Ladd W' Smith, PhD, DABT

1
Fragrance Material Science, Regulations, Issue
Management

• Ladd W. Smith, PhD, DABT
• President
• FDU Cosmetic Science/Perfumery October 17, 2006

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WOULD YOU LIKE A COCKTAIL?

• Butanol
• Iso Amyl Alcohol
• Hexanol
• Phenyl Ethanol
• Tannin
• Benzyl Alcohol
• Caffeine
• Geraniol
• Quercetin
• 3-Galloyl Epicatchin
• Inorganic Salts

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HOW ABOUT A CUP OF TEA?www.senseaboutscience.org

• Butanol
• Iso Amyl Alcohol
• Hexanol
• Phenyl Ethanol
• Tannin
• Benzyl Alcohol
• Caffeine
• Geraniol
• Quercetin
• 3-Galloyl Epicatchin
• Inorganic Salts

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EXTERNAL REGULATION

• European Statutes Cosmetics Directive 7th
  Amendment, Dangerous Substances and Preparations
  Directives, Individual Material Opinions
• International Hazard Communication Standards
  Flavor Fragrance Ingredient Data Sheets
• U.S. Consumer Product Safety Act
• U.S. Food, Drug and Cosmetics Act
• EU Registration, Evaluation and Authorization of
  Chemicals (REACH)

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PUBLIC POLICY SCIENCE

• Legislators and regulators want to protect public
  health and the environment
• Industry wants to avoid harming public health and
  the environment
• The public wants to feel safe

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FRAGRANCE USE
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WHAT ARE FRAGRANCE MATERIALS?
Diphenyl Ether
b-Pinene
Terpineol
Geraniol
Methyl Salicylate
d-limonene
Methyl Dihydrojasmonate
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SPECIAL CONSIDERATIONS

• Fragrances are meant to be noticed, so they are
  easy to identify as problems
• Fragrance materials are diverse in structure,
  aroma, substantivity, adverse effects
• Industry doesnt have a history of being
  regulated
• Much of industry regulatory effort reactive
• Industry still contains much commercial and
  organizational diversity

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RESEARCH INSTITUTE FOR FRAGRANCE MATERIALS (RIFM)

• A nonprofit corporation formed in 1966 to gather
  and analyze scientific data, to engage in testing
  and evaluation, to distribute information, to
  cooperate with official agencies and to encourage
  uniform safety standards related to the use of
  fragrance ingredients.

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VISION

• To be the International Scientific Authority for
  the Safe Use of Fragrance Materials

MISSION

• Engage in research and evaluation of fragrance
  materials through an independent Expert Panel
• Determine safety in use
• Gather, analyze and publish scientific
  information
• Distribute scientific data and safety assessment
  judgments to RIFM members, industry associations
  and other interested parties
• Maintain an active dialogue with official
  international agencies

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MEMBER CATEGORIES

• ACTIVE (58, 1)
• Manufacture and/or sale or distribution at other
  than the retail level
• SUPPORTING (17)
• Manufacture for sale or distribution at the
  retail level of consumer products
• ASSOCIATE (2)
• Brokers or dealers engaged in a business related
  to the fragrance industry

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RIFM BOARD OF DIRECTORS
IFF, Inc. New York, NY Manheimer, div of
Mastertaste Teterboro, NJ Citrus and Allied
Essences Lake Success, NY Wessel Fragrances,
Inc. Englewood Cliffs, NJ Bedoukian Research,
Inc. Danbury, CT
Takasago Intl Corp. Japan JFFMA Japan
Quest International UK CPL Aromas UK
Robertet, Inc. France Givaudan Fragrances Corp.
Switzerland Firmenich, Inc. Switzerland EFFA
Belgium IFRA Belgium
Symrise Germany Fragrance Resources
Germany BASF Germany
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RIFM EXPERT PANEL (REXPAN)
Hachiro Tagami, MD Tohoku Univ. School of
Medicine, Sendai, Japan
Jon M. Hanifin, MD Oregon Health Sciences
Univ I. Glenn Sipes, PhD. (Chair) University of
Arizona Donald V. Belsito, M.D.Univ. of Kansas
Medical Center David R. Bickers, MD Columbia
University, NY Adrianne E. Rogers, MD Boston
Univ. School of Medicine

