BCF data against existing data from Tolls et al 2000 Footer Date Month

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4 ADDITIONAL MODELING SUPPORT FOR IN VIVO BCF STUDIES

5 ADDITIONAL MODELING SUPPORT FOR IN VIVO BCF STUDIES Phys-chem properties (K OW, K MW, pka, Δ OW, Δ MW, k B ) Organism properties (Size, body composition) Steady-state BCFs Rate Constants Test Conditions (bulk ph, T, Dissolved O 2 ) Uptake & elimination curves (i.e., dynamic model)

6 ADDITIONAL MODELING SUPPORT FOR IN VIVO BCF STUDIES 15 g fish, 5% lipid ph = 8.2 PRIMARY C10 amine

7 ADDITIONAL MODELING SUPPORT FOR IN VIVO BCF STUDIES 250g fish, 7% lipid ph = 8.2 PRIMARY C10 amine

8 ADDITIONAL MODELING SUPPORT FOR IN VIVO BCF STUDIES Among chemicals (P, S, T, C10, 12, 14, 16) 3X difference in uptake rate constant Small (15 g) vs Large (250 g) fish 2X difference in uptake rate constant QACs Uptake will be slower

9 ADDITIONAL MODELING SUPPORT FOR IN VIVO BCF STUDIES 1. Finalize test chemical selection 2. Finalize test conditions/fish 3. Generate property estimates 4. Simulate uptake kinetics 5. Provide output to SU 6. Evaluate model performance 7. Attempt to modify for QACs

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11 ECO37 leverage projects ECCC priority surfactants: K MW via COSMOmic ERASM Tissue distribution

12 ECCC calculate K MW via COSMOmic which chemicals are feasible for ECO37? 46 high priority surfactants 6 amines 3 diamines 11 quats 18 sulfate/sulfonates 4 disulfonates 1 carboxylate 27 lower priority surfactants 9 amines 3 diamines 8 quats 7 sulfate/sulfonates 4 disulfonates petroleum based: branched representatives included: COSMOmic predictions for all linear alkylamines, benzalkonium, dialkylamine, SO 3-, SO 4-, CO 2 -

13 ECCC ECCC priority surfactants: K MW via COSMOmic 1:1 Close alignment experimental vs. COSMOmic COSMOmic logk DMPC-W 3x 3x COSMOmic can include QACs COSMOmic needs more validation for anionic surfactants COSMOmic poor for ethoxylated 19 monoprotic cationic surfactants Experimental logk MW SDS & C 8-1-LAS

14 logk DMPC-w (COSMOmic) logk DMPC-w (COSMOmic) logk DMPC-w (COSMOmic) ECCC ECCC priority surfactants: K MW via COSMOmic logkdmpc-w cation logkdmpc-w anion -6 logkdmpc-w SO 3 /SO 4 logkdmpc-w neutral logd MW ph7.4 (logd* approach) -2-4 logk DMPC-w cation logk DMPC-w anion -6 logk DMPC-w SO 3 /SO 4 logk DMPC-w neutral logk MW ph7.4 (logd incl approach) -2-4 logk DMPC-w cation logk DMPC-w anion -6 logk DMPC-w SO 3 /SO 4 logk DMPC-w neutral logk MW (BIONIC MW EPI) logd * ignore contribution ionic species logd* 3.1 log units lower affinity ionic species Δ MW : ion type specific lower affinity ionic species

15 logk DMPC-w (COSMOmic) logk DMPC-w (COSMOmic) ECCC ECCC priority surfactants: K MW via COSMOmic? experiments feasible logk DMPC-w cation logk DMPC-w anion logk DMPC-w SO 3 /SO 4 logk DMPC-w neutral logk MW (BIONIC MW ACD) 10 than 6 EPI logk DMPC-w cation logk DMPC-w anion logk DMPC-w neutral logk DMPC-w dication logk DMPC-w dianion ACD/Labs seems to give more 8 realistic predictions for SO 3 /SO 4 COSMOmic similar as logp for neutrals COSMOmic excludes logp uncertainty COSMOmic can include QACs COSMOmic includes 3D-structure effects -6 mechanistically (e.g., branching, dialkylamine) COSMOmic logkadditional MW,N (from weight EPISuite of logp) evidence (WoE), + exp. feasibility

16 ERASM Tissue-water partitioning coefficients for surfactants objectives Sorption phases Membrane lipids POPC liposome: data available? Storage lipids triolein or fish oil as surrogate Proteins Albumin or protein extracted from fish? Possible test compounds Neutral surfactants C 12 EO 4 Anionic surfactants C 12 SO 4 Cationic surfactants C 12 TMAC Increasing number of carbon atoms, or SO 3-, or different EO-chain 16

17 fish oil-water instead of octanol-water stirring does not emulsify protein/liposome-water membrane dialysis easy separation + sampling sink / source fish oil Harvard Apparatus Teflon Dialyzer set 10 kda pore membrane equilibrates < 1 day TRANSIL system higher throughput for membranes clean sample vial stirring beans 17

18 Utrecht Case-study: BCF scheme In progress Surfactant type specific choices / WoE options K OW for neutral form as starting point? Include biotransformation if necessary Include Koc if necessary But, main focus on K MW,I for ionic surfactants: calculate by K OW + Δ MW or COSMOmic Membrane-water distribution coefficient (K MW,N & K MW,I ) D MW Estimate K OW,N from K MW,I? (e.g. logk OW,N ~ logk MW,I + Δ MW ) shorter analogue available / accepted? No No Yes IAM-HPLC chromatography Yes sorption to protein(s) Calculate BCF with BIONIC is experimental K MW feasible? Yes high throughput assay sufficient? No liposome dialysis or SSLM Lower tier assessment Predict K MW,I Higher tier assessment Approach K MW,I Highest tier assessment Assess K MW,I

19 ECO37 in vitro surfactant testing ERASM : tissue components (L/kg) logk sorbent-water oil BSA nonionic C12EO4 mem oil BSA cationic C12TMAC oil bsa mem mem oil oil BSA anionic C12SO4 bsa mem mem TISSUE composition: 1% membrane factor 20 20% protein (1.3 log units) RELEVANCE of albumin

20 relevance of protein albumin - chicken muscle protein Henneberger, Goss, Endo DOI: /acs.est.6b01417 various structural proteins - chicken = fish = pig Endo, Bauerfeind, Goss, DOI: /es303379y

21 milestone Planned for end of 2017 Combine newest insights + availability data in critical review on surfactant bioaccumulation assessment

22 ECO37 in vitro surfactant testing updated planning for a select set of surfactants: partition coefficients to albumin: BSA standard (bovine) trout muscle protein purified relevant for blood - QIVIVE custom prepared (EPA-Duluth?) liver S9 homogenate can be prepared at EPA-Duluth

23 ECO37 in vitro surfactant testing extra focus zwitterionic surfactants C12/C14 (pk a 2.6) quat cation, with ionizable anion spacer distance C12 C10/C12/C14 (pk a 4.5) quat cation, ionic anion spacer distance C10/C alkylamine-n-oxide

24 ECO37 in vitro surfactant testing extra cationic surfactants tallow-analogue is ECCC high priority: CAS: Morpholinium C16-analogue is ECCC low priority product: CAS: C12-alkyldiamine C12-alkyltriamine extreme testing COSMOmic

25 ECO37 in vitro surfactant testing dianion - extra anionic surfactants ECCC high priority product: CAS: COSMOmic logk MW = 5.7 dinonyl-naphthalenesulfonates - - ECCC high priority product: CAS: COSMOmic logk MW ~ ECCC high priority product: CAS: COSMOmic logk MW ~