Dechloro Dihydroxy Difluoro Ethylcloprostenolamide

Hazard statements (CLP)

H225, H302, H319, H360

Code

Statements

H225

Highly Flammable liquid and vapour

SECTION 2: Hazards identification

Classification of the substance or mixture

Signal word

Warning

Hazard statements

H225 Highly flammable liquid and vapor. H302 Harmful if swallowed. H319 Causes serious eye irritation. H360 May damage fertility or the unborn child.

Prevention

P201 Obtain special instructions before use. P210 No smoking. Keep away from heat, sparks, open flames, and hot surfaces. P264 Wash skin thoroughly after handling. P270 Do not eat, drink or smoke when using this product. P280 Wear protective gloves/ eye protection/ face protection.

Response

P301, P312 If swallowed, call a Poison Center or doctor if you feel unwell. P308, P313 If exposed or concerned, get medical attention/advice. P330 Rinse mouth. P305, P351, P338 If case of contact with eyes, flush eyes with plenty of water. After initial flushing, remove contact lenses, if present. Continue rinsing for several minutes. P337, P313 If eye irritation persists, get medical advice/ attention. 370, P378 In case of fire: Use dry sand, dry chemical or alcohol‐resistant foam to extinguish. P405, P233, P235 Store in well‐ventilated place. Keep container tightly closed. Keep cool. P501 Dispose of contents/ container to an approved waste disposal plant.