• Prof. Magnus BruzeMalmo University Hospital
• Prof. Peter CalowInstitut for Miliovurdering DE
• Prof. Dr. Helmut A. Greim
• Neuherberg Institut für Toxikologie
• Jean-Hilaire Saurat, MD
• Universitaire de Geneve

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RIFM EXPERT PANEL ADJUNCTS
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MATERIAL SAFETY RESPONSIBILITY
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ANNUAL SAFETY EXPENDITURES( million U.S.)
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RIFM BUDGET
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COMPREHENSIVE RESEARCH PLAN (000 U.S.)
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2006 RESEARCH TESTING
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SCIENCE CHALLENGES

• Fragrance Allergy
• Dermatologists report increased reactions
• Respiratory
• Your perfume makes me sick
• Environmental Occurrence
• Headline Fragrance material found in tuna
• Knowledge Research, Database, REXPAN
• How can you assure product safety?
• REACH EU Chemical Safety Regulation
• What is known about fragrances?

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1. FRAGRANCE ALLERGY

• Reduce Incidence of Clinical Disease, Regulations
• Quantitative Risk Assessment (ongoing)
• Testing
• IFRA Standards
• Epidemiology/prevalence (2003 2010)
• Clinical/diagnostic Studies
• Elicitation Threshold (2004 2009)
• Supply of Materials (ongoing)
• Oxidation (2003 2007)
• Developing alternative methods (ongoing)
• Leveraged through dermatologists

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2. CHEMICAL INTOLERANCE

• Understand and Manage Exposure
• Internal/external advisory groups (ongoing)
• 3 Exposure scenarios characterized (done)
• Clinical study underway (2006)
• 9 Surrogate materials
• Normal and asthmatic populations
• Lung function and cellular measurements
• Skin patch tests for sensitivity
• Determine safety in use
• Systemic effects (2007 - ?)

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3. ENVIRONMENTAL PATHWAYS
ATMOSPHERE
SURFACE WATERS
DOWN THE DRAIN DISPOSAL
SEDIMENTS
2000- 2004
2005 - 2008
Ongoing PBT/list analyses Focused testing
FOOD CHAIN
2009- ?
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4. DATABASE
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PUBLICATION PROCESS
Publication IFRA Standard

• Database

REXPAN Conclusion
Budget
Study
Group
Database
Gaps
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CONSORTIUM TESTING

• RIFM group selection, REXPAN agreement on data
  needs, then IFRA Scientific Committee review
• If high volume group material, and impacts both
  suppliers and users, then RIFM such as
  dimyrcetol and linalool developmental and
  methylionone repeated dose studies
• Request for data via IFRA Information Letter
  otherwise on unsupported list
• RIFM send additional letter with data needs and
  costs to producers and interested parties,
  organize consortium Rose Crystals
• Next grouping of epoxides is high structural
  interest but low volume good for consortium
  approach
• Allocates cost to manufacturers

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ORGANIZATIONAL RELATIONSHIPS
B O A R D O FD I R E C T O R S
I F R A
MEMBER ASSOCIATIONS
R I F M
E X P E R TP AN E L
C U S T O M E RA S S O C I A T I O N S
COLIPA AISE CTFA SDA
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IFRA ORGANIZATION
IFRA International Fragrance Association
Other Regions (South America, Australia, New
Zealand)
Europe
North America
Asia/Pacific
JFFMAJapanese Fragrance Flavors Association
Other NationalAssociations(China, Singapore)
EFFA European Flavor and Fragrance Association
FMAFragrance Materials Association of the US
National MemberAssociationse.g. Brazil
National European Associations
Company Membership
Company Membership
Company Membership
Company Membership
Company Membership
Potential members Korea, Colombia, Argentina
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RELATIONSHIPS
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IFRA STANDARDS
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INDUSTRY SELF-POLICING

• IFRA Code of Practice
• National Association bylaws require adherence
• Good Manufacturing Practice and use guidelines,
  definitions, labeling claims
• Intellectual property
• IFRA Standards
• Specified - 13, Prohibited - 64, Restricted - 52
• IFRA Compliance Program
• Assurance from member associations
• Verification through 3rd party analysis
• Protocols for collection of consumer products,
  sample preparation, communication of violation,
  corrective action, confidential information

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FRAGRANCE PRODUCT SAFETY
Member Companies
Research Testing
IFRA
RIFM
Code of Practice Standards
REXPAN
Safety Evaluations
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(No Transcript)
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PARACELSUS (1493 1541)

• What is there that is not a poison?
• All things are poison and nothing (is) without
  poison.
• Solely the dose determines that a thing is not a
  poison.

