annual meetingrifm poster display 5:15 pm cocktail reception and networking 6:15 pm dinner guest...

09.12.19

THE CHART HOUSEWEEHAWKEN, NJ

6

16

ANNUALMEETING

We proudly

represent our

industry with

passion and

enthusiasm,

promoting

the beauty,

benefits and

safety of

fragrance.

At Arylessence,

our fragrance

creativity

enhances the

world around us.

(800) 553-2440

www.arylessence.com

RIFM Annual Meeting Ad 6.2018.indd 1 6/20/2019 11:42:02 AM

3

AGENDA3:30 PM

REGISTRATION4:00 PM

BUSINESS MEETINGCommunicating Our Science

5:00 PMRIFM POSTER DISPLAY

5:15 PMCOCKTAIL RECEPTION AND

NETWORKING

6:15 PMDINNER

GUEST SPEAKERMelissa Marshall, FounderPresent Your Science

Science Not Communicated Is Science Not Done: Present Your Science Powerfully

RAFFLE FOR CHARITYOne lucky winner will receive $500 for their favorite charity.The raffle will take place during dessert. Winner must be present.

Welcome to RIFM’s 53rd Annual Meeting

RESEARCH INSTITUTE FOR FRAGRANCE MATERIALS

Dr. Bickers’ CareerDr. Bickers earned his first degree—an A.B. in Classics (Pre-Medical)—in 1963 from Georgetown University. He received his MD from the University of Virginia School of Medicine in Charlottesville in 1967. From 1967–1968, Dr. Bickers interned in Internal Medicine at the University of Iowa Medical Center in Iowa City, Iowa. Thereafter, he served as a Medical Officer in the United States Air Force from 1968–1970, assigned to a base in U-Tapao, Thailand, and to Hamilton Air Force base in California. From 1970–1973, Dr. Bickers was a resident in Dermatology at the Skin and Cancer Unit of the New York University Medical Center in New York City, after which he took on the role of Assistant Professor of Dermatology at the College of Physicians & Surgeons of Columbia University in New York City from 1973–1977. During this time and subsequently, Dr. Bickers was an NIH-funded trainee and an RJ Reynolds Scholar in Clinical Medicine (1976–1977), working in the laboratory of Professor Attallah Kappas at the Rockefeller University Hospital in New York City. While there, he was a research fellow in the laboratory of the late

A Study in Scientific ExcellenceTHE FIRST ANNUAL RIFM BOARD OF DIRECTORS EXCELLENCE IN FRAGRANCE SCIENCE AWARD:

David R. Bickers, MD, Carl Truman Nelson Professor and Chairman Columbia University Medical Center

Professor Alvito Alvares. From 1977–1993, he served as Professor and Chairman of the Department of Dermatology at Case Western Reserve University School of Medicine in Cleveland, Ohio. Since 1994, Dr. Bickers has been the Carl Truman Nelson Professor and Chair of the Department of Dermatology at the Vagelos College of Physicians & Surgeons of Columbia University Irving Medical Center in New York City. Dr. Bickers was Chair of the Expert Panel for Fragrance Safety from 2003–2005 and Vice-Chair from 2006–2012. Dr. Bickers is currently a Trustee Emeritus and former Vice-Chair of the Board of Trustees of the American University of Beirut in Lebanon and chairs the Committee for VISION 2020 at its Medical Center.

Dr. Bickers’ WorkEarly in his career, Dr. David R. Bickers conducted studies that led to the discovery of xenobiotic-metabolizing cytochrome P-450 in mammalian and human skin and showed that these enzymes are involved in the initiation of non-melanoma skin cancer (NMSC), including basal cell and squamous cell carcinoma by environmental carcinogens. More recently, Dr. Bickers has studied the role of sunlight in inducing these types of tumors, using a mechanism-driven targeted approach to cancer chemoprevention designed to lead to clinical trials in skin cancer–susceptible

populations. This strategy resulted in the successful use of a targeted

drug in human subjects with Gorlin syndrome, a dominantly inherited disorder in which affected individuals develop dozens to hundreds of basal cell carcinomas of the skin. This syndrome is associated with

overactivity of the Sonic Hedgehog signaling pathway, and Dr. Bickers has successfully completed clinical trials in these patients showing that orally administered vismodegib, a potent inhibitor of Sonic hedgehog signaling, substantially reduces their tumor burden.

ABOUT THE RIFM BOARD OF DIRECTORS EXCELLENCE IN FRAGRANCE SCIENCE AWARD

The RIFM Board of Directors, acknowledging the importance of excellence in science to the fragrance industry’s ongoing commitment to human health and the environment, has established an annual award to recognize individuals around the world who have shown outstanding dedication to the advancement of fragrance science. The award honors those whose contributions meet the highest standards in the industry for excellence and distinction by conducting original research and publishing in peer-reviewed journals on topics of fragrance chemistry, biochemistry, molecular biology, physiology, biotechnology, toxicology, medicine, psychology, and public health.

The RIFM Excellence in Fragrance Science Award is intended to provide timely recognition of original and significant contributions to fragrance science and may not be presented every year. A selection subcommittee appointed by the Board of Directors reviews all nominated candidates and recommends a finalist to the full Board of Directors for approval.

4

2019 ANNUAL MEETING

5

Melissa Marshall is on a mission: to transform how scientists, engineers, and technical professionals present their work. That’s because she believes that even the best technical ideas are destined to remain undiscovered unless presented in a clear and compelling way that sparks innovation and drives adoption.

For a decade, she’s traveled around the world to work with Fortune 100 corporations, institutions, and universities, teaching the proven

Melissa Marshall Talks Nerdy to UsMELISSA MARSHALL, FOUNDER

PRESENT YOUR SCIENCEScience Not Communicated Is Science Not Done:

Present Your Science Powerfully

strategies she’s mastered through her consulting work and during her time as a faculty member at Penn State University.

Melissa is internationally known for her popular TED Talk entitled “Talk Nerdy to Me,” which has over 2 million views (and counting). Melissa is the founder of Present Your Science, a consulting company that provides on-site group workshops, conference sessions, and 1:1 coaching.