2.1 Classification of the substance or mixture

GHS Classification in accordance with 29 CFR 1910 (OSHA HCS) Flammable liquids, (Category 2) Eye irritation (Category 2A), H319 Acute toxicity, Oral (Category 4), H302 Toxic to reproduction, (Category 1B), H360 Target organ systemic toxicity, (Category 3) 2.2 GHS Label elements, including precautionary statements Pictogram: Signal word: Warning Hazard statements: H225 Highly flammable liquid and vapor. H302 Harmful if swallowed. H319 Causes serious eye irritation. H360 May damage fertility or the unborn child. Prevention statements: P201 Obtain special instructions before use. P210 No smoking. Keep away from heat, sparks, open flames, and hot surfaces. P264 Wash skin thoroughly after handling. P270 Do not eat, drink or smoke when using this product. P280 Wear protective gloves/ eye protection/ face protection. Response statements: P301, P312 If swallowed, call a Poison Center or doctor if you feel unwell. P308, P313 If exposed or concerned, get medical attention/advice. P330 Rinse mouth. P305, P351, P338 If case of contact with eyes, flush eyes with plenty of water. After initial flushing, remove contact lenses, if present. Continue rinsing for several minutes. P337, P313 If eye irritation persists, get medical advice/ attention. 370, P378 In case of fire: Use dry sand, dry chemical or alcohol‐resistant foam to extinguish. P405, P233, P235 Store in well‐ventilated place. Keep container tightly closed. Keep cool. P501 Dispose of contents/ container to an approved waste disposal plant. _____________________________________________________________________________ Section 3: Composition/Information on Ingredients 3.1 Hazardous Components CAS # Chemical Name Composition 1185851‐52‐8 Dechloro Dihydroxy Difluoro Ethylcloprostenolamide (3D) 10.0% 64‐17‐5 Ethyl alcohol 90.0% For the full text of the H‐Statements, see Section 16 _____________________________________________________________________________ Section 4: First Aid Measures 4.1 General Advice: Consult a physician. Show this safety data sheet to the doctor. Move out of dangerous area. If Inhaled: Move person into fresh air. If not breathing, give artificial respiration. Consult a physician. In case of skin contact: Wash off with soap and plenty of water. Remove contaminated clothing/ shoes, and consult a physician if symptoms occur. Wash clothing before reuse. In case of eye contact: Rinse eyes thoroughly with plenty of water for at least 15 minutes. Have eyes examined by medical personnel. If swallowed: Never give anything by mouth to an unconscious person. Rinse mouth with water. Consult a physician. Do NOT induce vomiting unless directed to do so by medical personnel. 4.2 Most important symptoms and effects, both acute and delayed The most important symptoms and effects are described in the labelling (see section 2.2) and/or in section 11. Exposure can cause: diarrhea, dizziness, fever, flushing, headache, hypotension, nausea, shivering, vomiting. May cause anemia, cough, CNS depression, drowsiness, headache, heart damage, lassitude, liver damage, narcosis, reproductive effects, and/or teratogenic effects. 4.3 Indication of any immediate medical attention and special treatment needed No data available. _____________________________________________________________________________ Section 5: Fire Fighting Measures 5.1 Extinguishing media Suitable media: Use water spray, alcohol‐resistant foam, dry chemical or carbon dioxide. Unsuitable media: A solid water stream may be insufficient. 5.2 Flammable properties and hazards Can release vapors that form explosive mixtures at temperatures at or above the flashpoint. Container explosion may occur under fire conditions. Emits toxic fumes under fire conditions. Sensitive to static discharge. Vapors can travel to a source of ignition and flash back. Hazardous decomposition products (carbon oxides) formed under fire conditions. Flash point: 14oC (closed cup) Autoignition: 393oC Explosive limits: LEL: 3.3% at 25oC UEL: 19.0% at 25oC 5.3 Advice for firefighters Wear self‐contained breathing apparatus for firefighting if necessary. Wear full protective gear to prevent contact with skin and eyes. Material is flammable as it is diluted in ethyl alcohol. 5.4 Further Information Use water spray to cool unopened, fire‐exposed containers. _____________________________________________________________________________ Section 6: Accidental Release Measures 6.1 Personal precautions, protective equipment and emergency procedures Use personal protective equipment. Avoid breathing vapors, mist or gas. Ensure adequate ventilation. Remove all sources of ignition. Evacuate personnel to safe location. Beware of vapors accumulating to form explosive concentrations. Vapors can accumulate in low areas. For personal protection see section 8. 6.2 Environmental precautions Do not let product enter drains. 6.3 Methods and materials for containment and cleaning up Soak up with inert absorbent material and dispose of as hazardous waste. Keep in suitable, closed containers for disposal. Dispose of according to local regulations. _____________________________________________________________________________ Section 7: Handling and Storage 7.1 Precautions for safe handling Avoid contact with skin and eyes. Avoid inhalation of vapor or mist. Use explosion‐proof equipment. Keep away from sources of ignition ‐ No smoking. Take measures to prevent the buildup of electrostatic charge. For precautions see section 2.2. 7.2 Conditions for safe storage, including any incompatibilities Keep container tightly closed in a cool, dry and well‐ventilated place. Keep away from heat, sparks, and flame. Recommended storage temperature 2‐8°C. Store under inert gas. Hygroscopic. 7.3 Specific end use(s) Apart from the uses mentioned in section 1.2 no other specific uses are stipulated. _____________________________________________________________________________ Section 8: Exposure Controls/Personal Protection 8.1 Control parameters Components with workplace control parameters Control CAS # Chemical Name Value Parameters Basis Dechloro Dihydroxy Difluoro 1185851‐52‐8 No data. Ethylcloprostenolamide (3D) TWA USA. ACGIH Threshold 64‐17‐5 Ethyl alcohol PEL 1,000 ppm STEL Limit Values (TLV) USA. Occupational 1,000 ppm Exposure Limits (OSHA) ‐ 64‐17‐5 Ethyl alcohol (continued) TWA 1,900 mg/m3 Table Z‐1 Limits for Air Contaminants USA. NIOSH 1,000 ppm 64‐17‐5 Ethyl alcohol (continued) TWA Recommended Exposure 1,900 mg/m3 Limits 8.2 Exposure controls Appropriate engineering controls Handle in accordance with good industrial hygiene and safety practice. Wash hands before breaks and at the end of workday. Use process enclosures, local exhaust ventilation, or other engineering controls to control airborne levels. Personal protective equipment Eye/face protection Use equipment for eye protection tested and approved under appropriate government standards such as NIOSH (US) or EN 166(EU). Skin protection Handle with compatible chemical‐resistant gloves. Gloves must be inspected prior to use. Use proper glove removal technique (without touching glove's outer surface) to avoid skin contact with this product. Dispose of contaminated gloves after use in accordance with applicable laws and good laboratory practices. Wash and dry hands. Body Protection Wear flame retardant and antistatic lab coat/protective clothing. The type of protective equipment must be selected per concentration and amount of dangerous substance at the specific workplace. Respiratory protection Where risk assessment shows air‐purifying respirators are appropriate use a full‐face respirator with multi‐ purpose combination (US) or type ABEK (EN 14387) respirator cartridges as a backup to engineering controls. If the respirator is the sole means of protection, use a full‐face supplied air respirator. Use respirators and components tested and approved under appropriate government standards such as NIOSH (US) or CEN (EU). Control of environmental exposure Do not let product enter drains. Do not release to the environment. _____________________________________________________________________________ Section 9: Physical and Chemical Properties 9.1 Information on basic physical and chemical properties Appearance Form: Liquid solution Odor No data available. Melting point No data available. Boiling point No data available. Flash point 14°C (57.2°F) ‐ closed cup Evaporation rate No data available. Flammability (solid, gas) No data available. Upper/lower flammability Upper explosion limit: 19% (V) at 25oC. or explosive limits Lower explosion limit: 3.3% (V) at 25oC. Vapor pressure 43 mm Hg at 20oC. Vapor density No data available. Relative density No data available. Water solubility No data available. Autoignition temperature 363oC (685.4 °F). Viscosity No data available. Explosive properties No data available. Oxidizing properties No data available. _____________________________________________________________________________ Section 10: Stability and Reactivity 10.1 Reactivity No data available. 10.2 Stability Stable under recommended storage conditions. 10.3 Possibility of hazardous reactions No data available. 10.4 Conditions to avoid Heat, flames, sparks. 10.5 Incompatible materials Alkali metals, strong oxidizing agents, peroxides, ammonia, and bases. 10.6 Hazardous decomposition products Carbon oxides (CO, CO2) Other decomposition products ‐ No data available. In the event of fire: see Section 5. _____________________________________________________________________________ Section 11: Toxicological Information 11.1 The toxicological effects of this compound have not been thoroughly studied. Routes of entry Eye contact, inhalation, ingestion. Toxicity to animals Ethyl alcohol: Acute oral toxicity (LD50): 10,470 mg/kg (Rat). Acute dermal toxicity (LD50): 15,800 mg/kg (Rabbit). Acute inhalation toxicity (LC50): 30,000 mg/L – 4 hour (Rat). Irritation/corrosion Ethyl alcohol: Skin irritation (rabbit): moderate, 20mg (24 hr). Eye irritation (rabbit): moderate (OECD Test Guideline 405) Chronic effects on humans Ethyl alcohol ‐ Investigated as a mutagen, reproductive effector, and tumorigen. Carcinogenicity – Ethyl alcohol Carcinogenicity ‐ Mouse ‐ Oral Tumorigenic: Equivocal tumorigenic agent by RTECS criteria. Liver: Tumors. Blood: Lymphomas including Hodgkin's disease. Ethyl alcohol RTECS number: KQ6300000. See RTECS entry for complete information. IARC: No component of this product present at levels greater than or equal to 0.1% is identified as probable, possible or confirmed human carcinogen by IARC. NTP: No component of this product present at levels greater than or equal to 0.1% is identified as a known or anticipated carcinogen by NTP. OSHA: No component of this product present at levels greater than or equal to 0.1% is identified as a carcinogen or potential carcinogen by OSHA. Further toxicological information The toxicological effects of this product have not been thoroughly studied. _____________________________________________________________________________ Section 12: Ecological Information 12.1 Toxicity Avoid release into the environment. Runoff from fire control or dilution water may cause pollution. Ethyl alcohol: Toxicity to fish: (LC50) ‐ Pimephales promelas (fathead minnow) ‐ 14,200 mg/l ‐ 96 h Toxicity to daphnia and other aquatic (LC50) ‐ Ceriodaphnia dubia (water flea) ‐ 5,012 mg/l ‐ 48 h invertebrates: NOEC ‐ Daphnia magna (Water flea) ‐ 9.6 mg/l ‐ 9 d Toxicity to algae: (EC50) ‐ Chlorella vulgaris (Fresh water algae) ‐ 275 mg/l ‐ 72 h (OECD Test Guideline 201) 12.2 Persistance and degradability Ethyl alcohol: Biodegradability ‐ Result: 95 % ‐ Readily biodegradable. Section 13: Disposal Considerations 13.1 Waste disposal method Dispose in accordance with local, state and federal regulations. _____________________________________________________________________________ Section 14: Transportation Information 14.1 DOT (US) – Land transport Proper shipping name: Ethyl alcohol solution Hazard class: 3 – FLAMMABLE LIQUID UN/NA Number: 1170 Packing Group: II Labels: 14.2 IMDG – Sea transport Proper shipping name: Ethyl alcohol solution Hazard class: 3 – FLAMMABLE LIQUID UN Number: 1170 Packing Group: II EMS‐No: F‐E, S‐D 14.3 IATA/ICAO – Air transport Proper shipping name: Ethyl alcohol solution Hazard class: 3 – FLAMMABLE LIQUID UN Number: 1170 Packing Group: II IATA Classification: 3 14.4 ADR/RID (Europe) – Land transport Proper shipping name: Ethyl alcohol solution Hazard class: 3 – FLAMMABLE LIQUID UN Number: 1170 Packing Group: II 14.5 Additional transport information Transport in accordance with local, state, and federal regulations. _____________________________________________________________________________ Section 15: Regulatory Information SARA 302 Components No chemicals in this material are subject to the reporting requirements of SARA Title III, Section 302. SARA 313 Components This material does not contain any chemical components with known CAS numbers that exceed the threshold (De Minimis) reporting levels established by SARA Title III, Section 313. SARA 311/312 Hazards Fire Hazard, Acute Health Hazard, Chronic Health Hazard Massachusetts/Pennsylvania/New Jersey Right To Know Components Ethyl Alcohol CAS: 64‐17‐5 Revision Date: 2007‐03‐01 California Prop. 65 Components This product does not contain any chemicals known to State of California to cause cancer, birth defects, or any other reproductive harm. _____________________________________________________________________________ Section 16: Other Information Full text of H‐Statements referred to under sections 2 and 3 Acute Tox. Acute toxicity Eye Irrit. Eye irritation Flam Liq. Flammable liquids H225 Highly flammable liquid and vapor. H302 Harmful if swallowed. H319 Causes serious eye irritation. HMIS Rating Health Hazard: 2 Chronic Health Hazard: * Flammability: 3 Physical Hazard: 0 NFPA Rating Health Hazard: 2 Fire Hazard: 3 Reactivity Hazard: 0 Company Policy or Disclaimer DISCLAIMER: This information is believed to be accurate and represents the best information currently available to us. However, we make no warranty of merchantability or any other warranty, express or implied, with respect to such information, and we assume no liability resulting from its use. Users should make their own investigations to determine the suitability of the information for their purposes. Revision Date: 26‐OCT‐2017 Amount of Product A Applied to Eyelashes Per Brushstroke A B C D E Applicator - Applicator – Amount of Dry Amount of Post- Wet Product A On Application Product A Applied to Sample Weight of Applicator (Single Brush Applicator Weight of Stroke) Eyelashes Applicator With Without Product A [B – A] [C – D] Product A 1 3814 3823 9 3819 4 2 3850 3855 5 3854 1 3 3860 3866 6 3863 3 4 3827 3834 7 3833 1 5 3812 3818 6 3815 3 6 3855 3861 6 3857 4 7 3846 3855 9 3852 3 8 3876 3881 5 3880 1 9 3814 3821 7 3818 3 10 3828 3831 3 3830 1 Average 3838.2 mg 3844.5 mg 6.3 mg 3842.1 mg 2.4 mg Explanation of measurements: The fine brush applicator that is part of the Product A container was weighed dry (without any product on the brush) [Column A] and after the brush was dipped into the vial to coat the brush with Product A solution [Column B]. All measurements are in milligrams (mg). Ten separate brushes were used in the study [“Sample” Column]. The