The Fates of Endocrine Disruptors in Consumer Products: Bisphenol A

Prepared by Dr. Matthew A. DeNardo for the One Health One Planet Conference on March 8, 2018 at Phipps Conservatory The Fates of Endocrine Disruptors in Consumer Products: Bisphenol A

Prepared by Dr. Matthew A. DeNardo for the One Health One Planet Conference on March 8, 2017 at Phipps Conservatory The Fates of Endocrine Disruptors in Consumer Products: Bisphenol A

Prepared by Dr. Matthew A. DeNardo for the One Health One Planet Conference on March 8, 2017 at Phipps Conservatory A multidisciplinary investigation of the technical and environmental performances of TAML/peroxide elimination of Bisphenol A compounds from water. Green Chemistry doi:10.1039/C7GC01415E

Prepared by Dr. Matthew A. DeNardo for the One Health One Planet Conference on March 8, 2017 at Phipps Conservatory HO OH

Bisphenol A HO OH

Phenol Bisphenol A HO OH

Phenol Phenol Bisphenol A A

HO OH

Phenol Phenol Bisphenol A A

HO OH

Phenol Phenol Bisphenol A

+ O H 1 + 2 + H2O HO Δ HO OH Acetone Phenol Bisphenol A Water A

HO OH

Phenol Phenol Bisphenol A

+ O H 1 + 2 + H2O HO Δ HO OH Acetone Phenol Bisphenol A Water

+ A

HO OH

Phenol Phenol Bisphenol A

+ O H 1 + 2 + H2O HO Δ HO OH Acetone Phenol Bisphenol A Water

Bhandari 2015 HO OH Bisphenol A HO OH Bisphenol A HO OH Bisphenol A HO OH Bisphenol A O Cl Cl NaOH (Phosgene) (Sodium o C Hydroxide)O, 25 H 2

HO OH Bisphenol A O Cl O O Cl NaOH (Phosgene) O O O O (Sodium o C Hydroxide)O, 25 Bisphenol A Polycarbonate H 2

HO OH Bisphenol A

Conseil 2015 O Cl O O Cl NaOH (Phosgene) O O O O (Sodium o C Hydroxide)O, 25 Bisphenol A Polycarbonate H 2

HO OH Bisphenol A

Conseil 2015 O Cl O O Cl NaOH (Phosgene) O O O O (Sodium o C Hydroxide)O, 25 Bisphenol A Polycarbonate H 2

HO OH Bisphenol A

Conseil 2015 O Cl O O Cl NaOH (Phosgene) O O O O (Sodium o C Hydroxide)O, 25 Bisphenol A Polycarbonate H 2

O HO OH Bisphenol A Cl Epichlorohydrin Conseil 2015 O Cl O O Cl NaOH (Phosgene) O O O O (Sodium o C Hydroxide)O, 25 Bisphenol A Polycarbonate H 2

O HO OH Bisphenol A Cl Epichlorohydrin Conseil 2015

O O

O O Bisphenol A Diglycidyl Ether (BADGE) O Cl O O Cl NaOH (Phosgene) O O O O (Sodium o C Hydroxide)O, 25 Bisphenol A Polycarbonate H 2

O HO OH Bisphenol A Cl Epichlorohydrin Conseil 2015

O O

O O Bisphenol A Diglycidyl Ether (BADGE) O Cl O O Cl NaOH (Phosgene) O O O O (Sodium o C Hydroxide)O, 25 Bisphenol A Polycarbonate H 2

O HO OH Bisphenol A Cl Epichlorohydrin Conseil 2015

O O

O O Bisphenol A Diglycidyl Ether (BADGE)

Bhandari 2015 O Cl O O Cl NaOH (Phosgene) O O O O (Sodium o C Hydroxide)O, 25 Bisphenol A Polycarbonate H 2

O HO OH Bisphenol A Cl Epichlorohydrin Conseil 2015

O O

O O Bisphenol A Diglycidyl Ether (BADGE)

Bhandari 2015 O Cl O O Cl NaOH (Phosgene) O O O O (Sodium o C Hydroxide)O, 25 Bisphenol A Polycarbonate H 2

O HO OH Bisphenol A Cl Epichlorohydrin Conseil 2015

O O

O O Bisphenol A Diglycidyl Ether (BADGE)

Bhandari 2015 O Cl O O Cl NaOH (Phosgene) O O O O (Sodium o C Hydroxide)O, 25 Bisphenol A Polycarbonate H 2

O HO OH Bisphenol A Cl Epichlorohydrin Conseil 2015

O O

O O Bisphenol A Diglycidyl Ether (BADGE)

Bhandari 2015 What Are the Consequences of The Mass Production of BPA? Production Production Production Production Production Production Production Production Production

• Contamination of Air Production

• Contamination of Air • Contamination of Water What Are the Concentrations of BPA in Industrial Effluents? BPA Detected in Industrial Effluents Effluent Country Year Range Mean Ref. -1 -1 Production Use (µg L ) (µg L ) Chemical Industry Austria 2000 2.5–50 18 Furhacker 2000 Paper Production Austria 2000 28–72 41 DisposalDisposalFurhacker 2000 • Contaminated Leachate and Recycling • Contaminated Air Streams Paper Production Japan 2002 0.2–370 • Combustion?59 Fukazawa 2002 • Contaminatedand Recycling Air Streams • ContaminatedPlastics Wastewaters Nigeria• Contaminated2015 Foods108– 130 Mackinwa 2015 • Contaminated Beverages Manufacturing • Contaminated Products163 and Recycling Recycling • Contaminated Recycled Cellulose Fiber • Contaminated Air Streams and Waters BPA Detected in Industrial Effluents Effluent Country Year Range Mean Ref. -1 -1 Production Use (µg L ) (µg L ) Chemical Industry Austria 2000 2.5–50 18 Furhacker 2000 Paper Production Austria 2000 28–72 41 DisposalDisposalFurhacker 2000 • Contaminated Leachate and Recycling • Contaminated Air Streams Paper Production Japan 2002 0.2–370 • Combustion?59 Fukazawa 2002 • Contaminatedand Recycling Air Streams • ContaminatedPlastics Wastewaters Nigeria• Contaminated2015 Foods108– 130 Mackinwa 2015 • Contaminated Beverages Manufacturing • Contaminated Products163 and Recycling Recycling • Contaminated Recycled Cellulose Fiber • Contaminated Air Streams and Waters BPA Detected in Industrial Effluents Effluent Country Year Range Mean Ref. -1 -1 Production Use (µg L ) (µg L ) Chemical Industry Austria 2000 2.5–50 18 Furhacker 2000 Paper Production Austria 2000 28–72 41 DisposalDisposalFurhacker 2000 • Contaminated Leachate and Recycling • Contaminated Air Streams Paper Production Japan 2002 0.2–370 • Combustion?59 Fukazawa 2002 • Contaminatedand Recycling Air Streams • ContaminatedPlastics Wastewaters Nigeria• Contaminated2015 Foods108– 130 Mackinwa 2015 • Contaminated Beverages Manufacturing • Contaminated Products163 and Recycling Recycling • Contaminated Recycled Cellulose Fiber • Contaminated Air Streams and Waters BPA Detected in Industrial Effluents Effluent Country Year Range Mean Ref. -1 -1 Production Use (µg L ) (µg L ) Chemical Industry Austria 2000 2.5–50 18 Furhacker 2000 Paper Production Austria 2000 28–72 41 DisposalDisposalFurhacker 2000 • Contaminated Leachate and Recycling • Contaminated Air Streams Paper Production Japan 2002 0.2–370 • Combustion?59 Fukazawa 2002 • Contaminatedand Recycling Air Streams • ContaminatedPlastics Wastewaters Nigeria• Contaminated2015 Foods108– 130 Mackinwa 2015 • Contaminated Beverages Manufacturing • Contaminated Products163 and Recycling Recycling • Contaminated Recycled Cellulose Fiber • Contaminated Air Streams and Waters BPA Detected in Industrial Effluents Effluent Country Year Range Mean Ref. -1 -1 Production Use (µg L ) (µg L ) Chemical Industry Austria 2000 2.5–50 18 Furhacker 2000 Paper Production Austria 2000 28–72 41 DisposalDisposalFurhacker 2000 • Contaminated Leachate and Recycling • Contaminated Air Streams Paper Production Japan 2002 0.2–370 • Combustion?59 Fukazawa 2002 • Contaminatedand Recycling Air Streams • ContaminatedPlastics Wastewaters Nigeria• Contaminated2015 Foods108– 130 Mackinwa 2015 • Contaminated Beverages Manufacturing • Contaminated Products163 and Recycling Recycling • Contaminated Recycled Cellulose Fiber • Contaminated Air Streams and Waters BPA Detected in Industrial Effluents Effluent Country Year Range Mean Ref. -1 -1 Production Use (µg L ) (µg L ) Chemical Industry Austria 2000 2.5–50 18 Furhacker 2000 Paper Production Austria 2000 28–72 41 DisposalDisposalFurhacker 2000 • Contaminated Leachate and Recycling • Contaminated Air Streams Paper Production Japan 2002 0.2–370 • Combustion?59 Fukazawa 2002 • Contaminatedand Recycling Air Streams • ContaminatedPlastics Wastewaters Nigeria• Contaminated2015 Foods108– 130 Mackinwa 2015 • Contaminated Beverages Manufacturing • Contaminated Products163 and Recycling Recycling • Contaminated Recycled Cellulose Fiber • Contaminated Air Streams and Waters Luo 2014 Lee 2004 NeBRA 2007 Luo 2014 Lee 2004 NeBRA 2007 Luo 2014 Lee 2004 NeBRA 2007 What Are the Concentrations of BPA in Municipal Influents? Concentrations of BPA Detected in Municipal Wastewater Treatment Plant Influents Production Use Country Year Range (µg L-1) Mean Ref. -1 DisposalDisposal (µg •L Contaminated) Leachate • Contaminated Air Streams Austria 2000 10–37 21• Combustion?Furhacker

• Contaminated Air Streams 2000 • Contaminated Wastewaters • Contaminated Foods Canada 2004 • 0.16Contaminated–28.1 Beverages — Lee 2004 • Contaminated Products Germany 2008 <0.02–12.2 3.67 RecyclingHohne 2008 • Contaminated Recycled Cellulose Fiber • Contaminated Air Streams and Waters Luo 2014 Lee 2004 NeBRA 2007 Luo 2014 Lee 2004 NeBRA 2007 Luo 2014 Lee 2004 NeBRA 2007 Luo 2014 Lee 2004 NeBRA 2007 Luo 2014 Lee 2004 NeBRA 2007 Luo 2014 Lee 2004 NeBRA 2007 Luo 2014 Lee 2004 NeBRA 2007 What Are the Concentrations of BPA in WWTP Effluents? Concentrations of BPA Detected in WWTP Effluents Country Year Range (µg L-1) Mean Ref. (µg L-1) Austria 2000 <0.5–2.5 1.5 Furhacker Canada 2004 0.01–17.3 — Lee 2004 EU 2008 3.13–45 — EU 2008 EU 2008 <0.02–7.6 0.52 Hohne US 1999 <0.01–2.7 — Barber 1999 Concentrations of BPA Detected in WWTP Effluents Country Year Range (µg L-1) Mean Ref. (µg L-1) Austria 2000 <0.5–2.5 1.5 Furhacker Canada 2004 0.01–17.3 — Lee 2004 EU 2008 3.13–45 — EU 2008 EU 2008 <0.02–7.6 0.52 Hohne US 1999 <0.01–2.7 — Barber 1999 Concentrations of BPA Detected in WWTP Effluents Country Year Range (µg L-1) Mean Ref. (µg L-1) Austria 2000 <0.5–2.5 1.5 Furhacker Canada 2004 0.01–17.3 — Lee 2004 EU 2008 3.13–45 — EU 2008 EU 2008 <0.02–7.6 0.52 Hohne US 1999 <0.01–2.7 — Barber 1999 Concentrations of BPA Detected in WWTP Effluents Country Year Range (µg L-1) Mean Ref. (µg L-1) Austria 2000 <0.5–2.5 1.5 Furhacker Canada 2004 0.01–17.3 — Lee 2004 EU 2008 3.13–45 — EU 2008 EU 2008 <0.02–7.6 0.52 Hohne US 1999 <0.01–2.7 — Barber 1999 Luo 2014 Lee 2004 NeBRA 2007 Luo 2014 Lee 2004 NeBRA 2007 Luo 2014 Lee 2004 NeBRA 2007 Luo 2014 Lee 2004 NeBRA 2007 What Are the Concentrations of BPA in Surface Waters? Surface Water Concentrations of BPA Country Watershed Max Median / Ref. (µg L-1) Avg / Range (µg L-1) US Multiple 12 Med: 0.14 Kolpin 2002 Brazil Atibaia 13 Avg: 4.6 Montagner China Dongguan 56 Avg: 6.5 Tang 2012 Japan Nagara 22.2 Avg: 4.8 Funakoshi Portugal Multiple — Range: Azevedo 0.07–4 2001 Surface Water Concentrations of BPA Country Watershed Max Median / Ref. (µg L-1) Avg / Range (µg L-1) US Multiple 12 Med: 0.14 Kolpin 2002 Brazil Atibaia 13 Avg: 4.6 Montagner China Dongguan 56 Avg: 6.5 Tang 2012 Japan Nagara 22.2 Avg: 4.8 Funakoshi Portugal Multiple — Range: Azevedo 0.07–4 2001 Surface Water Concentrations of BPA Country Watershed Max Median / Ref. (µg L-1) Avg / Range (µg L-1) US Multiple 12 Med: 0.14 Kolpin 2002 Brazil Atibaia 13 Avg: 4.6 Montagner China Dongguan 56 Avg: 6.5 Tang 2012 Japan Nagara 22.2 Avg: 4.8 Funakoshi Portugal Multiple — Range: Azevedo 0.07–4 2001 Surface Water Concentrations of BPA Country Watershed Max Median / Ref. (µg L-1) Avg / Range (µg L-1) US Multiple 12 Med: 0.14 Kolpin 2002 Brazil Atibaia 13 Avg: 4.6 Montagner China Dongguan 56 Avg: 6.5 Tang 2012 Japan Nagara 22.2 Avg: 4.8 Funakoshi Portugal Multiple — Range: Azevedo 0.07–4 2001 Surface Water Concentrations of BPA Country Watershed Max Median / Ref. (µg L-1) Avg / Range (µg L-1) US Multiple 12 Med: 0.14 Kolpin 2002 Brazil Atibaia 13 Avg: 4.6 Montagner China Dongguan 56 Avg: 6.5 Tang 2012 Japan Nagara 22.2 Avg: 4.8 Funakoshi Portugal Multiple — Range: Azevedo 0.07–4 2001 What Are the Effects of Fish Exposures to These BPA Concentrations? Embryonic and Early- Life Staged Fish