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DEFINITIONS

• Toxicity - adverse effect on biological
  system (inherent)
• Hazard - ability to do harm (endpoint)
• Risk - probability of harm under specific
  conditions of use
• Safety - absence of harm or risk
• Threshold - dose where effects evident
• Exposure - condition of being unprotected,
  subject to some influence

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GOALS

• Characterize toxicity in animal models to
  identify potential problems in short/long term
  studies
• Identify circumstances under which toxicity
  occurs
• Evaluate extent to which toxicity data can be
  extrapolated to humans
• Recommend safe levels of exposure

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RISK ASSESSMENT

• Qualitative Is the agent capable of eliciting a
  toxic reaction (at some dose)?
• Quantitative What is the expected magnitude or
  probability of the toxic reaction at different
  doses?

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CHEMICAL INTERACTIONS

• Additive 2 3 5
• Synergistic 2 3 20
• Potentiation 0 2 10
• Antagonism 4 6 8
• 4 (-4) 0
• 4 0 1
• Effects Functional, Chemical, Dispositional,
  Receptor

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BASIC CONCEPTS

• Effects in animals, when properly qualified, are
  applicable to humans
• Methods may not exist to establish a threshold
  for long term effects/cancer
• Animals usually are exposed at high doses to
  increase the likelihood of discovering a possible
  toxic effect (in humans)
• Materials should be assessed in terms of human
  risk, rather than as safe or unsafe

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ACCEPTABLE

• No-effect level divided by safety or
  uncertainty factor
• Factors 10 if good human data
• 100 if good chronic animal data
• 1000 if limited data
• Example 100 mg/kg/day (no effects)
• 100-fold safety
• Acceptable 1 mg/kg/day

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ACUTE TOXICITY TESTS

• Single dose
• Lethal dose by expected route of exposure
• Precise number not necessary
• Use limit data no deaths at x dose
• Usually in rodents
• Factors such as age, gender, nutrition, housing,
  vehicle, rate of administration, handling can
  affect outcome

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ORAL LD50

• Animals fasted overnight
• Geometric spacing of doses 0.5, 5, 50, 500,
  5000 mg/kg
• Observe 1, 2, 4 hr and daily for 14 days
• Determine number of deaths at 14 days
• Body weights
• Gross examination/autopsy
• May include limited clinical chemistry

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ACUTE TOXICITY

• Dermal LD50
• Albino rabbits
• Clipped skin
• 24 hr skin contact
• Limit 2 g/kg
• Inhalation LC50
• 4 hr exposure
• 14 day mortality
• Sometimes see concentration x time constant

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CRITICISMS, ALTERATIVES

• Only measures death
• Inhumane, large number of animals
• Hard to extrapolate to humans
• The three Rs
• Reduce the number of animals
• Refine the method, gentler procedures
• Replace the test with in vitro method,
  predictions

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RELATIVE ACUTE TOXICITY
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PRIMARY EYE IRRITATION

• Typical in vivo protocol
• Rabbit eye with 0.1 ml or 100 mg
• Score up to 7 days or until effects subside
• Being replaced by in vitro studies, isolated
  corneal preparations, corneal cells in culture,
  or predictions from pH of material

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PRIMARY SKIN IRRITATION

• Typical in vivo protocol
• Clipped rabbit skin
• 0.5 ml liquid or 0.5 g solid
• Occlusion for 4 hr
• Score erythema and edema after 24 72 hr
• Also being replaced with in vitro techniques and
  predictions

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IMMUNOTOXICITY

• Undesirable or unintentional effects of chemical
  agents on the immune system and response
• Enhancement Increased responses to allergens or
  promotion of autoimmune responses
• Suppression Increased infectious disease or
  failure to control tumors
• Immune Sensitization Allergic response to the
  chemical

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FORMULATION ADDITIVES - EFFECTS

