Fragrance Ingredient Safety Assessments - Research Institute for ...

FRAGRANCE INGREDIENT
SAFETY ASSESSMENTS –
THE GROUP APPROACH
EPIDEMIOLOGY & QRA
UPDATE
Anne Marie Api, PhD
Vice President, Human Health Sciences
Research Institute for Fragrance Materials, Inc.
CTFA Annual Meeting
March 1, 2007

RIFM SCIENTIFIC PROGRAM
RESEARCH & TESTING
DATABASE
PUBLICATIONS
Respiratory Safety Program
Fragrance Allergy
Human Health Methodology
• Epidemiology Study
• Elicitation Threshold
• Oxidation Research
• Quantitative Risk Assessment
In vitro Sensitization
Environmental Methodology
Group Health/
Environmental Testing
Use Level Testing
High priority materials (proactive
program) – fill data gaps for
multiple endpoints to allow
completion of group summaries
Support of IFRA Standards
CTFA Mar 2007 AM Api

FOUR IMPORTANT
PUBLICATIONS
• Human Health Criteria Document
Reg. Tox. & Pharm., 31, 166-181, 2000
• Environmental Framework Document
Env. Tox. & Chemistry, 21, 1301-1308, 2002
• RIFM Expert Panel Safety Evaluation
Process – Reg. Tox. & Pharm., 37 (2), 218-
273, 2003
• Industry Exposure Consideration
Practices - Reg. Tox. & Pharm., 36, 246-
252, 2002
CTFA Mar 2007 AM Api

GROUP APPROACH
• Used by many groups for quite some
time
OECD process
US EPA
Joint FAO/WHO Expert Committee on Food
Additives (JECFA)
FEMA Expert Panel (flavors)
RIFM Expert Panel (fragrances)
• Successful example in the OECD
process
Solvents propyl acetate and butyl acetate
Both are easily metabolized by esterases
to the corresponding acid and alcohol,
which are the ultimate active molecules.
CTFA Mar 2007 AM Api

GROUP APPROACH
• Chemical structure helps to predict
transdermal absorption
metabolism
disposition
functional groups that can influence
toxicity
• Group safety evaluations can
demonstrate that within a congeneric
group similar biochemical fate and
toxicological potential can be exhibited
• It can be shown that the group is
efficiently detoxicated to yield the same
or similar metabolites.
CTFA Mar 2007 AM Api

RIFM GROUP APPROACH
• 88% are structurally simple,
Low molecular weight
Predominantly semi-volatile substances
Consisting of carbon, hydrogen and oxygen
• Majority can be assigned to several
homologous groups of structurally
related materials
~ 2,100 chemically defined fragrance
ingredients
22 Groups (e.g. Acids, Acetals, Alcohols)
> 150 Subgroups (e.g. Straight chain
saturated, straight chain unsaturated etc.)
CTFA Mar 2007 AM Api

RIFM GROUPINGS FOR
FRAGRANCE INGREDIENTS
Ketones
10%
Volume of
Hydrocarbons
4%
Musks
6%
Aldehydes
15%
Use
Other
8%
Alcohols
23%
Esters
34%
Number of
Materials
Esters
33%
Hydrocarbons
4%
Alcohols
16%
Aldehydes
10%
Musks
0.3%
Other
26%
Ketones
12%
CTFA Mar 2007 AM Api

RIFM GROUP APPROACH
• Basis majority of safety evaluations
Can reasonably predict some degree of
consistency of metabolism and toxicity
For most, it can be shown that the group is
efficiently detoxicated to yield the innocuous
metabolites
Low systemic exposure levels (many below
thresholds of toxicological concern)
• Existing information for a group
may need to submit a fragrance ingredient
to full toxicological testing OR
it may be necessary to test one or more
particular members of a group to obtain
more robust data to solidify assessment of
the class as a whole
CTFA Mar 2007 AM Api

CRITERIA DOCUMENT DIRECTS
TEST PROGRAM & GROUP SELECTION
• High priority - linalool and linalyl acetate
• Linalool & Related Ester Group
Linalool
Linalyl acetate
Linalyl benzoate
Linalyl butyrate
Linalyl cinnamate
Linalyl formate
Linalyl hexanoate
Linalyl isobutyrate
Linalyl isovalerate
Linalyl phenylacetate
Linalyl propionate
• Evaluation of linalool will support linalyl
ester group (11) AND non-cyclic terpene
alcohol group (46)
CTFA Mar 2007 AM Api

GROUP SUMMARY IMPACT
• For the first time, REXPAN makes a
conclusion in a peer-reviewed, scientific
publication
• Exposure data (from IFRA) is included.
Use Levels (dermal & systemic)
Worldwide Volume of Use (in ranges)
• Expeditious
• Greatly reducing animal testing
• Cost Saving
Low volume materials will NOT need the
same amount of test data.
CTFA Mar 2007 AM Api