Bio

2019 ANNUAL MEETING

5

RIFM Science Poster Presentations


6

What 30 Years of Evaluating Fragrance Ingredients with a Human Repeat Insult Patch Test Have Taught Us

Gretchen Ritacco1, Mihwa Na1, Devin O’Brien1, Maura Lavelle1, Anne Marie Api1, David A. Basketter2

1Research Institute for Fragrance Materials 2DABMEB Consultancy Ltd.

PRESENTED BY

Mihwa Na Maura Lavelle

How Chemical Doppelgängers Save Time, Money, and Animal Lives

Mihir S. Date1, Francisco Rodríguez-Ropero1, Chaitra V. Deodhar1, Dan Salvito1, Anne Marie Api1

1Research Institute for Fragrance Materials

PRESENTED BY

Mihir S. Date Francisco Rodríguez-Ropero

Chaitra V. Deodhar

New Screening Tool Helps Safeguard Future Generations by Identifying Which Materials to Push Forward in the Testing Pipeline

Sai Yee Tsang1 and Anne Marie Api1


PRESENTED BY

Sai Yee Tsang

2019 ANNUAL MEETING

7

Compiling a Dataset to Refine the Threshold of Toxicological Concern (TTC) for Inhalation Exposure

Nikaeta Sadekar1, Kaushal Joshi1, Jane Rose2, Danielle Botelho1, Anne Marie Api1

1Research Institute for Fragrance Materials2Procter & Gamble

PRESENTED BY

Nikaeta Sadekar

Can an Egg Help Save Animal Lives?

Yax Thakkar1, Anne Marie Api1, K.D. Brunnemann2, J.D. Duan2, T. Kobets2, G.M. Williams2

1Research Institute for Fragrance Materials 2New York Medical College

PRESENTED BY

Yax Thakkar

400 Materials Are About to be Removed from RIFM’s Safety Assessment Program. Are Yours on the List?

Gretchen Ritacco1, Mary Ann Cancellieri1, Danielle Botelho1, and Anne Marie Api1


PRESENTED BY

Gretchen Ritacco Mary Ann Cancellieri

What Fish in vitro Assays Can Tell Us About the Bioaccumulation of Complex Mixtures

Aurelia Lapczynski1, Karla Johanning2

1Research Institute for Fragrance Materials 2KJ Scientific

PRESENTED BY

Aurelia Lapczynski

RIFM Science Poster Presentations (continued)

Expanding an Existing Dataset Has Refined the Exposure Threshold Levels for Systemic Toxicological Concern

Atish Patel1a, Kaushal Joshi1, Sanket Gadhia1, Jane Rose2, Michael Laufersweiler3, Susan P. Felter2, Anne Marie Api1

1Research Institute for Fragrance Materials 2Procter & Gamble aNow at FMC

PRESENTED BY

Kaushal Joshi Sanket Gadhia

The RIFM Flavor and Fragrance Database Is the Most Comprehensive, Worldwide Source of Toxicology Data, Literature, and General Information Specific to Fragrance and Flavor Raw Materials

PRESENTED BY

Christen Sachse-Vasquez Mary Mircovich

Nancy Nowinski Jill Bohan

Molly Gilmore Meghan Sullivan


8

2019 ANNUAL MEETING

9

KAUSHAL JOSHIKaushal Joshi (Genotoxicity) was the invited speaker at St. John’s University’s 2018 Dean’s Hour Careers in Toxicology event and was asked to participate in Graduate Student Mentoring at the Society of Toxicology in 2019.

GRETCHEN RITACCOGretchen Ritacco (Phototoxicity/photoallergy) has been invited to give a Symposium Talk, Photosafety Evaluation of Fragrance Materials: A Tiered Approach Using Both Alternative Methods and Confirmatory Testing in Humans, at the Clinical Photosafety Symposium, 17th International Congress on Photobiology/18th Congress of the European Society for Photobiology, August 25–30, 2019.

RIFM Scientists: Gaining Recognition

NIKAETA SADEKARNikaeta Sadekar (Respiratory) has served as Junior Councilor for the Society of Toxicology (SOT)’s Ethical, Legal, Forensics, and Societal Issues (ELFSI) Specialty Section since May 2019; before that, she was SOT’s Post-Doctoral Representative. In April 2019, she was enlisted as a Judge at New York State Science and Engineering Fair; in January 2019 she served as Newsletter Editor for the American Society of Cellular and Computational Toxicology; and in December 2018, she was tapped for the FIFRA EPA Scientific Advisory Panel.

YAX THAKKARYax Thakkar (Genotoxicity) was appointed as New Investigator Co-Chair for a Special Interest Group session on “New Technologies” at EMGS 2019 and invited to serve as a Grand Award Judge at Intel ISEF 2019 in the Cell and Molecular Biology category.

Yax Thakkar and Kaushal Joshi (Genotoxicity) were honored with the Genetic Toxicology Association (GTA) 2018 Early Stage Investigator Award for their abstract The BlueScreen HCTM Assay to Predict the Genotoxic Potential for Fragrance Materials and snagged an Environmental Mutagenesis and Genomics Society 2018 (EMGS) New Investigator Poster Presentation Runner-up distinction.

ANNE MARIE API Anne Marie Api received the Philippe Shubik Distinguished Scientist Award from The Toxicology Forum in 2018. The global award, given annually, honors an individual who has had a long and productive career in the field of toxicology and has made significant and noteworthy contributions to the field.

10

GENOTOXICITYRIFM has completed the testing of 1448 materials in the BlueScreen Assay. In accordance with the acceleration of its genotoxicity testing program, RIFM has requested 570 materials to date for testing in an Ames assay and in vitro micronucleus test (MNT).

A manuscript for peer-reviewed publication is under development to summarize the BlueScreen data on chemically defined fragrance materials. This paper will demonstrate the effectiveness of using the BlueScreen Assay in safety assessments.

Similar to the procedure used for chemically defined fragrance materials, BlueScreen has been utilized to screen materials as an initial step to prioritize genetic toxicity testing for Natural Complex Substance (NCS) materials. These materials have proceeded into further tier genotoxicity assays.

Quartz Bio has been contracted to extract and parse the raw data from reports on the materials screened and

Advancing RIFM’s Science

tested using the BlueScreen Assay, the Ames assay, and the MNT. Customized plots of cytotoxic and genotoxic data for each material were constructed for use as an interactive visualization tool. This tool is currently available to RIFM members and is an excellent example of a RIFM research project that became a tool for RIFM scientists and now a tool for RIFM members.