• Hydration water, creams, lotions, occlusion
• Delipidization solvents, ionic surfactants
• Protein Denaturation solvents, ionic surfactants
• Vasodilation nicotinates
• Enzyme Induction/Inhibition polyaromatic
  hydrocarbons, benzpyrene

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DIFFUSION IS FAVORED BY

• Large surfaces area for transfer
• Small molecular weight
• Lipid solubility
• Low octanol/water coefficient (1 4)
• Non polar metabolites
• Non-ionized state
• Good dissolution in membrane environment
• Thin membrane
• High concentration gradient

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ABSORPTION VS. PENETRATION

• Penetration Amount of material which gets to
  targets within the skin (should be correlated to
  local cutaneous activity)
• Absorption Amount of material which goes
  through the skin but is then further
  diffused/transported into blood (should be
  correlated with systemic activity)

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BODY SITE DIFFERENCES

• Rate of penetration and absorption differs across
  body sites due to anatomy (skin thickness, lipid
  composition) and physiology (blood flow,
  distribution of blood vessels, number of
  follicles)
• Scrotum gt Forehead gt Axilla gt Scalp gt Back gt
  Abdomen gt Palm and Plantar surfaces

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ANATOMICAL CONSIDERATIONS

• Primary barrier to absorption is the stratum
  corneum (outer, skin layer)
• Dead keratinocytes embedded in a lipid matrix,
  through which most materials are absorbed to some
  degree
• Lipid matrix secreted by cells in lower layers
• Basal layer of viable keratinocytes which migrate
  to surface and are shed
• Dermis (next layer) and vasculature

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SKIN SENSITIZATION

• Guinea pigs and humans
• Maximization (id), Buehler Assay (patch), Human
  Repeated Insult Patch Test (patch)
• Tests for induction of sensitization
• Periodic injection or skin patching over 3 weeks
• Rest period, then single challenge
• Score irritation during induction and look for
  sensitization response after challenge
• Contrast with elicitation patch testing in
  dermatology clinic
• Start with mix then try to isolate sensitivity to
  individual materials

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LOCAL LYMPH NODE ASSAY

• Material applied to mouse ears on days 1, 2, 3
• Inject 3H-thymidine iv day 3
• Sensitized T cells in draining lymph nodes
  proliferate, incorporating radiolabel into DNA
• Degree of proliferation equates with
  sensitization potential
• Calculate Stimulation Index and EC3 value
• Rank potency, x factor of ½ or 2
• Accepted as alternative method

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SUBACUTE/SUBCHRONIC TOXICITY

• To determine the effects of repeated dosing,
  cumulative toxicity, target organs, no-effect
  level
• Typical protocol in rodents
• 14 to 90 days of daily dosing
• Control 3 graded doses by expected route
• Clinical observations
• Body weight, food consumption, nutritional status
• Hematology, clinical chemistry, urinalysis
• Full gross and microscopic pathological
  examination

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TYPES OF GENETIC DAMAGE

• Gene mutations
• Base substitutions
• Deletions/additions, frameshifts
• Chromosome aberrations
• Structural changes (large deletions,
  rearrangements, breaks)
• Numerical changes (gain or loss of whole
  chromosomes aneuploidy)

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GENETIC TOXICITY ASSAYS

• Primary DNA damage
• Adducts (32P-post labeling/antibody)
• Breaks (alkaline elution)
• Repair (Unscheduled DNA Synthesis)
• Gene Mutation
• Bacteria (Salmonella/Ames Assay, E. coli)
• Mammalian cells (Chinese Hamster Ovary, Mouse
  Lymphoma)
• Transgenic Mice (MutaMouse)

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GENETIC TOXICITY ASSAYS

• Chromosome Mutation
• Chromosome aberration in rodents, humans
• Micronucleus assays (in vitro, mouse bone marrow)
• Toxicogenomics
• Gene expression patterns (microarrays)
• Protein expression patterns (proteomics)

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CHRONIC TOXICITY

• Long term (lifetime ) effects/chronic
  carcinogenesis bioassay
• Both sexes, 2 species
• Same procedures as subacute/subchronic
• Criticisms Doses may be too high, metabolic
  pathways may be overloaded and therefore not
  relevant to humans, for cancer may not see same
  type of tumors

