Formulating With Safer Alkanolamine Options. 06 July 2016, Wednesday Innovation Seminar Theatre Dr. Yeo Kim Long

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2 Formulating With Safer Alkanolamine Options 06 July 2016, Wednesday Innovation Seminar Theatre Dr. Yeo Kim Long

3 Overview Introduction to ANGUS Nitrosamines Formation of nitrosamines Nitrosamines are harmful The ANGUS Solution 3

4 Legacy of Making the Best Better The world s only company dedicated to nitroalkanes and their derivatives Unique production expertise spanning over 70 years Extensive track record of industry innovation and leadership Solutions-driven, multifunctional additives for a broad range of applications and markets Regional Customer Application Centers to address the local needs of our customers Strong focus on Responsible Care and product stewardship Year 1928 Event Purdue University chemist Henry B. Hass begins nitroalkanes research 1934 First nitroalkane patent granted 1935 Commercial Solvents Corporation (CSC) enters licensing agreement with Purdue University 1940 CSC begins commercial nitroalkane production International Minerals and Chemical Corporation (IMC) purchases CSC and creates separate nitroalkanes division Alberta Natural Gas buys nitroalkanes business, forming ANGUS Chemical Company 1999 Dow Chemical purchases ANGUS 2014 ANGUS AMP granted VOC-exempt status 2015 Golden Gate Capital (GGC) investment group seeks to unleash the growth potential of ANGUS 4

5 Chemistry ANGUS is the only manufacturer in the world that uses propane nitration technology to create a unique set of products. Propane Technology innovator with over 70 years of nitration expertise Nitroalkanes (Nitromethane, Nitroethane) Nitration of propane yields our nitroalkane products Nitroalcohols Nitroalcohols are formed via the reaction of nitroalkanes and aldehydes Aminoalcohols (AMP, TRIS AMINO ) Aminoalcohols are formed via the reduction of nitroalcohols Aminoalcohol Derivatives (ZOLDINE, ALKATERGE ) Aminoalcohols are converted to derivatives via reactions with aldehydes or carboxylic acids 5

6 Key Market Focus Personal Care Life Sciences Industrial Specialties ANGUS is focused and aligned to drive innovation, enabling ANGUS and our customers to deliver sustainable growth. 6

7 Global Reach, Local Focus 7

8 Nitrosamine 8

9 Nitrosamines What is it? Can be converted from primary, secondary and tertiary amines by nitrosating agents under physiological conditions Secondary and tertiary amines form very stable nitrosamines 9

10 Nitrosamines What is it? Presence of an α-hydrogen permits formation of a very stable carcinogenic nitrosamine α-h present α-h absent Tromethamine CAS Triethanolamine CAS

11 Common Carcinogenic nitrosamines Nitrosamine N-nitrosodiethanolamine (NDELA) N-nitrosobis (2-hydroxypropyl)amine (NBHPA) N-nitrosodiisopropanolamine N-nitrosomorpholine N-nitrosomethylstearylamine Source DEA/TEA BHPA DIPA Morpholine Dimethylstearylamine 11

12 Nitrosamine Formation 12

13 Common Nitrosating Agents: Species Acidic medium Neutral medium Slightly basic medium (ph = 7.5) H 2 ONO + NO + *YNO HNO 2 N 2 O 3 Y is a non-basic nucleophile. It can be neutral as well. Nitrite (NO 2- ) and nitrous acid (HNO 2 ) are the primary precursors of nitrosating agents 13

14 Overview of Generating Nitrosating Agents N 2 O 3 Active nitrosating agents are underlined M. L. Douglass, B. L. Kabacoff, G. A. Anderson, M. C. Cheng, The chemistry of nitrosamine formation, inhibition and destruction. (1978). Journal of the Society of Cosmetic Chemists, 29(9),

15 Generation of N 2 O 3 NO X NO/NO 2 (from the environment) HNO 2 2 NO H 2 O 2 HNO 2 + H 2 O NO + NO 2 + H 2 O 2 HNO 2 NO 2 - Hydrolysis of NO x HNO 2 H + + NO 2-15

16 Generation of N 2 O 3 In neutral or alkaline environment, NO x forms nitrites M. L. Douglass, B. L. Kabacoff, G. A. Anderson, M. C. Cheng, The chemistry of nitrosamine formation, inhibition and destruction. (1978). Journal of the Society of Cosmetic Chemists, 29(9),

17 Sources of NOx Industrial Transportation 17 Agriculture

18 Secondary Amine Nitrosation Most reactive to nitrosation out of the different classes of amines Kane Ikeda and Kenneth G. Migliorese, Helene Curtis, Analysis of nitrosamines in cosmetics. (1990). J. Soc. Cosmet. Chem, 41,

19 Tertiary Amine Nitrosation Tertiary amine converts to a secondary amine that will follow the same nitrosation pathway of secondary amine Iminium ion M. L. Douglass, B. L. Kabacoff, G. A. Anderson, M. C. Cheng, The chemistry of nitrosamine formation, inhibition and destruction. (1978). Journal of the Society of Cosmetic Chemists, 29(9), Kane Ikeda and Kenneth G. Migliore, Helene Curtis, Analysis of nitrosamines in cosmetics. (1990). J. Soc. Cosmet. Chem, 41,

20 Primary Amine Nitrosation Attacks N instead of O. O is more electronegative; hence the electron density of the triple bond will be more attracted to O than N. This makes N more electron deficient more prone to nucleophilic attack by amine Will be converted into Nitrogen, Alcohols and Alkenes in the presence of nucleophile 20