amount of Product A on each brush before application to the eyelashes is shown in Column C [Col. B – Col. A]. Each brush was weighed again immediately after it was used to apply Product A to the upper eyelashes, as directed by the package instructions for use. The amount of Product A applied to the upper eyelashes by each brush stroke is shown in Column E [Col. D – Col. B]. Amount of Product A applied to the eyelashes: The range of Product A that was applied per brushstroke to the upper eyelashes was 1-4 mg and the average was 2.4 mg. The maximum amount of Product A applied per brushstroke was 0.072 mg. Amount of DDDE applied to eyelashes per brushstroke: The concentration of DDDE in Product A is 0.018%. Therefore, the amount of DDDE that was applied to the eyelashes per brushstroke is: Average: 0.018% x 2.4 mg = 0.00018 x 2.4 mg = 0.000432 mg (or 0.432 µg) Range: 0.00018 mg - 0.00072 mg (or 0.18 µg - 0.72 µg) Procedure 1: In Procedure 1, the same tube of product was used with different applicators. Ten applicators were used; each applicator was used for 2 applications. Insertion Method A: the applicator was inserted into the tube, applicator was twisted on all the way, removed, weighed, swiped across a measured length of mink eyelashes, and reweighed. Insertion Method B: the applicator was inserted into the tube, applicator was only pushed down to contact the neck of the tube, applicator was removed, weighed, swiped across a measured length of mink eyelashes and reweighed. Procedure 2: In Procedure 2, the same applicator was used with different tubes of product. Each tube was used for 2 applications. Insertion Method A: the applicator was inserted into the tube, applicator was twisted on all the way, removed, weighed, swiped across measure length of mink eyelashes, and reweighed. Insertion Method B: the applicator was inserted into the tube, applicator was only pushed down to contact the neck of the tube, applicator was removed, weighed, swiped across a measured length of mink eyelashes, and reweighed. Measurements (in mg): Average Amount Procedure 1 Applied (mg) Insertion Method A 1.999 Insertion Method B 2.422 Procedure 2 Insertion Method A 1.287 Insertion Method B 1.725 Distributed for Comment Annex Only -- Do 5 Not Cite or Quote CURRICULUM VITAE CURRENT POSITIONS Jan 15 - Non-executive Director, Locate Bio Locate Bio is an innovative orthobiologics company with a proprietary, regenerative medicine pipeline, delivering exciting orthobiologics products that have great disruptive potential. Jan 05 - President, Ian Wilding Associates Limited (IWAL) IWAL is a company established to provide my consultancy services in early drug development, product lifecycle management, commercial /strategic management and due diligence. Through the Company, I am currently working with 30 pharmaceutical and biotech drug development companies in Europe, USA and Japan – over 85% of consultancy revenues arise from collaborations with non-UK companies. Oct 01 - Special Professor, School of Pharmacy, Nottingham University The School of Pharmacy at Nottingham is ranked 5th in the world in the 2021 QS World Rankings for pharmacy and pharmacology. The School came joint 1st in the UK on quality of research for Pharmacy Schools in the 2014 Research Excellence Framework and is the only School of Pharmacy to have 100% of research at 4* in the 'Impact on Society’ category. PREVIOUS ROLES 1990- 2004 Founder and Chief Executive, Pharmaceutical Profiles Limited (PP) • PP was established as a spinout company from Nottingham University in 1990 to commercialise the use of radionuclide imaging to visualise drug delivery in the gastrointestinal and respiratory tract of healthy volunteers and patients. • I exited from the company via a 3i backed MBO in 2005 and by that time I had developed the company into a niche exploratory clinical trials business employing 110 people and with a turnover of 10million GBP. • In 2004, PP received Frost & Sullivan's prestigious Excellence in Technology Award for its pioneering efforts to enhance the adoption of innovative technologies in early phase drug development. • As well as having management responsibility for PP, I also worked extensively in a business development role and via “peer to peer” selling interfaced with project teams in pharmaceutical and biotech companies in the US, Europe and Japan. • In 1999, VC investment was obtained to fund the development of a remote controlled capsule (Enterion™) which enabled site specific delivery within the human intestine to evaluate drug absorption and therapeutic properties. The patent protected capsule, of which I was the key inventor, has now been dosed to several thousand subjects in over 250 clinical studies for worldwide pharma and biotech companies. 2002 - 2009 Non-Executive and Founding Director, BioCity Nottingham BioCity Nottingham is the largest bioscience innovation & incubation centre in Europe and was established via a unique collaboration between Nottingham Trent University, the University of Nottingham and the East Midlands Development Agency. 2004 - 2013 Board Advisor, Molecular Profiles Limited Molecular Profiles (now Juniper Pharma Services) is a contract research organisation providing global clients pharmaceutical development services (formulation & analytical development, clinical trial manufacturing up to Phase IIa), advanced analytical support and expert consultation for intellectual property issues. The Company was acquired by Columbia Labs in September 2013. Curriculum Vitae – Dr Ian Wilding Page 1 November 2021 2006 - 2010 Non-Executive Chairman and Investor Director, R5 Pharmaceuticals Limited (R5) R5 Pharmaceuticals was established in 2006 to provide formulation development, analytical chemistry and GMP services to the global biotech and pharmaceutical industry. The company was acquired by Aesica in June 2010 and is widely acknowledged as one of the leading providers of pharmaceutical dosage form development across Europe. Shortly after exit in 2010, we received the ‘Venture Capital Backed Team of the Year’ award from the British Venture Capital Association for our work at R5. 2007 - 2012 Non-executive Director, Photopharmica Limited (PPA) PPA was a product development company focused on infection control and wound healing using photodynamic therapy. In October 2011, the Company announced that in a phase IIb study its lead product had produced a substantial and significant reduction in the bacterial load of chronic leg ulcers. 2007 - 2014 Director and Scientific Advisor, Modern Biosciences plc (MBS) MBS is a drug development company that sources late-stage discovery projects from academia and spin-out companies, conducts early proof-of-principle clinical studies and subsequently out-licenses the resulting programs to the pharmaceutical industry. 2007 – 2020 Director and VP Development, Zysis Limited Zysis was a specialty pharma company working on the reformulation, development and commercialisation of CNS products in the psychiatry and neurology arena. An oral aripiprazole once-weekly maintenance product intended to improve adherence and therefore clinical outcomes in schizophrenia and bipolar disorder therapy will shortly enter phase II development. 2009 - 2013 Board Advisor, Heron Evidence Development Limited HERON was one of the largest independent providers of evidence-based strategy, research and communication services to global biopharmaceutical clients prior to its sale to Parexel. With expertise and methodologies that align evidence development and economic evaluation with pricing, reimbursement, and market access planning, the Company works with clients to quantify and communicate product value and commercial opportunity on a global basis. 2010 - 2013 Member of the Board of Directors at Bend Research Based in Oregon USA, Bend Research specialises in the advancement, development and commercialisation of pharmaceutical & health science technologies. The Company focuses on developing a deep scientific understanding of clients’ challenging drug development problems and by applying novel solutions advances difficult compounds to market. The Company was acquired by Capsugel in September 2013. QUALIFICATIONS 2015 Doctor of Laws honoris causa, Monash University, Melbourne, Australia 2013 Fellowship of the Academy of Pharmaceutical Sciences of Great Britain 1985- 1988 Ph.D., Department of Pharmaceutical Sciences, Nottingham University 1984 -1985 MRPharmS, Royal Pharmaceutical Society of Great Britain 1981-1984 B.Pharm First Class, Department of Pharmaceutical Sciences, Nottingham University FDA INTERACTION 1997 – 1998 Expert scientist for the FDA in the area of Food Effects on Drug Bioavailability 1999 onwards Frequent speaker at internal FDA training meetings 2002 FDA Expert scientist at Advisory Committee on Food Effect Guidelines and BCS Development Curriculum Vitae – Dr Ian Wilding Page 2 November 2021 PREVIOUS INNOVATION ROLES 2006 – 2008 FP7 Advisory Committee on SMEs, European Commission 2005 – 2006 Governance Board, Nottingham Science City April 2004 EU Informal Competitiveness Council, Dromoland Castle (Irish Presidency) 2004 – 2006 Innovation EM (Science and Industry Council, East Midlands) 2003 – 2007 University of Nottingham Institute for Enterprise and Innovation (UNIEI) Advisory and Strategy Board 2002 - 2006 CBI Technology and Innovation Committee Curriculum Vitae – Dr Ian Wilding November 2021 Page 3 Latanoprost Travoprost Tafluprost Bimatoprost DDDE (Xalatan®) (Travatan-Z®) (Zioptan®) (Lumigan®) (Latisse®) (Product A) Concentration (%) 0.005%1 0.004%2 0.0015%3 0.03%4 0.03%5 0.018% Concentration (mg/ml) 0.056 0.04 0.0150 0.307 0.308 0.180 Drops/mL9 29.5 34.6 n/a10 33.3 n/a Quantity of solution 0.0338 mL11 0.0289 mL12 0.15 mL13 0.03 mL14 0.0015 mL15 2.4 mg applied / application Quantity of 0.001695 mg16 0.00116 mg17 0.00225 mg18 0.009 mg19 0.00045 mg20 0.000432 mg prostaglandin analog applied per application 1.7 µg 1.16 µg 2.25 µg 9.0 µg 0.45 µg 0.432 µg Treat Treat Alopecia Eyelash Intended Use Glaucoma (Grow Conditioner Eyelashes) Site of application Eye Skin at base of Eyelashes upper eyelashes Fine Brush Method of application Fine Brush Eye drop Applicator Contains Thickener No Yes Effect of product on Decreases IOP None 1 Xalatan package insert, http://www.xalatan.com/content/prescribing-information.aspx 2 Travatan-Z package insert, http://www.alcon.com/en/alcon-products/glaucoma.aspx. 3 Zioptan package insert, http://www.merck.com/product/usa/pi_circulars/z/zioptan/zioptan_pi.pdf. 4 Lumigan package insert, http://www.lumigan.com/ 5 Latisee package insert, http://www.lumigan.com/, https://media.allergan.com/actavis/actavis/media/allergan-pdf-documents/product-prescribing/20170829-LATISSE- USPI-72303US17.pdf. 6 Concentration expressed as a percentage represents the number of grams per 100 mL of solution for wt/vol concentrations. (H. Vance, PharmD, JD; http://en.wikipedia.org/wiki/Mass_concentration_(chemistry)#Usage_in_biology). 0.005% = 0.005 mg/100 mL = 0.05 mg/mL. 7 Lumigan package insert, 8 Lumigan package insert. 9 VHA Drug Class Review: Ophthalmic Prostaglandin Analogs, Pharmacy Benefits Management Strategic Healthcare Group, Table 12 (June 2011) 10 Unlike the other ophthalmic prostaglandin analogs, Zioptan is preservative free. (See Therapeutic Class overview: Ophthalmic Prostaglandin Analogues, UMass Medical School (May 2012), https://www.medicaid.nv.gov/Downloads/provider/Ophthalmic%20Prostaglandin%20Analogues.pdf. It is supplied as a sterile solution in translucent low density polyethylene single-use containers packaged in foil pouches (10 single-use containers per pouch). Each single-use container has 0.3 mL solution corresponding to 0.0045 mg tafluprost. Each container has enough solution to treat both eyes, so 0.00225 mg (0.0045 mg/2 = 0.00225 mg) would be applied to each eye. 11 1 mL / 29.5 drops/mL = 0.0338 mL/drop. 12 1 mL / 34.6 drops/mL = 0.0289 mL/drop. 13 Zioptan package insert, Section 2; Zioptan website, (”Each single-use container contains enough solution to treat both eyes.”) http://www.zioptan.com/zioptan/hcp/dosing-information.html. 14 There are 33.3 drops/mL. Each drop = 1 mL / 33.3 drops = 0.03 mL. 15 According to the manufacturer (Allergan), the amount of bimatoprost solution applied per application of Latisse is approximately 5% of the amount of bimatoprost solution applied as eye drop of Lumigan. (Allergan report to FDA Advisory Committee on Latisse clinical study, p. 5.) 16 1 mL = 0.05 mg. 1 mL = 29.5 drops. Each drop = 0.05 mg/mL / 29.56 drops = 0.001695 mg/drop. 17 1 mL = 0.04 mg. 1 mL = 34.6 drops. Each drop = 0.04 mg/mL / 34.6 drops = 0.00116 mg/drop. 18 Each container contains 0.0045 mg tafluprost and enough solution to treat both eyes. (See Note 10, above.) 50% of 0.0045 mg = 0.0025 mg. SECOND EXPERT REPORT OF DR IAN WILDING ON REVITALASH ADVANCED EYELASH CONDITIONER DATED 21ST NOVEMBER 2021 1 Introduction 1.1 I have worked as a pharmaceutical scientist for over 30 years. I obtained my PhD in 1988 from the Department of Pharmaceutical Sciences at Nottingham University and was the principal founder of Pharmaceutical Profiles, a phase 1 clinical research organisation, to commercialise the use of nuclear medicine imaging to visualise drug delivery in humans in 1990. I grew the company to over 100 people with an annual turnover of 10 million GBP before selling the business in 2005. During that time, I also co-supervised several PhD students on a variety of research topics within the field of pharmaceuticals. I received the Career Achievement Award in Oral Drug Delivery from the Controlled Release Society in 2005 and became a Special Professor in the School of Pharmacy at the University of Nottingham in 2001. In 2015, I received an honorary doctorate from Monash University in recognition of my outstanding contribution as a scientific innovator and leader in drug development. I am also an Eminent Fellow of both the Academy of Pharmaceutical Sciences of Great Britain and the Controlled Release Society. 1.2 My up-to-date summary curriculum vitae is at Exhibit IW18. 1.3 Since leaving Pharmaceutical Profiles, I have consulted widely for pharmaceutical and biotechnology companies on formulation strategy for drug development, pharmacokinetic interpretation of clinical data, design of early-stage exploratory clinical studies and CMC regulatory strategy. In particular, my expertise has been relied upon by the US FDA (Food & Drug Administration), the UK MHRA (Medicines & Healthcare products Regulatory Agency) and various European health regulatory authorities. 1.4 I have co-authored and published in excess of 250 scientific papers, abstracts and patents, many of them relating to the field of drug delivery and pharmacokinetics. An updated list of my publications is at Exhibit IW19. 1.5 I have been asked by Keystone Law, solicitors for Athena Cosmetics, Inc. (“Athena”), to review an opinion issued by the Scientific Committee on Consumer Safety (SCCS) dated 27 September 2021 on “Prostaglandins and prostaglandin-analogues used in cosmetic products”, which sought to review two prostaglandin analogues (“PGAs”) used in eyelash conditioners, namely Isopropyl Cloprostenate (CAS 7 157283-66-4) (which I will refer to as “ICP” for brevity) and Ethyl Tafluprostamide or dechloro dihydroxy difluoro ethylcloprostenolamide, abbreviated commonly to “DDDE” (CAS 1185851-52-8) (the “SCCS Report”). DDDE is the PGA used in RevitaLash Advanced (“RLA”). I understand that this report will be submitted to the SCCS in Athena's follow up to the SCCS report to assist the SCCS in their evaluation of the safety of DDDE for use in eyelash products. 