RIFM INFOX-Tokyo, Japan-18 May 2005 - Research Institute for ...
RIFM INFOX-Tokyo, Japan-18 May 2005 - Research Institute for ...
RIFM INFOX-Tokyo, Japan-18 May 2005 - Research Institute for ...
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COMPREHENSIVE SCIENCE AND ADVOCACY IN THE NEW ORGANIZATION<br />
Ladd W. Smith, Ph.D.<br />
ABSTRACT<br />
For many years, <strong>RIFM</strong> has <strong>for</strong>med its scientific program around a core of priority materials, selected by<br />
chemical structure, production volume, known effects and product use. Annual budgets were prepared to<br />
include specific projects within testing and research categories. Over the last years, these procedures have<br />
been acknowledged through publication of criteria documents <strong>for</strong> both human health and environmental<br />
effects. Subsequently, all fragrance materials have been placed into chemical groups, as detailed in the Expert<br />
Panel's publication on its safety evaluation process. Further, the published linalool and related esters Group<br />
Summary and Fragrance Material Reviews provide the first results of the combination of these processes.<br />
Currently, 7 additional structural groups are in various stages of completion, beginning with preliminary<br />
assessment and progressing through data accumulation, <strong>RIFM</strong> Expert Panel evaluation and conclusion, and<br />
ending with publication in the peer-reviewed literature.<br />
Through a series of interactions involving the Board, <strong>RIFM</strong> staff, industry technical representatives and the<br />
Expert Panel, a more strategic approach developed a multiple year view and placed research and testing<br />
projects into functional categories. While designed as a realistic indicator of industry fragrance material safety<br />
needs, it retains sufficient flexibility to shift priorities over time and among technical areas. It also more<br />
clearly identifies specific projects within each category, <strong>for</strong> budgeting purposes and <strong>for</strong> communication of<br />
plans and results.<br />
The respiratory safety project was developed to address questions of individual susceptibility to common<br />
fragrance materials. Its exposure-oriented approach characterizes typical product applications as related to<br />
potential biological effects. The fragrance allergy category complements outreach to clinical and research<br />
dermatologists with projects to develop scientific data on auto-oxidation, epidemiology and elicitation<br />
threshold. Since methodology research is science's tool development <strong>for</strong> future use, human health projects<br />
address alternatives to animal testing and skin absorption prediction, while environmental projects extend<br />
ongoing soil fate studies to investigate similar degradation and biotrans<strong>for</strong>mation processes in sediment and<br />
marine media. Group criteria document testing provides the basis <strong>for</strong> safety evaluations through the<br />
identification of short term and long term hazard endpoints. Use level support testing directly addresses<br />
material content in product <strong>for</strong>mulations and provides the scientific basis <strong>for</strong> setting IFRA Standards.<br />
Scientific data are most useful when collected in a planned manner, evaluated by established criteria and<br />
delivered to multiple audiences in various <strong>for</strong>mats to be used <strong>for</strong> understanding and decision-making. To<br />
accomplish that, the resources of <strong>RIFM</strong> and IFRA have been combined through a global alliance of the two<br />
organizations. IFRA will be the umbrella name <strong>for</strong> the new organization, while <strong>RIFM</strong> will remain a separate<br />
legal entity and will retain its scientific independence, as will its Expert Panel. A new position of Director<br />
General will coordinate ef<strong>for</strong>ts through a Joint Executive Committee. All scientific programs will be part of<br />
the <strong>RIFM</strong> budget and IFRA advocacy activities will be increased substantially. The goal is to create a stronger<br />
industry, with a more visible compliance program, and to include more companies and more associations<br />
worldwide.
COMPREHENSIVE<br />
SCIENCE AND ADVOCACY<br />
IN THE NEW<br />
ORGANIZATION<br />
Ladd W. Smith, PhD, DABT<br />
<strong>RIFM</strong> In<strong>for</strong>mation Exchange<br />
JFFMA – <strong>Tokyo</strong><br />
<strong>May</strong> <strong>18</strong>, <strong>2005</strong>
“Sound Science”<br />
William Hartmann<br />
“In ideal science, the glory goes not<br />
to the person who wins the argument<br />
but to the person who brings the best<br />
data to the table … Scientists, being<br />
human, do not always meet the ideal,<br />
but good evidence always beats<br />
rhetoric in the long run.”<br />
LWS - <strong>INFOX</strong> <strong>Tokyo</strong>, <strong>May</strong> <strong>18</strong>, <strong>2005</strong>
NEW ORGANIZATION<br />
<br />
• IFRA to be name of “umbrella”<br />