Metcalfe 2001 Saili 2012 Lee 2012 Wang 2010 Chung 2011 Lam 2011 Gibert 2011 Embryonic and Early- Life Staged Fish • Alteration of Gene Expression

Metcalfe 2001 Saili 2012 Lee 2012 Wang 2010 Chung 2011 Lam 2011 Gibert 2011 Embryonic and Early- Life Staged Fish • Alteration of Gene Expression • Reduction of Heart Rate Metcalfe 2001 Saili 2012 Lee 2012 Wang 2010 Chung 2011 Lam 2011 Gibert 2011 Embryonic and Early- Life Staged Fish • Alteration of Gene Expression • Reduction of Heart Rate • Decreased Eye Pigmentation Metcalfe 2001 Density Saili 2012 Lee 2012 Wang 2010 Chung 2011 Lam 2011 Gibert 2011 Embryonic and Early- Life Staged Fish • Alteration of Gene Expression • Reduction of Heart Rate • Decreased Eye Pigmentation Metcalfe 2001 Density Saili 2012 • Accelerated Development Lee 2012 Wang 2010 Chung 2011 Lam 2011 Gibert 2011 Embryonic and Early- Life Staged Fish • Alteration of Gene Expression • Reduction of Heart Rate • Decreased Eye Pigmentation Metcalfe 2001 Density Saili 2012 • Accelerated Development Lee 2012 • Delayed Hatching of Embryos Wang 2010 Chung 2011 Lam 2011 Gibert 2011 Embryonic and Early- Life Staged Fish • Alteration of Gene Expression • Reduction of Heart Rate • Decreased Eye Pigmentation Metcalfe 2001 Density Saili 2012 • Accelerated Development Lee 2012 • Delayed Hatching of Embryos Wang 2010 • Hyperactivity in Larva Chung 2011 Lam 2011 Gibert 2011 Embryonic and Early- Life Staged Fish • Alteration of Gene Expression • Reduction of Heart Rate • Decreased Eye Pigmentation Metcalfe 2001 Density Saili 2012 • Accelerated Development Lee 2012 • Delayed Hatching of Embryos Wang 2010 • Hyperactivity in Larva Chung 2011 • Testis-Ova in Males Lam 2011 Gibert 2011 Embryonic and Early- Life Staged Fish • Alteration of Gene Expression • Reduction of Heart Rate • Decreased Eye Pigmentation Metcalfe 2001 Density Saili 2012 • Accelerated Development Lee 2012 • Delayed Hatching of Embryos Wang 2010 • Hyperactivity in Larva Chung 2011 • Testis-Ova in Males Lam 2011 • Learning Deficits in Adult Males Gibert 2011 Adult Fish Crain 2007 Sohoni 2001 Lahnsteiner 2005 Hatef 2012 Hayashi 2007 Villenueve 2012 Liu 2012 Qin 2013 Adult Fish • Alteration of gene expression Crain 2007 including stimulation of Sohoni 2001 vitellogenin synthesis in males Lahnsteiner 2005 (vtg is a precursor of egg yolk Hatef 2012 protein and is a biomarker for Hayashi 2007 exposure to oestrogens) Villenueve 2012 Liu 2012 Qin 2013 Adult Fish • Alteration of gene expression Crain 2007 including stimulation of Sohoni 2001 vitellogenin synthesis in males Lahnsteiner 2005 (vtg is a precursor of egg yolk Hatef 2012 protein and is a biomarker for Hayashi 2007 exposure to oestrogens) Villenueve 2012 • Reduction in male sperm quality Liu 2012 Qin 2013 Adult Fish • Alteration of gene expression Crain 2007 including stimulation of Sohoni 2001 vitellogenin synthesis in males Lahnsteiner 2005 (vtg is a precursor of egg yolk Hatef 2012 protein and is a biomarker for Hayashi 2007 exposure to oestrogens) Villenueve 2012 • Reduction in male sperm quality Liu 2012 • Delayed or no ovulation in Qin 2013 females Luo 2014 Lee 2004 NeBRA 2007 Luo 2014 Lee 2004 NeBRA 2007 Luo 2014 Lee 2004 NeBRA 2007 Luo 2014 Lee 2004 NeBRA 2007 Luo 2014 Lee 2004 NeBRA 2007 Luo 2014 Lee 2004 NeBRA 2007 Luo 2014 Lee 2004 NeBRA 2007 Luo 2014 Lee 2004 NeBRA 2007 Luo 2014 Lee 2004 NeBRA 2007 Luo 2014 Lee 2004 NeBRA 2007 Luo 2014 Lee 2004 NeBRA 2007 Luo 2014 Lee 2004 NeBRA 2007 Luo 2014 Lee 2004 NeBRA 2007 Luo 2014 Lee 2004 NeBRA 2007 Production

• Contamination of Air • Contamination of Water Production

• Contamination of Air • Contamination of Water • Contamination of Soil Production

Use

• Contamination of Air • Contamination of Water • Contamination of Soil Production

Use

• Contamination of Air • Contamination of Water • Contamination of Soil Production

Use

• Contamination of Air • Contamination of Water • Contamination of Soil Production

Use

• Contamination of Air • Contamination of Water • Contamination of Foods • Contamination of Soil Canned Goods: the liquid phases of canned ar2chokes, green beans, corn, mushrooms, peas, and mixed vegetables, the homogenized liquid and solid contents of canned fruit products including coconut cream, coconut milk, lychees, mangoes, olives, peaches, light pineapples, tomatoes, tomato juice and tomato paste, and fruit pieces and cocktails, the homogenized liquid and solid contents of canned vegetable products including asparagus, baked beans in tomato sauce, green beans, beetroot, carrots, corn, mount elephants, mushrooms, peas, jalapeño peppers, potatoes, and goulash, the homogenized liquid and solid contents of canned soups including cream of chicken, chicken and white wine, potato, tomato, and Tom Kha, the homogenized liquid and solid contents of canned sauces of many varie2es including demi-glace, fond de volaille, gra2n, meat, tomato, and white, the homogenized liquid and solid contents of canned pastas in tomato sauce, the homogenized liquid and solid contents of canned seafood including Japanese sand lance, mackerel, pilchards in tomato sauce, salmon, sardine, sardine in tomato sauce shrimp, squid, tuna, and fish and vegetable mixtures, the homogenized liquid and solid contents of canned meats including chicken, corned beef, fish balls, ham, hot dogs, and pork, the homogenized liquid and solid contents of canned quail eggs, the homogenized liquid and solid contents of desserts including evaporated milk and creamed rice, the solids of canned crushed tomatoes, young peas, corn, haricot beans, red kidney beans, len2ls, mushrooms, tuna in oil, and sardines in oil, mackerel filet in tomato sauce, and canned dinners. Brotons 1995 Braunrath 2005 Thomson 2005 Yonekubo 2008 Goodson 2002 Grumetto 2008 Rastkari 2011 Mungia-Lopez 2002 Maragou 2006 Yoshida 2001 Sakhi 2014 Canned Goods: the liquid phases of canned ar2chokes, green beans, corn, mushrooms, peas, and mixed vegetables, the homogenized liquid and solid contents of canned fruit products including coconut cream, coconut milk, lychees, mangoes, olives, peaches, light pineapples, tomatoes, tomato juice and tomato paste, and fruit pieces and cocktails, the homogenized liquid and solid contents of canned vegetable products including asparagus, baked beans in tomato sauce, green beans, beetroot, carrots, corn, mount elephants, mushrooms, peas, jalapeño peppers, potatoes, and goulash, the homogenized liquid and solid contents of canned soups including cream of chicken, chicken and white wine, potato, tomato, and Tom Kha, the homogenized liquid and solid contents of canned sauces of many varie2es including demi-glace, fond de volaille, gra2n, meat, tomato, and white, the homogenized liquid and solid contents of canned pastas in tomato sauce, the homogenized liquid and solid contents of canned seafood including Japanese sand lance, mackerel, pilchards in tomato sauce, salmon, sardine, sardine in tomato sauce shrimp, squid, tuna, and fish and vegetable mixtures, the homogenized liquid and solid contents of canned meats including chicken, corned beef, fish balls, ham, hot dogs, and pork, the homogenized liquid and solid contents of canned quail eggs, the homogenized liquid and solid contents of desserts including evaporated milk and creamed rice, the solids of canned crushed tomatoes, young peas, corn, haricot beans, red kidney beans, len2ls, mushrooms, tuna in oil, and sardines in oil, mackerel filet in tomato sauce, and canned dinners. Cox 2017 Canned Goods: the liquid phases of canned ar2chokes, green beans, corn, mushrooms, peas, and mixed vegetables, the homogenized liquid and solid contents of canned fruit products including coconut cream, coconut milk, lychees, mangoes, olives, peaches, light pineapples, tomatoes, tomato juice and tomato paste, and fruit pieces and cocktails, the homogenized liquid and solid contents of canned vegetable products including asparagus, baked beans in tomato sauce, green beans, beetroot, carrots, corn, mount elephants, mushrooms, peas, jalapeño peppers, potatoes, and goulash, the homogenized liquid and solid contents of canned soups including cream of chicken, chicken and white wine, potato, tomato, and Tom Kha, the homogenized liquid and solid contents of canned sauces of many varie2es including demi-glace, fond de volaille, gra2n, meat, tomato, and white, the homogenized liquid and solid contents of canned pastas in tomato sauce, the homogenized liquid and solid contents of canned seafood including Japanese sand lance, mackerel, pilchards in tomato sauce, salmon, sardine, sardine in tomato sauce shrimp, squid, tuna, and fish and vegetable mixtures, the homogenized liquid and solid contents of canned meats including chicken, corned beef, fish balls, ham, hot dogs, and pork, the homogenized liquid and solid contents of canned quail eggs, the homogenized liquid and solid contents of desserts including evaporated milk and creamed rice, the solids of canned crushed tomatoes, young peas, corn, haricot beans, red kidney beans, len2ls, mushrooms, tuna in oil, and sardines in oil, mackerel filet in tomato sauce, and canned dinners. Cox 2017 Unexpected Foods

Basheer 2004, Sakhi 2014 Vivacqua 2003, Cao 2009 Unexpected Foods • baby food products in glass jars with metal lids

Basheer 2004, Sakhi 2014 Vivacqua 2003, Cao 2009 Unexpected Foods • baby food products in glass jars with metal lids • whole eggs packaged in cardboard Basheer 2004, Sakhi 2014 Vivacqua 2003, Cao 2009 Unexpected Foods Randomly Selected • baby food Fresh Foods products in glass jars with metal lids • whole eggs packaged in cardboard Basheer 2004, Sakhi 2014 Vivacqua 2003, Cao 2009 Unexpected Foods Randomly Selected • baby food Fresh Foods products in glass • fresh cherries jars with metal lids • whole eggs packaged in cardboard Basheer 2004, Sakhi 2014 Vivacqua 2003, Cao 2009 Unexpected Foods Randomly Selected • baby food Fresh Foods products in glass • fresh cherries jars with metal • courgettes lids • whole eggs packaged in cardboard Basheer 2004, Sakhi 2014 Vivacqua 2003, Cao 2009 Unexpected Foods Randomly Selected • baby food Fresh Foods products in glass • fresh cherries jars with metal • courge8es lids • eggplants • whole eggs packaged in cardboard Basheer 2004, Sakhi 2014 Vivacqua 2003, Cao 2009 Unexpected Foods Randomly Selected • baby food Fresh Foods products in glass • fresh cherries jars with metal • courgettes lids • eggplants • whole eggs packaged in • medlars cardboard Basheer 2004, Sakhi 2014 Vivacqua 2003, Cao 2009 Unexpected Foods Randomly Selected • baby food Fresh Foods products in glass • fresh cherries jars with metal • courgettes lids • eggplants • whole eggs packaged in • medlars cardboard • oranges Basheer 2004, Sakhi 2014 Vivacqua 2003, Cao 2009 Unexpected Foods Randomly Selected • baby food Fresh Foods products in glass • fresh cherries jars with metal • courgettes lids • eggplants • whole eggs packaged in • medlars cardboard • oranges Basheer 2004, Sakhi 2014 Vivacqua 2003, Cao 2009 • peaches Unexpected Foods Randomly Selected • baby food Fresh Foods products in glass • fresh cherries jars with metal • courge8es lids • eggplants • whole eggs packaged in • medlars cardboard • oranges Basheer 2004, Sakhi 2014 Vivacqua 2003, Cao 2009 • peaches • peppers Unexpected Foods Randomly Selected • baby food Fresh Foods products in glass • fresh cherries jars with metal • courgettes lids • eggplants • whole eggs packaged in • medlars cardboard • oranges Basheer 2004, Sakhi 2014 Vivacqua 2003, Cao 2009 • peaches • peppers • tomatoes Unexpected Foods Randomly Selected Seafoods • baby food Fresh Foods products in glass • fresh cherries jars with metal • courgettes lids • eggplants • whole eggs packaged in • medlars cardboard • oranges Basheer 2004, Sakhi 2014 Vivacqua 2003, Cao 2009 • peaches • peppers • tomatoes Unexpected Foods Randomly Selected Seafoods • baby food Fresh Foods • white clams products in glass • fresh cherries jars with metal • courgettes lids • eggplants • whole eggs packaged in • medlars cardboard • oranges Basheer 2004, Sakhi 2014 Vivacqua 2003, Cao 2009 • peaches • peppers • tomatoes Unexpected Foods Randomly Selected Seafoods • baby food Fresh Foods • white clams products in glass • fresh cherries • crabs jars with metal • courge8es lids • eggplants • whole eggs packaged in • medlars cardboard • oranges Basheer 2004, Sakhi 2014 Vivacqua 2003, Cao 2009 • peaches • peppers • tomatoes Unexpected Foods Randomly Selected Seafoods • baby food Fresh Foods • white clams products in glass • fresh cherries • crabs jars with metal • courgettes lids • blood cockles • eggplants • whole eggs packaged in • medlars cardboard • oranges Basheer 2004, Sakhi 2014 Vivacqua 2003, Cao 2009 • peaches • peppers • tomatoes Unexpected Foods Randomly Selected Seafoods • baby food Fresh Foods • white clams products in glass • fresh cherries • crabs jars with metal • courgettes lids • blood cockles • eggplants • whole eggs • fish packaged in • medlars cardboard • oranges Basheer 2004, Sakhi 2014 Vivacqua 2003, Cao 2009 • peaches • peppers • tomatoes Unexpected Foods Randomly Selected Seafoods • baby food Fresh Foods • white clams products in glass • fresh cherries • crabs jars with metal • courgettes lids • blood cockles • eggplants • whole eggs • fish • medlars packaged in • prawn cardboard • oranges Basheer 2004, Sakhi 2014 Vivacqua 2003, Cao 2009 • peaches • peppers • tomatoes Unexpected Foods Randomly Selected Seafoods • baby food Fresh Foods • white clams products in glass • fresh cherries • crabs jars with metal • courge8es lids • blood cockles • eggplants • whole eggs • ﬁsh • medlars packaged in • prawn cardboard • oranges Basheer 2004, Sakhi 2014 • squid Vivacqua 2003, Cao 2009 • peaches • peppers • tomatoes Produc*on