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REPRODUCTIVE TOXICITY

• Similar exposure procedures as chronic
• Also called Segment I study
• Parental generations exposed during maturation
  and/or reproductive cycles
• Measure reproductive performance
• Matings, litters, live births, lactation,
  neonatal effects, survival to weaning, behavioral
  performance
• Can examine transfer of material in mothers
  milk, can cross control and treated to examine
  effects of treatment, can have 2 and 3 generation
  studies where offspring are exposed before
  conception

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DEVELOPMENTAL TOXICITY

• Also called teratology study, Segment II
• Pregnant females (in utero exposure) (rats days
  6 15)
• Pups examined before birth
• Look for embryotoxicity, delayed development,
  abnormalities and overt malformations
• Perinatal and postnatal studies (Segment III)
• Fetal development, growth and lactation, post
  weaning growth and reproduction of litters

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FRAGRANCE MATERIAL DOSSIER

• Acute mammalian toxicity 15,000
• Genetic toxicity 35,000
• Skin effects 70,000
• Repeated dose toxicity 200,000
• Skin absorption 20,000
• Reproduction/developmental 515,000
• Biodegradation 5,000
• Acute aquatic toxicity 35,000
• Chronic aquatic toxicity 25,000
• TOTAL 920,000

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CAUSE-EFFECT RELATIONSHIP
RESPONSE DOSE EXPOSURE SOURCE
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THE OBSERVATION
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THE QUESTION
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RISK ASSESSMENT OBJECTIVES

• Balance risks and benefits
• Set target levels of risk
• Set priorities for program activities
• Estimate residual risks and extent of risk
  reduction after steps are taken to reduce risks

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ELEMENTS OF RISK ASSESSMENT
National Research Council, 1983, Science
Judgment in Risk Assessment, 1994, National
Academy Press
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WHY RISK ASSESSMENT?

• To make (informed) decision
• To manage (risk)

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HUMAN RISK ASSESSMENT

• No-effect level in animals
• Divide by 100
• No-effect level in humans
• A safe level of exposure

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SAFETY FACTORS

• Common
• 10 for intraspecies variation
• 10 for interspecies variation
• Also
• 10 for severe effect or sensitive population

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COMMON ELEMENTS

• Objective
• Data Analysis
• Critical Effect
• Uncertainty
• Extrapolation
• Peer Review

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THRESHOLD LIMIT VALUE hexachlorocyclopentadiene

• Objective Chemical inter. exposure
• Data Acute toxicity
• Effect Irritation
• Uncertainty Time Weighted Average
• Extrapolation (Average) employees
• Review TLV Committee
• Result Exposure Level

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PESTICIDE TOLERANCE myclobutanil

• Objective Fungicide food use
• Data Food additive petition
• Effect Liver, testes
• Uncertainty Uncertainty factor
• Extrapolation Consumers
• Review EPA, public
• Result Acceptable food residue

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FRAGRANCE SAFETY EVALUATION

• OBJECTIVE No Sensitization Under Conditions
  of Use
• DATA Human Repeated Insult Patch Test
• EFFECT No Effect Level for Sensitization
• UNCERTAINTY Safety Factor, Individual
  Variability
• EXTRAPOLATION Concentration in Final Product
• REVIEW RIFM Expert Panel, IFRA Scientific
  Committee

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CROSSING THE STREET

• Objective Safe passage
• Data Observation
• Effect Trauma of collision
• Uncertainty Arbitrary value judgment
• Extrapolation Individual(s)
• Review Peers/fellow crossers
• Result Decision to Wait

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Contact Dermatitis, 2001, 45, 333-340
Understanding fragrance allergy using an
exposure-based risk assessment approach
G. FRANK GERBERICK, MICHAEL K. ROBINSON, SUSAN
P. FELTER, IAN R. WHITE AND DAVID A. BASKETTER
Based on induction of sensitization
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DERMAL SENSITIZATION OF FMs

• QRA Approach
• Based on general (quantitative) exposure-based RA
• Weight of Evidence approach to NOEL setting
• Limits for different product categories
• Some more restrictive
• Some less restrictive

• Current Practice
• Based on qualitative scientific principles
• TWO Product Categories
• Skin Contact NOEL/10
• Non-Skin Contact NOEL

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QRA FOR DERMAL SENSITIZATION
Application to induction of skin sensitization -
also a threshold phenomenon