RIFM has been working toward the use of non-animal methods in genotoxicity testing. We are working in conjunction with the International Organization of the Flavor Industry (IOFI) to compile data that will support the validation of the 3D reconstructed skin micronucleus test and 3D skin COMET assay as a unique animal alternative in genotoxicity testing. Along with the validation of the 3D skin model, RIFM is also optimizing and validating a novel egg-based (in ovo) animal alternative model, which will be

322

materials are currently under evaluation or have been completed in the Ames assay.

464materials have undergone or are currently underway in the in vitro MNT.


For over 45 years, Bedoukian Research Inc. has provided superior quality products to serve your aroma chemical needs. Today, we offer more than

350 high impact molecules, while providing custom manufacturing services to the pharmaceutical and

specialty chemical industries.

Supplying High Quality Materials Since 1972

www.bedoukian.com

a live system with fully functioning liver metabolism capabilities and hence is expected to mimic the outcome observed in the in vivo studies.

Additionally, RIFM is also working on identifying a high-throughput screening tool/s (Multiflow and/or ToxTracker), which can accurately identify the mechanism of genotoxicity for fragrance materials and eventually help make an informed decision for proper selection of a follow-up testing strategy or develop a genotoxicity threshold based on the identified mechanism.

SENSITIZATIONThe collaborative effort in supporting the development of a non-animal alternative approach for hazard and potency estimation for skin sensitization was continued by RIFM in

2019. RIFM had previously generated data on DPRA, PPRA, KeratinoSens, U-Sens, h-CLAT, and SENS-IS for nearly 100 materials that had historical animal and/or human data. In 2019, kinetic DPRA was added to this battery of in vitro tests. The kinetic DPRA is a non-animal alternative experiment measuring the rates of skin protein binding, which represents a key event in skin sensitization. Currently, 69 chemicals are scheduled to be assayed using the kinetic DPRA. The results of this project will provide substantial information to RIFM for developing a non-animal testing strategy for assessing skin sensitization hazard and potency.

With the data gathered from the non-animal alternative experiments, RIFM is collaborating with Edelweiss Connect to construct a predictive

model using Bayesian Network. The model will aim to incorporate the non-animal testing data with existing animal and human data to estimate the skin sensitization potency of an untested chemical.

In addition, RIFM recognizes that the evaluation of the non-animal alternatives and the predictive model for skin sensitization potency are highly dependent on the availability of a reliable animal and human dataset whose potency is well characterized. To that end, all RIFM-conducted human repeat insult patch test (HRIPT) data were compiled in a manuscript to be submitted. The compilation of the available murine LLNA data and analysis in comparison with the available human data are also in progress. Furthermore, in collaboration with Dr. Frank Gerberick, RIFM is

For over 45 years, Bedoukian Research Inc. has provided superior quality products to serve your aroma chemical needs. Today, we offer more than

350 high impact molecules, while providing custom manufacturing services to the pharmaceutical and

specialty chemical industries.

Supplying High Quality Materials Since 1972

www.bedoukian.com

2019 ANNUAL MEETING


working to categorize fragrance materials based on all available information, including available human data, animal data, in vitro data, and chemical structures. The results of these projects will be imperative in evaluating and increasing the predictiveness of the non-animal alternative methods.

EXPOSURERIFM partnered with Creme Global, a well-established partner to industry for modeling exposure to cosmetics and foods, whose methodology is accepted by regulators, to develop an aggregate exposure model for fragrance materials used in any fragranced product. The model provides detailed probabilistic aggregate exposure for consumers. The benefits of the model for RIFM members include:u�Avoiding over-estimation of exposure (the model replaces the previous overly conservative and unrealistic methods for estimating aggregate exposure).

u�Providing a solid scientific basis for IFRA limits for systemic effects.

u�A more realistic evaluation of fragrance ingredients.

u�Saving time and money by reducing the need for toxicity testing.

u�Satisfying regulators’ request for aggregate exposure data.

The Creme RIFM Aggregate Exposure Model is a strategic tool in the RIFM safety assessments because it is used to calculate the total exposure to fragrance materials. In addition, this tool has an optimization tool to estimate the concentration in product categories that will yield a specific P95 aggregate exposure per unit body weight. This tool allows RIFM to maximize the fragrance concentrations in products yet remain below a safe exposure threshold. This process allows RIFM to make informed decisions about the maximum acceptable fragrance concentration levels on the product category level. If deemed necessary by the Expert Panel, this

information is then provided to IFRA for inclusion in an IFRA Standard.The Aggregate Exposure Task Force, with Creme Global, developed a model to calculate aggregated exposure to fragrance ingredients from all routes of exposure. The model is now in use, and from 2017 to June 2019, 11 concentration

surveys were performed. These surveys, which included more than 1600 fragrance materials, are open to all companies for participation.Over the last 24 months, the Creme RIFM Aggregate Exposure work has continued to expand the model to include:u�Household cleaning products, as well as additional cosmetic and personal care products.

u�Habits and practices data from other countries.

u�Increased representation of the European population.

u�Updated habits and practices survey data conducted by Kantar Worldpanel (Kantar) 2013–2014.

u�Habits and practices data for subjects in the 13–17 age group for Europe and the US.

Another enhancement currently being worked on is to develop a program to allow RIFM the ability to run the optimization tool. Exposure assessments in batch mode is another goal for 2019. Currently, RIFM can only run one material at a time. This will provide RIFM with a more effective means of calculating the maximum concentration value (batch optimization tool) and exposure data for the safety assessments. In addition, this will help us enter the exposure data into the RIFM Database by computer file and therefore eliminate the need for data entry by a staff member. This

The life science business of Merck operatesas MilliporeSigma in the U.S. and Canada.

12

2019 ANNUAL MEETING

will be both more efficient and less prone to data entry mistakes.RIFM is collaborating with Cosmetics Europe and the Personal Care Products Council to obtain both habits and practices data as well as exposure or amounts data in Europe and the USA on baby products. This will further enhance the Creme RIFM Model and will address questions that we often receive from regulators.