Use

• Contamination of Air • Contamination of Water • Contamina0on of Foods • Contamination of Soil Production

Use

• Contamina(on of Air • Contamina(on of Water • Contamination of Foods • Contamina(on of Soil Produc*on

Use

• Contamination of Air • Contamination of Water • Contamina0on of Foods • Contamination of Soil • Contamina0on of Beverages Canned Beverages

Tateoka 2014, Cao 2009, Sakhi 2014, Braunrath 2005, Biles 1997, Ackerman 2010, Takao 1999, Kang 2002 Cao 2008, Kuo 2004 Canned Beverages • canned beers

Tateoka 2014, Cao 2009, Sakhi 2014, Braunrath 2005, Biles 1997, Ackerman 2010, Takao 1999, Kang 2002 Cao 2008, Kuo 2004 Canned Beverages • canned beers • decaffeinated and non-decaffeinated coffees • soft drinks including diet and regular ginger ales

Tateoka 2014, Cao 2009, Sakhi 2014, Braunrath 2005, Biles 1997, Ackerman 2010, Takao 1999, Kang 2002 Cao 2008, Kuo 2004 Canned Beverages • canned beers • energy drinks • decaffeinated and non-decaffeinated coffees • soft drinks including diet and regular ginger ales • diet and regular root beers • diet and regular colas

Tateoka 2014, Cao 2009, Sakhi 2014, Braunrath 2005, Biles 1997, Ackerman 2010, Takao 1999, Kang 2002 Cao 2008, Kuo 2004 Canned Beverages • canned beers • energy drinks • decaffeinated and non-decaffeinated • orange and lemon soft drinks coffees • soft drinks including diet and regular ginger ales • diet and regular root beers • diet and regular colas

Tateoka 2014, Cao 2009, Sakhi 2014, Braunrath 2005, Biles 1997, Ackerman 2010, Takao 1999, Kang 2002 Cao 2008, Kuo 2004 Canned Beverages • canned beers • energy drinks • decaffeinated and non-decaffeinated • orange and lemon soft drinks coffees • flavoured and unflavoured soda • soft drinks including diet and regular waters ginger ales • diet and regular root beers • diet and regular colas

Tateoka 2014, Cao 2009, Sakhi 2014, Braunrath 2005, Biles 1997, Ackerman 2010, Takao 1999, Kang 2002 Cao 2008, Kuo 2004 Canned Beverages • canned beers • energy drinks • decaffeinated and non-decaffeinated • orange and lemon soft drinks coffees • flavoured and unflavoured soda • soft drinks including diet and regular waters ginger ales • teas and tonic waters • diet and regular root beers • diet and regular colas

Tateoka 2014, Cao 2009, Sakhi 2014, Braunrath 2005, Biles 1997, Ackerman 2010, Takao 1999, Kang 2002 Cao 2008, Kuo 2004 Canned Beverages • canned beers • energy drinks • decaffeinated and non-decaffeinated • orange and lemon soft drinks coffees • flavoured and unflavoured soda • soft drinks including diet and regular waters ginger ales • teas and tonic waters • diet and regular root beers • infant and follow up formulas • diet and regular colas

6.2 µg L-1 of BPA in her breastmilk

Tateoka 2014, Cao 2009, Sakhi 2014, Braunrath 2005, Biles 1997, Ackerman 2010, Takao 1999, Kang 2002 Cao 2008, Kuo 2004 Canned Beverages • canned beers • energy drinks • decaffeinated and non-decaffeinated • orange and lemon so+ drinks coffees • flavoured and unflavoured soda • so+ drinks including diet and regular waters ginger ales • teas and tonic waters • diet and regular root beers • infant and follow up formulas • diet and regular colas

6.2 µg L-1 of BPA in her breastmilk

Tateoka 2014, Cao 2009, Sakhi 2014, Braunrath 2005, Biles 1997, Ackerman 2010, Takao 1999, Kang 2002 Cao 2008, Kuo 2004 Canned Beverages • canned beers • energy drinks • decaffeinated and non-decaffeinated • orange and lemon soft drinks coffees • flavoured and unflavoured soda • soft drinks including diet and regular waters ginger ales • teas and tonic waters • diet and regular root beers • infant and follow up formulas • diet and regular colas

6.2 µg L-1 of BPA in her breastmilk

6.2 µg L-1 of BPA ca. 30 µg L-1 of BPA in her breastmilk in her breastmilk

Tateoka 2014, Cao 2009, Sakhi 2014, Braunrath 2005, Biles 1997, Ackerman 2010, Takao 1999, Kang 2002 Cao 2008, Kuo 2004 Production

Use

• Contamination of Air • Contamination of Water • Contamina0on of Foods • Contamination of Soil • Contamina0on of Beverages Produc*on

Use

• Contamination of Air • Contamination of Water • Contamination of Foods • Contamination of Soil • Contamination of Beverages Production

Use

• Contamination of Air • Contamination of Water • Contamina0on of Foods • Contamination of Soil • Contamina0on of Beverages • Contamina0on of Products Vandenberg 2013, Zalko 2011, Biedermann 2010, Dodson 2012 • When we touch receipts, BPA is transferred to the skin

Vandenberg 2013, Zalko 2011, Biedermann 2010, Dodson 2012 • When we touch receipts, BPA is transferred to the skin • The amount transferred to the skin increases by a factor of 10 when skin is wet or greasy • The BPA can then migrate into the skin • Migra?on increases when a vector such as hand cream or lo?on is present Vandenberg 2013, Zalko 2011, Biedermann 2010, Dodson 2012 • When we touch receipts, BPA is transferred to the skin • The amount transferred to the skin increases by a factor of 10 when skin is wet or greasy • The BPA can then migrate into the skin • Migra?on increases when a vector such as hand cream or lo?on is present Vandenberg 2013, Zalko 2011, Biedermann 2010, Dodson 2012 • When we touch receipts, BPA is transferred to the skin • The amount transferred to the skin increases by a factor of 10 when skin is wet or greasy • The BPA can then migrate into the skin • Migration increases when a vector such as hand cream or lotion is present Vandenberg 2013, Zalko 2011, Biedermann 2010, Dodson 2012 • When we touch receipts, BPA is transferred to the Contaminated skin Personal • The amount transferred to the skin increases by a Care-Hygiene factor of 10 when skin is wet or greasy Products • The BPA can then migrate into the skin • Migration increases when a vector such as hand cream or lotion is present Vandenberg 2013, Zalko 2011, Biedermann 2010, Dodson 2012 • When we touch receipts, BPA is transferred to the Contaminated skin Personal • The amount transferred to the skin increases by a Care-Hygiene factor of 10 when skin is wet or greasy Products • The BPA can then migrate into the skin • Cleansers • Migration increases when a vector such as hand cream or lotion is present Vandenberg 2013, Zalko 2011, Biedermann 2010, Dodson 2012 • When we touch receipts, BPA is transferred to the Contaminated skin Personal • The amount transferred to the skin increases by a Care-Hygiene factor of 10 when skin is wet or greasy Products • The BPA can then migrate into the skin • Cleansers • Migration increases when a vector such as hand • Condi+oner cream or lotion is present Vandenberg 2013, Zalko 2011, Biedermann 2010, Dodson 2012 • When we touch receipts, BPA is transferred to the Contaminated skin Personal • The amount transferred to the skin increases by a Care-Hygiene factor of 10 when skin is wet or greasy Products • The BPA can then migrate into the skin • Cleansers • Migration increases when a vector such as hand • Condi+oner cream or lotion is present • Shaving cream Vandenberg 2013, Zalko 2011, Biedermann 2010, Dodson 2012 • When we touch receipts, BPA is transferred to the Contaminated skin Personal • The amount transferred to the skin increases by a Care-Hygiene factor of 10 when skin is wet or greasy Products • The BPA can then migrate into the skin • Cleansers • Migra?on increases when a vector such as hand • Conditioner cream or lo?on is present • Shaving cream Vandenberg 2013, Zalko 2011, Biedermann • Lotions 2010, Dodson 2012 • When we touch receipts, BPA is transferred to the Contaminated skin Personal • The amount transferred to the skin increases by a Care-Hygiene factor of 10 when skin is wet or greasy Products • The BPA can then migrate into the skin • Cleansers • Migra?on increases when a vector such as hand • Conditioner cream or lo?on is present • Shaving cream Vandenberg 2013, Zalko 2011, Biedermann • Lotions 2010, Dodson 2012 • Shampoo • When we touch receipts, BPA is transferred to the Contaminated skin Personal • The amount transferred to the skin increases by a Care-Hygiene factor of 10 when skin is wet or greasy Products • The BPA can then migrate into the skin • Cleansers • Migra?on increases when a vector such as hand • Conditioner cream or lo?on is present • Shaving cream Vandenberg 2013, Zalko 2011, Biedermann • Lotions 2010, Dodson 2012 • Shampoo • Bar soap • When we touch receipts, BPA is transferred to the Contaminated skin Personal • The amount transferred to the skin increases by a Care-Hygiene factor of 10 when skin is wet or greasy Products • The BPA can then migrate into the skin • Cleansers • Migration increases when a vector such as hand • Conditioner cream or lotion is present • Shaving cream Vandenberg 2013, Zalko 2011, Biedermann • Lotions 2010, Dodson 2012 • Shampoo • Bar soap • Sunscreen • When we touch receipts, BPA is transferred to the Contaminated skin Personal • The amount transferred to the skin increases by a Care-Hygiene factor of 10 when skin is wet or greasy Products • The BPA can then migrate into the skin • Cleansers • Migration increases when a vector such as hand • Conditioner cream or lotion is present • Shaving cream Vandenberg 2013, Zalko 2011, Biedermann • Lotions 2010, Dodson 2012 • Shampoo • Bar soap • Sunscreen • Toothpaste • When we touch receipts, BPA is transferred to the Contaminated skin Personal • The amount transferred to the skin increases by a Care-Hygiene factor of 10 when skin is wet or greasy Products • The BPA can then migrate into the skin • Cleansers • Migration increases when a vector such as hand • Condi+oner cream or lotion is present • Shaving cream Vandenberg 2013, Zalko 2011, Biedermann • Lo+ons 2010, Dodson 2012 • Shampoo • Bar soap • Sunscreen • Toothpaste • Face and body wash Produc*on

Use

• Contamination of Air • Contamination of Water • Contamination of Foods • Contamination of Soil • Contamination of Beverages • Contamination of Products Production

Use

• Contamina(on of Air • Contamina(on of Water • Contamination of Foods • Contamina(on of Soil • Contamination of Beverages • Contamination of Products Produc*on