1.6 I have previously provided an expert report on the safety of the cosmetic product RevitaLash Advanced in a report dated 14 August 2013. I understand that this was submitted as Annex 6 to Athena’s original submission to the European Commission 1 call for data on prostaglandins and their analogues used in cosmetic products, that submission dated 20 October 2020 (“Athena’s 2020 Submission"). 1.7 I confirm that I understand my duty as an expert and that I have complied with, and will continue to comply with, that duty. 2 Instructions 2.1 I have been asked to give my opinion on the following issues raised in the SCCS Report: (a) At page 21 of the SCCS Report, it states that “Within the remit of the SCCS, safety assessment are based on assessment of the ingredients and not cosmetic formulations. Test results relating to cosmetic formulations have therefore not been taken into consideration in this Opinion.” (i) First question: If an ingredient is only presented in a final formulation and experimental data indicates that final formulation is safe for cosmetic use, is it reasonable to conclude that the ingredient itself is safe at the effective dilution level for that particular formulation? (ii) Second question: In this instance, with the final formulation for RevitaLash Advanced, is it reasonable to rely on the data submitted to the SCCS to assess whether DDDE is safe up to a concentration level of 0.018%? If so, why is that? If not, why not? (b) Third question: At page 40 of the SCCS Report in Annex 1, the SCCS concludes, under the sub-title “Human data”: “For pharmacological treatment of intra-ocular pressure, a daily dose of one drop with a PGA is prescribed. This implies, depending on the type of analogue, a dose of 0.75 – 2.5 μg per eye per day. In the absence of data on skin absorption from the application of an eyelash growth formulation, assuming a dermal absorption of 50% and full transfer from the eye-lid conjunctiva to the eye, a maximum exposure of the eye of 0.36 μg DDDE and 2.5 μg isopropyl cloprostenate can theoretically be estimated. These doses are in the same order of magnitude as those used for the epi-ocular pharmacological treatment of intra-ocular pressure.” (i) Is this calculation of a maximum exposure of the eye of 0.36 μg correct? (ii) Can you comment on this conclusion? (c) Fourth question: At page 40 of the SCCS Report in Annex 1, under the sub-title “Human data”, the SCCS concludes: “The SCCS review of the open literature has indicated that PGAs caused serious adverse effects in ocular and periocular tissues in some glaucoma patients after direct eye applications (Nakakura et al., 2015, Shah et al., 2013; Wang et al., 2014). These data indicate a concern for the manifestation of serious and irreversible histological changes after consumer exposure to the PGAs in cosmetic products.” (i) Do you share that concern? (ii) If so, why? If not, why not? 2 do you understand “very low concentrations” to mean? 2.2 For the purpose of this report, I have made reference to the following documents: (a) the SCCS Report (b) Athena’s 2020 Submission (c) “A Review of the Main Considerations for Formulation Development in Preclinical Toxicology Studies”, Saunders, International Journal of Toxicology 2021, Vol. 40(6) 551–556 (“Saunders, 2021”) (Exhibit IW20) (d) “Tolerable Levels of Nonclinical Vehicles and Formulations Used in Studies by Multiple Routes in Multiple Species With Notes on Methods to Improve Utility”, Gad et al, International Journal of Toxicology 2016, Vol. 35(2) 95-178, (Exhibit IW21) (e) “Amount of RevitaLash Advanced and DDDE Applied Per Brush Stroke to Eyelashes”, (Exhibit IW22) (also at page 102 of Athena’s 2020 Submission) (f) “The SCCS Notes of Guidance for the Testing of Cosmetic Ingredients and their Safety Evaluation, 11th Revision”, 30-31 March 2021, (“SCCS/1628/21") (Exhibit IW23) (g) ECHA “Guidance on information requirements and chemical safety assessment Chapter R.7c: Endpoint specific guidance”, published in June 2017 (Exhibit IW24) (h) “Modeling the human skin barrier — Towards a better understanding of dermal absorption”, O.G. Jepps et al, Advanced Drug Delivery Reviews 65 (2013) 152–168 at 156, column 1, lines 5-8 (Exhibit IW25) (i) “Enhancing the Growth of Natural Eyelashes: The Mechanism of Bimatoprost-Induced Eyelash Growth”, Cohen, Dermatological Surgery 2010 Sep;36(9):1361-71 at (Exhibit IW9 to my first report) (j) Evalulab Evaluation of Ocular Safety (Exhibit IW14 to my first report) (k) Package insert for RLA (also at Annex 7 at page 84 of Athena’s 2020 Submission) (Exhibit IW26) (l) “A new look at the safety and tolerability of prostaglandin analogue eyedrops in glaucoma and ocular hypertension”, Katsanos et al, Expert Opinion on Drug Safety, 16 June 2021 (https://www.tandfonline.com/doi/full/10.1080/14740338.2022.1996560) (Exhibit IW27) 3 Summary 3.1 Briefly, and for the reasons that I develop more fully in this report, my overall conclusion is that, based on the totality of the available evidence, it would not have been scientifically unreasonable for the SCCS to reach a conclusion as to the safety of DDDE when used at a concentration of 0.018% in RLA. I understand the concern raised by the SCCS around the impact of ingredients applied close to the eyes however users of RLA are provided clear instructions to apply the product directly to 3 the eyelashes. Therefore, with correct usage, the quantity of DDDE that is likely to migrate to the eyelid and be available for dermal absorption (and thereby lead to local adverse effects) is negligible. In addition, I don't share the concern posed by the SCCS that in the rare situation that consumers use the product entirely incorrectly and apply 100% of the dose to the eyelid, the resulting eye exposure would be comparable to that of a 9µg dose of Bimatoprost (the closest predicate PGA to DDDE) dosed correctly directly to the eye for glaucoma treatment. Finally, there is compelling evidence of excellent safety (local & systemic) for a range of topically applied PGAs applied directly into the eye in drops and used for multiple months of treatment in glaucoma. I accept that with the chronic long-term administration of PGAs for therapeutic purposes, there is an increased risk of topical adverse effects. However, all the available "long-term safety and tolerability evidence" for RLA demonstrate that there are no reports of such topical adverse effects which is consistent with the extremely limited risk of any eye exposure from RLA containing 0.018% DDDE used correctly via application to the eyelashes or via dermal penetration of product applied incorrectly to the eyelids. 4 Opinion 4.1 First question: If an ingredient is only presented in a final formulation and experimental data indicates that final formulation is safe for cosmetic use, is it reasonable to conclude that the ingredient itself is safe at the effective dilution level for that particular formulation? (a) In the toxicological safety assessment of an active pharmaceutical ingredient (API) in drug development, it is rarely possible to administer neat API to any preclinical animal species by most dosage routes. Therefore, in the majority of cases, it is necessary to give the test item as part of a formulation which may vary between simple solutions or suspensions to complex drug delivery systems depending on the API biopharmaceutical properties e.g. solubility and proposed route of administration e.g. oral, topical. (b) It therefore seems a logical corollary that if the final product for cosmetic use is at the simple end of the spectrum of possible formulation strategies that the safety of the ingredient, within specific concentration ranges, could be extrapolated from the prior human experience of the finished product. (c) In Athena’s 2020 Submission, RLA was commonly referred to as “a preserved and thickened aqueous-based mixture of mainly emollient, skin conditioning and humectant agents used in formulating an eyelash conditioning solution”. Similar language is also used in the Intertek Toxicology Assessment provided in the same submission at Annex 5 (page 57). However, it appears that nobody has drilled down further on the broader role and quantities of excipient contained in RLA. To my mind that assessment is important in considering the suitability of RLA as a useful surrogate for a DDDE safety assessment formulation and therefore the potential of the entire RLA package to help assuage possible safety concerns around use of DDDE in a cosmetic setting. (d) As a skilled practitioner in the design of simple formulations for toxicology safety assessment of APIs, I bracketed the main RLA excipients into differing functional categories: (i) Solvents: Water is the primary solvent (97.729%). Glycerol (present at 0.608%), whilst not selected for this purpose in RLA, is commonly used as a 4 cosolvent in formulations so, in a broader deconstruction assessment of the RLA product, it could be considered in this context such that the overall solvent % is 98.337%. (ii) Buffers: It is common for a solution/suspension formulation to be buffered. Disodium phosphate (0.142%) and phosphoric acid (0.03%) are incorporated for this purpose, i.e. 0.172% in total. (iii) Preservatives: For a simple multi-dose toxicology formulation, preservatives would be a consideration and, in this case, phenoxyethanol (0.302%) and chlorphenesin (0.299%) are incorporated i.e. 0.601% in total. (iv) Suspending or thickening agent: Cellulose derivatives are commonly used for suspension formulations to ensure content uniformity - hydroxyethyl cellulose could fulfil such a role and is present in RLA at 0.36%. (e) This means that, in addition to the concentration of the ingredient of interest, DDDE (0.018%), the sub-total of all the drug and traditional safety assessment excipients suitable for a simple safety assessment formulation amount to 99.488% of the RLA product. (f) My perspective is reinforced by a couple of recent review articles. Saunders, 2021, (Exhibit IW20) explores the main considerations for the development of a formulation for preclinical safety assessment testing detailing both classes of excipients and their function specifically listing buffers and cosolvents. In the introduction at page 551, Saunders says: “…it is necessary that any formulation is shown to be stable and homogeneous under the conditions of the preclinical study and will need to be demonstrated by subsampling of the formulations during every GLP study. This is not just for reasons of quality alone but is also for ethical reasons. If a study is conducted and the formulation is found to be unstable, for example, the test item has precipitated out of solution prior to or during the dosing of the animals, this will affect the dosage that the animal received and require a repeat of that study” (g) An authoritative review by Gad et al, 2016, Exhibit IW21) identifies tolerable levels of nonclinical vehicles and formulations used in studies by multiple routes in multiple species and specifically references the majority of the RLA excipients described above in table 4 at pages 100-109. (h) Therefore, 99.5% of RLA can scientifically be argued to reflect a simple buffered, preserved solution/suspension formulation which would be designed to evaluate safety, tolerability etc for an API. The alternative construct is that only 0.5% of the excipients in the RLA product “prevent” the formulation from being considered as a simple presentation of DDDE for safety assessment purposes. (i) In the report reference is often made that the SCCS remit requires that “safety assessments are based on assessment of ingredients and not cosmetic formulations”. However, as argued above, presentation via a formulation provides the basis for such an assessment and whilst RLA per se is not designed for such a purpose only 0.5% of the product excipients would not be standard for that goal. It therefore seems a strange scientific decision to completely disregard a wide body of existing toxicological and human investigations in considering safety of DDDE at exactly the concentration utilised in RLA especially when 99.5% of the product is consistent with the principles of a formulation developed for such a safety assessment. 5 (j) It is therefore my contention that the data from a 99.5% “standard” formulation presentation could have been considered as body of evidence by the SCCS when assessing possible safety concerns for DDDE without materially diluting its remit to assess ingredients only. 4.2 Second question: In this instance, with the final formulation for RevitaLash Advanced, is it reasonable to rely on the data submitted to the SCCS to assess whether DDDE is safe up to a concentration level of 0.018%? If so, why is that? If not, why not? (a) As discussed at length in response to Q1, I don't believe that it is unreasonable to consider the entire set of available data to address the narrowly drafted question posed to the SCCS about DDDE. In fact, I would argue that it is scientifically perverse to ignore such an extensive data set which includes human testing and substantial market safety data. I would have much more sympathy with the position of SCCS if the question had not been qualified by concentration and had been more generically posed around safety of DDDE at any concentration, which is not generally realistic or appropriate and is not what is asked here. (b) I note that the final remark from the SCCS in the report is they will be ready to assess any evidence provided to support the safe use of PGAs in cosmetic products. I hope that now the SCCS has further evidence on the formulation principles delineated in response to Q1 above that would be required to test DDDE at all, that the Committee will be willing to consider RLA as a sufficiently simple formulation for it to act as surrogate for an ingredient safety assessment for DDDE in concentrations up to 0.018% (i.e. the maximum concentration at which all the testing has been done across all the tests (with one test at a higher concentration of 0.025%) and in a formulation supplied to consumers). This is especially important given the necessity to give the test item (DDDE) as part of such a formulation to make such an evaluation in the first instance 4.3 Third question: At page 40 of the SCCS Report in Annex 1, the SCCS concludes, under the sub-title “Human data”: “For pharmacological treatment of intra-ocular pressure, a daily dose of one drop with a PGA is prescribed. This implies, depending on the type of analogue, a dose of 0.75 - 2.5 μg per eye per day. In the absence of data on skin absorption from the application of an eyelash growth formulation, assuming a dermal absorption of 50% and full transfer from the eye-lid conjunctiva to the eye, a maximum exposure of the eye of 0.36 μg DDDE and 2.5 μg isopropyl cloprostenate can theoretically be estimated. These doses are in the same order of magnitude as those used for the epi-ocular pharmacological treatment of intra-ocular pressure.” Is this calculation of a maximum exposure of