• Director General (Brussels) to coordinate<br />
• Joint (International) Executive Committee<br />
• <strong>RIFM</strong> (and IFRA) to remain separate legal<br />
entities<br />
• All scientific programs within <strong>RIFM</strong> budget<br />
• <strong>RIFM</strong> research and testing budget has<br />
increased<br />
• <strong>RIFM</strong> science and Expert Panel remain<br />
independent<br />
LWS - <strong>INFOX</strong> <strong>Tokyo</strong>, <strong>May</strong> <strong>18</strong>, <strong>2005</strong>
FRAGRANCE MATERIAL REVIEW<br />
<br />
Peer-reviewed publication,<br />
IFRA Standard<br />
Data become part of dossier, database<br />
Report reviewed by REXPAN, conclusion<br />
Incorporated into budget<br />
(group category)<br />
Study sponsored at<br />
university or laboratory<br />
Group evaluation<br />
or<br />
material request<br />
<strong>RIFM</strong> preliminary<br />
assessment from<br />
database<br />
REXPAN<br />
determination of<br />
specific data needs<br />
LWS - <strong>INFOX</strong> <strong>Tokyo</strong>, <strong>May</strong> <strong>18</strong>, <strong>2005</strong>
<strong>RIFM</strong> DATABASE<br />
<br />
100000<br />
80000<br />
60000<br />
40000<br />
20000<br />
0<br />
2001 2002 2003 2004<br />
References 39000 41327 43000 47178<br />
Studies 84549 88569 92800 97745<br />
Ingredients 4460 4500 4566<br />
LWS - <strong>INFOX</strong> <strong>Tokyo</strong>, <strong>May</strong> <strong>18</strong>, <strong>2005</strong>
GROUP SUMMARY PROGRESS<br />
<br />
Alkyl Aryl Alc. (40)<br />
Cyl. Terp. Alc. (46)<br />
Ac. Terp. Alc. (33)<br />
Salicylates (<strong>18</strong>)<br />
Ionones (34)<br />
Sub. Cinnam. (55)<br />
Cinnamyl (3)<br />
Linalool, Est. (11)<br />
1998 1999 2000 2001 2002 2003 2004 <strong>2005</strong> 2006 2007<br />
LWS - <strong>INFOX</strong> <strong>Tokyo</strong>, <strong>May</strong> <strong>18</strong>, <strong>2005</strong>
<strong>RIFM</strong> PUBLICATIONS<br />
<br />
20<br />
15<br />
10<br />
5<br />
0<br />
1995 1997 1999 2001 2003<br />
LWS - <strong>INFOX</strong> <strong>Tokyo</strong>, <strong>May</strong> <strong>18</strong>, <strong>2005</strong>
www.rifm.org<br />
<br />
• <strong>Research</strong> theme<br />
• Revised look<br />
• Secure database<br />
access<br />
• Growing awareness –<br />
members and<br />
non-members are<br />
submitting questions<br />
through the web site<br />
• “White papers” being added as developed<br />
• Members Only section with technical detail<br />
LWS - <strong>INFOX</strong> <strong>Tokyo</strong>, <strong>May</strong> <strong>18</strong>, <strong>2005</strong>
TOTAL EXPENSE<br />
<br />
$6,000,000<br />
$5,000,000<br />
$4,000,000<br />
$3,000,000<br />
$2,000,000<br />
$1,000,000<br />
$-<br />
1971 1974 1977 1980 1983 1986 1989 1992 1995 1998 2001 2004<br />
LWS - <strong>INFOX</strong> <strong>Tokyo</strong>, <strong>May</strong> <strong>18</strong>, <strong>2005</strong>
EXPENSE/TESTING<br />
<br />
$6,000,000<br />
$5,000,000<br />
$4,000,000<br />
$3,000,000<br />
$2,000,000<br />
$1,000,000<br />
$-<br />
1971 1974 1977 1980 1983 1986 1989 1992 1995 1998 2001 2004<br />
LWS - <strong>INFOX</strong> <strong>Tokyo</strong>, <strong>May</strong> <strong>18</strong>, <strong>2005</strong>
TESTING AS % OF EXPENSE<br />
<br />
70%<br />
60%<br />
50%<br />
40%<br />
30%<br />
20%<br />
1981 1984 1987 1990 1993 1996 1999 2002<br />
LWS - <strong>INFOX</strong> <strong>Tokyo</strong>, <strong>May</strong> <strong>18</strong>, <strong>2005</strong>
<strong>RIFM</strong> BUDGET<br />
<br />
$7,000,000<br />
$6,000,000<br />
$5,000,000<br />
$4,000,000<br />
2003<br />
2004<br />
<strong>2005</strong><br />
$3,000,000<br />
$2,000,000<br />
$1,000,000<br />
$0<br />
Income<br />
Operations<br />
Science<br />
<strong>Research</strong>/Testing<br />
LWS - <strong>INFOX</strong> <strong>Tokyo</strong>, <strong>May</strong> <strong>18</strong>, <strong>2005</strong>
IFRA <strong>2005</strong> SCIENCE<br />
<br />
• Consultancy with Dr. Maibach<br />
• Literature survey project to address the issue of<br />
the selection criteria of the 26 ‘allergens’<br />
• Sponsorship of dermatology conferences, such as<br />
European SCD or International SCD<br />
• Support <strong>for</strong> the IVDK-German dermal database<br />
• All projects are intended to improve the<br />
relationship with the dermatological community<br />
to achieve a system of cooperation instead of<br />
confrontation in the long term<br />
LWS - <strong>INFOX</strong> <strong>Tokyo</strong>, <strong>May</strong> <strong>18</strong>, <strong>2005</strong>
IFRA <strong>2005</strong> SCIENCE<br />
<br />
• Support GREATER (Geography Referenced regional<br />
Exposure Assessment Tool <strong>for</strong> European Rivers)<br />
• R43 Limonene project with Prof. Karlberg<br />
Further insight into oxidation of limonene and the<br />
consequences <strong>for</strong> classification as a sensitizer – now<br />
developing adequate analytical methods<br />
• Shared costs <strong>for</strong> organizing the data which <strong>for</strong>ms the<br />
basis <strong>for</strong> the EFFA/IFRA/IOFI Labeling manual –<br />