• Determine potential (hazard) to induce
  sensitization
• Pre-clinical studies e.g. Guinea-Pig Test, Local
  Lymph Node Assay (LLNA)
• Human data (historical)
• Structure based predictive approach
• Dose response
• Determine the No-Expected-Sensitization
  Induction-Level (NESIL) based on the Weight of
  Evidence (WoE)
• Calculate Sensitization Assessment Factor (SAF)
• Exposure
• Dose metrics expressed in Dose/Area
• Understand consumer exposure in different product
  categories
• How consumer are exposed to a material in terms
  of amount, duration and frequency
• Risk characterization
• Acceptable exposure levels to fragrance
  ingredients that are dermal sensitizers can be
  determined in specific real life consumer product
  types

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IFRA PRODUCT CATEGORIES BASED ON QRA
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IFRA PRODUCT CATEGORIES BASED ON QRA
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IFRA STANDARD LIMITS FOR CITRAL BASED ON QRA
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QRA DERMAL SENSITIZATIONIMPACT ON AN EXISTING
IFRA STANDARD
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RIFM TESTING PROGRAM CHEMICAL GROUPINGS

• A means to defend structurally related materials,
  without having to test every material in the
  group
• 2,000 chemically defined fragrance ingredients
• 22 Groups (e.g. Acids, Acetals, Alcohols)
• gt 60 Subgroups (e.g. Straight chain saturated,
  straight chain unsaturated etc.)

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A HIGH PRIORITY MATERIAL

• Linalool
• Structural Alerts
• H2CCCOH (topical, acute/systemic and
  carcinogenicity/mutagenicity effects)
• Tertiary alcohols and their esters
  (acute/systemic effects)
• Structural Alert Combined Score 2, 2, 6
• Volume of use gt1000 metric tons (Score 16)
• Maximum Dermal use level 4.3 (fine fragrances)
  (Score 8)
• Total Score 34

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CRITERIA DOCUMENT DIRECTS TEST PROGRAM GROUP
SELECTION

• High priority - linalool and linalyl acetate
• Linalool Related Ester Group

Linalool Linalyl acetate
Linalyl hexanoate Linalyl isobutyrate Linalyl
isovalerate Linalyl phenylacetate Linalyl
propionate
Linalyl benzoate Linalyl butyrate Linalyl
cinnamate Linalyl formate

• Evaluation of linalool will support linalyl ester
  group (11) AND terpene alcohol group (34)

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GROUP SUMMARY IMPACT

• For the first time, REXPAN will make a conclusion
  in a peer reviewed scientific publication
• Exposure data (from IFRA) will be included
• Use Levels (dermal systemic)
• Worldwide Volume of Use (in ranges)
• Can the materials be used at higher levels? Yes,
  but the data needs to be reviewed again
• Low volume materials will NOT need the same
  amount of test data

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CRITERIA DOCUMENTS Human Health Environmental
Framework
CHEMICAL GROUPS 23 Structures Subgroups
SCIENTIFIC PROCESS
DATA NEEDS Gaps Clarification
STUDY REPORTS Effects No-effect Level
DATABASE Literature Companies
EXPOSURE DATA Volume of Use Top Ten
REXPAN EVALUATION Data Quality Conclusion
PUBLICATIONS Group Summary Fragrance Material
Review
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Current U.S. Activity

• EPA Design for the Environment (DfE)
• Formulater Initiative assists in designing
  environmentally preferable products
• Working with EPA, NSF Intl will review
  formulations for 500-1000 per ingredient
• Biased against fragrances
• FMA working with ACC coalition on alternative
• EPA Generic Scenario
• Commercial and consumer products
• Estimates of drum residue too high

90
Wal-Mart Chemical Assessment

• Letter to all suppliers
• Requested hazardous (all) ingredients undergo
  evaluation and/or preparation of MSDS
• No longer includes formulas fear would allow
  duplication of in-house generic
• WERCS is 3rd party as contractor

91
CA Activities

• Air Resources Board VOC restriction to eliminate
  2 fragrance exemption and fragranced dryer
  sheets
• Safe Cosmetics Act Dept. of Health Services now
  has resources, January unlikely, stakeholder
  meeting late this year
• Biomonitoring Bill volunteers can determine
  toxins using CDC database
• Chemical Test Methods analysis for import or
  manufacture, substantiate CBI, uses TSCA mixtures
  and FFDCA products, links to biomonitoring

