ANNEX 1 CHEMICAL AND PHYSICAL DATA ON COMPOUNDS USED IN COMBINED ESTROGEN–PROGESTOGEN CONTRACEPTIVES AND HORMONAL MENOPAUSAL THERAPY Annex 1 describes the chemical and physical data, technical products, trends in produc- tion by region and uses of estrogens and progestogens in combined estrogen–progestogen contraceptives and hormonal menopausal therapy. Estrogens and progestogens are listed separately in alphabetical order. Trade names for these compounds alone and in combination are given in Annexes 2–4. Sales are listed according to the regions designated by WHO. These are: Africa: Algeria, Angola, Benin, Botswana, Burkina Faso, Burundi, Cameroon, Cape Verde, Central African Republic, Chad, Comoros, Congo, Côte d'Ivoire, Democratic Republic of the Congo, Equatorial Guinea, Eritrea, Ethiopia, Gabon, Gambia, Ghana, Guinea, Guinea-Bissau, Kenya, Lesotho, Liberia, Madagascar, Malawi, Mali, Mauritania, Mauritius, Mozambique, Namibia, Niger, Nigeria, Rwanda, Sao Tome and Principe, Senegal, Seychelles, Sierra Leone, South Africa, Swaziland, Togo, Uganda, United Republic of Tanzania, Zambia and Zimbabwe America (North): Canada, Central America (Antigua and Barbuda, Bahamas, Barbados, Belize, Costa Rica, Cuba, Dominica, El Salvador, Grenada, Guatemala, Haiti, Honduras, Jamaica, Mexico, Nicaragua, Panama, Puerto Rico, Saint Kitts and Nevis, Saint Lucia, Saint Vincent and the Grenadines, Suriname, Trinidad and Tobago), United States of America America (South): Argentina, Bolivia, Brazil, Chile, Colombia, Dominican Republic, Ecuador, Guyana, Paraguay, Peru, Uruguay, Venezuela Eastern Mediterranean: Afghanistan, Bahrain, Djibouti, Egypt, Iran (Islamic Republic of), Iraq, Jordan, Kuwait, Lebanon, Libyan Arab Jamahiriya, Morocco, Oman, Pakistan, Qatar, Saudi Arabia, Somalia, Sudan, Syrian Arab Republic, Tunisia, United Arab Emi- rates, Yemen Europe: Albania, Andorra, Armenia, Austria, Azerbaijan, Belarus, Belgium, Bosnia and Herzegovina, Bulgaria, Croatia, Cyprus, Czech Republic, Denmark, Estonia, Finland, France, Georgia, Germany, Greece, Hungary, Iceland, Ireland, Israel, Italy, Kazakhstan, Kyrgyzstan, Latvia, Lithuania, Luxembourg, Malta, Monaco, Netherlands, Norway, Poland, Portugal, Republic of Moldova, Romania, Russian Federation, San Marino, –375– 376 IARC MONOGRAPHS VOLUME 91 Serbia and Montenegro, Slovakia, Slovenia, Spain, Sweden, Switzerland, Tajikistan, The Former Yugoslav Republic of Macedonia, Turkey, Turkmenistan, Ukraine, United Kingdom of Great Britain and Northern Ireland, Uzbekistan South-East Asia: Bangladesh, Bhutan, Democratic People’s Republic of Korea, Democratic Republic of Timor-Leste, India, Indonesia, Maldives, Myanmar, Nepal, Sri Lanka, Thailand Western Pacific: Australia, Brunei Darussalam, Cambodia, China, Cook Islands, Fiji, Japan, Kiribati, Lao People’s Democratic Republic, Malaysia, Marshall Islands, Micro- nesia (Federated States of), Mongolia, Nauru, New Zealand, Niue, Palau, Papua New Guinea, Philippines, Republic of Korea, Samoa, Singapore, Solomon Islands, Tokelau, Tonga, Tuvalu, Vanuatu, Viet Nam 1. Estrogens 1.1 Conjugated estrogens The term ‘conjugated estrogens’ refers to mixtures of at least eight compounds, inclu- ding sodium estrone sulfate and sodium equilin sulfate, that are derived wholly or in part from equine urine, are plant-based or are manufactured synthetically from estrone and equilin. Conjugated estrogens contain as concomitant components the sodium sulfate conjugates of 17α-dihydroequilin, 17β-dihydroequilin and 17α-estradiol (Pharmacopeial Convention, 2004). 1.1.1 Nomenclature Sodium estrone sulfate Chem. Abstr. Serv. Reg. No.: 438-67-5 Chem. Abstr. Name: 3-(Sulfooxy)-estra-1,3,5(10)-trien-17-one, sodium salt IUPAC Systematic Name: Estrone, hydrogen sulfate sodium salt Synonyms: Estrone sodium sulfate; estrone sulfate sodium; estrone sulfate sodium salt; oestrone sodium sulfate; oestrone sulfate sodium; oestrone sulfate sodium salt; sodium estrone sulfate; sodium estrone-3-sulfate; sodium oestrone sulfate; sodium oestrone-3- sulfate; 3-sulfatoxyestra-1,3,5(10)-trien-17-one, sodium salt Sodium equilin sulfate Chem. Abstr. Serv. Reg. No.: 16680-47-0 Chem. Abstr. Name: 3-(Sulfooxy)-estra-1,3,5(10),7-tetraen-17-one, sodium salt IUPAC Systematic Name: 3-Hydroxyestra-1,3,5(10),7-tetraen-17-one, hydrogen sulfate, sodium salt Synonyms: Equilin, sulfate, sodium salt; equilin sodium sulfate; sodium equilin 3-mono- sulfate; sodium equilin sulfate ANNEX 1 377 1.1.2 Structural and molecular formulae and relative molecular mass Sodium estrone sulfate O CH3 H HH NaO SO 3 C18H21O5S.Na Relative molecular mass: 372.4 Sodium equilin sulfate O CH3 HH NaO SO 3 C18H19O5S.Na Relative molecular mass: 370.4 1.1.3 Chemical and physical properties From Gennaro (2000) and American Hospital