the eye of 0.36 μg correct? Can you comment on this conclusion? (a) My PhD was on the use of modelling and simulation (“M&S”) to predict the in vivo behaviour of drug delivery systems based on a range of inputs. In the absence of actual in vivo data, M&S (however simple) can play an invaluable role in helping to establish understanding and qualify risk, so I support the idea of scenario mapping as envisaged by the SCCS. However, the credibility of any simulation/ projection/ prediction is critically dependent on the quality of the assumptions and the rigour in their application. With that sentiment, I am struggling to understand and justify the approach used by the SCCS to assert a maximum exposure to the eye of 0.36 μg DDDE following use of RLA. (b) The context of this assessment in Annex 1 of the SCCS report suggests it was one of the important factors considered by the Committee in reaching their decision to 6 conclude that there is a basis for serious concern around the use of DDDE (as a prostaglandin analogue) in cosmetic products. As a consequence, I feel it is important to review the assumptions and context around this assessment in detail and evaluate the validity of the conclusion. (c) As a reminder, the instructions for RLA use are to apply a thin line of product directly to the eyelashes. According to “in use” studies (Exhibit IW22), typically 1 to 4mg of RLA is applied to the eyelashes per brush stroke. The concentration of DDDE in RLA is 0.018%. Therefore, at most, 0.72 µg of DDDE (4mg of RLA x 0.00018 = 0.00072 mg (or 0.72 µg)) is applied to the eyelashes per brushstroke. RLA contains cellulose gum to act as a “viscosity increasing agent”. While no data on the actual viscosity of RLA are available, based on my personal observation, the RLA formulation holds its form as an applied thin line along the eyelashes without propensity to drip. Therefore, it is highly unlikely any of the very small amount of DDDE that is applied to the eyelashes with normal use would be transferred onto the eyelid or into the eye – therefore the quantity of DDDE that is likely to be misapplied to or migrate to the eyelid and be available for dermal absorption with correct use of the product is negligible. (d) However, in the rare situation that consumers use the product entirely incorrectly and apply 100% of the dose (0.72 µg) to the eyelid and none to the eyelashes what is the likely outcome? The SCCS reference in their report an excerpt from the ICP ingredient dossier in which the calculated dermal absorption (via QSAR, Episuite 1.0) was 10% on the basis of a molecular weight of 476D and a partition coefficient of 5.15. However, for the purposes of the estimate of maximum exposure, the SCCS choose to ignore the calculated value of 10% for ICP and utilise 50% for both ICP and DDDE as the default figure according to SCCS/168/21 (Exhibit IW23) where "only inadequate dermal absorption data are available”. (e) The most recent version of this ECHA “Guidance on information requirements and chemical safety assessment Chapter R.7c: Endpoint specific guidance” was published in June 2017 (“ECHA Guidance”) (Exhibit IW24). That guidance states at page 228 that “Percutaneous absorption through intact skin is highly dependent on the physico- chemical properties of substances, and in particular of molecular weight and lipophilicity. Molecules above a certain molecular weight are unlikely to cross intact skin, and substances which are either too lipophilic or too hydrophilic have a low skin penetration. Cut off points at a molecular weight of 500 and log P values below -1 or above 4 have been used to set a conservative default absorption factor at 10% cutaneous absorption”. (f) A further decision tree is provided in the ECHA Guidance, Figure R.7.12-5 on the broader interpretation of dermal absorption risk which allows for latitude when the ingredient doesn't meet the absolute criteria around molecular weight and lipophilicity. (g) Both ICP or DDDE meet the criteria of log P above 4 (5.15 and 5.03, respectively) but are smaller than the 500Da molecular weight cut-off. However, as reported above, the EPIsuite software calculated a 10% dermal absorption for ICP which is presumably due to the very high lipophilicity of this PG analogue, despite not meeting the molecular weight cut-off. This is consistent with established transdermal science that for “highly hydrophilic drugs… penetration is limited primarily by the [stratum corneum], while for increasingly lipophilic drugs the effects of the aqueous layer become more significant “choking” the flux of such drugs into the skin…” (O.G. Jepps et al, Advanced Drug Delivery Reviews 65 (2013) 152–168 at 156, column 1, lines 5-8 (Exhibit IW25)). (h) Moving back to the current SCCS report, I believe the decision to select a default 50% dermal absorption for both ICP and DDDE is overly simplistic. In terms of ICP, it would 7 have been scientifically sensible to consider the 10% calculated dermal absorption value which would lower the estimate of maximal exposure from 2.5µg to 0.05µg. Overall the biopharmaceutics properties of ICP and DDDE are similar with nearly identical lipophilicity (and thereby choking effect on penetration). As a consequence, it would not be unreasonable to assume a 10% dermal absorption for DDDE in the absence of the corresponding calculated value. However, taking a highly conservative approach, I have assumed that the dermal penetration for DDDE was double IPC at 20%. (i) The low suggested dermal penetration for DDDE is also consistent with the findings for Bimatoprost which, as a prostamide analogue, is in the same structural class as DDDE. In a review article from Cohen (see Dermatological Surgery 2010 Sep;36(9):1361-71 at Exhibit IW9 to my first report) it is stated that low ocular levels occur when drug solution is applied topically to the eyelid margin and that the barrier formed by the skin, ensures that absorption of active drug across the cutaneous surface into ocular tissues is minimal. (j) Leaving other reasonable scientific assumptions aside, including that RLA is not applied to the eyelids other than in error in minimal quantities, based on a 20% dermal penetration estimate of the entire amount that is applied, the maximum exposure of the eye to DDDE from RLA applied inadvertently to the eyelid would be 0.144 µg. (k) The SCCS state in Annex 1 of the report that “For pharmacological treatment of intra- ocular pressure, a daily dose of one drop with a PGA is prescribed. This implies, depending on the type of analogue, a dose of 0.75 - 2.5 μg per eye per day”. I am struggling with this interpretation of current clinical practice in IOP treatment by the SCCS. It is my understanding from the Athena’s 2020 Submission that Latanoprost, Travoprost, Tafluprost and Bimatoprost are used at the following dose per application 1.7µg, 1.16µg, 2.25µg and 9µg so a range of 1.16 - 9µg not 0.75 - 2.5 μg . (l) Bimatoprost is often grouped with the other prostaglandin analogues but as a prostamide, it is structurally diverse from the others. As already discussed, DDDE is structurally similar to Bimatoprost and structurally diverse from Latanoprost, Travoprost and Tafluprost. (m) The SCCS state that the maximum exposure of DDDE in the eye is “in the same order of magnitude as those used for pharmacological treatment of intra-ocular pressure (IOP)”. I disagree with this assertion. (n) Based on the analysis above the comparison of relevance is 0.144 µg for DDDE using a conservative 20% dermal penetration from RLA applied incorrectly to the eyelid compared with the 9µg dose for Bimatoprost dosed correctly to the eye as a topical drop for direct delivery. I don't view these two values as being comparable. (o) My analysis is supported by data showing that normal use of RLA has no effect on IOP. I have been provided with a report of a human study carried out by Evalulab, Inc. in which the safety and tolerability of a product called “Enhanced Peptide Conditioner TEA 0.025%” (a previous formulation of RLA) was evaluated (Exhibit IW14 to my first report, also at Annex 11 at page 132 of Athena’s 2020 Submission). I have been informed by Athena that “TEA” is the same molecule as “DDDE”, which is in the current formulation of RLA. I note that the concentration of TEA in the tested product in this study is greater (0.025%) than the concentration of DDDE (0.018%) in RLA. The study involved 20 female volunteers who self-administered the preparation daily after being given instructions to apply product along the upper eyelashes in the same way they would apply eyeliner for a period of four weeks. I note that the instructions on how to apply 8 RLA differ in that RLA is applied to the eyelashes themselves, rather than as eyeliner (current instructions in package insert for RLA at Exhibit IW26 (also at Annex 7 at page 84 of Athena’s 2020 Submission)). A certified ophthalmologist measured the IOP in each eye of each user on day 0 and day 28. The results of this “in-use” study, using user-controlled administration, demonstrate DDDE does not cause a significant reduction in IOP, even where a large proportion (if not 100%) is applied to the eyelid itself. 4.4 Fourth question: At page 40 of the SCCS Report in Annex 1, under the sub-title “Human data”, the SCCS concludes: “The SCCS review of the open literature has indicated that PGAs caused serious adverse effects in ocular and periocular tissues in some glaucoma patients after direct eye applications (Nakakura et al., 2015, Shah et al., 2013; Wang et al., 2014). These data indicate a concern for the manifestation of serious and irreversible histological changes after consumer exposure to the PGAs in cosmetic products.” Do you share that concern? If so, why? If not, why not? (a) I am not a clinical practitioner skilled in the treatment of glaucoma so cannot comment on the nuances of the long-term safety of PGAs in treatment of ophthalmic disease and its subsequent impact on consumer use of cosmetic PGA products. However, I am a skilled drug development scientist, and I am clear that the risk/benefit analysis for any specific drug therapy requires significantly more rigour that a general, non- specific search of the open literature. In my own search, I found a very recent authoritative, broad-ranging review (October 2021) published in “Expert Opinion on Drug Safety” on the “safety and tolerability of prostaglandin analogue eyedrops in glaucoma and ocular hypertension” (Katsanos et al 2021 (Exhibit IW27)). The review critically examines key evidence, and identifies gaps in current knowledge, on the safety and tolerability of available and emerging IOP-lowering PGAs. (b) The authors state “As a drug class, PGAs demonstrate several advantages compared to the other available IOP-lowering medications: they are presently the most efficacious class of medications for 24-hour IOP lowering, they possess an excellent systemic safety profile, and they are conveniently dosed once daily. These advantages explain why PGAs currently comprise the first line and first choice therapy in managing glaucoma. However, despite the availability of a significant body of evidence concerning their efficacy, the long-term safety and tolerability profiles of these as well as other available IOP-lowering drugs, have attracted less attention. In part, the scarcity of long-term safety and tolerability evidence with PGAs may reflect regulatory requirements that focus mostly on short-term efficacy outcomes. Indeed, registration trials are principally designed to detect differences (or lack thereof) in IOP lowering over a period of a few months and this is the standard time period of safety and tolerability monitoring of the various topical glaucoma medications.”. The authors go on to state that the “treatment of glaucoma is lifelong and can last for decades in many patients. Consequently, the true safety and tolerability profile of a given agent may only become evident from long-term post-marketing studies and cumulative clinical experience following years of administering therapy”. (c) I interpret the Katsanos et al review paper as providing evidence of excellent safety (local or systemic) for a range of topically applied PGAs applied directly into the eye in drops and used for multiple months of treatment. However, on chronic long-term administration, there is an increased risk of topical adverse effects, such as 9 conjunctival hyperaemia, pigmentation of the iris and/or periocular skin, hypertrichosis, periorbital fat atrophy, and ocular surface irritation. (d) The authors conclude that “for the reasons delineated in this review PGAs have evolved into an indispensable therapeutic option in the current glaucoma armamentarium. Indeed, no other IOP-lowering drug class appears to offer similar advantages as yet. Their versatility has enabled clinicians worldwide to employ PGAs in several clinical algorithms. Consequently, PGAs have successfully been employed in stepwise glaucoma therapy as fixed, or unfixed options. Thus, it is reasonable to assume that PGAs will continue to play a key role in glaucoma therapy of the future.” (e) This suggests that the limited risk of local adverse effects with topical PGA therapy is vastly outweighed by the clinical benefit of their effectiveness in treatment of glaucoma and is a perception that is unlikely to change in the near future. (f) I accept the risk/benefit analysis will be different for the use of PGAs in consumer cosmetic products. However, crucially the already low risk of these topical adverse effects with IOP PGA therapeutics is further reduced with a 0.018% DDDE product such as RLA in the consumer setting. The increased viscosity of RLA and the barriers to permeation posed by the anatomical layers of the eye, ensure it is highly unlikely RLA will have a pharmacological effect on the eye when applied as directed to the eyelashes. (g) Finally, Intertek evaluated Undesirable effects (UEs) that had been reported by RLA users over the course of two years (2011 - 2013) to an EU distributor. During that time, 125,409 units of RLA had been sold by the distributor. A total of 9 self-reported, but unconfirmed, UEs were reported to the distributor (and no SUEs – I understand from Athena that none have ever been reported to date). That is 0.00717% of the number of sold units. Intertek's assessment of these reported UEs was that they “suggest that some sensitive individuals may adversely react to this product.” However, Intertek went on to conclude that, “Under normal or reasonably foreseeable conditions of use, a product made to this formulation is unlikely to produce an abnormally high number of adverse reactions. The product gives users the level of safety they can reasonably expect when used as directed.” (h) In Athena’s 2020 Submission, Athena summarised these UE observations as follows: “the adverse reactions/UEs that have been reported by users of RLA are typical in nature to those associated with other cosmetic products used in the vicinity of the eyes, specifically mascara and eyeliner.” (i) It therefore appears from the “long-term safety and tolerability evidence” for RLA that there are no reports of the local adverse effects that have been reported with chronic long-term treatment of glaucoma following direct instillation of pharmacological relevant doses into the eye. (j) Therefore, for the reasons cited in response to this question (and others in this report), I don't concur with the SCCS that these data indicate a concern for the manifestation of serious and irreversible histological changes after consumer exposure of DDDE in RLA as a cosmetic product. 