an important tool to ensure a harmonized approach –<br />
the basis <strong>for</strong> decisions taken be<strong>for</strong>e 2000 needs to be<br />
reorganized and revised<br />
LWS - <strong>INFOX</strong> <strong>Tokyo</strong>, <strong>May</strong> <strong>18</strong>, <strong>2005</strong>
<strong>2005</strong> RESEARCH & TESTING<br />
<br />
Respiratory<br />
Fragrance Allergy<br />
Human Methods<br />
Environ. Methods<br />
Group Testing<br />
Use Levels<br />
LWS - <strong>INFOX</strong> <strong>Tokyo</strong>, <strong>May</strong> <strong>18</strong>, <strong>2005</strong>
COMPREHENSIVE<br />
<br />
RESEARCH PLAN<br />
• Respiratory Safety<br />
Simulated exposures, clinical study<br />
UNDERSTAND/MANAGE EXPOSURE<br />
AND EFFECTS<br />
• Fragrance Allergy<br />
Auto-oxidation, elicitation threshold, epidemiology<br />
REDUCE INCIDENCE OF CLINICAL<br />
ALLERGY<br />
• Human Health Methodology<br />
In vitro sensitization, skin absorption model<br />
DEVELOP ALTERNATIVE METHODS<br />
LWS - <strong>INFOX</strong> <strong>Tokyo</strong>, <strong>May</strong> <strong>18</strong>, <strong>2005</strong>
COMPREHENSIVE<br />
<br />
RESEARCH PLAN<br />
• Environmental Methodology<br />
Soil fate, biotrans<strong>for</strong>mation, marine assessments<br />
PREDICT/MONITOR ENVIRONMENTAL<br />
FATE<br />
• Group Testing (criteria documents)<br />
Human health and environmental endpoints<br />
EVALUATE GROUPS/INDIVIDUALS<br />
• Use Level Testing<br />
Skin sensitization, photoallergy<br />
SUPPORT SAFE USE<br />
LWS - <strong>INFOX</strong> <strong>Tokyo</strong>, <strong>May</strong> <strong>18</strong>, <strong>2005</strong>
COMPREHENSIVE<br />
RESEARCH PLAN ($000)<br />
2000<br />
<strong>18</strong>00<br />
1600<br />
1400<br />
1200<br />
1000<br />
800<br />
Respiratory Safety<br />
Fragrance Allergy<br />
Human Health Methods<br />
Environmental Methods<br />
Group Testing<br />
Use Level Testing<br />
600<br />
400<br />
200<br />
0<br />
2001 2002 2003 2004 <strong>2005</strong> 2006 2007 2008 2009<br />
LWS - <strong>INFOX</strong> <strong>Tokyo</strong>, <strong>May</strong> <strong>18</strong>, <strong>2005</strong>
THE “NEW” IFRA<br />
Joint Executive Committee<br />
Director General<br />
<strong>RIFM</strong>:<br />
Science<br />
Expert Panel<br />
IFRA:<br />
Advocacy<br />
Communication<br />
LWS - <strong>INFOX</strong> <strong>Tokyo</strong>, <strong>May</strong> <strong>18</strong>, <strong>2005</strong>
GLOBAL ALLIANCE<br />
<br />
Stronger industry – Suppliers and Users<br />
Technical Advocacy<br />
Visible Compliance Program<br />
More Regional and National Associations<br />
More Companies<br />
“ … the fragrance authority …”<br />
LWS - <strong>INFOX</strong> <strong>Tokyo</strong>, <strong>May</strong> <strong>18</strong>, <strong>2005</strong>
BIOGRAPHY<br />
LADD W. SMITH, Ph.D.<br />
Ladd Smith is trained as a scientist and enjoys the strategic challenges of general technical<br />
management. Since 1998, he has been president of the <strong>Research</strong> <strong>Institute</strong> <strong>for</strong> Fragrance Materials, Inc.,<br />
an international organization, which evaluates the safety of fragrance ingredients.<br />
Previously, he was responsible <strong>for</strong> product stewardship at Occidental Chemical. Prior positions at GE<br />
Plastics and Dupont involved health care cost containment, regulatory affairs and laboratory research.<br />
During his career, he has assumed leadership roles on association boards and committees, has helped<br />
develop graduate and cooperative education programs and has published on subjects including health<br />
and environmental research, in<strong>for</strong>mation management and risk assessment.<br />
Dr. Smith received his doctorate in pharmacology from the Medical College of Virginia, his masters in<br />
bioengineering from Clemson University and his bachelors in zoology from the University of South<br />
Florida. He is a diplomate of the American Board of Toxicology and currently serves as the president of<br />
its Board. He also serves on the Advisory Board of the Center <strong>for</strong> Alternatives to Animal Testing of the<br />
Bloomberg School of Public Health at Johns Hopkins University.
THE IFRA SCIENTIFIC COMMITTEE AND<br />
ITS ROLE IN THE FRAGRANCE INDUSTRY<br />
William R. Troy, Ph.D.<br />
ABSTRACT<br />
The IFRA Scientific Committee is charged by the Board of IFRA with assuring the safe use of<br />
fragrances by the membership and by the user community. To achieve this objective, a group of<br />
technical experts, chosen <strong>for</strong> their differing spheres of expertise, meet three times per year to<br />
address issues pertaining to fragrance safety. There is a close working relationship with <strong>RIFM</strong><br />
staff, and a <strong>for</strong>malized interaction with the <strong>RIFM</strong> Expert Panel (REXPAN) as regards the<br />
development of IFRA Standards. The IFRA Scientific Committee, and REXPAN—together with<br />
the staffs of IFRA and <strong>RIFM</strong>—constitute the “science arm” of the new, global fragrance<br />
organization.