Use

• Contamination of Air • Contamination of Water • Contamination of Foods • Contamination of Soil • Contamination of Beverages • Contamination of Products • Contamination of People What Are the Concentra-ons of BPA in People? Human Tissue and Fluid Concentrations of BPA and Total BPA. Refs: vom Saal 2007, NHANES 2003, Kuruto-Niwa 2007, Ye 2006 Fluid or Tissue n % Range (µg L-1) Central Tendency Positive / Mean (µg L-1) Foetal, Child, and — — — Central Tendency: Adult Fluids and 0.3–4.4 µg L-1 Tissues BPA Urine of Americans 2,517 92.6% 0.3–149 µg L-1 Mean: 5.2 µg L-1 Over 6 Years Old Total BPA Total BPA Colostrum of Japanese 101 100% 1–7 µg L-1 Total Mean: 3.41 µg L-1 Mothers BPA Total BPA Breast Milk of 20 90% <0.3–6.3 µg L-1 Mean: 1.3 µg L-1 American Mothers of BPA BPA Human Tissue and Fluid Concentrations of BPA and Total BPA. Refs: vom Saal 2007, NHANES 2003, Kuruto-Niwa 2007, Ye 2006 Fluid or Tissue n % Range (µg L-1) Central Tendency Positive / Mean (µg L-1) Foetal, Child, and — — — Central Tendency: Adult Fluids and 0.3–4.4 µg L-1 Tissues BPA Urine of Americans 2,517 92.6% 0.3–149 µg L-1 Mean: 5.2 µg L-1 Over 6 Years Old Total BPA Total BPA Colostrum of 101 100% 1–7 µg L-1 Total Mean: 3.41 µg L-1 Japanese Mothers BPA Total BPA Breast Milk of 20 90% <0.3–6.3 µg L-1 Mean: 1.3 µg L-1 American Mothers of BPA BPA Human Tissue and Fluid Concentrations of BPA and Total BPA. Refs: vom Saal 2007, NHANES 2003, Kuruto-Niwa 2007, Ye 2006 Fluid or Tissue n % Range (µg L-1) Central Tendency Positive / Mean (µg L-1) Foetal, Child, and — — — Central Tendency: Adult Fluids and 0.3–4.4 µg L-1 Tissues BPA Urine of Americans 2,517 92.6% 0.3–149 µg L-1 Mean: 5.2 µg L-1 Over 6 Years Old Total BPA Total BPA Colostrum of Japanese 101 100% 1–7 µg L-1 Total Mean: 3.41 µg L-1 Mothers BPA Total BPA Breast Milk of 20 90% <0.3–6.3 µg L-1 Mean: 1.3 µg L-1 American Mothers of BPA BPA Human Tissue and Fluid Concentrations of BPA and Total BPA. Refs: vom Saal 2007, NHANES 2003, Kuruto-Niwa 2007, Ye 2006 Fluid or Tissue n % Range (µg L-1) Central Tendency Positive / Mean (µg L-1) Foetal, Child, and — — — Central Tendency: Adult Fluids and 0.3–4.4 µg L-1 Tissues BPA Urine of Americans 2,517 92.6% 0.3–149 µg L-1 Mean: 5.2 µg L-1 Over 6 Years Old Total BPA Total BPA Colostrum of Japanese 101 100% 1–7 µg L-1 Mean: 3.41 µg L-1 Mothers Total BPA Total BPA Breast Milk of 20 90% <0.3–6.3 µg L-1 Mean: 1.3 µg L-1 American Mothers of BPA BPA Human Tissue and Fluid Concentrations of BPA and Total BPA. Refs: vom Saal 2007, NHANES 2003, Kuruto-Niwa 2007, Ye 2006 Fluid or Tissue n % Range (µg L-1) Central Tendency Positive / Mean (µg L-1) Foetal, Child, and — — — Central Adult Fluids and Tendency: 0.3– Tissues 4.4 µg L-1 BPA Urine of Americans 2,517 92.6% 0.3–149 µg L-1 Mean: 5.2 µg L-1 Over 6 Years Old Total BPA Total BPA Colostrum of Japanese 101 100% 1–7 µg L-1 Total Mean: 3.41 µg L-1 Mothers BPA Total BPA Breast Milk of 20 90% <0.3–6.3 µg L-1 Mean: 1.3 µg L-1 American Mothers of BPA BPA What Are Human Health Effects of These Exposures? Richter 2004, Shelby 2008, Vandenberg 2013 A Panel from the Na/onal Ins/tute for Environmental Health and Safety

Richter 2004, Shelby 2008, Vandenberg 2013 A Panel from the National Institute for Environmental Health and Safety • “Confident” of human effects on the male reproductive tract arising from adult exposures • “Confident” of effects on the organization of the reproductive tract of males, the brain, and metabolism arising from developmental exposures Richter 2004, Shelby 2008, Vandenberg 2013 A Panel from the National US National Toxicology Institute for Environmental Program Panel and the US Health and Safety Food and Drug Administration • “Confident” of human effects on the male reproductive tract arising from adult exposures • “Confident” of effects on the organization of the reproductive tract of males, the brain, and metabolism arising from developmental exposures Richter 2004, Shelby 2008, Vandenberg 2013 A Panel from the Na/onal US Na/onal Toxicology Ins/tute for Environmental Program Panel and the US Health and Safety Food and Drug Administra/on • “Confident” of human effects • “Some concern” for effects on on the male reproduc6ve tract the brain, behavior, and male arising from adult exposures prostate gland arising from • “Confident” of effects on the foetus, infant, and child organiza6on of the exposures reproduc6ve tract of males, the brain, and metabolism arising from developmental exposures Richter 2004, Shelby 2008, Vandenberg 2013 What Effects Have Been Reported To Arise From Exposures Of Human Cells To These BPA Concentrations? Studies of Exposures of Human Cells to the Concentrations of BPA Observed in Foetal, Child, and Adult Fluids and Tissues Indicate That: Studies of Exposures of Human Cells to the Concentrations of BPA Observed in Foetal, Child, and Adult Fluids and Tissues Indicate That: • BPA can be as potent as estradiol, an endogenous hormone Prins 2014 Studies of Exposures of Human Cells to the Concentrations of BPA Observed in Foetal, Child, and Adult Fluids and Tissues Indicate That: • BPA can be as potent as estradiol, an endogenous hormone Prins 2014 • Long-term exposure may significantly affect human immunity Watanabe 2003 Studies of Exposures of Human Cells to the Concentrations of BPA Observed in Foetal, Child, and Adult Fluids and Tissues Indicate That: • BPA can be as potent as estradiol, an endogenous hormone Prins 2014 • Long-term exposure may significantly affect human immunity Watanabe 2003 • Exposure of the developing human prostate epithelium increases its susceptibility to hormonal carcinogenesis Prins 2014 Studies of Exposures of Human Cells to the Concentrations of BPA Observed in Foetal, Child, and Adult Fluids and Tissues Indicate That: • BPA can be as potent as estradiol, an endogenous hormone Prins 2014 • Long-term exposure may significantly affect human immunity Watanabe 2003 • Exposure of the developing human prostate epithelium increases its susceptibility to hormonal carcinogenesis Prins 2014 • Exposure may adversely effect metabolic homeostasis Ben-Jonathan 2009, Hugo 2008 Production

Use

Disposal

DisposalDisposal • Contaminated Leachate • Contaminated Air Streams • Combustion? In • Contaminated Air Streams • Contaminated Wastewaters • Contaminated Foods • Contaminated Beverages • Contaminated Products Fates of the 258 million tons of municipal solid waste generatedProduc/on in the US in 2014.Use Ref: USEPA 2014 Million Percent Percent Percent Waste tons (mt) Landfilled RecycledDisposalDisposalCombusted • Contaminated Leachate Paper and Paperboard 69 28 • Contaminated65 Air Streams7 Plastics 33 76 • Combustion?10 15 In • ContaminatedTextiles Air Streams 16 65 16 19 • RubberContaminated and WastewatersLeather • Contaminated8 Foods51 18 32 • Contaminated Beverages • Contaminated Products Fates of the 258 million tons of municipal solid waste generatedProduc/on in the US in 2014.Use Ref: USEPA 2014 Million Percent Percent Percent Waste tons (mt) Landfilled RecycledDisposalDisposalCombusted • Contaminated Leachate Paper and Paperboard 69 28 • Contaminated65 Air Streams7 Plastics 33 76 • Combustion?10 15 In • ContaminatedTextiles Air Streams 16 65 16 19 • Contaminated Wastewaters • Contaminated Foods Rubber and Leather • Contaminated8 Beverages51 18 32 • Contaminated Products Production

Use

Disposal

Use

Disposal

Use

Disposal • Contamination of Air

Use

Disposal • Contamination of Air • Contamination of Water

• Contamination of Air • Contamination of Water • Contamination of Foods • Contamination of Soil • Contamination of Beverages • Contamination of Products • Contamination of People Fates of the 258 million tons of municipal solid waste generatedProduction in the US in 2014.Use Ref: USEPA 2014 Million Percent Percent Percent Waste tons (mt) Landfilled RecycledDisposalDisposalCombusted • Contaminated Leachate Paper and Paperboard 69 28 • Contaminated65 Air Streams7 Plastics 33 76 • Combustion?10 15 In • ContaminatedTextiles Air Streams 16 65 16 19 • RubberContaminated and WastewatersLeather • Contaminated8 Foods51 18 32 • Contaminated Beverages • Contaminated Products Fates of the 258 million tons of municipal solid waste generatedProduction in the US in 2014.Use Ref: USEPA 2014 Million Percent Percent Percent Waste tons (mt) Landfilled RecycledDisposalDisposalCombusted • Contaminated Leachate Paper and Paperboard 69 28 • Contaminated65 Air Streams7 Plastics 33 76 • Combustion?10 15 In • ContaminatedTextiles Air Streams 16 65 16 19 • RubberContaminated and WastewatersLeather • Contaminated8 Foods51 18 32 • Contaminated Beverages • Contaminated Products

Polycarbonate Fates of the 258 million tons of municipal solid waste generatedProduction in the US in 2014.Use Ref: USEPA 2014 Million Percent Percent Percent Waste tons (mt) Landfilled RecycledDisposalDisposalCombusted • Contaminated Leachate Paper and Paperboard 69 28 • Contaminated65 Air Streams7 Plastics 33 76 • Combustion?10 15 In • ContaminatedTextiles Air Streams 16 65 16 19 • RubberContaminated and WastewatersLeather • Contaminated8 Foods51 18 32 • Contaminated Beverages • Contaminated Products

Polycarbonate 60% of the produced BPA Fates of the 258 million tons of municipal solid waste generatedProduction in the US in 2014.Use Ref: USEPA 2014 Million Percent Percent Percent Waste tons (mt) Landfilled RecycledDisposalDisposalCombusted • Contaminated Leachate Paper and Paperboard 69 28 • Contaminated65 Air Streams7 Plastics 33 76 • Combustion?10 15 In • ContaminatedTextiles Air Streams 16 65 16 19 • RubberContaminated and WastewatersLeather • Contaminated8 Foods51 18 32 • Contaminated Beverages • Contaminated Products

Polycarbonate BPA 60% of the produced BPA Fates of the 258 million tons of municipal solid waste generatedProduction in the US in 2014.Use Ref: USEPA 2014 Million Percent Percent Percent Waste tons (mt) Landfilled RecycledDisposalDisposalCombusted • Contaminated Leachate Paper and Paperboard 69 28 • Contaminated65 Air Streams7 Plastics 33 76 • Combustion?10 15 In • ContaminatedTextiles Air Streams 16 65 16 19 • RubberContaminated and WastewatersLeather • Contaminated8 Foods51 18 32 • Contaminated Beverages • Contaminated Products

Polycarbonate BPA 60% of the produced BPA Concentrations of BPA Detected in Landfill Leachate Country Year Range (µg L-1) Average Ref. (µg L-1) Germany 2002 4,200–25,000 14,067 Schwarzbauer Germany 2003 500–5,000 — Wintgens Japan 1999 ca. 500–7,500 — Yamada Japan 1996 <0.5–17,200 269 Yamamoto Norway 2015 0.7–200 66.5 Morin Philippines 2003 ca. 9,000 — Urase Sweden 2000 4–136 — Paxeus Concentrations of BPA Detected in Landfill Leachate Country Year Range (µg L-1) Average Ref. (µg L-1) Germany 2002 4,200–25,000 14,067 Schwarzbauer Germany 2003 500–5,000 — Wintgens Japan 1999 ca. 500–7,500 — Yamada Japan 1996 <0.5–17,200 269 Yamamoto Norway 2015 0.7–200 66.5 Morin Philippines 2003 ca. 9,000 — Urase Sweden 2000 4–136 — Paxeus Concentrations of BPA Detected in Landfill Leachate Country Year Range (µg L-1) Average Ref. (µg L-1) Germany 2002 4,200–25,000 14,067 Schwarzbauer Germany 2003 500–5,000 — Wintgens Japan 1999 ca. 500–7,500 — Yamada Japan 1996 <0.5–17,200 269 Yamamoto Norway 2015 0.7–200 66.5 Morin Philippines 2003 ca. 9,000 — Urase Sweden 2000 4–136 — Paxeus Concentrations of BPA Detected in Landfill Leachate Country Year Range (µg L-1) Average Ref. (µg L-1) Germany 2002 4,200–25,000 14,067 Schwarzbauer Germany 2003 500–5,000 — Wintgens Japan 1999 ca. 500–7,500 — Yamada Japan 1996 <0.5–17,200 269 Yamamoto Norway 2015 0.7–200 66.5 Morin Philippines 2003 ca. 9,000 — Urase Sweden 2000 4–136 — Paxeus Fates of the 258 million tons of municipal solid waste generatedProduction in the US in 2014.Use Ref: USEPA 2014 Million Percent Percent Percent Waste tons (mt) Landfilled RecycledDisposalDisposalCombusted • Contaminated Leachate Paper and Paperboard 69 28 • Contaminated65 Air Streams7 Plastics 33 76 • Combustion?10 15 In • ContaminatedTextiles Air Streams 16 65 16 19 • RubberContaminated and WastewatersLeather • Contaminated8 Foods51 18 32 • Contaminated Beverages • Contaminated Products

Polycarbonate 95% of the produced BPA Fates of the 258 million tons of municipal solid waste generatedProduction in the US in 2014.Use Ref: USEPA 2014 Million Percent Percent Percent Waste tons (mt) Landfilled RecycledDisposalDisposalCombusted • Contaminated Leachate Paper and Paperboard 69 28 • Contaminated65 Air Streams7 Plastics 33 76 • Combustion?10 15 In • ContaminatedTextiles Air Streams 16 65 16 19 • RubberContaminated and WastewatersLeather • Contaminated8 Foods51 18 32 • Contaminated Beverages • Contaminated Products