10 What do you understand “very low concentrations” to mean? (a) In considering this question, I went back to the SCCS report to assess in further detail the approach to addressing concentrations. This is especially important when the starting concentration of DDDE in RLA is only 0.018% which would be considered by most pharmaceutical scientists to already be a “very low” concentration. (b) As discussed above topical prostaglandin analogues for the treatment of glaucoma include Latanoprost, Travoprost, Tafluprost and Bimatoprost and the starting concentration of each in the commercial products is 0.005%, 0.004%, 00015% and 0.03%, respectively. These would again be considered very low concentrations by pharmaceutical scientists which identifies a problem with “qualitative” use of language around concentrations. This is because if the starting concentration of the API in the product is very low, the delivered dose per application has to also be very low and therefore for these products intended for treatment of IOP by direct instillation in the eye the effective concentrations are therefore by default “very low”. (c) Interestingly, there are a couple of instances in the report where the SCCS use the phrase “very high” concentrations and that is when discussing the outcome of the in vitro chromosomal aberration test in human lymphocytes, in which an increased frequency of aberrations were observed at “very high concentrations (2320 μg /mL)”. Importantly when utilising a qualitative term, the Committee took the opportunity to qualify the concentration, so the reader has a benchmark to understand the language and thereby assess relative risk. (d) In contrast the phrase “very low concentration” has no such reference point and as explained above has no meaning in this context as the starting concentration and subsequent amounts entering the eye from inadvertent application of RLA to the eyelid would have to be considered to be “very low”. STATEMENT OF TRUTH I confirm that insofar as the facts stated in my report are within my own knowledge, I have made clear which they are and I believe them to be true, and that the opinions I have expressed represent my true and complete professional opinion. Digitally signed by Ian Ian Wilding Signed by Dr Ian Wilding Date: 2021.11.21 Wilding 15:16:32 Z Date 21st November 2021 11 C a t a r a c t a n d R e f r a c t i v e S u r g e r y D i p l o m a t e , A m e r i c a n B o a r d o f O p h t h a l m o l o g y July 23, 2015 Re: Expert Opinion on Warning Label re: Use During Ocular Disorder Dear : I have been asked to provide an expert opinion on the present warning label for , which states, “IF YOUR ARE BEING TREATED FOR ANY OCULAR DISORDER (INCLUDING GLAUCOMA…USE ONLY UNDER THE SUPERVISION OF YOUR PHYSICIAN OR OPHTHALMOLOGIST” (the “Warning”). Specifically I have been asked if that particular warning is necessary or appropriate based on available information regarding the physiological effect of when used as directed. To help formulate my opinion, I have been provided with and have reviewed a binder of documents, a list of which is attached as Exhibit 1 to this expert opinion report. In addition, I have reviewed pertinent literature, and rely on clinical experience from my medical practice and those of my colleagues as reported at ophthalmology meetings. is a cosmetic product that is applied directly to the upper eyelashes with a fine applicator brush. is a multi-ingredient product consisting of ingredients that are commonly used in cosmetic products and a novel, proprietary ingredient developed by , dechloro dihydroxy difluoro ethylcloprostenol- amide (DDDE). All of the ingredients used in have been assigned an INCI (International Nomenclature of Cosmetic Ingredients) name (#1 in Exhibit 1). Because DDDE is a novel, proprietary ingredient, I will focus my analysis in this report on DDDE. DDDE is a prostaglandin F2α analog. Several different prostaglandin F2α analogs have been used as topical glaucoma medications (referred to collectively herein as “ophthalmic prostaglandin analogs”) for almost two decades. There is an extensive published literature on the safety of ophthalmic prostaglandin analogs. Although the ophthalmic prostaglandin analogs are different molecules from DDDE, the safety literature on the ophthalmic prostaglandin analogs is relevant to my analysis of the safety of DDDE in but must be considered in view of significant differences between and the ophthalmic prostaglandin analogs. The ophthalmic prostaglandin analogs are applied directly to the eye as an eye drop, whereas is applied directly to the upper eyelashes with a fine applicator brush. A thickener in functions to prevent migration of from the eyelashes into the eye, thereby preventing ocular surface exposure to DDDE. Understanding these differences, I have reviewed the literature on ophthalmic prostaglandin analogs, as described below. In addition, as a practicing ophthalmologist, I have relied on my extensive experience in the clinical treatment of glaucoma, including use of ophthalmic prostaglandin analogs. For your convenience, I have attached my Curriculum Vitae to this report as Exhibit 2. OPHTHALMIC PROSTAGLANDIN ANALOGS Xalatan®, which has the active prostaglandin analog, Latanoprost, was first approved by the FDA in 1996 as a glaucoma eye drop medication. The FDA approved Bimatoprost, in 2001 for use in the glaucoma eye drop medication Lumigan®. A third medication, Travatan®, which contains Travoprost, was also approved by the FDA for the treatment of glaucoma in 2001. The ophthalmic prostaglandin analogs, which are applied as eye drops, have ocular effects resulting from direct absorption by ocular membranes but also potentially have systemic effects resulting from absorption through the nasolacrimal duct. After topical administration of eye drops, 80% of the volume drains through the nasolacrimal duct and is absorbed systemically, bypassing hepatic metabolism. As an example, the use of ophthalmic timolol, a beta blocker (not an ophthalmic prostaglandin analog), has been associated with serious respiratory and cardiac events attributable to systemic absorption. Scientific evidence indicates that all of the ophthalmic prostaglandin analogs have a similar and excellent safety profile. This is consistent with my extensive clinical 1 experience in treating patients with ophthalmic prostaglandin analogs. Even though the ophthalmic prostaglandin analogs differ from DDDE in that they are applied directly to the eye as an eye drop (and DDDE is applied directly to the upper eyelashes with a fine applicator brush) and are different molecules, their clinical safety profile is relevant to my analysis for two reasons. First, their safety profile represents a ‘worst case scenario’ of ocular exposure to prostaglandin F2α analogs. Second, there is extensive safety data available on the ophthalmic prostaglandin analogs from their history of widespread clinical use. 1 Alm A, et. al., Side Effects Associated with Prostaglandin Analog Therapy, Surv Ophthal.53:S93-S105, Nov.2008. LITERATURE REVIEW Search Terms Glaucoma accounts for over 10 million visits to physicians per year in the United States.2 A significant amount of these patients are being treated with ophthalmic prostaglandin analogs. Additionally, bimatoprost, the active ingredient in the ophthalmic prostaglandin analog, Lumigan®, is also present in the product, Latisse®, which has been approved by the FDA to grow eyelashes. Latisse® is applied to the skin at the base of the upper eyelashes. To determine if the Warning is necessary or appropriate I first performed a pubmed search looking for adverse effects from the use of ophthalmic prostaglandin analogs. I combined the search terms side effects, ocular disorders, cataract, and macula with each of lantanoprost, bimatoprost, travaprost, Latisse, DDDE (the full chemical name), as well as prostaglandin. Pertinent articles (along with their pertinent references and related citations) were then reviewed to determine any safety concerns and side effects regarding the use of ophthalmic prostaglandin analogs in patients with ocular disorders. Review of Relevant Literature The literature search revealed an excellent review article entitled, “Side Effects Associated with Prostaglandin Analog Therapy.”3 The article notes that many ocular and periocular side effects such as periocular pigmentation, conjuctival hyperemia, and iris darkening are associated with the use of prostaglandin analog eye drops. Except for the iris darkening these were typically benign side effects, however, it should be noted that in a patient with iris melanoma or nevus, induced darkening of the iris could make evaluating the lesion more difficult. Additional ocular disease including cystoid macular edema (CME), anterior uveitis, and reactivation of herpes simplex have been noted to have an association with the use of ophthalmic prostaglandin analog eye drops, but no proof of a causal relationship was determined.4 Thus, there is no absolute contraindication for the use of ophthalmic prostaglandin analog eye drops in patients with a risk of developing these disorders but the clinician must be aware of the risks in patients who have had complicated cataract surgery (and are at higher risk of developing CME), prior anterior uveitis, or prior herpes keratitis. The mechanism of action with regards to these ocular side effects is thought to be due to the absorption of the ophthalmic prostaglandin analog directly into the eye when applied to the ocular surface as an eye drop. As explained above, topical ocular medications applied as eye drops have the potential for systemic 2 Center for Disease Control and Prevention/National Center for Health Stati stics, 2010 & 1995 3 Alm A, et. al., Side Effects Associated with Prostaglandin Analog Therapy, Surv Ophthal.53:S93-S105, Nov.2008. 4 Ibid. at p. S102. absorption. However, since the side effects noted above only occurred in the eye receiving the eye drop, systemic absorption did not contribute to the side effect CLINCAL EXPERIENCE I perform about 1500 glaucoma patient examinations per year and have done so now for at least the past 15 years. The majority of these patients who take topical medications are using or have used one of the ophthalmic prostaglandin analog drugs. Most of these patients are over 50 and have concurrent ocular disease, such as blepharitis, cataracts, macular disease, or dry eye. My clinical experience is similar to that described in the literature cited above. I have never been required to stop use in my patients of ophthalmic prostaglandin analogs due to any interaction with a specific ocular disease process except in a few patients with risk factors, such as CME noted above. In addition, pre-existing lid disease, such as blepharitis has not worsened with prostaglandin analog eye drops in my clinical experience, even though eye drops would migrate directly onto the lid margin with blinking. I have had to discontinue use of ophthalmic prostaglandin analogs in my glaucoma patients due to local allergy or adverse cosmetic effects such as conjunctival hyperemia. But all of these patients were using eye drops which are absorbed into the eye and are also placed directly on the surface of the eye, unlike Eye drops, due to their absorption into the eye and placement on the conjunctiva and cornea would be expected to have an occasional adverse interaction such as the CME. Because is applied to the upper eyelashes and contains a thickener to prevent migration from the site of application, as explained below, side effects associated with the ophthalmic prostaglandin analogs would not be expected to be associated with DDDE in ASSESSSMENT OF POTENTIAL PHYSIOLOGICAL EFFECTS OF The potential physiological effect of is largely determined by where it is applied and the properties of the product. is distinctly different from the ophthalmic prostaglandin analog products both in where and how it is applied and in its viscous formulation. is applied directly to the upper eyelashes with a fine applicator brush. In contrast, the ophthalmic prostaglandin analogs are applied as eye drops directly to the surface of the eye. Also, contains cellulose gum, which provides sufficient viscosity to prevent migration from the eyelashes to the ocular surface (conjunctiva and cornea). Potential Ocular Absorption In my previous study (#13 in Exhibit 1), I noted that did not migrate from the site of application into the eye. Further, review of the Evalulab study provided to me (#5 and #6 in Exhibit 1) indicates no statistical change in the intraocular pressure (IOP) in subjects using for 4 weeks. By contrast, Latisse®, which is the same solution as the ophthalmic prostaglandin analog, Lumigan® but approved by the FDA to grow eyelashes when applied to the eyelid at the base of the upper eyelashes, does not contain a viscosity agent and did produce a statistically significant reduction in IOP.5 Based on my review of scientific data, including the amount of DDDE present in each application of there would not be any expected ocular exposure associated with the use of in accordance with the package instructions and, therefore, any absorption of DDDE through the ocular membranes is highly unlikely (see below). Potential Systemic Absorption As noted above, the mechanism of systemic absorption for the topical ocular medications is through the nasolacrimal duct. In contrast to topical ophthalmic prostaglandin analogs, is not applied to the ocular surface as an eye drop or in any other form. The directions clearly state that it is to be applied in a thin line directly to the upper eyelashes above the level of the skin. As noted in the section above on ocular exposure to due to the viscous nature of and the placement upon the eyelashes, no migration into the eye would be expected. Thus, no expected systemic absorption from the ocular surface or nasolacrimal duct would be expected. This would leave possible skin absorption as another route for potential systemic effects. Dr. Ian Wilding’s report (#12 in Exhibit 1) noted that the skin is an effective barrier to systemic absorption. Based on review of his report and the supporting literature, I would not expect any clinically significant systemic amount of DDDE to occur via skin absorption, both due to the effective barrier of the skin and the minimal amount of potential migration of from the lashes to the eyelid margin and skin. CONSUMER COMPLAINTS In reviewing the log of consumer complaints supplied to me (#10 in exhibit 1), the majority of complaints relate to allergic irritation and sensitivity to which can occur with any cosmetic product. None of the complaints indicate systemic absorption of The paucity of complaints also speaks to the overall high safety and tolerance of The profile of consumer complaints does not raise concerns about ocular safety. CONCLUSION For all the foregoing reasons, I do not see any scientific basis for the requirement of the cosmetic product, being used under the supervision of a physician or ophthalmologist in patients being treated for ocular disorders, including glaucoma. 