Future planning will include looking into exposure for products in Category 8 (Products with significant ano-genital exposure [tampon]) and Category 11 (Products with intended skin contact but a minimal transfer of fragrance to the skin from inert substrate [Feminine hygiene pad]) as well as expanding to different regions of the world. RIFM signed a Memorandum of Understanding with Dr. Young-Joo Lee from the Department of Bioscience and Biotechnology, Sejong University in Korea, who is gathering exposure data in the South Korean population.Finally, there are several manuscripts being developed to detail all

the enhancements made to the Model. Future projects may include a mechanism for combining concentration data from multiple CAS numbers and including zero concentrations in the surveys.

NOT SUPPORTED MATERIALS

In order to complete a Safety Assessment, RIFM toxicologists need exposure data; if there are data gaps, they may also need samples for testing. Materials without concentration survey data or materials that cannot be sourced for testing are added to RIFM’s Not Supported list for each calendar year. At the end of the calendar year, that list is locked, and the list enters a 12-month grace period. During this time, materials can be removed from the list, provided that RIFM receives the missing concentration survey data and/or sample for testing. Any material still on the list after the 12-month grace period will be permanently removed

from RIFM’s Safety Assessment program, and its RIFM ID numbers will be stripped. The updated lists are posted quarterly on our website (rifm.org) in the Members area. In addition, we have been conducting quarterly webinars, open to members and non-members alike to socialize the list to our stakeholders and provide updates on the materials currently on the list. Our next webinars will be held on September 17th and November 19th, 2019.

PHOTOTOXICITY/PHOTOALLERGY

RIFM employs a robust phototoxicity testing program in support of our Safety Assessments for fragrance materials. We continue to acquire UV/Vis absorption spectra (OECD test guideline 101) in order to calculate a molar absorption coefficient (MAC) for all materials. UV/Vis spectral analyses have been conducted for nearly all synthetic fragrance materials. All materials that demonstrate significant

The life science business of Merck operatesas MilliporeSigma in the U.S. and Canada.


absorbance, defined by an MAC above the benchmark of concern (1000 L ∙ mol-1 ∙ cm-1), are then moved into higher-tier testing. First, materials with the potential for phototoxicity are tested in the hazard-based 3T3-Neutral Red Uptake (NRU) phototoxicity assay (OECD test guideline 432). Materials that are predicted to be phototoxic in the 3T3-NRU assay are then moved on to the risk-based EpiDerm 3D-skin phototoxicity assay. Human phototoxicity tests are conducted to confirm a no-effect level for phototoxicity. Currently, RIFM is developing a manuscript on the tiered-testing approach used to assess phototoxicity. The planned manuscript will also function as an updated criteria document for photo safety, containing both more details on our approach and illustrating it with examples of materials that have gone through the entire stepwise-testing paradigm.

RIFM’s photoallergy research program has recently shifted direction to focus primarily on in vitro assays. Many of these assays are not yet commercially available, so collaboration is currently being planned. The project will start with a pilot study testing a small group of well-characterized phototoxicants and photoallergens in a battery of in vitro assays. The results of this pilot study will inform our decision to move a larger group of materials that have not been cleared for photoallergy into the in vitro assays.

THE THRESHOLD OF TOXICOLOGICAL CONCERN (TTC)

TTC is an approach based on the concept that reasonable assurance of safety can be given, even in the absence of chemical-specific toxicity data, provided the exposure is

sufficiently low, i.e., that an exposure level can be defined below which there is no significant risk to human health. TTC remains an important tool in RIFM’s safety assessment process. It is an animal alternative method, and to date, RIFM has saved approximately 200,000 animals through the use of the TTC. Since TTC is a strategic tool, RIFM has several research projects aimed at supporting the TTC concept.

1 Bolstering the Existing Database Supporting TTC with Toxicity Data for Fragrance-Related Materials — A Collaborative Research Project with Procter & Gamble This is a collaborative project with Procter & Gamble aimed to bolster the TTC approach for support of fragrance materials and specifically to strengthen the Cramer Class II threshold. The RIFM Database was reviewed with a goal of identifying fragrance materials with data that

RIFM employs a robust phototoxicity testing

program in support of our safety assessments for

fragrance materials


14

15

2019 ANNUAL MEETING

can be added to the existing TTC databases. The RIFM Database identified a total of 476 chemicals that were added to the existing TTC databases. The combined dataset bolsters the threshold for Cramer Class II to include a total of 111 chemicals. The existing TTC database was enhanced by including toxicity data for fragrance materials, which provides further support for the use of TTC as a tool to conduct safety assessments for fragrance chemicals. This work is currently in its final stages of a manuscript for peer-reviewed publication.

2 Internal TTC — A Collaborative Research Project with Cosmetics Europe The concept of TTC is central to risk assessment as it establishes acceptable low-level exposure values for chemicals with limited toxicological data. However, the

existing TTC limits are derived from external exposures. In collaboration with Cosmetics Europe, RIFM, along with other members, focuses on developing this concept further to represent the internalized human exposure to chemicals. To substantiate this effort, RIFM is working toward developing internal TTC (iTTC) limits by accounting for toxicokinetic and toxicodynamic parameters. Furthermore, these efforts underscore the importance of TTC and iTTC as an important alternative to animal testing.

3 Uncertainty in Hazard Assessment: A Comparison Of TTC Versus Chemical-Specific Approaches — A Collaborative Research Project with ILSI Europe The current probabilistic approach of setting non-cancer TTC is often perceived as accepting higher risks in evaluating the safety of chemicals with limited toxicity

data. This stems from the lack of published literature describing the sources of uncertainty within the TTC approach. In collaboration with ILSI Europe, RIFM intends to examine quantitative and qualitative uncertainties within the development and application of the TTC approach in comparison to the chemical-specific risk assessment. The ultimate goal of the project is to develop scientific knowledge of the sources of uncertainties specific to TTC and to substantiate its robustness.

4 Refining Inhalation TTC — A Collaborative Research Project with Procter & Gamble RIFM uses the existing approach developed by Carthew et al. (2009), which is applicable to the inhalation exposure assessments of fragrance materials. Since TTC is a strategic part of the RIFM safety assessment

15


process, RIFM initiated a research program to enhance the existing Carthew dataset of 92 materials. RIFM is in the process of expanding Carthew’s model by adding data on more than 200 materials.