Polycarbonate 95% of the produced BPA Production

Use

Disposal • Contamination of Air • Contamination of Water

Use

Disposal • Contamination of Air • Contamination of Water • Contamination of Soil

Use

Disposal • Contamination of Air • Contamination of Water • Contamination of Soil

Use

Disposal • Contamination of Air • Contamination of Water • Contamination of Soil

Use

Disposal • Contamination of Air • Contamination of Water • Contamination of Soil

Use

Disposal • Contamination of Air • Contamination of Water • Contamination of Soil

Use

Disposal • Contamination of Air • Contamination of Water • Contamination of Soil

Use

Disposal • Contamination of Air • Contamination of Water • Contamination of Soil

• Contamination of Air • Contamination of Water • Contamination of Foods • Contamination of Soil • Contamination of Beverages • Contamination of Products • Contamination of People Recycling • Contamination of Recycled Cellulose Fiber • Contamination of Air, Water, and Soil Worldwide Contamination of Recycled Cellulose Fiber (RCF) Worldwide Contamination of Recycled Cellulose Fiber (RCF) Worldwide Contamination of Recycled Cellulose Fiber (RCF) Worldwide Contamination of Recycled Cellulose Fiber (RCF) Worldwide Contamination of Recycled Cellulose Fiber (RCF) Worldwide Contamination of Recycled Cellulose Fiber (RCF) Worldwide Contamination of Recycled Cellulose Fiber (RCF) Worldwide Contamination of Recycled Cellulose Fiber (RCF)

EU 2008 Worldwide Contamination of Recycled Cellulose Fiber (RCF)

Liao 2011, Gehring 2014, Nordstrom 2013

EU 2008 Production

Use

Disposal • Contamination of Air • Contamination of Water • Contamination of Soil

Use

Disposal • Contamination of Air • Contamination of Water • Contamination of Soil

Use

DisposalDisposal • Contaminated Air • Contaminated Water • Contaminated Soil

• Contaminated Air • Contaminated Water • Contaminated Foods • Contaminated Soil • Contaminated Beverages • Contaminated Products • Contaminated People Recycling • Contaminated Recycled Cellulose Fiber • Contaminated Air, Water, and Soil Use

DisposalDisposal • Contaminated Air • Contaminated Water • Contaminated Soil

• Contaminated Foods • Contaminated Beverages • Contaminated Products • Contaminated People Recycling • Contaminated Recycled Cellulose Fiber • Contaminated Air, Water, and Soil DisposalDisposal • Contaminated Air • Contaminated Water • Contaminated Soil

Recycling • Contaminated Recycled Cellulose Fiber • Contaminated Air, Water, and Soil

• Remove BPA from landfill leachate • Remove BPA from landfill leachate and WWTP influent • Remove BPA from landfill leachate and WWTP influent • Remove BPA from landfill • Remove BPA from RCF leachate and WWTP processing solutions influent • Remove BPA from landfill • Remove BPA from RCF leachate and WWTP processing solutions influent • Remove BPA from landfill • Remove BPA from RCF leachate and WWTP processing solutions influent

• Convert >99% of BPA in near- neutral pH lab water, a simulant of landfill leachate and WWTP influent, to an insoluble form • Convert >99% of BPA in near- neutral pH lab water, a simulant of landfill leachate and WWTP influent, to an insoluble form • Reduce the solution phase acute

toxicity (takes EC50 of 21 to >100) • Convert >99% of BPA in near- neutral pH lab water, a simulant of landfill leachate and WWTP influent, to an insoluble form • Reduce the solution phase acute

toxicity (takes EC50 of 21 to >100) • Remove all solution phase oestrogenicity (yeast assay) • Convert >99% of BPA in near- neutral pH lab water, a simulant of landfill leachate and WWTP influent, to an insoluble form • Reduce the solution phase acute

toxicity (takes EC50 of 21 to >100) • Remove all solution phase oestrogenicity (yeast assay) • Show no toxicity to zebrafish • Convert >99% of BPA in near- • Convert >99.9 of BPA in pH ≥11 neutral pH lab water, a simulant lab water, a simulant of RCF

of landfill leachate and WWTP processing solutions, to CO, CO2, influent, to an insoluble form acetone, and trace formate • Reduce the solution phase acute

of landfill leachate and WWTP processing solutions, to CO, CO2, influent, to an insoluble form acetone, and trace formate • Reduce the solution phase acute • Reduce the solution phase acute

toxicity (takes EC50 of 21 to >100) toxicity (takes EC50 of 23 to >100) • Remove solution phase oestrogenicity (yeast assay) • Show no toxicity to zebrafish Phipps Conservatory University of Auckland Richard Piacentini Naresh Singhal Sarah States L. James Wright Yusuf Onundi CMU’s IGS Terrence J. Collins Oregon State University Colin P. Horwitz Robert L. Tanguay Evan S. Beach Lisa Truong Alexander D. Ryabov Michael T. Simonich Soumen Kundu Matthew R. Mills Thank You All For Your Ryan T. Malecky Attention! Bethany A. Drake

About Bisphenol A >> Information Sheets Join the Bisphenol- A mailing list. Bisphenol A Synthesis and Use email address About Bisphenol A What Is BPA? Submit More Info Human Health & Safety

Environmental Safety Bisphenol A (BPA) is an important industrial chemical that is used primarily to make polycarbonate plastic and epoxy resins, both of which are used in a Scientific Publications wide variety of applications. For example, polycarbonate is used in eyeglass Press Room lenses, medical equipment, water bottles, digital media (e.g., CDs and DVDs), cell phones, consumer electronics, computers and other business equipment, electrical equipment, household appliances, safety shields, construction glazing, sports safety equipment, and automobiles. Among the many uses for epoxy resins are industrial floorings, adhesives, industrial protective coatings, powder coatings, automotive primers, can coatings and printed circuit boards.

Bisphenol A First Synthesized in Germany

Thomas Zincke of the University of Marburg, Germany, first reported synthesis of bisphenol A. Zincke acknowledged in his paper that the synthesis of BPA, from phenol and acetone, was based on chemical reactions previously reported by others as well as unpublished work (from thesis dissertations) conducted at the University of Marburg. His paper reporting the synthesis of BPA and a number of related compounds was published in 1905. (Zincke, T., 1905, "Mittheilungen aus dem chemischen Laboratorium der Universitat Marburg," Justus Leibigs Annals Chemie, vol. 343, pages 75-99).

Bisphenol A Developed Commercially in the 1950s

In 1953, Dr. Hermann Schnell of Bayer in Germany and Dr. Dan Fox of General Electric in the United States independently developed manufacturing processes for a new plastic material, polycarbonate, using BPA as the starting material.

Polycarbonate plastic was found to have a unique combination of very useful properties, in particular optical clarity, shatter-resistance and high heat- resistance. These characteristics have made polycarbonate an important part of everyday life in a wide variety of applications.

Commercial production began in 1957 in the United States and in 1958 in Europe when large-scale uses for polycarbonate plastic and epoxy resins were developed. About this same time, epoxy resins were developed with the versatility to meet a wide range of industrial and consumer needs. Commercial production of BPA has grown worldwide along with the continued growth of the uses for these materials.

Learn more about the versatility and many uses of polycarbonate plastic.

About Bisphenol A | Human Health & Safety | Environmental Safety Scientific Publications | Press Room

About Bisphenol A >> Information Sheets Join the Bisphenol- A mailing list. Bisphenol A Synthesis and Use email address About Bisphenol A What Is BPA? Submit More Info Human Health & Safety

Bisphenol A Developed Commercially in the 1950s

Learn more about the versatility and many uses of polycarbonate plastic.

About Bisphenol A | Human Health & Safety | Environmental Safety Scientific Publications | Press Room

About Bisphenol A >> Information Sheets Join the Bisphenol- A mailing list. Bisphenol A Synthesis and Use email address About Bisphenol A What Is BPA? Submit More Info Human Health & Safety

Bisphenol A Developed Commercially in the 1950s

Learn more about the versatility and many uses of polycarbonate plastic.

About Bisphenol A | Human Health & Safety | Environmental Safety Scientific Publications | Press Room

About Bisphenol A >> Information Sheets Join the Bisphenol- A mailing list. Bisphenol A Synthesis and Use email address About Bisphenol A What Is BPA? Submit More Info Human Health & Safety

Bisphenol A Developed Commercially in the 1950s

Learn more about the versatility and many uses of polycarbonate plastic.

About Bisphenol A | Human Health & Safety | Environmental Safety Scientific Publications | Press Room

About Bisphenol A >> Information Sheets Join the Bisphenol- A mailing list. Bisphenol A Synthesis and Use email address About Bisphenol A What Is BPA? Submit More Info Human Health & Safety

Thomas Zincke of the University of Marburg, Germany, first reported synthesis of bisphenol A. Zincke acknowledged in his paper that the synthesis of BPA, from phenol and acetone, was based on chemical reactions previously reported by others as well as unpublished work (from thesis dissertations) conducted at the University of Marburg. His paper reporting the synthesis of BPA and a number of related compounds was published in 1905. (Zincke, T., 1905, "Mittheilungen aus dem chemischen Laboratorium der Universitat Marburg,"+ Justus Leibigs Annals Chemie, vol. 343, pages 75-99).

Bisphenol A Developed Commercially in the 1950s

Learn more about the versatility and many uses of polycarbonate plastic.

About Bisphenol A | Human Health & Safety | Environmental Safety Scientific Publications | Press Room

About Bisphenol A >> Information Sheets Join the Bisphenol- A mailing list. Bisphenol A Synthesis and Use email address About Bisphenol A What Is BPA? Submit More Info Human Health & Safety

Thomas Zincke of the University of Marburg, Germany, first reported synthesis of bisphenol A. Zincke acknowledged in his paper that the synthesis of BPA, from phenol and acetone, was based on chemical reactions previously reported by others as well as unpublished work (from thesis dissertations) conducted at the University of Marburg. His paper reporting the synthesis of BPA and a number of related compounds was published in 1905. (Zincke, T., 1905, "Mittheilungen aus dem chemischen Laboratorium der Universitat Marburg,"+ Justus Leibigs Annals Chemie, vol. 343, pages 75-99).

Zincke reported key physical properties of BPA (e.g., molecular composition, melting point, solubility in common solvents) but did not propose any application or use for BPA or the other materials he synthesized.. А. Dianin, 1891, J. Russian Physical Chemistry Society, 23: 488- Bisphenol A Developed Commercially517. in the 1950s

Learn more about the versatility and many uses of polycarbonate plastic.

About Bisphenol A | Human Health & Safety | Environmental Safety Scientific Publications | Press Room

About Bisphenol A >> Information Sheets Join the Bisphenol- A mailing list. Bisphenol A Synthesis and Use email address About Bisphenol A What Is BPA? Submit More Info Human Health & Safety

Bisphenol A Developed Commercially in the 1950s

Learn more about the versatility and many uses of polycarbonate plastic.

About Bisphenol A | Human Health & Safety | Environmental Safety Scientific Publications | Press Room

About Bisphenol A >> Information Sheets Join the Bisphenol- A mailing list. Bisphenol A Synthesis and Use email address About Bisphenol A What Is BPA? Submit More Info Human Health & Safety

Bisphenol A Developed Commercially in the 1950s

Learn more about the versatility and many uses of polycarbonate plastic.

About Bisphenol A | Human Health & Safety | Environmental Safety Scientific Publications | Press Room

About Bisphenol A >> Information Sheets Join the Bisphenol- A mailing list. Bisphenol A Synthesis and Use email address About Bisphenol A What Is BPA? Submit More Info Human Health & Safety

Bisphenol A Developed Commercially in the 1950s

Learn more about the versatility and many uses of polycarbonate plastic.

About Bisphenol A | Human Health & Safety | Environmental Safety Scientific Publications | Press Room

X =

Prolonged X = oestrus (40 days)

Prolonged X = oestrus = (40 days)

Prolonged Endocrine X = oestrus = activity (40 days)

Proc. Roy. Soc. 1938

The Royal Society is collaborating with JSTOR to digitize, preserve, and extend access to Proceedings of the Royal Society of London. Series B, Biological Sciences. ® www.jstor.org

Proc. Roy. Soc. 1938 on December 8, 2016

The Royal Society is collaborating with JSTOR to digitize, preserve, and extend access to Proceedings of the Royal Society of London. Series B, Biological Sciences. ® www.jstor.org

Proc. Roy. Soc. 1938 on December 8, 2016

The Royal Society is collaborating with JSTOR to digitize, preserve, and extend access to Proceedings of the Royal Society of London. Series B, Biological Sciences. ® www.jstor.org