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7TH AMENDMENT TO THE COSMETICS DIRECTIVE

• The official terminology is Directive 2003/15/EC
  of the European Parliament and of the Council of
  27 February 2003, amending Council Directive
  76/768/EEC.
• In the most simple terms, the 7th Amendment lists
  26 substances identified by the (former) SCCNFP
  as likely to cause allergenic reactions in
  fragrance-sensitive consumers. The intent is to
  keep the consumer informed, as the 7th amendment
  requires the presence of these substances to be
  mentioned in the list of ingredients (in addition
  to the word "parfum" or "fragrance"). This goal
  is to have this information improve the diagnosis
  of contact allergies among such sensitive
  consumers and enable them to avoid the use of
  cosmetic products which they do not tolerate.

93
THE CONTENTS OF THE 7TH AMENDMENT

• Ban of animal tests on finished cosmetic
  products Immediate Application
• Ban of animal tests on ingredients and
  combinations of ingredients as soon as validated
  alternatives are available, and in any case 3
  years after implementation of 7th amendment (2
  extra years possible)
• Claims Only if neither the finished product, nor
  its prototype, nor any of the ingredients have
  ever been tested on animals, including for
  purposes outside the scope of the Cosmetics
  Directive

94
TOXICITY DOMAINS
95
LABELING CURRENT STATUS

• The word perfume or aroma is still
  allowed/valid for use
• The 26 allergens must be labeled in accordance
  with Annex III restrictions, as stated in
  Amendment 28
• Thresholds of 0.001 for leave-on products and of
  0.01 for rinse-off products
• Thresholds could be discussed later
• Regarding Amendment 28, the EP seems not to urge
  full labeling at least full labeling not
  inserted in compromise package

96
26 ALLERGENS AND IFRAStandards exist

• Cinnamyl Alcohol
• Cinnamic Aldehyde
• Citral
• Eugenol
• Farnesol
• Isoeugenol
• Hydroxycitronellal

• d-Limonene
• Linalool
• Lilial
• Lyral
• Methyl heptine carbonate
• Oakmoss
• Treemoss

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26 ALLERGENS AND IFRAMaterials without Standards

• ?-Amylcinnamyl Alcohol
• ?-amylcinnamaldehyde
• Anisyl alcohol
• Benzyl alcohol
• Benzyl benzoate
• Benzyl cinnamate

• Benzyl salicylate
• dl-Citronellol
• Coumarin
• Geraniol
• ?- Hexylcinnamaldehyde
• ?-Iso-Methylionone

98
CATEGORIZATION OF THE DOMESTIC SUBSTANCES LIST

• Ministers of Environment and Health were required
  (S.73,CEPA 1999) to categorize the 23,000
  substances on the DSL by September 14, 2006
• Categorization is a prioritization process that
  involves the systematic identification of
  substances on the DSL that should be subject to
  screening assessment (Section 74, CEPA 1999)
• The DSL includes discrete organics (50), UVCBs
  (20), polymers (20) and inorganics (10)
• DSL categorization is a precedent setting
  activity no other jurisdiction has implemented
  such a program
• Important considerations
• process is scientifically sound but practical
• allow sufficient and efficient stakeholder input

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DOMESTIC SUBSTANCES LIST
SCREENING LEVEL RISK ASSESSMENT
100
WHY GET INVOLVED?

• Decisions relied heavily on QSAR
• Conservative assumptions, incomplete information
• Information needed to respond to decisions
• Major effort to respond to Sec 71 surveys
• Use patterns, exposure, formulation, chemical
  quantities, toxicology data
• (mis-)Identification of substances as P, B or iT
• Ensure assumptions used in exposure and risk
  assessment are correct

101
ENVIRONMENTAL CATEGORIZATION

• Environment Canada is responsible for identifying
  substances, based on available information that
• Are persistent (P) or bioaccumulative (B), in
  accordance with the P and B regs, and inherently
  toxic to non-human organisms, as determined by
  lab or other studies (s.73 (1)(b))