SAFETY EVALUATION
PUBLICATIONS
GROUP SUMMARY
Author: REXPAN
Safety
Evaluation
Monographs
FMR
Author:
RIFM
STAFF
FMR
Author:
RIFM
STAFF
FMR
Author:
RIFM
STAFF
Material
Details
CTFA Mar 2007 AM Api

GROUP SUMMARIES (FMRs)
‘98 ‘99 ‘00 ‘01 ‘02 ‘03 ‘04 ‘05 ‘06 ‘07 ‘08 ‘09 ‘10
Linalool (11)
Cinn. Alc., Acid, Ald. (3)
Ionones (35)
3 Sub. Cinn. Grps (55)
Salicylates (18)
Non-Cyclic Terpene
Alcohols (46)
Cyclic Terpene Alcohols
(33)
Esters Acetates Cyclic (30) ?
Aryl Alkyl Alcohol (40)
Aryl Aldehydes (20)
Alcohols Branched
Chain (56)
Aryl Alkyl Aldehydes Cinn.
& Propionald. (21)
Esters Acetates
Terpenes Cyclic (31)
Ketone Cyclopentanones (26)
Esters Acetates Aryl Alkyl (22)

GROUP SUMMARIES (FMRs)
• 2003 Linalool and Related Esters (11)
• 2005 Cinnamic Ald., Acid, Alc. (3)
• 2006 (90)
Ionones (36)
Salicylates (18)
Substituted Cinnamyl esters (25)
• Total 2006: 5 groups; 104 FMRs
• Goal 2007 (109)
Cyclic & Non-cyclic Terpene Alcohols (65)
Substituted Cinnamyl Aldehydes (33)
Substituted Cinnamyl Phenyl Propyl (11)
• Goal 2016: 56 groups; >1300 FMRs
CTFA Mar 2007 AM Api

RELATIONSHIP TO REACH
• RIFM Database and groups to support
fragrance industry
• Utilize the same group approach
Fragrance group used as an example in a
REACH Implementation Projects (RIP)
RIFM peer-reviewed documents have a
higher standing in regulatory decisions
• Testing sponsored by RIFM conducted
will meet REACH requirements
CTFA Mar 2007 AM Api

THE FRAGRANCE AUTHORITY
Human
Health
Methodology
Respiratory
Safety
Program
Group
Criteria
Document
Testing
RIFM
Use Level
Testing
CTFA Mar 2007 AM Api
FRAGRANCE
ALLERGY
Environmental
Methodology
Program

FRAGRANCE ALLERGY
RESEARCH PROGRAM
Other
Clinical Diagnostic
Tests
Elicitation
Threshold
Epidemiology Study
Other Clinical
Diagnostic Tests
Other Clinical
Diagnostic
Tests
Quantitative
Risk
Assessment
Oxidation
Research
Supplying
Patch Test
Materials
CTFA Mar 2007 AM Api

EPIDEMIOLOGY: SO WHAT?
• How common is fragrance
allergy?
CTFA Mar 2007 AM Api
Population based studies
are the only method for
obtaining accurate
prevalence data
• Bring data to the table
• Unprecedented fragrance
study design
• Assist in future policy
decisions
• May be useful in making
future decisions to decrease
reactions to fragrance
ingredients
• Continue to expand
scientifically based
interactions & collaborations
with dermatology community

EPIDEMIOLOGY: RESOLVING
KEY QUESTIONS
• Geographical Regions
Italy, Sweden, The
Netherlands, Germany
(East & West), Portugal
There is NO
statistically significant
difference in incidence
rates to the fragrance
mix among countries in
Europe
• Fragrance materials
2 Fragrance mixes + 14
materials that
comprise it
Use tools currently
used by patch testers
CTFA Mar 2007 AM Api

EPIDEMIOLOGY: RESOLVING
KEY QUESTIONS
KEY QUESTIONS
• Fragrance materials
Positive patch test does
NOT mean clinically
relevant
Interpret data based on
population not
individual
• Study Design
Addresses the concerns
involving those
fragrance ingredients
where most of the
published literature is
focused
Addresses the concerns
“head-on” and does not
avoid any issues
CTFA Mar 2007 AM Api

EPIDEMIOLOGY: STUDY
FEEDBACK
• Conclusion of WHO IPCS Skin
Sensitization Workshop:
Prevalence studies in general
population are needed
• German BfR: Encouraged the
plans for the RIFM study
• REXPAN will review data,
interpretations & render their
opinion & recommendations
about the data as well as
publication of the study
agrees & unanimously
supports RIFM’s
sponsorship of the study
noted that the study cannot
address emerging issues
that are not defined yet.
CTFA Mar 2007 AM Api