5 Dermal Sensitization Threshold (DST) — A Collaborative Research Project with Lhasa Limited Where skin exposure is low, it is possible to conduct a risk assessment using the DST, a process similar to TTC, such that a level can be determined for any chemical where there is no appreciable risk of skin sensitization, even when the chemical has not been tested for sensitization. As with TTC, the DST is a strategic aspect of the RIFM safety assessment process as well as an important animal alternatives tool.

As such, RIFM and Lhasa Limited have embarked on a collaboration to bolster the data supporting the DST. Additional sensitization data have been reviewed and analyzed, and a manuscript is in preparation.

DEVELOPMENTAL AND REPRODUCTIVE TOXICITY RIFM has been engaging with developmental toxicity research partners and exploring alternative methods to animal testing.

We have collaborated with Stemina Biomarker Discovery in their in vitro devTOX quickPredict assay, which uses the metabolic profile of Ornithine and Cystine (O/C ratio) for the predictive developmental toxicity potential. A blinded pilot test for ten fragrance ingredients using the devTOX quickPredict assay was initiated and completed, and the result is generally consistent with the available in vivo data. Specific details of the assay and the results of the pilot test will be presented during the poster session of RIFM’s Annual Meeting.

We will also be pursuing and collaborating with Biobide, a CRO that specializes in zebrafish testing for developmental toxicity. In order to comply with animal alternative guidelines, the zebrafish assay (Teratotox assay) is performed during the first four days post fertilization (dpf), after which the larvae will start feeding independently and then be considered to be animals.

Though there is no one animal alternative model that can replace in vivo animal testing, RIFM’s goal is to have a battery of animal alternative assays to support the safe use of fragrance materials for developmental toxicity. For now, the devTOX quickPredict and Teratotox assays can be fast and efficient screening tools to help safeguard future generations by identifying which materials to push forward in the testing pipeline.

RESPIRATORY RESEARCH 1 Confirming Known Respiratory

Sensitizers The list of known respiratory sensitizers is primarily based on occupational exposure cases. There are less than 100 known respiratory sensitizers. However, clear supporting scientific evidence is not always available on these materials. In order to confirm known respiratory sensitizers, RIFM has commissioned a review to help categorize these materials based on strong, weak, and anecdotal evidence.

2 Differentiating Between Respiratory and Dermal Sensitizers The key to differentiating between skin and respiratory sensitizers is to outline and understand the mechanism of respiratory sensitization. There is a proposed Adverse Outcome Pathway (AOP) for respiratory sensitization, which, in theory, lays out the key events

necessary for ultimately resulting in respiratory sensitization. RIFM has been engaged in working along this proposed AOP for respiratory sensitization, in collaboration with different groups (Rutgers, IIVS, Liverpool John Moores University UK, SenzaGen), to establish the initial interactions and their biomarker signatures followed by the activation of the immune response.

3 Human Precision-Cut Lung Slices (hPCLS) This is a moderate through-put ex vivo model that uses human lung tissue from donors. The complexity of this model is comparable to the in vivo models, which makes it the most relevant animal alternative system for the scientific quest of understanding respiratory sensitization. The ongoing project is focused on identifying the early release markers resulting from the tissue-chemical interactions, which eventually lead to immune activation and possibly respiratory sensitization.

4 Establishing Odor Thresholds The unique value of the fragrance industry is that it caters to the sense of smell. It is common to think that if you can smell a fragrance, then the exposure must be very high. However, with the sensitivity of olfaction in humans, you need very little exposure to be able to detect scent. Establishing odor thresholds scientifically will help dispel this incorrect association between sense of smell and exposure. This will also assist in defining low exposure with respect to the TTC concept.

Environmental SciencesRIFM continues to evaluate fragrance materials for their environmental risk and hazard potential in support of the RIFM Risk assessment program.

16

Raising the standard of excellence

Toxicology Regulatory Affairs

Medical AffairsPharmacovigilance

FMD K&L, a valued partner for the Life Science industries for more than 21 years, have continuously earned the trust of being an extended partner for several large, medium and small innovator companies for their strategic business engagements. We constantly strive to raise the standard of excellence through accuracy and efficiency by combining our domain and technology expertise.

20 Offices around the world 1500+ staff across all centers Global and regional presence ISO 27001 & 9001, GDPR

certified

US UK Armenia India China The Philippines [email protected]

Services we provide

Artificial intelligence and Machine LearningPatented AI Digital Product Safety Platform for LifesciencesDrug Discovery, Trials, Patients, Sites, Manufacturing, Pharmacovigilance, Supply Chain, Marketing

Smart Document ReviewEnd-to-end lifecycle management for creation, versioning, authoring, QC reviews, publishing and integration to other systems

Literature, Safety Efficacy

Reports

AI-Empowered application for Literature & Safety Reporting for generating safety and efficacy reports such as Toxicology, PADER, PBREPSUR

AI Case Management

AI Integrated Optical Character Reader Real-time check to identify duplicate cases Triage based on existing corpus of ADR-

Drug association Measure key performance indicators

2019 ANNUAL MEETING

As a result, several environmental studies have been conducted, including octanol-water partition coefficient (Kow) evaluation, water solubility, hydrolysis, biodegradation potential of the target material and its metabolites, acute and chronic ecotoxicity Studies (Daphnia magna Immobilization and reproduction study, algae growth inhibition study, fish early life stage study), and fish bioaccumulation assays. All studies are conducted according to internationally recognized OECD guidelines and fulfill regulatory criteria.

Complementary to the environmental testing program, RIFM continues to support a robust research program. Currently, RIFM is sponsoring several research efforts dedicated to understanding

and evaluating (including method development) Natural Complex Substances, especially their bioaccumulation potential. Bioaccumulation of materials in fish is one of the key drivers for the classification of materials (PBT) by multiple regulatory bodies. It is a complicated process involving an understanding of absorption, distribution, metabolism, or elimination of a material in living systems with metabolism and its rate being least known.

RIFM’s Research Includes:1 Determine the Bioaccumulation of

mixtures – Stockholm University Bioaccumulation of natural complex substances (NCS) was investigated in fish bioaccumulation assays (OECD

305; feeding study) using benchmark methods developed by the University. Lab-made mixtures (known fragrance materials with measured BCF [Bioaccumulation Factor]), as well as two essential oils (pine oil and cedarwood oil) were evaluated, and the results are being reviewed. A future technology transfer to the commercial environmental lab is planned.