I<br />
F<br />
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A<br />
THE IFRA SCIENTIFIC COMMITTEE<br />
AND ITS ROLE IN THE FRAGRANCE<br />
INDUSTRY<br />
<strong>RIFM</strong> <strong>INFOX</strong> – <strong>18</strong> <strong>May</strong> <strong>2005</strong><br />
William Troy, Ph.D.<br />
Chairman, IFRA<br />
Scientific Committee
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Mission<br />
• Mission: To monitor the safety<br />
evaluation activities of IFRA with the<br />
objective of assuring the continued safe<br />
use of fragrances by the membership<br />
and by the user community<br />
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Activities<br />
• To develop and implement procedures as<br />
necessary to achieve the primary mission<br />
• To evaluate, communicate and implement<br />
product safety in<strong>for</strong>mation<br />
• To act in concert with <strong>RIFM</strong> concerning safety<br />
evaluation and to assist in the implementation<br />
of recommendations arising from <strong>RIFM</strong>’s<br />
activities<br />
3
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Activities (cont’d)<br />
• To document the Standards to be adopted by IFRA<br />
based on the scientific conclusions of the REXPAN<br />
• To monitor and publish on a regular basis the usage<br />
of and exposure to fragrance ingredients within<br />
specified geographical areas from which priorities <strong>for</strong><br />
evaluating and/or testing raw materials can be<br />
established<br />
• To safeguard the uncompromising independence and<br />
integrity of <strong>RIFM</strong>, through adherence to a defined<br />
protocol <strong>for</strong> operation and communication<br />
4
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IFRA Scientific Committee<br />
• Membership limited to 10-12 12 technical<br />
representatives from fragrance supplier<br />
companies<br />
• Areas of expertise represented:<br />
Toxicology<br />
Chemistry<br />
Environmental science<br />
Perfumery<br />
Regulatory affairs<br />
5
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SC Members<br />
• Toru Asakoshi<br />
<br />
T. Hasegawa<br />
• Gunda Bertram<br />
<br />
Symrise<br />
• Veronique Epstein<br />
<br />
Givaudan<br />
• Robert Fellous<br />
<br />
IFF<br />
• Antoine Gaillard<br />
<br />
Givaudan<br />
• Matsuo Hiroyuki<br />
<br />
Takasago<br />
• John Middleton<br />
Quest<br />
• Philippe Racine<br />
Robertet<br />
• Kevin Renskers<br />
Takasago<br />
• Ken Schrankel<br />
IFF<br />
• Bill Troy (Chairman)<br />
Firmenich<br />
6
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Association Staff Liaison<br />
• IFRA<br />
Matthias Vey<br />
IFRA Scientific<br />
Director<br />
Audrey Martin<br />
Scientific<br />
In<strong>for</strong>mation<br />
Specialist<br />
• <strong>RIFM</strong><br />
Ladd Smith<br />
<strong>RIFM</strong> President<br />
Anne Marie Api<br />
<strong>RIFM</strong> Scientific<br />
Director<br />
7
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IFRA Scientific Committee<br />
• Meetings held 3X per year<br />
U.S.<br />
Europe<br />
<strong>Japan</strong> (March 2004)<br />
• Agenda is such that 2 days required <strong>for</strong><br />
the meeting<br />
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IFRA Scientific Committee<br />
• SC can identify issues <strong>for</strong> REXPAN to<br />
address<br />
• SC gathers in<strong>for</strong>mation <strong>for</strong> REXPAN to<br />
review<br />
• SC responsible <strong>for</strong> the IFRA Standards<br />
process<br />
• SC responsible <strong>for</strong> recommending<br />
changes to the Code<br />
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SC Agenda Topics<br />
• Non-skin contact restrictions<br />
Cinnamic aldehyde, Eugenol<br />
• Classification of complex natural<br />
materials<br />
DPD, customers<br />
Industry impact<br />
10
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SC Agenda Topics (cont’d)<br />
• Fragrance material quality<br />
Hydroperoxides – limonene, linalool<br />
Atranol/chloroatranol<br />
– the mosses<br />
Benzene, toluene, etc., residues<br />
Polyaromatic hydrocarbons (PAH) in<br />
wood tar derivatives – cade, , birch<br />
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SC Agenda Topics (cont’d)<br />
• Interaction of fragrance ingredients<br />
Additivity?<br />
Synergism?<br />
Quenching?<br />
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IFRA Code - Annex 1<br />
• Annex 1 contains the Safety Standards<br />
<strong>for</strong> Fragrance Ingredients<br />
• “Fragrance ingredients should be used<br />
only after satisfactory evaluation”<br />
ref. Human health criteria publication<br />
• Consideration of skin effects – irritation,<br />
sensitization, photo effects<br />
13
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IFRA Code - Annex 1<br />
• Systemic toxicity relative to exposure<br />
• Environmental effects<br />
• Data <strong>for</strong> ingredient evaluation may<br />
come from published literature,<br />
structure-activity review, health and<br />
safety legislation<br />
• If inadequate data exists, a testing<br />
program is constructed<br />
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IFRA Code of Practice & Standards<br />
38th Amendment was issued March 2004<br />
Currently:<br />
• > 100 Standards <strong>for</strong> fragrance ingredients<br />
• 36 Standards prohibiting the use of certain<br />
fragrance ingredients*<br />
• 50 ingredients are limited <strong>for</strong> their use in<br />
fragrance compounds<br />
• 14 raw materials: special purity criteria<br />
* plus 24 ‘other materials’ banned due to insufficient data<br />