EPIDEMIOLOGY: STATUS
• Phase I – Questionnaire validation (2005)
A fully validated questionnaire was developed that
showed good reliability, validity and repeatability
• Phase II – Pilot clinical (2006)
Preliminary study to gather data from all regions
using validated methods & full study design. Allow
flexibility & an opportunity to ask questions about
the full study design
Goals (100 subjects/region, selected from the
electoral rolls; equal number of control subjects to
test subjects; RIFM monitors)
Obtain a measured estimate of the prevalence of
contact allergy to fragrance ingredients with
confidence intervals (The experts predicted that
the prevalence would be

EPIDEMIOLOGY: STATUS
• Phase III – Full study (2007-2009)
Goals (2500 subjects/region, selected
from the electoral rolls; equal number of
control subjects to test subjects; RIFM
monitors):
Determine the prevalence of contact allergy to
fragrance ingredients with confidence
intervals
Conduct the subgroup analyses that will
correlate clinical manifestations with fragrance
sensitization and allow comparison within and
between countries
Provide a baseline for measuring success of
QRA Implementation
CTFA Mar 2007 AM Api

DERMAL SENSITIZATION
RISK ASSESSMENT OF FMs
Old Practice
Based on qualitative
scientific principles
TWO Product Categories
‣ Skin Contact = NOEL/10
‣ Non-Skin Contact = NOEL
CTFA Mar 2007 AM Api
NEW QRA Approach
Based on general
(quantitative) exposurebased
RA
Weight of Evidence
approach to NOEL
setting
Limits for 11 different
product categories
‣ Some more restrictive
than before
‣ Some less restrictive
than before

IFRA PRODUCT CATEGORIES
BASED ON QRA
IFRA Category
Category 1
Category 2
Category 3
Category 4
Category 5
Category 6
Category 7
Category 8
Category 9
Category 10
Category 11
Examples of Products
Lip Products, Toys, Insect Repellents
Deodorants/Antiperspirants
Hydroalcoholic Products for Shaved Skin, Eye Products,
Men’s Facial Cream & Balms, Tampons
Hydroalcoholic Products for Unshaved Skin, Hair
Styling Aids & Sprays, Body Creams
Women’s Facial Cream/Facial Make-up/ Facial Wipes
Mouthwash, Toothpaste
Intimate Wipes, Baby Wipes
Make-up Remover, Hair Styling Aids Non-Spray, Nail
Shampoo, Rinse-Off Conditioners, Bar Soap, Feminine
Hygiene Pads & Liners
Detergents, Hard Surface Cleaners, Diapers
All Non-Skin or incidental skin contact products
CTFA Mar 2007 AM Api

IFRA STANDARD LIMITS FOR
CITRAL BASED ON QRA
IFRA
Cat.
Examples of Product Type
Citral
QRA
1 Lip Products 0.04%
2 Deodorant/Antiperspirant 0.05%
3 Hydroalc., Shaved Skin 0.2%
4 Hydroalc., Unshaved Skin 0.6%
5 Women Facial Cream 0.3%
6 Mouthwash 1.0%
7 Intimate Wipes 0.1%
8 Fem. Hygiene Pad, Liner 1.4%
9 Bar Soaps 5.0%
10 Shampoo 2.5%
11 Non-skin; Incidental Skin Limited
CTFA Mar 2007 AM Api

QRA IMPLEMENTATION
STATUS
• Technical dossier & Informational
booklet published on RIFM (& IFRA)
websites
www.rifm.org/pub/publications.asp
• 40 th Amendment May 2006 - Citral,
Farnesol, Phenylacetaldehyde, Tea Leaf
Absolute
• Publications - in preparation
For peer-reviewed scientific journals
For trade press
• Implementation guidance - users &
customers – on going
QRA Implementation Workshop Jan. 23, 2007
CTFA Mar 2007 AM Api

QRA IMPLEMENTATION
FUTURE FOCUS
• 42 nd Amendment (2007) – about 40-50 fragrance
ingredients (new and existing)
• 43 rd Amendment (2008) about 40 fragrance
ingredients (new and existing)
• Key goal (2011): review all chemically defined
fragrance ingredients with structural alerts for
dermal sensitization that are used > 1 metric ton
per year on a worldwide basis.
• REXPAN: Compliance with IFRA Standards
• Future Meetings
Wednesday March 28, 2007 1:30 PM; Symposium at
Society of Toxicology Meeting, Charlotte, North
Carolina, USA
Friday July 13, 2007 Fragrance Mini-Symposium at 9 th
Contact Dermatitis State-of-the-Art Issues, Hershey PA
USA
CTFA Mar 2007 AM Api

MORE INFORMATION
Research Institute for
Fragrance Materials, Inc.
Tel.: +1-201.689.8089
amapi@rifm.org
RIFM: www.rifm.org
IFRA: www.ifraorg.org
CTFA Mar 2007 AM Api