Formulary Service (2005) (a) Description: Buff-coloured, odourless or with a slight characteristic odour, amorphous powder (from natural sources); white to light buff, odourless or with a slight odour, crystalline or amorphous powder (synthetic) (b) Solubility: Soluble in water 1.1.4 Technical products and impurities Conjugated estrogens contain 52.5% min. and 61.5% max. sodium estrone sulfate and 22.5% min. and 30.5% max. sodium equilin sulfate; the total of sodium estrone sulfate and sodium equilin sulfate is 79.5% min. and 88.0% max. of the labelled content of conjugated estrogens. Conjugated estrogens contain as concomitant components (as sodium sulfate conjugates) 13.5% min. and 19.5% max. 17α-dihydroequilin, 0.5% min. and 4.0% max. 17β-dihydroequilin and 2.5% min. and 9.5% max. 17α-estradiol of the labelled content of conjugated estrogens (Pharmacopeial Convention, 2004). Conjugated estrogens are available as tablets for oral administration, as a liquid for parenteral injection and as a 0.0625% vaginal cream (American Hospital Formulary Service, 2005). 378 IARC MONOGRAPHS VOLUME 91 Conjugated estrogens (natural) are a mixture that contains the sodium salts of the water- soluble sulfate esters of estrone and equilin derived wholly or in part from equine urine or prepared synthetically from estrone and equilin. Conjugated estrogens (natural) also contain conjugated estrogenic substances of types that are excreted by pregnant mares and include δ8,9-dehydroestrone, 17α-dihydroequilenin, 17β-dihydroequilenin, 17α-dihydroequilin, 17β-dihydroequilin, equilenin, 17α-estradiol and 17β-estradiol (American Hospital Formu- lary Service, 2005). Conjugated estrogens (synthetic) are a mixture of conjugated estrogens that are prepared synthetically from plant sources (i.e. soya and yams). Conjugated estrogens (synthetic) are commercially available as preparations that contain a mixture of nine of the 10 known con- jugated estrogenic substances that are present in currently available commercial prepara- tions of conjugated estrogens (natural). However, in contrast to currently available prepara- tions of conjugated estrogens (natural), the conjugated estrogenic substances present in conjugated estrogens (synthetic) are prepared entirely synthetically (American Hospital Formulary Service, 2005). 1.1.5 Use Conjugated estrogens are used mainly in the treatment of menopausal disorders (e.g. vasomotor symptoms, vulvar and vaginal atrophy) and for the prevention and treatment of osteoporosis. Conjugated estrogens are usually administered orally at a dose of 0.3– 1.25 mg/day (American Hospital Formulary Service, 2005). Table 1 presents comparative global data on sales of conjugated estrogens in 1994, 1999 and 2004 (IMS Health, 2005). The regions are broadly as those defined by WHO. Table 1. Conjugated estrogens used in combined estrogen– progestogen menopausal therapy (thousands of standard unitsa) Region 1994 1999 2004 Africa 7 980 10 814 9 780 Eastern Mediterranean 51 3 102 1 683 Europe 448 555 508 776 192 332 North America 9 250 1 039 067 217 181 South America 15 330 103 701 32 713 South-East Asia 1 162 1 992 9 555 Western Pacific 17 521 70 675 27 576 Total 499 848 1 738 126 490 820 From IMS Health (2005) a Standard units are sales in terms of standard dose units; the standard dose unit for oral products is one tablet or capsule. ANNEX 1 379 1.2 Ethinylestradiol 1.2.1 Nomenclature Chem. Abstr. Serv. Reg. No.: 57-63-6 Deleted CAS Reg. No.: 77538-56-8; 406932-93-2 Chem. Abstr. Name: (17α)-19-Norpregna-1,3,5(10)-trien-20-yne-3,17-diol IUPAC Systematic Name: 19-Nor-17α-pregna-1,3,5(10)-trien-20-yne-3,17-diol Synonyms: Ethinylestradiol; 17-ethinylestradiol; 17-ethinyl-3,17-estradiol; 17α-ethi- nyl-3,17-dihydroxy-Δ1,3,5-estratriene; 17α-ethinylestradiol; 17α-ethinyl-17β-estra- diol; 17α-ethinylestra-1,3,5(10)-triene-3,17β-diol; 17α-ethinyl-1,3,5(10)-estratriene- 3,17-diol; ethinyloestradiol; 17-ethynyl-3,17-dihydroxy-1,3,5-oestratrione; ethynyl- estradiol; 17-ethynylestradiol; 17α-ethynylestradiol; 17-ethynylestra-1,3,5(10)-triene- 3,17β-diol; ethynyloestradiol; 19-Nor-17α-pregna-1,3,5(10)-trien-20-yne-3,17β-diol 1.2.2 Structural and molecular formulae and relative molecular mass OH CH3 C CH H HH HO C20H24O2 Relative molecular mass: 296.4 1.2.3 Chemical and physical properties of the pure substance From O’Neil (2001) and Sweetman (2005), unless otherwise specified (a) Description: White to creamy or slightly yellowish white, odourless, crystalline powder (b) Melting-point: 182–184 °C (c) Solubility: Practically insoluble in water; soluble in acetone (1 part in 5), ethanol (1 part in 6), chloroform (1 part in 20), dioxane (1 part in 4), diethyl ether (1 part in 4) and vegetable oils α 20 ° ° (d) Optical rotation: [ ]D , less than –27 to