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Process <strong>for</strong> the IFRA Standards<br />
• Basis <strong>for</strong> the IFRA-Standards is a safety<br />
evaluation (risk assessment) of the safety<br />
data <strong>for</strong> a fragrance ingredients by REXPAN<br />
(<strong>RIFM</strong> Expert Panel), an independent panel<br />
of experts consisting of toxicologists,<br />
dermatologists and pharmacologists as well<br />
as an associated group of specialists in<br />
areas like environmental protection<br />
• The final decision on the content (impact) of<br />
the IFRA Standards is solely in the hands of<br />
REXPAN, not IFRA<br />
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The Future<br />
• An even closer working relationship <strong>for</strong><br />
IFRA Scientific Committee and <strong>RIFM</strong><br />
scientists/REXPAN<br />
• Implementation of an advocacy arm of<br />
IFRA will make maximum use of<br />
industry science in promoting our<br />
program<br />
17
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ARIGATO GOZAIMASU!<br />
<strong>18</strong>
BIOGRAPHY<br />
William R. Troy, Ph.D.<br />
Dr. William R. Troy, Vice President, General Manager, Product Safety & Regulatory Affairs, has direct<br />
responsibility <strong>for</strong> all aspects of the safety and legislative compliance of flavors, fragrances and aromachemicals <strong>for</strong><br />
Firmenich North America, and indirect responsibility <strong>for</strong> the same in Latin America and Asia/Pacific. He oversees<br />
the safety testing and U.S. registration of all new aromachemicals, and is the primary customer contact at Firmenich<br />
North America <strong>for</strong> all issues relating to product safety and legislation.<br />
Dr. Troy began his career with Revlon, in their <strong>Research</strong> Center, where he undertook a special program that focused<br />
on the examination of aging in the skin. He gradually progressed into a role in the toxicology group there, where he<br />
developed an inhalation safety program <strong>for</strong> testing the company’s aerosol products. After 5 years at Revlon he<br />
moved on to Avon Products, <strong>Research</strong> & Development group, as an Inhalation Toxicologist with responsibility <strong>for</strong><br />
design and construction of a state-of-the-art inhalation toxicology laboratory. He held various management positions<br />
in the Toxicology Department over the next 10 years, eventually assuming responsibility <strong>for</strong> the Regulatory Affairs<br />
group as well. In 1985 he moved from Toxicology and Regulatory Affairs to Product Development as Manager of<br />
Fragrance Products R&D category. In 1987 he became R&D Product Development Director <strong>for</strong> Fragrance Products,<br />
with responsibility <strong>for</strong> development of all new fragrances and fragranced products as well. After 20 years at Avon,<br />
he accepted his current position at Firmenich.<br />
Dr. Troy holds undergraduate and graduate degrees in Biology, as well as a Ph.D. in Experimental Pharmacology<br />
from St. Johns University, Jamaica, New York.<br />
Dr. Troy holds positions in many of the professional organizations within the fragrance industry including Board<br />
member, of the Fragrance Materials Association and Chairman, of the Fragrance Materials Association Scientific<br />
Affairs Committee; the Flavor and Fragrance High Production Volume Chemicals Consortium; the Flavor Extract<br />
Manufacturers Association International Regulatory Affairs Committee; and the International Fragrance Association<br />
Scientific Committee. He is a Delegate of the U.S. Flavor Industry to the International Organization of Flavor<br />
Industries Technical Experts Committee and is also a Member of the International Fragrance Association<br />
Communications Working Group, the Joint Fragrance Materials Association/Flavor Extract Manufacturers<br />
Association Environmental Subcommittee and the Joint CTFA/FMA SAC Liaison Committee<br />
Dr. Troy has authored a number of publications on the fragrance industry, its operation and the safety evaluation of<br />
fragrance materials.
MMDHA: ASSAYS OF DERMAL ABSORPTION AND<br />
SYSTEMIC & DEVELOPMENTAL TOXICITY<br />
Adrianne E. Rogers, M.D.<br />
Boston University School of Medicine<br />
ABSTRACT<br />
MMDHCA is a commercially available fragrance ingredient. World-wide annual use is greater than100<br />
metric tons. Human exposure occurs primarily via the skin. Maximum average dermal exposure<br />
(hydroalcoholics) is 2.9%. Systemic exposure is calculated to be 0.12 mg/kg/day. Three studies have been<br />
per<strong>for</strong>med by <strong>RIFM</strong>. In vitro skin absorption studies showed that 42% of the applied dose was absorbed<br />
at 24 hours and 50% at 48 hours. In a 13-week study in rats of MMDHA toxicity by dermal application<br />
(150-600 mg/kg/day), there was no mortality or effect on body weight, feed consumption, organ weights<br />
or gross appearance, sperm counts and morphology or estrous cycles in any group. The skin showed<br />
erythema, edema, desquamation, atonia, fissuring, erosion, ulceration, hyperkeratinization and<br />
inflammation in all groups, with severity related to dose. The changes resolved after 4 weeks except <strong>for</strong><br />
slight dermal fibrosis. The NOAEL and NOEL were 0.05 g/kg/day based on toxicity in the skin<br />
(inflammation, erosion). The NOEL was greater than 0.3 g/kg based on systemic toxicity. In a study in<br />
rats of MMDHA maternal & developmental toxicity, the maternal NOAEL was 125 mg/kg/day, and the<br />
developmental NOAEL was greater than 250 mg/kg/day.