Proc. Roy. Soc. 1938

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Proc. Roy. Soc. 1938

Proc. Roy. Soc. 1940

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Proc. Roy. Soc. 1938

Proc. Roy. Soc. 1940

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Proc. Roy. Soc. 1938

Proc. Roy. Soc. 1940

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Proc. Roy. Soc. 1938

Proc. Roy. Soc. 1940

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© 1936 Nature Publishing Group June, 1944 ESTROGENICACTIVITY OF 4,4'-DIHYDROXYDIPHENYLMETHANES 967 anhydrous calcium sulfate and 5 g. of the hydrazone of ethanol produced 2,4,6-triisopropylphenylace~ide. It 2,4,6-triisopropylphenylglyoxal was covered with 75 cc. was recrystallized from ethanol; m. p. 170-171 . of dry ether and stirred for twelve hours at room tempera- Anal. Calcd. for CnHnNO: C, 78.11; H, 10.41. ture. The ether was decanted through a filter paper and Found: C, 78.15; H, 10.57. the black residue washed by decantation with a total of 100 cc. of dry ether. Removal of the ether left the diazo 2,4,6-Triisopropylbenzyl Cye1~ide.~~-2,4,6-Triiiopropyl- compound as a yellow powder, which decomposed ex- benzyl chloride, prepared by the chloromethylation of plosively at 125 '. After recrystallization from methanol 1,3,5-trii~opropylbenzene,~6was converted to the corre- it was found to decompose at 104"; yield 4.5 g. sponding cyanide by treatment with cuprous cyanide. A It was covered with water and a pinch of silver oxide was mixture of 149 g. of the chloride, 57.8 g. of cuprous cyanide added. The mixture was boiled for thirty minutes. Eight and 60 cc. of dry pyridine was heated at 21&220° for grams of potassium hydroxide pellets was added and the ninety minutes. When the mixture had cooled to 150" it boiling continued for fifteen minutes. A solid was re- was poured into a mixture of 500 g. of ice and 200 cc. of moved by filtration and recrystallized from et?. It ammonium hydroxide. The mixture was allowed to stand overnight, and the crude nitrile was collected a formed pale yellow crystals melting at 204-205 , This on substance was not identified. When the filtrate was acidi- filter and distilled, b. p. 129-130' (4 mm.); m. p. 81-82'; fied the 2,4,6-triisopropylphenylacetic acid was precipi- yield 64%. tated. It was recrystallized ff;om75% acetic acid and then Anal. Calcd. for C17HzIN: C, 83.89;H, 10.35. Found: from ligroin; m. p. 146-146.5 . A mixture with an authen- C, 83.40; H, 10.26. tic specimen of the acid (see below) showed no depression in melting point. summary (b) The hydrolysis of 2,4,6-triisopropylbenzylcyanide Methods of synthesis of hindered aldoketenes could not be effected satisfactorily with 50-t3070 sulfuric have been studied. acid. The method of Redemann and Lucasl' for the saponification of esters, however, was found to be suitable. The cis and trans enol benzoates of desoxymesi- A mixture of 67 g. of the pure nitrile, 500 cc. of diethylene toin have been prepared. Hydrolysis was found glycol, 100 g. of potassium hydroxide and 20 cc. of water to convert them to desoxymesitoin, showing that was heated under reflux for twelve hburs and poured into the cis and trans enols of desoxymesitoin were un- water. The 2,4,6-triisopropylphenylaceticacid, precipi- tated by acidification of the mixture, was recrystallized stable and ketonized rapidly. The corresponding from aqueous ethanol; m. p. 144-145'; yield 85%. cis and trans acetates were also prepared. These Anal. Calcd. for CI7HneOn:C, 77.80; H, 9.99. Found: results confirm the conclusion reached earlier that C,78.08; H, 9.67. the dehydration product of hydromesitoin or iso- Hydrolysis of the nitrile with potassium hydroxide and hydromesitoin is 1, 1-dimesitylvinyl alcohol. (15) Fuson, Horning, Ward, Rowland and Marsh, THISJOURNAL, (13) This preparation was carried out by Dr. M. L. Ward. 64, 30 (1942). (14) Redemann and Lucas, Ind. Eng. Chcm., Anal. Ed., 0, 521 (1937). URBANA,ILLINOIS RECEIVEDMARCH 13, 1944

The Relation of Estrogenic Activity to Structure in Some 4,4'-Dihydroxydiphenyl- methanes'