21 Secondary and Tertiary amines Convert into Stable Nitrosamines 21

22 Why Should We Be Concerned? 22

23 Nitrosamines are Harmful 23

24 Why should we be concerned? 80-90% of N-nitroso compounds are carcinogenic 1,2 Environmental level exposure may lead to the formation of malignant tumors (cancer). Organisation International Agency for Research on Cancer (IARC) European Union (EU) Environmental Protection Agency (EPA) Classification Group 2A Probably carcinogenic to humans Category 2 - Presumed to have carcinogenic potential for humans largely based on animals evidence Likely to be carcinogenic to humans Nitrosation of volatile amines at the workplace [MAK Value Documentation, 1990]. The MAK Collection for Occupational Health and Safety Ikeda and Migliorese. (1990). Analysis Of Nitrosamines In Cosmetics. J. Soc. Cosmet. Chem., 41, pp

25 Nitrosamines May Cause Cancer 25

26 Cancer Formation Overview DNA mutation Mutant protein formation Cell cycle dysregulation Uncontrolled cell division and growth 26

27 The Central Dogma Fidelity of DNA and RNA critical to ensure correct amino acid added during protein synthesis 27

28 Point Mutation Due to Nitrosamines Preferred Non-preferred Formation of diazonium cation from nitrosamine via Cyt P450 O(6)-methylation of guanine (G) O(6)-methylguanine (meg) preferentially pairs with thymidine (T) instead of cytidine (C) 28

29 Point Mutation Due to Nitrosamines meg A base pair mismatch results in propagation of genetic code error G T T C A A mg T T C A A * If error uncorrected mg T T TA A A T T T A A O(6)-methylation of guanine Complementary strand will be replicated as ATT Unstable mg C base pairing During DNA replication, mg forms more stable base pair with T Genetic code is now TAA instead of CAA T instead of C is added 29

30 Cancer Formation Base pair mismatch results in wrong message DNA G T T C A A RNA C A A Amino acid Glycine mg T T C A A mg T T TA A O(6)-methylation Replication * If error uncorrected Replication A T T T A A UAA STOP 30

31 Cancer Formation Base pair mismatch results in malformed proteins DNA G T T C A A RNA C A A Amino acid Glycine mg T T C A A mg T T TA A * If error uncorrected A T T T A A UAA STOP A 38 amino acid protein may become a 30 amino acid mutant protein Mutant protein cannot function properly 31

32 Nitrosamines May Cause Cancer Secondary amines like DEA, and tertiary amines like TEA, can be easily converted into stable nitrosamines Cytochrome P450 in the body converts nitrosamines into diazonium ions Diazonium ions cause O(6)-methylation of guanine O(6)-methylated guanine mismatches with thymidine instead of cytidine 32

33 Nitrosamines May Cause Cancer Nonsense mutation can result in the formation of mutant protein Mutant protein can be critical to cell cycle control Uncontrolled cell division 33

34 The ANGUS Solution 34

35 ANGUS ULTRA PC TM Primary Amines Primary Amine Functionality CH 3 CH 3 C CH 2 OH NH 2 HOCH 2 HOCH 2 CH 3 CH 2 OH C CH 2 OH C CH 2 OH NH 2 NH 2 AMP-ULTRA TM PC INCI: aminomethyl propanol CAS: EiNECS: AMPD TM ULTRA PC INCI: aminomethyl propanediol CAS: EiNECS: TRIS AMINO TM ULTRA PC INCI: Tromethamine CAS: EiNECS: No α-hydrogen 35

36 Globally-compliant European Cosmetics Regulation 1223/2009 (replacing European Cosmetics Directive 76/768/EEC and its latest amendments) Brazil ANVISA Mercosur Resolution on Cosmetics and Personal Care Products The Ministry of Health (MOH) of the People s Republic of China Hygienic Standards for Cosmetics (2007 version) KOREA: A KFDA revision of the regulations on cosmetic raw materials ( ) The 2008 ASEAN Cosmetics Directive (Annex updated Feb-2011) Minimum Purity 99% Maximum secondary amine content 0.5% Maximum nitrosamine content 50 µg/kg (ppb) Must store in nitrite-free containers 36

37 Globally Compliant REACH-registered Compliant with global chemical control inventories USA - TSCA Canada - DSL EU - EINECS China - IECSC Taiwan Japan - ENCS Korea - KECI Philippines - PICCS Australia - AICS New Zealand - NZIOC 37

38 Globally Compliant and High Purity Product pka Mw Appearance FP/MP, 0 C AMP-ULTRA TM PC 1000 INCI: aminomethyl propanol Anhydrous solid 30 AMP-ULTRA TM PC 2000 INCI: aminomethyl propanol Low viscositiy liquid (5% water) 13 AMP-ULTRA TM PC 3000 INCI: aminomethyl propanol Low viscosity liquid (11% water) -3 AMPD TM ULTRA PC INCI: aminomethyl propandiol Crystalline solid 100 TRIS AMINO TM ULTRA PC INCI: tromethamine Crystalline solid

39 Global Reach, Local Focus 39

40 Conclusion Secondary and tertiary amines may convert into stable nitrosamine Nitrosamines may induce nonsense mutations in the genome, resulting in mutant proteins Mutant proteins may induce cancer formation ANGUS ULTRA PC TM range of primary amines are globally compliant solutions to avoid nitrosamine formation in formulated personal care products ANGUS provides global support for your formulating needs 40

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42 Thank You. Questions? ANGUS 42 Confidential - Do not share without permission