DERMAL ABSORPTION AND SUBCHRONIC TOXICITY<br />
OF Α-METHYL-1,3-BENZODIOXOLE-5-<br />
PROPIONALDEHYDE<br />
ANNE MARIE API, AURELIA LAPCZYNSKI, DANIEL A. ISOLA<br />
AND I. GLENN SIPES<br />
ORAL (GAVAGE) DEVELOPMENTAL TOXICITY STUDY OF<br />
αMETHYL-3,4-METHYLENE-DIOXYHYDROXINNAMIC ALDEHYDE IN RATS<br />
CHARLES RIVER LABORATORY, ARGUS DIVISION<br />
FINAL REPORT<br />
FEBRUARY <strong>18</strong>, <strong>2005</strong><br />
1
O<br />
O<br />
O<br />
Figure 1. Structure of α-Methyl-1,3-benzodioxole-5-propionaldehyde (MMDHCA)<br />
2
MMDHCA is a commercially available<br />
fragrance ingredient widely used in fine<br />
fragrances, cosmetics, household<br />
cleaners, and detergents. World-wide<br />
annual use is >100 metric tons.<br />
Human exposure occurs primarily via the<br />
skin. Maximum average dermal exposure<br />
(hydroalcoholics) is 2.9%. Systemic<br />
exposure is calculated to be 0.12<br />
mg/kg/day.<br />
3
ORAL LD 50 IN RATS = 3.6 G/KG (CI 3.25 -3.9)<br />
DERMAL LD 50 IN RABBITS = >2 G/KG<br />
IN VIVO IP MOUSE MICRONUCLEUS ASSAYS =<br />
NEGATIVE UP TO 725 MG/KG<br />
AMES ASSAYS = NEGATIVE<br />
IN VITRO CHROMOSOME ABERRATION ASSAY<br />
IN CHO CELLS = POSITIVE<br />
4
Human skin epidermal membrane preparations<br />
(breast or abdomen) mounted in diffusion cells with<br />
stratum corneum facing the donor chamber<br />
Diffusion area approximately 1cm 2<br />
Donor chamber: 20 μl of 1% benzyl - 14 c-mmdhca<br />
Reception chamber: 50/50 ethanol/water<br />
Samples 2, 8, 24, 36, 48 hours from receptor chamber<br />
Residual samples: membrane wipes and 10 tape<br />
strips, digested membrane, donor chamber<br />
Evaporative loss at 24, 48 hours<br />
5
24 HOURS: 42% OF APPLIED DOSE<br />
48 HOURS: 50% OF APPLIED DOSE<br />
RESIDUAL SAMPLES: 17%<br />
EVAPORATIVE LOSS: 19%<br />
RECOVERY: 86% OF APPLIED DOSE<br />
6
90<br />
80<br />
70<br />
% Applied Dose<br />
60<br />
50<br />
40<br />
30<br />
20<br />
10<br />
0<br />
2 8 24 36 48<br />
Time (hours)<br />
Receptor phase Remaining epidermis Evaporative loss<br />
Surface wipe Tape strips Donor chamber<br />
Figure 2. Percutaneous absorption of MMDHCA following application to<br />
human skin. 14 C-MMDHCA was applied to human skin epidermal membranes<br />
and its penetration into the receptor phase was determined over time. Results<br />
are presented as the percent of applied dose.<br />
7
Dose range finding study<br />
Crl: (sd) rats, 5/sex/dose<br />
MMDHCA, 96.8% pure applied neat to intact clipped dorsal skin,<br />
0, 0.3, 0.6, 1.0 g/kg/day x 17 days<br />
13-week study, 15 rats/sex/dose<br />
0.05, 0.15, 0.3 g/kg/day (0.043-0.259 ml/kg/day or reverse<br />
osmosis water, 0.259 ml/kg/day with semioccusive dressing <strong>for</strong><br />
6-7 hours.<br />
Clinical, laboratory, necropsy observation.<br />
8
Dose range finding study (0.3, 0.6, 1.0 g kg/day)<br />
No mortality or effect on body weight, feed consumption.<br />
SKIN: Erosion, Ulceration, Acanthosis, Hyperkeratosis,<br />
Parakeratosis, Dermal Inflammation: All Doses<br />
LABORATORY: ↑ Neutrophils: All Doses<br />
↑ Eosinophils: M, 0.6 and 1.0 g/kg/day<br />
↓ Albumin: F, 1.0 g/kg/day<br />
↑ Cholesterol: F, 1.0 G/KG/DAY<br />
CONCLUSION: Use 0.05, 0.15, 0.3, g/kg/day <strong>for</strong> 13-week<br />
study<br />
9
―<br />
13 WEEK STUDY<br />
No mortality or effect on body weight, feed consumption, organ<br />
weights or gross appearance, sperm counts and morphology,<br />
estrous cycles in any group<br />
SKIN: Dermal irritation (erythema, edema, desquamation,<br />
atonia, fissuring, erosion, ulceration, hyperkeratinization,<br />
inflammation) in all groups, severity related to dose. Resolved<br />
after 4 weeks except slight dermal fibrosis<br />
LABORATORY: ↑ Neutrophils<br />
↑ Globulin<br />
All Groups<br />
10
Dermal Effect<br />
(Moderate Severity) a<br />
Number of Rats Affected<br />
(N=15/ group)<br />
Erythema<br />
Edema<br />
Atonia<br />
Desquamation<br />
Fissuring<br />
50<br />
1<br />
1<br />
1<br />
-<br />
-<br />
Male Dose<br />
(mg/kg/day)<br />
150<br />
2<br />
1<br />
1 b<br />
-<br />
-<br />
300<br />
4<br />
4<br />
2<br />
4<br />
2<br />
Female dose<br />
Dose (mg/kg/day)<br />
50<br />
4<br />
2<br />
2<br />
3<br />
1<br />
150<br />
3<br />
2<br />
1<br />
1<br />
1<br />
300<br />
5<br />
3<br />
3<br />
4<br />
5 C<br />
a. Animals in all dose groups showed mild effects<br />
b. This animal graded marked<br />
c. One of the 5 graded marked<br />
11
NOEL (13 WEEKS) < 0.05 G/KG/DAY<br />
BASED ON DERMAL TOXICITY<br />
NOEL (13 WKS) > 0.3 G/KG BASED<br />
ON SYSTEMIC TOXICITY<br />
12
―<br />
Pregnant CRL: CD Rats, 25/Group<br />