BY E. EMMETREID AND EDITHWILSON~ J. Am. Chem. Soc. 1944 Estrogenic activity has been noted by Dodds of the second series are plotted in Fig. 1. When and LawsonS in some 4,4'-dihydroxydiphenyl- our work was nearly completed, an article by methanes, (HOCaH6)2CRR'. It seemed worth- Campbell4 covering part of the Same ground ap- while to prepare a number of these to see how the peared. estrogenic activity varies with the size and char- The activity reaches a peak in the first serieg acter of the groups R and R'. Two series have with the methyl-propyl and in the second series a now been made: one, in which R is methyl and much higher peak at the propyl-propyl, which is R' varies from methyl to hexyl, and the other, ten times as potent as any of the others. The in which R and R' are identical and vary activities for ethyl-propyl and for propyl-butyl from methyl to amyl. Besides these several are borrowed from Campbell. For comparison compounds of different types, including the the data for the corresponding trams-4,4'-di- double one, (HOCsH&2(CH~)CH~CH~C(CHS)- hydroxy-a,(3-dialkylstilbeness are plotted in Fig. (CeH40H)2, from acetonyl-acetone have been 1, but they are in rat units per milligram while studied. In order to have comparable estro- ours are in the same units per gram. The ethyl- genic data, the known compounds have been ene derivatives are around a thousand times as prepared and tested along with the new. For active as the methane derivatives, yet the shapes better chemical characterization the benzoates of the two curves are strikingly alike except that of all of them have been prepared. The results the maximum is at the ethyl-ethyl in the one and are in Table I. The activities of the members at the propyl-propyl in the other. The rise is gradual through the methyl-ethyl in the one and (1) Original manuscript received October 20, 1942. (2) Present address: Biochemical Research Foundation, Newark, through the ethyl-propyl in the other. In both Del. (4) N. R. Campbell, ibid., BlSS, 628 (1940). (3) Dodds and Lawson, Proc. Roy. SOC. (London). Bins, 222 (6) Dodds, Goldberg, Lawsoa and Robinson, ibid., (London), (1938). B197, 140 (1939). June, 1944 ESTROGENICACTIVITY OF 4,4'-DIHYDROXYDIPHENYLMETHANESE. EMMETREID AND EDITEI967 WILSON Vol. 66 anhydrous calcium sulfate and 5 g. of the hydrazone of ethanol produced 2,4,6-triisopropylphenylace~ide. It 2,4,6-triisopropylphenylglyoxal was covered with 75 cc. was recrystallizedTABLEI from ethanol; m. p. 170-171 . an important part; the maxima are at ethyl- of dry ether and stirred for twelve hours at room tempera- Anal. Calcd. for CnHnNO: C, 78.11; H, 10.41. ture. The ether was decanted through a filter paper and Found: C, AND78.15; H, 10.57. ethyl and propyl-propyl. So far as the Same the black residue washed by decantation with a MELTINGtotal of POINTS ACTIVITIES 100 cc. of dry ether. Removal of the ether left the diazo 2,4,6-TriisopropylbenzylM. p.& Cye1~ide.~~-2,4,6-Triiiopropyl-Rat Benzoate compounds are concerned our results agree well compound as a yellow powder, which R decomposed ex- benzylR' chloride, oc.prepared u./g.by the m.chloromethylation p , *C with of those of Campbell except that our value for plosively at 125 '. After recrystallization from methanol 1,3,5-trii~opropylbenzene,~6was converted to the corre- it was found to decompose at 104";Methyl yield 4.5 g. Methy13s8J*Bsponding cyanide 155 by treatment28 with cuprous161 cyanide.propyl-propyl A is much higher. mixture of 149 g. of the chloride, 57.8 g. of cuprous cyanide It was covered with water and a Methylpinch of silver ethyl oxide was~A~JOJ~ 124 80 added. The mixture was boiled for thirty minutes. Eight and 60 cc. of dry pyridine was heated143 at 21&220° forThe methyl-i-bu tyl is considerably more active grams of potassium hydroxide pelletsMethyl was added and Propyle~a~loJ1*lzthe ninety minutes. 149 When the200 mixture had120 cooled to 150"than it the methyl-n-butyl. A methyl group in the boiling continued for fifteen minutes. A solid was re- was poured into a mixture of 500 g. of ice and 200 cc. of moved by filtration and recrystallizedMethyl from et?. Butyl?It ammonium hydroxide.Liq The402 mixture 72 was allowed4-position to in the cyclohexanone derivative raises stand overnight, and the crude nitrile was collected a formed pale yellow crystals meltingMethyl at 204-205 , ThisAmyl 101 35 118 itson activity, so does the p-methoxy group in the substance was not identified. When the filtrate was acidi- filter and distilled, b. p. 129-130' (4 mm.); m. p. 81-82'; fied the 2,4,6-triisopropylphenylaceticMethyl acid was precipi-Hexyl yield 64%. 88 50 114 methyl-9-methoxyphenyl. The double compound tated. It was recrystallized ff;om75% Methyl acetic acid and then&Propyl Anal. Calcd.194 for C17HzIN:50 C, 83.89;204H, 10.35. Found:from acetonyl-acetone shows as much activity from ligroin; m. p. 146-146.5 . A mixture with an authen- C, 83.40; H, 10.26. tic specimen of the acid (see below)Methyl showed no depressioni-Butyl'*" 153 summary200 116 as any except the propyl-propyl. This is remark- in melting point. Ethyl Ethyl'Jo~lz 204 200 163 able considering its high molecular weight and (b) The hydrolysis of 2,4,6-triisopropylbenzylcyanide Methods of synthesis of hindered aldoketenes could not be effected satisfactorilyPropyl with 50-t3070 sulfuricPropyl'*12 have been studied.154 2000 142 low solubility. acid. The method of Redemann and Lucasl' for the saponification of esters, however, wasButyl found to be suitable.Butyl6 The cis and170.5 trans enol20 benzoates 123 of 5desoxymesi- The estrogenic activities were determined by A mixture of 67 g. of the pure nitrile,Amyl 500 cc. of diethyleneAmyl toin have been148.5 prepared. 10 Hydrolysis94 was foundDr. Geschickter and Dr. Byrne by the standard glycol, 100 g. of potassium hydroxide and 20 cc. of water to convert them to desoxymesitoin, showing that was heated under reflux for twelvec-Pentanone6JJ1 hburs and poured into the cis and trans157 enols of'66 desoxymesitoin 205 weremethod. un- water. The acid, precipi- 2,4,6-triisopropylphenylaceticc-Hexanone6v1Ivla t 14 184 50 198 The melting points of the compounds of the tated by acidification of the mixture, was recrystallized stable and ketonized rapidly. The corresponding from aqueous ethanol; m. p. 144-145';4-Me-He~anone~~t~~J~ yield 85%. cis and trans 179acetates were200 also prepared.149.5 Thesetwo series show alternation, as do those of their Anal. Calcd. for CI7HneOn:C, H, Found: results confirm the conclusion reached earlier that Methyl77.80; 9.99. Phenyl', 119 1% 16 188 0 150 5 benzoates. C,78.08; H, 9.67. the dehydration product of hydromesitoin or iso- Hydrolysis of the nitrile with potassiumMethyl hydroxide p-Me0and hydromesitoin phenyl 245 is 1, 1-dimesitylvinyl 55 221 alcohol. Experimental Benzyl Benzyl16(15) Fuson, Horning,193 Ward, Rowland0 and223 Marsh, THISJOURNAL, (13) This preparation was carried out by Dr. M. L. Ward. The method of preparation was the same for all. The 64, 30 (1942). (14) Redemann and Lucas, Ind. Eng.(CHsC*CHz*)z" Chcm., Anal. Ed., 0, 521 302 d 200 24: ketone and three equivalents of phenol were piit into a (1937). URBANA,ILLINOIS RECEIVEDMARCH 13, glass-stoppered 1944 bottle and concentrated hydrochloric acid the activities drop off sharply as soon as the equal to about one-fifth of the phenol added. The mixture maxima are passed. Symmetry seems to play stood, with dccasional shaking, until the reaction seemed to be complete, which took from a day or two for the The Relation of Estrogenic Activity to Structure in Some 4,4'-Dihydroxydiphenyl-simpler ketones up to twenty weeks for some others. methanes' Hydrogen chloride was passed into the slow. ones from time to time. The condensations went much faster if, instead BY E. EMMETREID AND EDITHWILSON~ J. Am. Chem. Soc.of using 1944 aqueous hydrochloric acid, the ketone-phenol 2000 mixrure was saturated with hydrogen chloride, but the Estrogenic activity has been noted by Dodds of the second series are plotted in Fig. 1. Whenproducts so obtained were harder to purify. The mixtures and LawsonS in some 4,4'-dihydroxydiphenyl- our work was nearly completed, an articleturned by red in any case, but the purified compounds were methanes, (HOCaH6)2CRR'. It seemed worth- Campbell4 covering part of the Same groundcdorless. ap- The reaction product was poured into hot water, while to prepare a number of these to see how the peared. the unxsed reactants driven off with steam, and the residue estrogenic activity varies with the size and char- The activity reaches a peak in the first filteredserieg off or collected in ether according to its physical acter of the groups R and R'. Two series have with the methyl-propyl and in the second seriesstate. a The yields were high, 90% or better, even with the now been made: one, in which R is methyl and much higher peak at the propyl-propyl, whichhigher is ketones if they were given time enough. Acetic R' varies from methyl to hexyl, and the other, ten times as potent as any of the others. acid,The chloroform, acetone and toluene were used as sol- in which R and R' are identical and vary activities for ethyl-propyl and for propyl-butylvents. The low melting coinpounds were hard to purify from methyl to amyl. Besides these several are borrowed from Campbell. For comparisonas they tended to separate from solvents as liquids. Some compounds of different types, including the the data for the corresponding trams-4,4'-di-could be obtained pure only by saponification of the re- double one, (HOCsH&2(CH~)CH~CH~C(CHS)- hydroxy-a,(3-dialkylstilbeness are plotted incrystallized Fig. beiizoates. The benzoates were made by the (CeH40H)2, from acetonyl-acetone have been 1, but they are in rat units per milligram Schotteli-Daumannwhile method. All melting points were studied. In order to have comparable estro- ours are in the same units per gram. The ethyl-determined with the aid of a thermometer calibrated for genic data, the known compounds have been ene derivatives are around a thousand times3-inch as immersion. The analyses of new compounds are active as the methane derivatives, yet the shapes prepared and tested along with the new. For I in Table 11. better chemical characterization the benzoates of the two curves are strikingly- J alike except that of all of them have been prepared. The resultsi.-*-==1.=,- the maximum is at the ethyl-ethyl in the one and TABLEI1 are in Table I. The activities of theR membersMe Me atEt the Et propyl-propyl Pr Pr Buin the Amother. The rise is ANALYSES gradual through the methyl-ethyl in the one and (1) Original manuscript received October 20, 1942.R' Me Et Et Pr Pr Bu Bu Am Carbon, % Hydrogen, % (2) Present address: Biochemical Research Foundation, Newark, through the ethyl-propyl in the other. In both R R' Calcd. Found Calcd. Found Del. Fig. 1.-Estrogenic activity(4) N. R. Campbell,related ibid.,to sizes BlSS, 628of R(1940). and R': (3) Dodds and Lawson, Proc. [email protected],rat SOC. (London). Bins, 222u./g. (HOCsH&CRR';(6) Dodds, Goldberg, Lawsoa --0--- and Robinson, -e--, ibid., (London),Rlcthyl amyl 80.28 79.41 8.45 8.51 (1938). rat u./mg. HOC3,CR:B197, CR'GH40H 140 (1939). XIrthyl hexyl" 80.54 78.50 8.72 8.64 Ik5iizoate XO.(il 79.91 6.77 6.63 (6) Campbell gives m. p. of Bu-Bu 166". (7) Zincke, Ann., Sa,85 (1905) Aiiiyl aniyl 81.17 80.98 9.41 9.50 (8) v. Braun, ibid., 474, 1 (1929). Methyl i-propyl 79.69 79.53 7.81 7.99 (e) Zincke, ibid., 1169, 205 (1908). I-Methyl-c-heranoiie 81.13 81.10 7.47 8.02 (10) Easson, Harrison, McSwiney and Pyman. Quorl J, and Year Methyl p-MeO-phenyl 78.75 78.39 6.25 6.45 Book of Pharmacy, 7, 509 (1934). (11) McGrcal, Niederl and Niederl, TUISJOURNAL, 61,345 (1939). nciizpl benzyl 85.26 85.70 6.31 6.34 (12) Dianin, J. Rusr. Phys.-Chcm. Soc., 28, 488, 523, 601 (1891). (CH~CCHZ-)~ 79.19 79.30 6.60 6.79 (13) Schmidlin and Lang, Ber., 43, 2806 (1910). The low carbon is probably due to adsorbed water. (14) 1. G. Farbenind., German patent 467,728 (1927); [Chrm.ribs., On account of the low m. p. the compound wasdifficult to 48, 1729 (1929).] dry. The bcnzoate gave satisfactory figures. (15) I. G.Farbenind., German patent 604,406 (1932); [Chctn. Abs., 99, 855 (1936).] summary (16) Zincke, Ann., 563, 265, 280 (1908). (17) Amann and Fonrobert, U.S. patent 1,614,172 (1927); [Chrm. A number of 4,4'-dihydroxy-diphenylmethanes, Abs., P1, 805 (1927). J (HOCaH&CRR', have been prepared and their June, 1944 ESTROGENICACTIVITY OF 4,4'-DIHYDROXYDIPHENYLMETHANESE. EMMETREID AND EDITEI967 WILSON Vol. 66 anhydrous calcium sulfate and 5 g. of the hydrazone of ethanol produced 2,4,6-triisopropylphenylace~ide. It 2,4,6-triisopropylphenylglyoxal was covered with 75 cc. was recrystallizedTABLEI from ethanol; m. p. 170-171 . an important part; the maxima are at ethyl- of dry ether and stirred for twelve hours at room tempera- Anal. Calcd. for CnHnNO: C, 78.11; H, 10.41. ture. The ether was decanted through a filter paper and Found: C, AND78.15; H, 10.57. ethyl and propyl-propyl. So far as the Same the black residue washed by decantation with a MELTINGtotal of POINTS ACTIVITIES 100 cc. of dry ether. Removal of the ether left the diazo 2,4,6-TriisopropylbenzylM. p.& Cye1~ide.~~-2,4,6-Triiiopropyl-Rat Benzoate compounds are concerned our results agree well compound as a yellow powder, which R decomposed ex- benzylR' chloride, oc.prepared u./g.by the m.chloromethylation p , *C with of those of Campbell except that our value for plosively at 125 '. After recrystallization from methanol 1,3,5-trii~opropylbenzene,~6was converted to the corre- it was found to decompose at 104";Methyl yield 4.5 g. Methy13s8J*Bsponding cyanide 155 by treatment28 with cuprous161 cyanide.propyl-propyl A is much higher. mixture of 149 g. of the chloride, 57.8 g. of cuprous cyanide It was covered with water and a Methylpinch of silver ethyl oxide was~A~JOJ~ 124 80 added. The mixture was boiled for thirty minutes. Eight and 60 cc. of dry pyridine was heated143 at 21&220° forThe methyl-i-bu tyl is considerably more active grams of potassium hydroxide pelletsMethyl was added and Propyle~a~loJ1*lzthe ninety minutes. 149 When the200 mixture had120 cooled to 150"than it the methyl-n-butyl. A methyl group in the boiling continued for fifteen minutes. A solid was re- was poured into a mixture of 500 g. of ice and 200 cc. of moved by filtration and recrystallizedMethyl from et?. Butyl?It ammonium hydroxide.Liq The402 mixture 72 was allowed4-position to in the cyclohexanone derivative raises stand overnight, and the crude nitrile was collected a formed pale yellow crystals meltingMethyl at 204-205 , ThisAmyl 101 35 118 itson activity, so does the p-methoxy group in the substance was not identified. When the filtrate was acidi- filter and distilled, b. p. 129-130' (4 mm.); m. p. 81-82'; fied the 2,4,6-triisopropylphenylaceticMethyl acid was precipi-Hexyl yield 64%. 88 50 114 methyl-9-methoxyphenyl. The double compound tated. It was recrystallized ff;om75% Methyl acetic acid and then&Propyl Anal. Calcd.194 for C17HzIN:50 C, 83.89;204H, 10.35. Found:from acetonyl-acetone shows as much activity from ligroin; m. p. 146-146.5 . A mixture with an authen- C, 83.40; H, 10.26. tic specimen of the acid (see below)Methyl showed no depressioni-Butyl'*" 153 summary200 116 as any except the propyl-propyl. This is remark- in melting point. Ethyl Ethyl'Jo~lz 204 200 163 able considering its high molecular weight and (b) The hydrolysis of 2,4,6-triisopropylbenzylcyanide Methods of synthesis of hindered aldoketenes could not be effected satisfactorilyPropyl with 50-t3070 sulfuricPropyl'*12 have been studied.154 2000 142 low solubility. acid. The method of Redemann and Lucasl' for the saponification of esters, however, wasButyl found to be suitable.Butyl6 The cis and170.5 trans enol20 benzoates 123 of 5desoxymesi- The estrogenic activities were determined by A mixture of 67 g. of the pure nitrile,Amyl 500 cc. of diethyleneAmyl toin have been148.5 prepared. 10 Hydrolysis94 was foundDr. Geschickter and Dr. Byrne by the standard glycol, 100 g. of potassium hydroxide and 20 cc. of water to convert them to desoxymesitoin, showing that was heated under reflux for twelvec-Pentanone6JJ1 hburs and poured into the cis and trans157 enols of'66 desoxymesitoin 205 weremethod. un- water. The acid, precipi- 2,4,6-triisopropylphenylaceticc-Hexanone6v1Ivla t 14 184 50 198 The melting points of the compounds of the tated by acidification of the mixture, was recrystallized stable and ketonized rapidly. The corresponding from aqueous ethanol; m. p. 144-145';4-Me-He~anone~~t~~J~ yield 85%. cis and trans 179acetates were200 also prepared.149.5 Thesetwo series show alternation, as do those of their Anal. Calcd. for CI7HneOn:C, H, Found: results confirm the conclusion reached earlier that Methyl77.80; 9.99. Phenyl', 119 1% 16 188 0 150 5 benzoates. C,78.08; H, 9.67. the dehydration product of hydromesitoin or iso- Hydrolysis of the nitrile with potassiumMethyl hydroxide p-Me0and hydromesitoin phenyl 245 is 1, 1-dimesitylvinyl 55 221 alcohol. Experimental Benzyl Benzyl16(15) Fuson, Horning,193 Ward, Rowland0 and223 Marsh, THISJOURNAL, (13) This preparation was carried out by Dr. M. L. Ward. The method of preparation was the same for all. The 64, 30 (1942). (14) Redemann and Lucas, Ind. Eng.(CHsC*CHz*)z" Chcm., Anal. Ed., 0, 521 302 d 200 24: ketone and three equivalents of phenol were piit into a (1937). URBANA,ILLINOIS RECEIVEDMARCH 13, glass-stoppered 1944 bottle and concentrated hydrochloric acid the activities drop off sharply as soon as the equal to about one-fifth of the phenol added. The mixture maxima are passed. Symmetry seems to play stood, with dccasional shaking, until the reaction seemed to be complete, which took from a day or two for the The Relation of Estrogenic Activity to Structure in Some 4,4'-Dihydroxydiphenyl-simpler ketones up to twenty weeks for some others. methanes' Hydrogen chloride was passed into the slow. ones from time to time. The condensations went much faster if, instead BY E. EMMETREID AND EDITHWILSON~ J. Am. Chem. Soc.of using 1944 aqueous hydrochloric acid, the ketone-phenol 2000 mixrure was saturated with hydrogen chloride, but the Estrogenic activity has been noted by Dodds of the second series are plotted in Fig. 1. Whenproducts so obtained were harder to purify. The mixtures and LawsonS in some 4,4'-dihydroxydiphenyl- our work was nearly completed, an articleturned by red in any case, but the purified compounds were methanes, (HOCaH6)2CRR'. It seemed worth- Campbell4 covering part of the Same groundcdorless. ap- The reaction product was poured into hot water, while to prepare a number of these to see how the peared. the unxsed reactants driven off with steam, and the residue estrogenic activity varies with the size and char- The activity reaches a peak in the first filteredserieg off or collected in ether according to its physical acter of the groups R and R'. Two series have with the methyl-propyl and in the second seriesstate. a The yields were high, 90% or better, even with the now been made: one, in which R is methyl and much higher peak at the propyl-propyl, whichhigher is ketones if they were given time enough. Acetic R' varies from methyl to hexyl, and the other, ten times as potent as any of the others. acid,The chloroform, acetone and toluene were used as sol- in which R and R' are identical and vary activities for ethyl-propyl and for propyl-butylvents. The low melting coinpounds were hard to purify from methyl to amyl. Besides these several are borrowed from Campbell. For comparisonas they tended to separate from solvents as liquids. Some compounds of different types, including the the data for the corresponding trams-4,4'-di-could be obtained pure only by saponification of the re- double one, (HOCsH&2(CH~)CH~CH~C(CHS)- hydroxy-a,(3-dialkylstilbeness are plotted incrystallized Fig. beiizoates. The benzoates were made by the (CeH40H)2, from acetonyl-acetone have been 1, but they are in rat units per milligram Schotteli-Daumannwhile method. All melting points were studied. In order to have comparable estro- ours are in the same units per gram. The ethyl-determined with the aid of a thermometer calibrated for genic data, the known compounds have been ene derivatives are around a thousand times3-inch as immersion. The analyses of new compounds are active as the methane derivatives, yet the shapes prepared and tested along with the new. For I in Table 11. better chemical characterization the benzoates of the two curves are strikingly- J alike except that of all of them have been prepared. The resultsi.-*-==1.=,- the maximum is at the ethyl-ethyl in the one and TABLEI1 are in Table I. The activities of theR membersMe Me atEt the Et propyl-propyl Pr Pr Buin the Amother. The rise is ANALYSES gradual through the methyl-ethyl in the one and (1) Original manuscript received October 20, 1942.R' Me Et Et Pr Pr Bu Bu Am Carbon, % Hydrogen, % (2) Present address: Biochemical Research Foundation, Newark, through the ethyl-propyl in the other. In both R R' Calcd. Found Calcd. Found Del. Fig. 1.-Estrogenic activity(4) N. R. Campbell,related ibid.,to sizes BlSS, 628of R(1940). and R': (3) Dodds and Lawson, Proc. [email protected],rat SOC. (London). Bins, 222u./g. (HOCsH&CRR';(6) Dodds, Goldberg, Lawsoa --0--- and Robinson, -e--, ibid., (London),Rlcthyl amyl 80.28 79.41 8.45 8.51 (1938). rat u./mg. HOC3,CR:B197, CR'GH40H 140 (1939). XIrthyl hexyl" 80.54 78.50 8.72 8.64 Ik5iizoate XO.(il 79.91 6.77 6.63 (6) Campbell gives m. p. of Bu-Bu 166". (7) Zincke, Ann., Sa,85 (1905) Aiiiyl aniyl 81.17 80.98 9.41 9.50 (8) v. Braun, ibid., 474, 1 (1929). Methyl i-propyl 79.69 79.53 7.81 7.99 (e) Zincke, ibid., 1169, 205 (1908). I-Methyl-c-heranoiie 81.13 81.10 7.47 8.02 (10) Easson, Harrison, McSwiney and Pyman. Quorl J, and Year Methyl p-MeO-phenyl 78.75 78.39 6.25 6.45 Book of Pharmacy, 7, 509 (1934). (11) McGrcal, Niederl and Niederl, TUISJOURNAL, 61,345 (1939). nciizpl benzyl 85.26 85.70 6.31 6.34 (12) Dianin, J. Rusr. Phys.-Chcm. Soc., 28, 488, 523, 601 (1891). (CH~CCHZ-)~ 79.19 79.30 6.60 6.79 (13) Schmidlin and Lang, Ber., 43, 2806 (1910). The low carbon is probably due to adsorbed water. (14) 1. G. Farbenind., German patent 467,728 (1927); [Chrm.ribs., On account of the low m. p. the compound wasdifficult to 48, 1729 (1929).] dry. The bcnzoate gave satisfactory figures. (15) I. G.Farbenind., German patent 604,406 (1932); [Chctn. Abs., 99, 855 (1936).] summary (16) Zincke, Ann., 563, 265, 280 (1908). (17) Amann and Fonrobert, U.S. patent 1,614,172 (1927); [Chrm. A number of 4,4'-dihydroxy-diphenylmethanes, Abs., P1, 805 (1927). J (HOCaH&CRR', have been prepared and their June, 1944 ESTROGENICACTIVITY OF 4,4'-DIHYDROXYDIPHENYLMETHANES 967 anhydrous calcium sulfate and 5 g. of the hydrazone of ethanol produced 2,4,6-triisopropylphenylace~ide. It 2,4,6-triisopropylphenylglyoxal was covered with 75 cc. was recrystallized from ethanol; m. p. 170-171 . of dry ether and stirred for twelve hours at room tempera- Anal. Calcd. for CnHnNO: C, 78.11; H, 10.41. ture. The ether was decanted through a filter paper and Found: C, 78.15; H, 10.57. the black residue washed by decantation with a total of 100 cc. of dry ether. Removal of the ether left the diazo 2,4,6-Triisopropylbenzyl Cye1~ide.~~-2,4,6-Triiiopropyl- compound as a yellow powder, which decomposed ex- benzyl chloride, prepared by the chloromethylation of plosively at 125 '. After recrystallization from methanol 1,3,5-trii~opropylbenzene,~6was converted to the corre- it was found to decompose at 104"; yield 4.5 g. sponding cyanide by treatment with cuprous cyanide. A It was covered with water and a pinch of silver oxide was mixture of 149 g. of the chloride, 57.8 g. of cuprous cyanide added. The mixture was boiled for thirty minutes. Eight and 60 cc. of dry pyridine was heated at 21&220° for grams of potassium hydroxide pellets was added and the ninety minutes. When the mixture had cooled to 150" it boiling continued for fifteen minutes. A solid was re- was poured into a mixture of 500 g. of ice and 200 cc. of moved by filtration and recrystallized from et?. It ammonium hydroxide. The mixture was allowed to stand overnight, and the crude nitrile was collected a formed pale yellow crystals melting at 204-205 , This on substance was not identified. When the filtrate was acidi- filter and distilled, b. p. 129-130' (4 mm.); m. p. 81-82'; fied the 2,4,6-triisopropylphenylacetic acid was precipi- yield 64%. tated. It was recrystallized ff;om75% acetic acid and then Anal. Calcd. for C17HzIN: C, 83.89;H, 10.35. Found: from ligroin; m. p. 146-146.5 . A mixture with an authen- C, 83.40; H, 10.26. tic specimen of the acid (see below) showed no depression in melting point. summary (b) The hydrolysis of 2,4,6-triisopropylbenzylcyanide Methods of synthesis of hindered aldoketenes could not be effected satisfactorily with 50-t3070 sulfuric have been studied. acid. The method of Redemann and Lucasl' for the saponification of esters, however, was found to be suitable. The cis and trans enol benzoates of desoxymesi- A mixture of 67 g. of the pure nitrile, 500 cc. of diethylene toin have been prepared. Hydrolysis was found glycol, 100 g. of potassium hydroxide and 20 cc. of water to convert them to desoxymesitoin, showing that was heated under reflux for twelve hburs and poured into the cis and trans enols of desoxymesitoin were un- water. The 2,4,6-triisopropylphenylaceticacid, precipi- tated by acidification of the mixture, was recrystallized stable and ketonized rapidly. The corresponding from aqueous ethanol; m. p. 144-145'; yield 85%. cis and trans acetates were also prepared. These Anal. Calcd. for CI7HneOn:C, 77.80; H, 9.99. Found: results confirm the conclusion reached earlier that C,78.08; H, 9.67. the dehydration product of hydromesitoin or iso- Hydrolysis of the nitrile with potassium hydroxide and hydromesitoin is 1, 1-dimesitylvinyl alcohol. (15) Fuson, Horning, Ward, Rowland and Marsh, THISJOURNAL, (13) This preparation was carried out by Dr. M. L. Ward. 64, 30 (1942). (14) Redemann and Lucas, Ind. Eng. Chcm., Anal. Ed., 0, 521 (1937). URBANA,ILLINOIS RECEIVEDMARCH 13, 1944