2 In vitro (S9 and Hepatocytes) Bioaccumulation – KJ Scientific This research concentrates on metabolism potential and rate of fragrance materials in fish tissue (S9 and hepatocytes). With successful completion of evaluating four fragrance materials (melafleur, cyclabute, verdox, trimofix),

Raising the standard of excellence

Toxicology Regulatory Affairs

Medical AffairsPharmacovigilance

FMD K&L, a valued partner for the Life Science industries for more than 21 years, have continuously earned the trust of being an extended partner for several large, medium and small innovator companies for their strategic business engagements. We constantly strive to raise the standard of excellence through accuracy and efficiency by combining our domain and technology expertise.

20 Offices around the world 1500+ staff across all centers Global and regional presence ISO 27001 & 9001, GDPR

certified

US UK Armenia India China The Philippines [email protected]

Services we provide

Artificial intelligence and Machine LearningPatented AI Digital Product Safety Platform for LifesciencesDrug Discovery, Trials, Patients, Sites, Manufacturing, Pharmacovigilance, Supply Chain, Marketing

Smart Document ReviewEnd-to-end lifecycle management for creation, versioning, authoring, QC reviews, publishing and integration to other systems

Literature, Safety Efficacy

Reports

AI-Empowered application for Literature & Safety Reporting for generating safety and efficacy reports such as Toxicology, PADER, PBREPSUR

AI Case Management

AI Integrated Optical Character Reader Real-time check to identify duplicate cases Triage based on existing corpus of ADR-

Drug association Measure key performance indicators

Capturing the essence and intricacy of nature is at the root of our creative and technical solutions. Our extensive collection of botanical extracts, natural fragrances, and strain-specific cannabis terpenes is proof of our ability to develop the best olfactive experience for your needs. Contact us to learn more about how we capture the individual identity and natural properties of our full line of botanicals and aroma profiles. With over 100 years of mastering this art, we will craft a customized solution that captures your product’s essence.

THE ROOT OF OUR DIFFERENCE.

Bell Flavors and Fragrances, Inc. | www.bell�.com | info@bell�.com | 800-323-4387

two essential oils—pine oil and cedarwood oil, as well as their major components—are currently being evaluated.

3 HESI UVCB The HESI UVCB project is a collaboration between academia, regulatory authorities, and industry to determine methods for environmental UVCB Risk Assessments. A workshop was held in December 2018 from which a publication is being written regarding compositional assessment. In addition to RIFM and Robertet, participants included US EPA, Environment and Climate Change Canada, ECHA, and other industry stakeholders. A decision tree was developed to identify the role of lower-tier information (QA/QC product information,

basic chemistry) in risk evaluation. The next steps are with regard to exposure and are focused initially on identifying existing work to leverage. Dr. Todd Gouin, a RIFM consultant, will replace Dan Salvito on the committee as they move into exposure assessment. In addition, RIFM continues to support new method development for NCSs through an ECETOC Long Range Project: ECO42. The objectives of this project are to develop and test new approaches for fate-directed ecotoxicity assessment of UVCBs—including essential oils based on new combinations of analytical methods, dosing methods, fate-directed fractionation, toxicity testing, and models, to conduct a case study on selected UVCBs and to develop

a generic risk assessment strategy for UVCBs and to cross-fertilize and partially align the ongoing research activities related to UVCBs at three European research institutes.

Parallel to the above research efforts, RIFM has started modernization of its Environmental Framework for Fragrance Materials (Salvito et al., 2003). The project will include a review of the existing Environmental Framework, identification of opportunities to apply new approaches and tools to existing elements of the Framework (e.g., application of new QSARs), and examination of current higher-tier assessment practices and identification of opportunities for additional refinement of those higher-tier practices.


2019 ANNUAL MEETING

19

Capturing the essence and intricacy of nature is at the root of our creative and technical solutions. Our extensive collection of botanical extracts, natural fragrances, and strain-specific cannabis terpenes is proof of our ability to develop the best olfactive experience for your needs. Contact us to learn more about how we capture the individual identity and natural properties of our full line of botanicals and aroma profiles. With over 100 years of mastering this art, we will craft a customized solution that captures your product’s essence.

THE ROOT OF OUR DIFFERENCE.

Bell Flavors and Fragrances, Inc. | www.bell�.com | info@bell�.com | 800-323-4387

2019 ANNUAL MEETING

PEER-REVIEWED, PUBLISHED RESEARCH

1 Salicylic Acid Amplifies Carbachol-induced Bronchoconstriction in Human Precision-Cut Lung Slices. Jude, J., Botelho, D., Karmacharya, N., Cao, G.Y., Jester, W. and Panettieri, R.A. Respiratory Research 20:72, 2019.

2 Challenges in Working Toward an Internal Threshold of Toxicological Concern (iTTC) for Use in the Safety Assessment of Cosmetics: Discussions from the Cosmetics Europe iTTC Working Group Workshop. Corie A.Ellison, C. , Blackburn, K., Carmichael, P., Clewell, H., Cronin, M., Desprez, B., Escher, S., Ferguson, S., Grégoire,S., Hewitt, N., Hollnagel, H., Klaric, M., Patel, A., Salhi, S., Andreas, A., Schmitt, B., Wambaugh, J., Worth, A. Regulatory Toxicology and Pharmacology 103: 63–72, 2019.

RESEARCH PRESENTATIONS1 Validation of in vitro Reconstructed Skin Micronucleus

Assay as a Potential Animal Alternative Assay to Assess the Clastogenic and Aneugenic Potential for Fragrance Materials. Poster presentation at the Society of Toxicology 57th Annual Meeting, March 11–15, 2018.

2 An OECD 408 Dietary 90-Day Toxicity Study on 10-Undecenal. S. Tsang, A. Patel, and A.M. Api. Poster presentation at the Society of Toxicology 57th Annual Meeting, March 11–15, 2018.

3 Analysis of Fragrance Ingredients in Sens-IS Assay for Skin Sensitization. Parakhia, R., O’Brien, D., and Api, A. M. Poster presentation at the Society of Toxicology 57th Annual Meeting, March 11–15, 2018.