5 See Latisse® Prescribing Information. Since the product is not placed directly on the ocular surface and no migration onto the surface would be expected, should not exacerbate or interfere with the treatment of any ocular disorder. At most, occasional irritation or allergy as noted in the consumer logs, would occur as with any cosmetic product. If you have further questions please do not hesitate to contact me. Sincerely, Paul B. Donzis, M.D., M.B.A., Esq. Annex 10 E X P E R T R E P O R T Safety assessment of cosmetic products according regulation (EG) 1223/2009 Product: Author of expert report: V. NITSCHE, PhD Prinz Eugen Straße 6 1040 Wien authorized expert according § 73 LMSVG KOS 3593E 1120 This expert report consists of pages 1 - 16 SAFETY ASSESSMENT according the regulation (EG) 1223/2009 Product: Preparation: 031012-43, information of manufacturer of 10.03.2013 Manufacturer: EA Amsterdam, The Netherlands Distribution: EU: EA Amstedam, The Netherlands UK: Cardiff, Wales, CF10 2HH The assessment is based on a) the toxicological profile of the ingredients and raw materials and their available toxicological/dermatologic documentation, the tests on the finished product includ- ing microbiological tests, the safety data leaflets, the legal regulation and market observations. b) the chemical structure including the composition, the test procedures of the finished product and the raw materials and physical/chemical tests as well. c) the rate of exposure resulting from the typical intended use as indicated in the in- struction for use. For the protection of consumers, the voluntary and statutory warn- ings and other information are verified, which are listed in labeling, instructions for use and application instructions. Name of product: . With this designation, the type of application as a eyelash con- ditioner is clearly defined. Product: The product is a clear, colorless liquid with an characteristic odor. Packaging: The product is offered in 3.5 ml aluminum tubes with an applicator. The materials used are food-safe and may be used safely for the packaging of cosmetics. Elements of labeling: The elements defined in the regulation (EG) 1223/2009, Article 19 for the labeling of cosmetic products are met. Composition of the product: contains Aqua, Cellulose Gum, Chlorphenesin,Biotin, Glycerin, Phenoxyethanol, Swertia Japoni- ca Extract, Serenoa Serrulata Fruit Extract, Camellia Sinensis Leaf Extract, Panax Ginseng Root Extract, Triticum Vulgare Germ Protein,Pentylene Glycol, Calendula Officinalis Flower Extract, Butylene Glycol, Octapeptide-2, Biotinoyl Tripeptide-1, Ethyl Taflupros- tamide, Phosphoric Acid, Disodium Phosphate The CAS-numbers of the ingredients are listed in annex 1. The ingredients are indicated according the INCI nomenclature if listed. Further predictible application: Another forseeable application of the is not given because of the clearly instructions of use. Toxicological profile of single ingredients: Aqua Most of the cosmetic products contain water as a main component. From a toxicological point of view water is harmless. The water used in this product is purified, which means an adequate quality for cosmetics. Cellulose Gum: Cellulose Gum is a whitish powder with a characteristic odor that is used in cosmetics as a thickener. It is not irritating to the skin or eyes. A sensitizing effect is not known. The acute oral toxicity in the rat is 27,000 mg/kg (MSDS). The average molecular weight is 90,000 daltons. The ADI is indicated as "not specified". Cellulose Gum is rated as safe in cosmetic products by a toxicology expert panel (CIR, Cosmetic Ingredient Review, 20012) if the concentration does not exceed 20%. Chlorphenesin: Chlorphenesin is a white, crystalline substance that is used in cosmetics as a preservative. It is slightly irritating to the skin and very irritating to the eyes. A sensitiz- ing effect is possible. According to the Cosmetics Ordinance, chlorphenesin may be used as a preservative up to a concentration of 0.3%. Biotin: Biotin is a substance from the vitamin B complex and is used in cosmetics as a caring component. It is not irritating to the skin or eyes. A sensitizing effect is not known. Biotin has been assessed by a panel of toxicology experts (CIR, Cosmetic Ingredient Review, 2015) as safe in cosmetic products if a concentration of 1% is not exceeded. Glycerin: Glycerin, a clear and visvous liquid, is obtained by saponification of animal or vegetable fats. The glycerin used in this product is of vegetable origin. The substance is slightly irritating to skin and eyes. A sensitizing effect is unknown (OECD SIDS, March 2002). Its acute, oral toxicity in the rat is 12600 mg/kg (MSDS). A NOAEL of 2200 mg/kg from human Data is reported (CIR 2015). Phenoxyethanol: Phenoxyethanol is used in cosmetics as a solubilizer and preservative. According to the Cosmetics Regulation, phenoxyethanol may be used as a preserva- tive up to a concentration of 1%. A NOAEL of 500 mg/kg body weight is given (ECHA, Registration Dossier). Swertia Japonica Extract: Swertia Japonica Extract is an extract of the Japnese swamp star, which is used in Japanese folk medicine as a hairstrengthening agent. The plant belongs to the group of gentian plants with the ingredient swertiamarin, which is also found in the European gentian root. A panel of toxi- cology experts (Plants in Cosmetics, Volume II, Council of Europe, 2001) recom- mends a concentration of up to 7% for gentian root extracts as a safe use in cosmetic products. Serenoa Serrulata Fruit Extract: Serenoa Serrulata Fruit Extract is an extract of the saw palmetto fruit, which is used in cosmetics as an invigorating component. The extract is not irritating to the skin and eyes. A sensitizing effect is not known. Saw palmetto extract contains up to 0.16 % of the phytosterol ß-sitosterol (Penugonda K., Nutrients, 2013, 5, 3617-3633). A NOAEL of 210 mg/kg is given for beta-sitosterol (Mattilsynet 2012). Camellia Sinensis Leaf Extract: Camellia Sinensis Leaf Extract is a green tea extract with a characteristic smell that is used in cosmetics as a nourishing component. It does not irritate the eyes or skin and does not cause sensitization (MSDS). A toxicology expert panel (Plants in Cosmetics, Volume III, Council of Europe, 2006) gives a NOAEL of 450 mg/kg for the green tea ingredient methyl salicylate (fresh leaves: 20%). Dehydrolinalool (hotrienol) is contained in finished tea up to 70%. For dehydrolinalool, a NOAEL of 117 mg/kg body weight (ECHA, Registration Dossier Linalool) can be used analogously to linalool. Panax Ginseng Root Extract: Panax Ginseng Root Extract is a brownish extract of the ginseng root, which is used in cosmetics as a toning component. It is not irritating to eyes or skin. A sensitizing property is not known. A European committee of toxicology experts (Plants in Cosmetics, Volume I, Council of Europe, 2002) allows Panax Ginseng Root Extract (glycolic) to be used safely in cosmetics up to a concentration of 5%. Triticum Vulgare Germ Protein: Triticum Vulgare Germ Protein is a white, neutral smelling powder that is used in cosmetics as a hair conditioning component. It is not irritating to the eyes or skin and has no sensitizing properties. Wheat proteins are also ingested with food, so a toxic effect is not to be expected. Wheat proteins are judged to be safe in cosmetic products by a panel of toxicology experts (CIR, Cosmetic Ingredient Review, 2013) if the concentration does not exceed 1.7%. Pentylene Glycol: Pentylene Glycol is a colorless liquid with a characteristic odor that is used in cosmetics as a conditioning and solubilizing component. It is hardly irritating to the skin or eyes. A sensitizing effect is not known. This substance can be used safely when used in dilution. The acute oral toxicity in the rat is 2000 mg/kg. In a comparative study with other diols, pentylene glycol was found to be safe for use in cosmetics (Sundberg J.J., Expert Opin Investig Drugs. 2008, Apr; 17 (4): 601-10). A NOEL of 1000 mg/kg body weight is reported (CIR, Safety Assessment of Alkane Diols, 2016). Calendula Officinalis Flower Extract: Calendula Officinalis Flower Extract is a yellow liquid with a faint odor that is used in cosmetics as a nourishing component. It does not irritate the eyes or skin. A sensitizing effect is possible. A panel of toxicology experts (Plants in Cosmetics, Council of Europe, Volume 1, 2002) rated Calendula Officinalis Flower Extract as safe in cosmetic products up to a concentration of 10%. Calendula Officinalis Extract is judged to be safe in cosmetic products by a toxicology expert panel (CIR, Cosmetic Ingredient Review, 2015) if the concentration does not exceed 6%. Butylene Glycol: Butylene Glycol is a clear liquid which is used in cosmetics as a solvent. It is not irritant for skin and eyes and has no sensitizing properties. An expert panel of toxicologists (CIR, Cosmetic Ingredient Review, 2015) confirms the safe use of Butylene Glycol in cosmetics in concentration up to 89%. A NOAEL of 200 mg/kg bodyweight is reported (CIR, Alkane Diols, 2016). Octapeptide-2: Octapeptide-2 is a synthetic peptide that is used in cosmetics as a hair restorer. It is non-irritating to the skin and eyes and is non-sensitizing. For this peptide, a skin penetration of 0.01% (FDA) can be assumed, analogously to acetyl hexapeptide-8. Biotinoyl Tripeptide-1: Biotinoyl Tripeptide-12 is a synthetic peptide that is used in cos- metics as a hair restorer. It is non-irritating to the skin and eyes and is non-sensitizing. For this peptide, a skin penetration of 0.01% (FDA) can be assumed, analogously to acetyl hexapeptide-8. Biotinoyl Tripeptide-1 is assessed by a toxicology expert panel (CIR, Cosmetic Ingredient Review, 2014) as safe in cosmetic products if the concentration does not exceed 1%. Ethyl Tafluprostamide: Ethyl Tafluprostamide is a prostaglandin derivative with fatsoluble properties. It is used as a conditioner in hair products applied to the hair. It is not irritat- ing to skin. A sensitizing property is not known. A study of transdermal penetration of a topically applied prostaglandin reported penetration limited to the outer layer of the epidermis, which is devoid of blood vessels, and insignificant penetration to the vascu- larized dermis. (Transdermal delivery of prostaglandins, C.J.N. Oognejisofar, 1996, Univer- sity of Saskatchwan.). Transdermal penetration is proportional to the concentration of prostaglandin in the solution. (Oognejisofar, 1996). In the 1996 study, a 0.05% of PGE1 had a skin penetration rate of 1% over a period of 24 hours. Because the concentration of ethyl tafluprostamide used in this product is lower (0.018 %) and any incidental skin exposure to the conditioner would be brief, the 1% transdermal penetration rate is an upper limit. A NOAEL for Ethyl Tafluprostamide is not available. A NOAEL for tafluprost from a carcinogenicity study is given as 0.03 mg/kg body weight (Center For Drug Eval- uation And Research 2011, Pharmacology/Toxicology NDA Review And Evaluation Of Tafluprost. Application Number: 202514orig1s000). Phosphoric Acid: Phosphoric Acid is a colorless liquid that is used in cosmetics as a buff- ering component. If undiluted, it has a strong irritant effect on the eyes and skin and does not show any sensitizing effects. This substance can be used without hesitation when used as a dilution. An MTDI of 70 mg/kg body weight is given (JECFA 1982). Disodium Phosphate: Disodium Phosphate is a crystalline powder that is used in cosmet- ics as a buffer substance. It is slightly irritating to the skin and eyes. A sensitizing effect is not known. This substance can be used safely when used as a dilution. The acute oral toxicity in the rat is 17.5 g / kg (MSDS). The maximum tolerated daily dose (MTDI) is given as 70 mg/kg (JECFA, 2006). Determination of systemic exposure: The eyelash conditioner is used for eyelash care. The eyelash conditioner is applied with an eyeliner brush directly to the eyelashes. The product can be classified as a leave-on product. A quantity of application of 0.0024 g per day can be assumed for the eyelash conditioner (result of in-house investi- gations). Aqua: For water the assessment of systemic exposure can be omitted. Cellulose Gum: Cellulose gum is used in this product in a concentration of If 0.0024 g eyelash conditioner is used, a maximum systemic concentration of 0.00014 mg/kg could be achieved with 100% absorption through the skin. Cellulose gum is assessed by a toxicology expert panel (CIR, Cosmetic Ingredient Review, 20012) as safe in cosmetic products if the concentration does not exceed 20%. This means that this substance can be classified as safe for human health in the given concentration. Chlorphenesin: Chlorphenesin is used in this product in a concentration of If 0,0024 g Eyelash Conditioner is used, a systemic concentration of 0,00012 mg/kg could be achieved with complete absorption through the skin. According to the EU Cosmetic Regulation, chlorphenesin may be used as a preservative up to a concentration of 0.3%. This means that this substance can be classified as safe for human health in the given concentration. Biotin: Biotin is used in this product in a concentration of . If 0,0024 g Eyelash Condi- tioner is used, a systemic concentration of 0,0002 mg/kg could be achieved with com- plete absorption through the skin. Biotin has been assessed by a toxicology expert pan- el (CIR, Cosmetic Ingredient Re-view, 2015) as safe in cosmetic products if a concentra- tion of 1% is not exceeded. A risk to human health can thus be excluded and this sub- stance can be assessed as safe in the given concentration. Glycerin: Glycerin is used in this product in a concentration of If 0,0024 g Eyelash Conditioner is used, a systemic concentration of 0,00024 mg/kg could be achieved with complete absorption through the skin. A NOAEL of 2200 mg/kg per day from human data is given (CIR 2015). This results in a safety margin of 9166667. A risk to human health can thus be ruled out and this substance can be assessed as safe in the given concen- tration. Phenoxyethanol: Phenoxyethanol is used in this product in a concentration of If 0,0024 g Eyelash Conditioner is used, a systemic concentration of 0,00012 mg/kg could be achieved with complete absorption through the skin. According to the Cosmetics Regulation, phenoxyethanol may be used as a preservative up to a concentration of 1%. A NOAEL of 500 mg/kg body weight is given. This results in a safety margin of 4166667. This means that this substance can be classified as safe for human health in the given concentration. Swertia Japonica Extract: Swertia Japonica Extract is used in this product in a con- centration of . If 0,0024 g Eyelash Conditioner is used, a systemic concentration of 0,00000016 mg/kg could be achieved with complete absorption through the skin. A panel of toxicology experts (Plants in Cosmetics, Volume II, Council of Europe, 2001) recommends a concentration of up to 7% for gentian extracts as a safe use in cosmetic products. A risk to human health can thus be excluded and this substance can be assessed as safe in the given concentration. Serenoa Serrulata Fruit Extract: Serenoa Serrulata Fruit Extract is used in this product in a concentration