The Relation of Estrogenic Activity to Structure in Some 4,4'-Dihydroxydiphenyl- methanes'

anhydrous calcium sulfate and 5 g. of the hydrazone of ethanol produced 2,4,6-triisopropylphenylace~ide. It 2,4,6-triisopropylphenylglyoxal was covered with 75 cc. was recrystallized from ethanol; m. p. 170-171 . of dry ether and stirred for twelve hours at room tempera- Anal. Calcd. for CnHnNO: C, 78.11; H, 10.41. ture. The ether was decanted through a filter paper and Found: C, 78.15; H, 10.57. the black residue washed by decantation with a total of 100 cc. of dry ether. Removal of the ether left the diazo 2,4,6-Triisopropylbenzyl Cye1~ide.~~-2,4,6-Triiiopropyl- compound as a yellow powder, which decomposed ex- benzyl chloride, prepared by the chloromethylation of plosively at 125 '. After recrystallization from methanol 1,3,5-trii~opropylbenzene,~6was converted to the corre- it was found to decompose at 104"; yield 4.5 g. sponding cyanide by treatment with cuprous cyanide. A It was covered with water and a pinch of silver oxide was mixture of 149 g. of the chloride, 57.8 g. of cuprous cyanide added. The mixture was boiled for thirty minutes. Eight and 60 cc. of dry pyridine was heated at 21&220° for grams of potassium hydroxide pellets was added and the ninety minutes. When the mixture had cooled to 150" it boiling continued for fifteen minutes. A solid was re- was poured into a mixture of 500 g. of ice and 200 cc. of moved by filtration and recrystallized from et?. It ammonium hydroxide. The mixture was allowed to stand overnight, and the crude nitrile was collected a formed pale yellow crystals melting at 204-205 , This on substance was not identified. When the filtrate was acidi- filter and distilled, b. p. 129-130' (4 mm.); m. p. 81-82'; fied the 2,4,6-triisopropylphenylacetic acid was precipi- yield 64%. tated. It was recrystallized ff;om75% acetic acid and then Anal. Calcd. for C17HzIN: C, 83.89;H, 10.35. Found: from ligroin; m. p. 146-146.5 . A mixture with an authen- C, 83.40; H, 10.26. tic specimen of the acid (see below) showed no depression in melting point. summary (b) The hydrolysis of 2,4,6-triisopropylbenzylcyanide Methods of synthesis of hindered aldoketenes could not be effected satisfactorily with 50-t3070 sulfuric have been studied. acid. The method of Redemann and Lucasl' for the saponification of esters, however, was found to be suitable. The cis and trans enol benzoates of desoxymesi- A mixture of 67 g. of the pure nitrile, 500 cc. of diethylene toin have been prepared. Hydrolysis was found glycol, 100 g. of potassium hydroxide and 20 cc. of water to convert them to desoxymesitoin, showing that was heated under reflux for twelve hburs and poured into the cis and trans enols of desoxymesitoin were un- water. The 2,4,6-triisopropylphenylaceticacid, precipi- tated by acidification of the mixture, was recrystallized stable and ketonized rapidly. The corresponding from aqueous ethanol; m. p. 144-145'; yield 85%. cis and trans acetates were also prepared. These Anal. Calcd. for CI7HneOn:C, 77.80; H, 9.99. Found: results confirm the conclusion reached earlier that C,78.08; H, 9.67. the dehydration product of hydromesitoin or iso- Hydrolysis of the nitrile with potassium hydroxide and hydromesitoin is 1, 1-dimesitylvinyl alcohol. (15) Fuson, Horning, Ward, Rowland and Marsh, THISJOURNAL, (13) This preparation was carried out by Dr. M. L. Ward. 64, 30 (1942). (14) Redemann and Lucas, Ind. Eng. Chcm., Anal. Ed., 0, 521 (1937). URBANA,ILLINOIS RECEIVEDMARCH 13, 1944

The Relation of Estrogenic Activity to Structure in Some 4,4'-Dihydroxydiphenyl- methanes'

acter of the groups RSTRUCTURE and R'. Two series AND have THEIRwith the methyl-propyl ACTIVITY and in the second series a ULRICH xij now been made: one, in which R is methylA i and much higher peak at the propyl-propyl, which is R' varies from methyl to hexyl, andULRICH the other, V. SOLMSSENten times as potent as any of the others. The M V. in 0 which R and R' are identical and vary activities for ethyl-propyl and for propyl-butyl

from Researchmethyl to Laboratories amyl. Besides of these Hoffman several-La areRoche, borrowed Inc., from Nutley Campbell. 10, New For Jersey comparison SOLMSSE?; compounds of different types, including the the data for the corresponding trams-4,4'-di-

ci k double one, (HOCsH&2(CH~)CH~CH~C(CHS)- Received Aprilhydroxy-a,(3-dialkylstilbeness 13, 1945 are plotted in Fig. (CeH40H)2, from acetonyl-acetone have been 1, but they are in rat units perChem. milligram Rev. while 1945 studied. In order to have comparable estro- ours are in the same units per gram. The ethyl- 8 2 h genic data, the known compounds have been ene derivatives are around a thousand times as3 prepared and tested along with the new. For active as the methane derivatives, yet the shapes better chemical characterization the benzoates of the two curves are strikingly alike except that of all of them have been prepared. The results the maximum is at the ethyl-ethyl in the one and are in Table I. The activities of the members at the propyl-propyl in the other. The rise is gradual through the methyl-ethyl in the one and (1) Original manuscript received October 20, 1942. (2) Present address: Biochemical Research Foundation, Newark, through the ethyl-propyl in the other. In both Del. (4) N. R. Campbell, ibid., BlSS, 628 (1940). (3) Dodds and Lawson, Proc. Roy. SOC. (London). Bins, 222 (6) Dodds, Goldberg, Lawsoa and Robinson, ibid., (London), (1938). B197, 140 (1939). June, 1944 ESTROGENICACTIVITY OF 4,4'-DIHYDROXYDIPHENYLMETHANES 967

The Relation of Estrogenic Activity to Structure in Some 4,4'-Dihydroxydiphenyl- methanes'

About Bisphenol A >> Information Sheets Join the Bisphenol- A mailing list. Bisphenol A Synthesis and Use email address About Bisphenol A What Is BPA? Submit More Info Human Health & Safety

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Thomas Zincke of the University of Marburg, Germany, first reported synthesis of bisphenol+ A. Zincke acknowledged in his paper that the synthesis of BPA, from phenol and acetone, was based on chemical reactions previously reported by others as well as unpublished work (from thesis dissertations) conducted at the University of Marburg. His paper reporting the synthesisА. Dianin of ,BPA1891 and, J. a Russiannumber of Physical related compounds Chemistry was Society, published23 in: 1905.488-517. (Zincke, T., 1905, "Mittheilungen aus dem chemischen Laboratorium der Universitat Marburg," Justus Leibigs Annals Chemie, Prolongedvol. 343, pages 75-99). Endocrine Zincke reported key physical properties of BPAX (e.g.,= molecularoestrus composition,= melting point, solubility in common solvents) but did not propose any activity application or use for BPA or the other materials he synthesized..(40 days)

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Thomas Zincke of the UniversityO of Marburg, Germany, first reported NaOH O O synthesis of bisphenol(Sodium A. ZinckeCl acknowledgedCl in his paper that the synthesis Hydroxide) (Phosgene) HO of BPA, from OHphenol and acetone, was basedO on chemicalO reactionsO O previouslyBisphenol A reported by HothersO, 25 o Cas well as unpublished work (from thesis 2 Bisphenol A Polycarbonate dissertations) conducted at the University of Marburg. His paper reporting the synthesis of BPA and a number of related compounds was published in 1905. (Zincke, T., 1905, "Mittheilungen aus dem chemischen Laboratorium der Universitat Marburg," Justus Leibigs Annals Chemie, vol. 343, pages 75-99).

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Thomas Zincke of the University of Marburg, Germany, first reported synthesis of bisphenol+ A. Zincke acknowledged in his paper that the synthesis of BPA, from phenol and acetone, was based on chemical reactions previously reported by others as well as unpublished work (from thesis dissertations) conducted at the University of Marburg. His paper reporting the synthesisА. Dianin of ,BPA1891 and, J. a Russiannumber of Physical related compounds Chemistry was Society, published23 in: 1905.488-517. (Zincke, T., 1905, "Mittheilungen aus dem chemischen Laboratorium der Universitat Marburg," Justus Leibigs Annals Chemie, vol. 343, pages 75-99). Prolonged Zincke reported key physical properties of BPA (e.g., molecular composition, melting point, solubility in common solvents) but did not propose= anyoestrus application or use for BPA or the other materials he synthesized..(40 days) Bisphenol A Developed Commercially in the 1950s

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А. Dianin, 1891, J. Russian Physical Chemistry Society, 23: 488-517.

Prolonged Endocrine X = oestrus = activity (40 days) Contaminated RCF Products Contaminated RCF Products • Newspapers Contaminated RCF Products • Newspapers • Toilet Paper Contaminated RCF Products • Newspapers • Toilet Paper Contaminated RCF Products • Newspapers • Toilet Paper • Pizza Boxes Contaminated RCF Products • Newspapers • Toilet Paper • Pizza Boxes • Fried Chicken Boxes Contaminated RCF Products • Newspapers • Toilet Paper • Pizza Boxes • Fried Chicken Boxes • Fried Potato Boxes Contaminated RCF Products • Newspapers • Toilet Paper • Pizza Boxes • Fried Chicken Boxes • Fried Potato Boxes • Sandwich Boxes Contaminated RCF Products • Newspapers • Toilet Paper • Pizza Boxes • Fried Chicken Boxes • Fried Potato Boxes • Sandwich Boxes • Noodle Cups Contaminated RCF Products • Newspapers • Toilet Paper • Pizza Boxes • Fried Chicken Boxes • Fried Potato Boxes • Sandwich Boxes • Noodle Cups • Confectionary Boxes Contaminated RCF Products • Newspapers • Toilet Paper • Pizza Boxes • Fried Chicken Boxes • Fried Potato Boxes • Sandwich Boxes • Noodle Cups • Confectionary Boxes • General Food Storage Boxes Contaminated RCF Products • Newspapers • Toilet Paper • Pizza Boxes • Fried Chicken Boxes • Fried Potato Boxes • Sandwich Boxes • Noodle Cups • Confectionary Boxes • General Food Storage Boxes Liao 2011 Gehring 2004 Ozaki 2004 Lopez-Espinosa 2007 USEPA 2015