4 Refinements to Dermal Sensitization Quantitative Risk Assessment (QRA2) For Fragrance Ingredients and Systemic Toxicity. A.M. Api. Presentation to NYSCC & ASP Joint Meeting, March 22, 2018.

5 The BlueScreen HCTM Assay to Predict Genotoxic Potential for Fragrance Materials. Poster presentation at the Genetic Toxicology Association (GTA) Annual meeting. May 3–4, 2018.

6 IFRA Environmental Standards and RIFM Program Advances Update for 2018. A. Lapczynski, D.T. Salvito, C. Gonzalez, M. Vey. Poster presentation for SETAC Europe Annual Meeting, May 13–17, 2018.

7 Assessing Biotransformation and BCFs of Fragrance Materials Using in vitro Approaches Utilizing Rainbow Trout Liver S9 Fractions and Cryopreserved Hepatocytes. Aurelia Lapczynski, Dan Salvito, Karla Johanning. Poster presentation for SETAC Europe Annual Meeting, May 13–17, 2018.

8 Update to RIFM’s Safety Assessment Process and Human Health Research Plan. A.M. Api. Presentation to IIVS Science Advisory Panel Meeting, September 12, 2018.

Communicating RIFM’s Science9 Utilization of 3D Skin Micronucleus and COMET Assay

as an Animal Alternative Model for Genetox Positive Compound in Traditional in vitro Studies: A Case Study. Poster presentation at the Environmental Mutagenesis and Genomics Society (EMGS) Annual meeting. September 22–26, 2018.

10 Update to RIFM’s Safety Assessment Process and the RIFM Dermal Program. A.M. Api. Presentation to European Society of Contact Dermatitis (ESCD), October 17, 2018.

11 Summary of RIFM-Conducted Human Repeat Insult Patch Tests. G. Ritacco. Presentation at the 14th Congress European Society of Contact Dermatitis, October 18–20, 2018.

12 Fragrance Ingredient Update. A.M. Api. Presentation to Personal Care Products Council Science Symposium, October 31, 2018.

13 Follow-Up Photosafety Testing for a Subset of Fragrance Materials. G. Ritacco and A. M. Api. Poster presentation, American College of Toxicology 39th Annual Meeting, November 4–7, 2018

14 Validation of the in vitro Reconstructed Skin Micronucleus Assay as a Potential Animal Alternative for Fragrance Materials. American College of Toxicology (ACT). 2018. Poster presentation, American College of Toxicology 39th Annual Meeting, November 4–7, 2018

15 Assessing Biotransformation and BCFs of Fragrance Materials Using in vitro approaches utilizing rainbow trout liver S9 fractions and cryopreserved hepatocytes. Aurelia Lapczynski, Dan Salvito, Karla Johanning. Poster presentation at ETAC North America Annual Meeting, November 4–8, 2018

16 RIFM Safety Assessment Program Overview: Evaluation of Repeat Dose Toxicity. Botelho, D. Speaker at EPAA Partners Forum 2018 on Repeated-dose toxicity, November 19, 2018

17 Refinements to Dermal Sensitization Quantitative Risk Assessment (QRA2) For Fragrance Ingredients and Systemic Toxicity. A.M. Api. Presentation to the US Food and Drug Administration, December 6, 2018.

18 Genotoxicity Evaluation of α,ß-Unsaturated Aldehyde Class Of Fragrance Materials In The Alternative Chicken Egg Genotoxicity Assay (CEGA) Compared to the Results with Other Regulatory Approved in vitro and in vivo Genotoxicity Assays. Poster presentation at the Society of Toxicology 58th Annual Meeting, March 10–14, 2019.

19 3D Skin Micronucleus and COMET Assay as an Animal Alternative Model for Genotoxicity Positive Materials in Traditional in vitro Studies: A Case Study on p-Methoxycinnamaldehyde. Poster presentation at the Society of Toxicology 58th Annual Meeting, March 10–14, 2019.


20

20 An Enhanced Oral Gavage One-generation Reproductive Toxicity Study on Cyclamen Aldehyde. S. Tsang, F. Belmonte, A. Patel, and A.M. Api. Poster presentation at the Society of Toxicology 58th Annual Meeting, March 10–14, 2019

21 QRA2 Is a Comprehensive Risk Assessment Tool which Incorporates Aggregate Exposure and Revised Sensitization Assessment Factors. A.M. Api. Presentation to the US Food and Drug Administration, April 23, 2019.

22 RIFM Safety Assessment and Research Programs Continue to Progress and Expand. A.M. Api. Presentation to the IKW Technical Workshop, May 2, 2019

23 Summary of Human Repeat Insult Patch Tests Conducted by the Research Institute for Fragrance Materials, from 1999 to Present. G. Ritacco, D. O’Brien, M. Na, M. Lavelle, and A. M. Api. Poster presentation, Society of Investigative Dermatology 77th Annual Meeting, May 8–11, 2019.

24 Chicken Egg Genotoxicity Assay COMET/Nucleotide 32P Post Labeling (NPL) Assay (CEGA COMET/NPL) and Hen’s Egg Micronucleus (HET-MN) Assay as a Potential Animal Alternative Follow-up Assay to Address False Positive Outcome in Traditional in vitro Genotoxicity Assays. Poster presentation at the Genetic Toxicology Association (GTA) Annual meeting. May 8–10, 2019.

25 Analyzing Complex Mixtures for Bioaccumulation Potential Using the Trout in vitro Metabolism Assay (OECD TG 319A and 319B): A Case Study, Fir Oil (Pine Oil) a Natural Complex Substance (NCS). Aurelia Lapczynski, Dan Salvito, and Karla Johanning. Poster presentation at the SETAC EU Annual Meeting, May 26–30, 2019.

26 The RIFM approach to Dermal Sensitization – A Quantitative Risk Assessment (QRA) method. A.M. Api. Presentation at the ICMAD 38th Annual FDA Cosmetics Regulation Workshop, May 28, 2019.

27 How to Tackle RIFM NCS Risk Assessment. Botelho, D. Speaker at EFEO Annual Meeting, June 4, 2019.

28 Photosafety Evaluation of Fragrance Materials: A Tiered Approach Using Both Alternative Methods and Confirmatory Testing in Humans. G. Ritacco. Invited Symposium Talk, Clinical Photosafety Symposium, 17th International Congress on Photobiology/18th Congress of the European Society for Photobiology. August 25–30, 2019.