of . If 0,0024 g Eyelash Conditioner is used, a systemic concen- tration of 0,00000032 mg/kg could be achieved with complete absorption through the skin. ß-Sitosterol is contained up to 0.16 %. A NOAEL of 210 mg/kg is given for beta- sitosterol. This results in a acceptable margin of safety for ß-sitosterol. A risk to human health can thus be excluded and this substance can be assessed as safe in the given concentration Camellia Sinensis Leaf Extract: Camellia Sinensis Leaf is used in this product in a concen- tration of If 0,0024 g Eyelash Conditioner is used, a systemic concentration of 0,00000024mg/kg could be achieved with complete absorption through the skin. A committee of toxicology experts (Plants in Cosme-tics, Volume III, Council of Europe, 2006) gives a NOAEL of 450 mg/kg for the green tea ingredient methyl salicylate (fresh leaves: 20%). Dehydrolinalool (hotrienol) is contained in finished tea up to 70%. For de- hydrolinalool, a NOAEL of 117 mg/kg body weight (ECHA, Registration Dossier Linalool) can be used analogously to linalool. For methyl salicylate (up to 20%) with a NOAEL of 450 mg/kg, this results in a safety margin of 9375000000. This means that this extract can be classified as safe for human health at the given concentration. Panax Ginseng Root Extract: Panax Ginseng Root Extract is used in this product in a concentration of . After using 0,0024 g Eyelash Conditioner, a maximum systemic concentration of 0,0000004 mg/kg could be achieved. A European committee of toxicology experts (Plants in Cosmetics, Volume I, Council of Europe, 2002) allows Panax Ginseng Root Extract (glycolic) to be used safely in cosmetics up to a concentration of 5%. A risk to human health can thus be ruled out and this substance can be assessed as safe in the given concentration. Triticum Vulgare Germ Protein: Triticum Vulgare Germ Protein is used in this product at a concentration of . If 0.0024 g eyelash conditioner is used, a systemic concen- tration of 0.000000033 mg/kg could be achieved with complete absorption through the skin. Wheat proteins are also ingested with food, so a toxic effect is not to be expected. Wheat proteins are judged to be safe in cosmetic products by a panel of toxicology experts (CIR, Cosmetic Ingredient Review, 2013) if the concentration does not exceed 1.7%. A risk to human health can thus be ruled out and this substance can be assessed as safe in the given concentration. Pentylene Glycol: Pentylene Glycol is used in this product in a concentration of . If 0.0024 g of eyelash conditioner is applied, a systemic concentration of 0.000000033 mg/kg could be achieved with complete absorption through the skin. A NOEL of 1000 mg/kg body weight is reported. This results in a safety margin of 30303030303. This means that a risk to human health can be excluded and this sub- stance can be assessed as safe in the given concentration. Calendula Officinalis Flower Extract: Calendula Officinalis Flower Extract is used in this product in a concentration of . If 0.0024 g eyelash conditioner is applied, a systemic concentration of 0.00000048 mg/kg could be achieved with complete absorp- tion through the skin. A panel of toxicology experts (Plants in Cosmetics, Council of Europe, Volume 1, 2002) rated Calendula Officinalis Flower Extract as safe in cosmetic products up to a concentration of 10%. Calendula Officinalis Extract is judged to be safe in cosmetic products by a toxicology expert panel (CIR, Cosmetic Ingredient Re- view, 2015) if the concentration does not exceed 6%. Butylene Glycol: Butylene Glycol is used in this product in a concentration of If 0,0024 g Eyelash Conditioner is used, a systemic concentration of 0,0000032 mg/kg could be achieved with complete absorption through the skin. Butylene Glycol is judged to be safe in cosmetic products by a panel of toxicology experts (CIR, Cosmetic Ingredient Review, 2015) if the concentration does not exceed 89%. A NOAEL of 200 mg/kg body weight is reported. This results in a safety margin of 62500000. This means that any risk to human health can be excluded and this substance can be assessed as safe in the given concentration. Octapeptide-2: Octapeptide-2 is used in this product in a concentration of . If 0.0024 g eyelash conditioner is used, a systemic concentration of 0.000000002 mg/kg could be achieved with complete absorption through the skin. No toxic effects can be ascribed to this concentration (TTC). This means that this substance can be classified as safe for human health in the given concentration. Biotinoyl Tripeptide-1: Biotinoyl Tripeptide-1 is used in this product in a concentration of If 0.0024 g eyelash conditioner is used, a systemic concentration of 0.000000064 mg/kg could be achieved with complete absorption through the skin. Biotinoyl Tripeptide-1 is assessed by a toxicology expert panel (CIR, Cosmetic Ingredient Review, 2014) as safe in cosmetic products if the concentration does not exceed 1%. Ethyl Tafluprostamide: Ethyl Tafluprostamide is used in this product in a concentration of 0.018 %. If 0,0024 g Eyelash Conditioner is used, a systemic concentration of 0,000007 mg/kg could be achieved taking into account a skin penetration rate of 100 %. A safety margin of 4286 is calculated from a NOAEL of 0.03 mg/kg body weight (NOAEL is derived from a comparable Tafluprost study). A risk to human health can thus be excluded and this substance can be assessed as safe in the given concentration. Phosphoric Acid: Phosphoric Acid is used in this product at a concentration of . If 0.0024 g eyelash conditioner is used, a systemic concentration of 0.000012 mg/kg could be achieved with complete absorption through the skin. Phosphoric acid is bound in a buffer system and thus its acidic effect is limited. With an MTDI of 70 mg/kg, there is a safety margin of 583333333. At this use concentration, a risk to human health can be excluded and this substance can be assessed as safe in the given concentration. Disodium Phosphate: Disodium Phosphate is used in this product in a concentration of If 0,0024 g Eyelash Conditioner is used, a systemic concentration of 0,000056 mg/kg could be achieved with complete absorption through the skin.. With an MTDI of 70 mg/kg, analogous to the ADI, there is a safety margin of 125000000. This means that this substance can be classified as safe for human health at the given con- centration. Margin of Safety: The exact margin of safety can not be estimated because of missing NOAEL-values for most of the single components. The margin of safety derived from NOAEL should not be below 100. The classifications derived from toxicological expert reports (CIR, ADI, HSDB, OECD, TTC, JECFA, Plants in Cosmetics) are resulting in toxicologically safe levels. Calculation of Systemic Exposure Dose (SED): Calculation of SED was made in the chapter determination of systemic exposure. A listing of the calculations is given in annex 2. Stability of the cosmetic product: Microbiological stability: A micribiological test of the Eyelash Conditioner is performed. The product complies to the cosmetic regulation. Physicochemical stability: A shelftest during several months gives prove for the physicochemical stability of the product. The tested product showed no differences to initial values. Conditions of application and warnings: The Eyelash Conditioner should be used as an Eyelash Conditioner. Following warnings are indicated on the label: „Do not get in the eye“ „Rinse immediately with water if eye contact occurs” „If irritation develops, reduce frequency of use until the irritation resolves” „If irritation persists or is excessive, discontinue use and consult a physician” „Keep out of reach of children”. Prove of effect: No certain effect is praised that requires a proof of effectiveness. The good skin toler- ance is confirmed by a dermatological examination (patch test). The ocular tolerance is confirmed by a ophtalmological examination. Adverse effects: No adverse effects are registered. Results of assessment: All components of the product are documented with safety data leaflets or product specifications, confirming the harmlessness to the human health of the components in the given concentration and the typical intended use. There are no ingredients which are not allowed [Regulation (EG) 1223/2009, Annex II] or which are used in concentrations not covered by the cosmetic regulation [(EG) 1223/2009, Annex III)]. No allergenic substances have to be indicated on the label. Following warnings are indicated on the label: „Do not get in the eye“ „Rinse immediately with water if eye contact occurs” „If irritation develops, reduce frequency of use until the irritation resolves” „If irritation persists or is excessive, discontinue use and consult a physician” „Keep out of reach ofchildren”. The good skin tolerance is confirmed by a dermatological examination (patch test). The ocular tolerance is confirmed by a ophtalmological examination. The shelf life of the product is stated to be more than 30 months. This makes it necessary to keep the open jar with the indication of the shelf life after opening with 12 months in the label. A batch designation, the filling quantity and the distribution are also given in the labeling. The elements defined in the regulation (EG) 1223/2009, Article 19 for the labeling of cosmetic products are met. Taking into account the entire exposure of the present product to the human body there is no risk concerning the human health and safety when the product is applied in a usual and anticipated way. Vienna, 13 Nov 2020 _________________________________________ date signature (approved expert according § 73 LMSVG) P E R S O N A L R E C O R D Veit NITSCHE, PhD 1945: Born in Vienna 1963: Maturity, commencing university study of technical sciences 1972: Awarding of PhD of technical sciences (chemistry) 1973: Austrian Research Centre Seibersdorf (former SGAE), institutes of chemistry (labelled isotopes) and biology (biochemistry) 1974: Pharmakologische Untersuchungsgesellschaft, Vienna (pharmacology, toxicology, pharmacokinetics, biopharmaceutics) 1977: Head of Pharmakologische Untersuchungsgesellschaft in Vienna Since 1984: Head of CRO Biokinet GmbH, Vienna, clinical studies on pharmacokinetics and biopharmaceutics 1982 Scientific award of the Austrian Society for Dermatology 1990 Member of the Sientific Board of the First European Congress for Biopharma- ceutics and Pharmacokinetics (ECBP) 1997 Approved expert for cosmetics according § 50 LMG 1975 (now § 73 LMSVG 2006) 41 Publications , 031012-43 CAS# TRADE NAME % BY WEIGHT 7732-18-5 Purfied Aqua 9000-11-7 Cellulose Gum 9004-32-4 CMC400SF 104-29-0 Germazide C R10284 58-85-5 Biotin/D-Biotin 56-81-5 Glycerin 122-99-6 Phenoxetol 56-81-5 DL Swertia Ja- ponica GL 94167-11-0 7732-18-5 84604-15-9 Actiphyte of Saw Palmetto GL 56-81-5 335812-13 122-99-6 7732-18-5 ABS Green Tea 84650-60-2 Extract WS 122-99-6 7732-18-5 90045-38-8 Actiphyte of Ginseng GL 56-81-5 318120-13 122-99-6 7732-18-5 100684-25-1 Tensine GR 5343-92-0 Aqua 100,000% Solvent Cellulose Gum 100,000% Viscosity Increa- sing Agent Chlorphenesin 100,000% Preservative Hair Conditioning Biotin 100,000% Agent Hair Conditioning Glycerin 100,000% Agent; Humectant Phenoxyethanol 100,000% Preservative Hair Conditioning Glycerin 79,900% Agent; Humectant Swertia Japonica 20,000% Skin Conditioning Extract Agent Aqua 39,500% Solvent Serenoa Serrulata 20,000% Skin Conditioning Fruit Extract Agent Hair Conditioning Glycerin 39,500% Agent; Humectant *Phenoxyethanol 1,000% Preservative Aqua 79,000% Solvent Camellia Sinensis Leaf Extract 20,000% Emollient *Phenoxyethanol 1,000% Preservative Aqua 39,500% Solvent Panax Ginseng Root 20,000% Skin Conditioning Extract Agent Hair Conditioning Glycerin 39,500% Agent; Humectant *Phenoxyethanol 1,000% Preservative Aqua 89,500% Solvent Triticum Vulgare 5,500% Hair Conditioning (Wheat) Protein Agent Pentylene Glycol 5,000% Solvent KOS 3593E 1120 7732-18-5 84776-23-8 Actiphyte of Calendula GL 56-81-5 313640-13 122-99-6 7732-18-5 107-88-0 Octapeptide-2 Peptide Solution Not Referenced 107-88-0 7732-18-5 Biotinyl-GHK Solution Not Referenced Dechloro Dihyd- roxy Difluoro 0,2400% Ethylcloprosten- 122-99-6 olamide 7664-38-2 Phosphoric Acid 7558-79-4; 7782- Sodium Phospha- 85-6; 10140-65-5 te Dibasic 39,500% Solvent Calendula Officina- Skin Conditioning lis Flower Extract 20,000% Agent Hair Conditioning Glycerin 39,500% Agent; Humectant *Phenoxyethanol 1,000% Preservative Aqua 98,000% Solvent Butylene Glycol 1,950% Solvent Skin Conditioning Octapeptide-2 0,050% Agent Butylene Glycol 49,950% Solvent Aqua 49,950% Solvent Biotinoyl Tripeptide- Hair Conditioning 1 0,100% Agent Ethyl Tafluprostami- 7,500% Conditioning de Agent Phenoxyethanol 92,500% Preservative Phosphoric Acid 100,000% pH Adjustor Disodium Phosphate 100,000% Buffering Agent 1 Exposure to the cosmetic product Formula for the calculation of dermal exposure, Expderm (mg/kg/day): Expderm = (G × A) × F × R / K Bodyweight K (kg): Adult 60 kg Way of exposure: dermal Retention factor R: Leave-on-products = 1; Rinse-off- products <1 Application area A (cm²): Corresponding to instructions of manufacturer Amount of application G (mg/cm²): Frequency of Application F (x/day): a) Application site: Eyelashes b) Surface of application (Application area, A) [cm²] c) Quantity per application (G) 0,0024 (Applied quantity G) [g] d) Duration (based on product type, derived from it: Reten- Leave on tion factor, R) e) Frequency of use 1x /day (Frequency of Application, F) [x per day] f) Normal and reasonable forseeable expoisure route g) Target group of application: adults 60 kg (Bodyweight, K) [kg] h) Dermal exposure (Expderm) [mg/kg/day] 0,04 mg/kg/day i) Oral exposure j) Inhalation exposure 2 Exposure to the substances SED Bes tan dteil X  EXP derm  Konzentrat ion Bes tan dteil X [%] Permeation Haut [%]  100 Substance Concentration in Skin penetrati- SEDsubstance finished product [%] on [%] [mg/kg] Cellulose Gum Chlorphenesin Biotin Glycerin Phenoxyethanol Swertia Japonica Extract Serenoa Serrulata Fruit Extract Camellia Sinensis Leaf Extract Panax Ginseng Root Extract Triticum Vulgare Germ Protein Pentylene Glycol Calendula Officinalis Flower Extract Butylene Glycol Octapeptide-2 Biotinoyl Tripeptide-1 Ethyl Tafluprostamide 0,018 100 0,000007 Phosphoric Acid Disodium Phosphate Memorandum TO: Bart Heldreth, Ph.D. Executive Director - Cosmetic Ingredient Review FROM: Carol Eisenmann, Ph.D. Personal Care Products Council (PCPC) DATE: April 17, 2023 SUBJECT: Concentration of Use by FDA Product Category: Prostaglandin Analogues The listed prostaglandin analogues were included in a concentration of use survey. No uses were reported for any of these ingredients. Isopropyl Cloprostenate Dehydrolatanoprost Ethyl Tafluprostamide Ethyl Travoprostamide Bimatoprost Cyclopropylbimatoprost Cloprostenol Travoprost Dihydroxypropyl Didehydrolatanoprostamide Norbimatoprost Nortafluprost Trifluoromethyl Dehydrolatanoprost Methyl Bimatoprost Acidate Noralfaprostol Travoprostamide Isopropyl Dimethylnorcarboprostate Memorandum TO: Bart Heldreth, Ph.D. Executive Director - Cosmetic Ingredient Review FROM: Carol Eisenmann, Ph.D. Personal Care Products Council DATE: May 10, 2023 SUBJECT: Isopropyl Cloprostenate Consumer Product Testing Company. 2023. Use information for Isopropyl Cloprostenate in lash serum.