MMDHCA 62, 125, OR 250 mg/kg/day in corn<br />
oil, 10 ml/kg, or corn oil alone<br />
Gastric Gavage 1/Day, Gestation Days 7-17<br />
Caesarean Sectioning, Examination at Day 21<br />
13
Dosage Period<br />
a. Fetal evaluations (all fetuses: external examination; one-half the<br />
fetuses in each litter, soft tissue or skeletal examinations).<br />
b. Maternal evaluations (body weight, feed intake, clinical appearance,<br />
litter parameters, gross necropsy)<br />
14
15
Maternal weight gain and feed<br />
consumption: ↓ 250 mg/kg/day<br />
Pigment excretion around nose, mouth,<br />
vagina: 250 mg/kg<br />
Fetal Parameters: NO ABNORMALITIES<br />
Maternal NOAEL 125 mg/kg/day<br />
Developmental NOAEL >250 mg/kg/day<br />
16
BIOGRAPHY<br />
Dr. Adrianne E. Rogers<br />
Dr. Adrianne E. Rogers is the Professor & Associate Chair of Pathology and Director of the Office of<br />
Medical Education at Boston University. Her research focuses on breast cancer and the goals of her<br />
Medical Education programs at B.U. are Cancer Prevention and Control Education <strong>for</strong> Medical<br />
Students<br />
Dr. Rogers received her Bachelors degree, magna cum laude, in Biochemistry at Radcliffe College,<br />
Cambridge, Mass., her Doctor of Medicine, cum laude, at Harvard Medical School, Boston, Mass. and<br />
served as a <strong>Research</strong> Fellow in Pathology at the Mallory <strong>Institute</strong> and Harvard Medical School, Boston,<br />
Mass.<br />
She has been a member of the <strong>Research</strong> <strong>Institute</strong> <strong>for</strong> Fragrance Materials; Inc.; Expert Panel, since 1996<br />
and is on the Editorial Boards: J. of Nutritional Biochemistry; Nutrition & Cancer; Toxicology; Natural<br />
Standard (an online EBM-based review of herbals and other alternative therapies)<br />
Dr. Rogers has published numerous articles on her research.
QUANTITATAVE RISK ASSESSMENT FOR SENSITIZING FRAGRANCE MATERIALS<br />
Anne Marie Api, PhD<br />
ABSTRACT<br />
Many of the chemicals in common use today possess, to some degree, the potential to cause contact allergy.<br />
However, the fact that a chemical is a contact allergen does not mean it cannot be <strong>for</strong>mulated into a consumer<br />
product at safe levels. Based on the chemical, cellular and molecular understanding of contact allergy, it is<br />
possible to conduct an exposure-based risk assessment to determine safe levels in consumer products.<br />
Key steps of the risk assessment process are hazard identification, dose-response assessment, exposure<br />
assessment and risk characterization. These key elements have also been applied to induction of skin<br />
sensitization <strong>for</strong> fragrance ingredients. Using the principles of quantitative risk assessment, it is possible to<br />
determine acceptable exposure levels <strong>for</strong> fragrance materials in a variety of consumer products.<br />
No-effect sensitization induction levels (NESILs) <strong>for</strong> induction of sensitization <strong>for</strong> a group of fragrance<br />
allergens, were based on a weight of evidence approach, which considers all data including guinea pig, mice<br />
(LLNA) and human predictive tests. In addition, sensitization assessment factors (SAFs) specific <strong>for</strong> fragrance<br />
materials in the <strong>Research</strong> <strong>Institute</strong> <strong>for</strong> Fragrance Materials, Inc., (<strong>RIFM</strong>) scientific program, were determined<br />
in different product types and supported by scientific data. Exposure data are critical to any risk assessment<br />
and it is important to use the most robust data available as well as published human parameters data.<br />
Consumer exposure through normal product use can be calculated using these data. Using all these<br />
parameters, an acceptable exposure level (AEL) can be calculated and compared with the consumer exposure<br />
level (CEL). The ratio of the AEL to CEL must be favorable to support the safe use of the contact allergen.<br />
An example will be presented using the fragrance ingredient, cinnamic aldehyde, in three consumer product<br />
types (hydroalcoholic used on unshaved skin, deodorant/antiperspirant and shampoo). This new approach will<br />
be used by the International Fragrance Association (IFRA) as the basis to establish limits <strong>for</strong> Standards on<br />
sensitizing fragrance materials. Since the current IFRA Standards are limited to only two product categories<br />
(skin contact and non-skin contact products), this would be a significant enhancement to a more well-defined<br />
basis <strong>for</strong> such limits.