102
REACH PRINCIPLES

• Manufacturer/Importer has to prove that a product
  can be used safely

USER3 Consumer Prof. user
M/I
USER1 Compounder
USER2 Formulator
Info use, SDS, CSR
Chemical Agency
103
BASIC QUESTIONS

• Categorization approach
• Based on structural similarity
• Mixtures approach, definition, characterisation
• Ranking/extrapolation based on a scale with
  representatives
• Tool to identify critical combinations of
  properties/ hazards/exposure
• log Kow - skin penetration, bioconcentration
• adsorption/persistence - sediment, sludge
• volatility - inhalation
• tox/ecotox - use volume exposure scen

104
EXEMPTIONS

• Food
• Cosmetics
• Natural substances (Annex 2,3)
• Identify scenarios that are not covered
• food, cosmetics
• Identify natural substances with hazard
  classification
• Check relevance of hazard for use in fragrance
  mixture
• Prepare generic plea (scientific and legal) for
  exemption

105
APPLICATION TO FRAGRANCE MATERIALS

• First Tier Using only volume of use, molecular
  weight, and log Kow, Predicted Environmental
  Concentration/P No-effect EC ratios are
  determined
• Second Tier For all those materials with
  PEC/PNEC gt1
• ECOSAR was used as an alternate QSAR
• PEC/PNEC ratio re-determined

106
EXPOSURE CHARACTERIZATION PEC

• Model assumptions
• All the fragrance usage volume is discharged down
  the drain
• No volatilization occurs
• Both 1 and 2 treatment occurs
• Material removal during treatment is only the
  result of sorption (no biodegradation or
  biotransformation)
• Minimal dilution (a factor of 3) occurs at the
  mixing zone

107
EXPOSURE CHARACTERIZATION
108
PBT ISSUES

• International regulatory initiatives for
  evaluating potential PBTs
• Moving from risk based evaluations to hazard
  based criteria
• RIFMs efforts to evaluate the potential impact
  on fragrance materials
• Evaluating modeled and measured data against
  criteria
• Prioritizing research and testing to address data
  gaps

109
LIMITATIONS OF PBT MODELS

• Persistence
• Fragment based model/expert judgement assigns
  half-life
• Selected fragments may not adequately represent
  the behavior of the molecule
• Half-life in soil and sediment inferred from
  half-life in water
• Bioaccumulation
• Log Kow based QSAR with factors for certain
  structural components, if present
• Does not take metabolism or other removal
  mechanisms into account

110
LIMITATIONS OF PBT MODELS

• Toxicity
• Log Kow based QSARs for different structural
  groups
• Training set for some QSARs very limited
• In General
• These models can both underpredict and
  overpredict the environmental behavior of organic
  chemicals

111
PBTs AND FRAGRANCE MATERIALS

• RIFM Framework
• Focused on risk
• Prioritizes testing
• Supported by risk based assessment approaches
• European Union
• US EPA
• PBT Assessments
• Hazard Based
• Driven by Precautionary Principle
• Persistence in the environment, Bioaccumulation
  in organisms, Toxicity to organisms

Hazard Exposure
Budgetary efficiency
112
ONLY THREE OUTCOMES

• Better, worse, no change
• What is the likelihood of occurrence?
• What is the significance?
• What will you do?

113
BREAD IS NOT WYSIWIG

• 98 of convicted felons use bread
• 50 of children who eat bread scorebelow average
  on standardized tests
• Bread is made from dough and 1 pound of dough
  can suffocate a mouse
• It is a gateway food item leading touse of
  harder items such as butter
• 400 degrees F used to bake bread

114
THEREFORE

• No sale of bread to minors
• No advertising within 1000 ft of school
• A 300 federal tax to pay for illness
• No animal or human images for ads
• Establish bread-free zones
• NOT REALLY JUST THINK!

115
NATURAL SELECTIONAARP The Magazine, May/June
2006

• Organic food is 11 billion U.S. industry
• 50-100 premium vs. regular foods
• Organic farmers cant use
• toxic pesticides
• chemical herbicides
• or chemical fertilizers

116
SOUND SCIENCEWilliam Hartmann

• In ideal science, the glory goes not to the
  person who wins the argument but to the person
  who brings the best data to the table
  Scientists, being human, do not always meet the
  ideal, but good evidence always beats rhetoric
  in the long run.