29 Sources of Uncertainty in the Threshold of Toxicological Concern Approach. Bellion Ph., Hollnagel H.M., Buist H., Gadhia S., Gosling J.P., Lovell D.P., Melching-Kollmuss S., Worth A., Rito E. Abstract accepted for poster presentation, 55th Congress of the European Societies of Toxicology, Sep 8–11, 2019.

RESEARCH MANUSCRIPTS IN PROGRESS1 30 Years of Experience of Fragrance Evaluation in the

Human Repeated Insult Patch Test.2 Evaluation of the 90-day Subchronic Toxicity of

Dihydromyrcenol in Rats.3 Evaluation of a Combined Dermal Developmental and

Perinatal/Postnatal Reproduction Toxicity Study on PEA (Phenethyl Alcohol) in Rats.

4 Safety Evaluation of the Fragrance Citronellyl Nitrile in a Rat Oral One-Generation Reproduction Study with Perinatal/Postnatal Data.

5 Inhalation Dosimetry and Dose-Response Analysis of the Flavoring Agents Diacetyl, 2, 3 Pentanedione, and Acetoin in the Respiratory Tract.

6 Inhalation Dosimetry and Dose-Response Analysis of Fragrance Compounds in the Respiratory Tract.

7 In vitro Human Skin Penetration of the Fragrance Material HMPCC.

8 Bolstering the Existing Database Supporting the Non-Cancer Threshold of Toxicological Concern Values with Toxicity Data for Fragrance-Related Materials.

9 The BlueScreen HCTM Assay to Predict the Genotoxic Potential for Fragrance Materials.

10 Use of the EpiDerm 3D Reconstructed Skin Micronucleus Assay to Address Misleading Positive Results from in vitro Genotoxicity Assays for Fragrance Materials.

11 Oral 1-Generation Reproduction Study of Cyclamen Aldehyde in Rats: An Evaluation Through Sexual Maturity in the F1 Generation.

Sources of Knowledge and InnovationTHE RIFM FLAVOR AND FRAGRANCE DATABASE

The most comprehensive, worldwide source of toxicology data, literature and general information specific to fragrance and flavor raw materials continues to grow each year. A total of 73,800 total references were in the RIFM Database as of December 2018. Our more than 1100 RIFM Database subscribers from member companies all over the world contributed nearly 900 studies to keep the database as current and robust as possible.

2019 ANNUAL MEETING

21


22

NEW TOOLSThe Toxicology Database Search Engine (TDSE)Developed by RIFM staff and developers, the TDSE simultaneously searches multiple toxicology databases (i.e., RIFM Database for identity and Cramer Class information; ECHA REACH Dossiers, National Toxicology Program [NTP]; Hazardous Substances Data Bank [HSDB]; Carcinogenic Potency Database [CPDB]; EPA HPVIS; and the Japanese and EU OECD Existing Chemicals Databases) to generate a combined accessible output. This tool is available via the Tools and Models Link on the RIFM Database Home page.

Genotoxicity Data Visualization ToolThe RIFM Genotoxicity Data Visualization tool is a web-based solution that contains all of the RIFM-generated genotoxicity data in a visual format. The tool has an interactive graphical display of various genotoxicity test data for different chemical classes of fragrance materials. What began as a RIFM research project became a go-to tool for our scientists—and now for RIFM members—leading to accelerated fragrance innovation and minimizing the reliance on animal testing, among other advantages. This tool is available via the Tools and Models Link on the RIFM Database Home page.

Safety Assessment AppThe RIFM Safety Assessment Application tracks every material in the RIFM inventory to be written in the Safety Assessment Program across all seven toxicological endpoints. A joint project between the RIFM Technical Services and Safety Assessment teams, the application also allows the editing and publishing team to track the output of the Safety Assessment team: when drafts are posted to the RIFM Database and when they are submitted to Food and Chemical Toxicology for independent peer review. This allows us to maintain an efficient testing and writing pipeline. It has the added benefit of allowing RIFM to easily generate quarterly reports that provide awareness for our external audiences of what materials are undergoing testing, are currently being written, and what has been published.

RIFM continues to sponsor its own toxicological studies, of which more than 100 were added in 2018.

Robertet 03.16.17.indd 1 3/16/17 4:53 PM

23

Last year, RIFM identified the need to build out a dedicated communications team for its Safety Assessment program to enhance and speed the publication of our work.

Now fully staffed with three science-focused content developers, RIFM’s communications team has more than quadrupled the total number of peer-

Getting Our Word Outreviewed and published Safety Assessments on fragrance materials since launching in 2018.

By the end of 2019, Safety Assesments covering more than 1,000 materials will be available in the RIFM Database and submitted to Elsevier’s Food and Chemical Toxicology journal.

Beginning in 2019, the team began to build out a Communications Strategy, including a full rebranding, to ensure that the critical work being accomplished by RIFM’s professional staff of scientists is widely recognized, cited, and used—and that fragrance safety becomes synonymous with a RIFM Safety Assessment.

Robertet 03.16.17.indd 1 3/16/17 4:53 PM

2019 ANNUAL MEETING

Gary Sullivan Faiz SiddiqiLeah Jones

Talk to Us


RESEARCH INSTITUTE FOR FRAGRANCE MATERIALS, INC.

50 Tice Boulevard, Suite 325Woodcliff Lake, NJ 07677

phone: 1.201.689.8089 web: www.rifm.orgfax: 1.201.689.8090 email: [email protected]

24

NotesTalk to Us

2019 ANNUAL MEETING

25


26

Thank You to Our Generous Sponsors

PLATINUM

GOLD

SILVER

BRONZE

© C

omBy

Avm

NEW CAPTIVES IN

Every perfumer around the world has worked with Firmenich ingredients at least once in their life. Join them and discover new ingredients that represent Firmenich expertise in extraction technologies, sustainable sourcing, green chemistry and new floral notes with Muguet. www.firmenich.com/ingredients

SHARING INNOVATION 2019

FIRMENICH_SHARING INNOVATION 2019.indd 1 29/08/2019 16:40:03

IFF.com

annual meetingrifm poster display 5:15 pm cocktail reception and networking 6:15 pm dinner guest...

Documents