QUANTITATIVE RISK<br />
ASSESSMENT (QRA) FOR<br />
SENSITIZING FRAGRANCE<br />
MATERIALS<br />
Anne Marie Api, Ph.D.<br />
Scientific Director<br />
<strong>RIFM</strong> <strong>INFOX</strong><br />
MAY <strong>18</strong>, <strong>2005</strong><br />
AM API <strong>RIFM</strong> <strong>INFOX</strong> MAY <strong>2005</strong><br />
1
DERMAL SENSITIZATION OF FMs<br />
Current Practice<br />
Based on qualitative<br />
scientific principles<br />
TWO Product Categories<br />
‣ Skin Contact = NOEL/10<br />
‣ Non-Skin Contact = NOEL<br />
QRA Approach<br />
Based on general<br />
(quantitative) exposure-<br />
based RA<br />
Weight of Evidence<br />
approach to NESIL setting<br />
Limits <strong>for</strong> different<br />
product categories<br />
‣ Some more restrictive<br />
than be<strong>for</strong>e<br />
‣ Some less restrictive<br />
than be<strong>for</strong>e<br />
AM API <strong>RIFM</strong> <strong>INFOX</strong> MAY <strong>2005</strong><br />
2
PRIMARY VS. SECONDARY<br />
PREVENTION<br />
Prevention<br />
Primary Prevent<br />
Secondary<br />
Prevent ion<br />
• Induction<br />
• Acquire<br />
Sensitization<br />
• Premise of <strong>RIFM</strong><br />
testing and the<br />
basis <strong>for</strong> IFRA<br />
Standards on<br />
sensitization<br />
• Elicitation<br />
• Manifestation<br />
Sensitization in<br />
patients with allergic<br />
contact dermatitis<br />
• Concern from<br />
dermatologists<br />
AM API <strong>RIFM</strong> <strong>INFOX</strong> MAY <strong>2005</strong><br />
3
Contact Dermatitis, 2001, 45, 333-340<br />
Understanding fragrance<br />
allergy using an exposure-based<br />
risk assessment approach<br />
G. FRANK GERBERICK,<br />
MICHAEL K. ROBINSON,<br />
SUSAN P. FELTER, IAN R. WHITE<br />
AND DAVID A. BASKETTER<br />
Based on induction of sensitization<br />
AM API <strong>RIFM</strong> <strong>INFOX</strong> MAY <strong>2005</strong><br />
4
EXPOSURE-BASED<br />
RISK ASSESSMENT<br />
Apply the general principles,<br />
used in general (systemic)<br />
toxicology, to dermal<br />
sensitization<br />
AM API <strong>RIFM</strong> <strong>INFOX</strong> MAY <strong>2005</strong><br />
5
RISK ASSESSMENT PROCESS<br />
• Hazard identification<br />
Inherent ability of a material to cause an effect<br />
• Dose-response assessment<br />
Addresses the derivation of a NOEL<br />
Establishes the relationship between the level<br />
of exposure and probability that an adverse<br />
event will occur<br />
• Exposure assessment<br />
Uses habits and practices data and established<br />
human parameters data<br />
• Risk Characterization<br />
Where identified hazard is placed in the<br />
contact of the human experience<br />
AM API <strong>RIFM</strong> <strong>INFOX</strong> MAY <strong>2005</strong><br />
6
QRA FOR DERMAL SENSITIZATION<br />
Application to induction of skin sensitization - also<br />
a threshold phenomenon<br />
• Determine potential (hazard) to induce sensitization<br />
<br />
<br />
<br />
Pre-clinical studies e.g. Guinea-Pig Test, Local Lymph Node<br />
Assay (LLNA)<br />
Human data (historical)<br />
Structure based predictive approach<br />
• Dose Response<br />
<br />
<br />
<br />
Determine the No-Expected<br />
Expected-Sensitization Induction-Level<br />
(NESIL) based on the Weight of Evidence (WoE)<br />
Dose metrics: expressed in Dose/Area<br />
Calculate Sensitization Assessment Factor (SAF)<br />
• Exposure<br />
<br />
<br />
Understand consumer exposure in different product<br />
categories<br />
How consumer are exposed to a material in terms of<br />
amount, duration and frequency<br />
• Risk assessment conclusions<br />
AM API <strong>RIFM</strong> <strong>INFOX</strong> MAY <strong>2005</strong><br />
7
INFLUENCE OF AREA EXPOSED<br />
ON SENSITIZATION<br />
62.5μg g DNCB<br />
62.5μg g DNCB<br />
1.8 cm 2 Site<br />
Sensitization Rate<br />
85%<br />
8%<br />
AM API <strong>RIFM</strong> <strong>INFOX</strong> MAY <strong>2005</strong><br />
7.1 cm 2 Site<br />
Reviewed in Contact Dermatitis 1992, 27:281-286<br />
286<br />
8
SENSITIZATION ASSESSMENT<br />
FACTORS<br />
• Inter-individual Variability – genetic<br />
effects, sensitive populations,<br />
inherent barrier function, , age,<br />
gender and race<br />
• Vehicle or Product Matrix Effects –<br />
consideration of vehicle in the<br />
experimental situation to the<br />
product <strong>for</strong>mulation (irritants,<br />
penetration enhancers<br />
• Use Considerations – site of contact,<br />
skin integrity, occlusion<br />
AM API <strong>RIFM</strong> <strong>INFOX</strong> MAY <strong>2005</strong><br />
9
SENSITIZATION ASSESSMENT<br />
FACTORS<br />
Inter-individual Variability<br />
10<br />
1 3<br />
10<br />
Vehicle or Product Matrix Effects<br />
1 3<br />
10<br />
Use Considerations<br />
Felter et al. . 2002 Contact Dermatitis 47: 257-266<br />
266<br />
AM API <strong>RIFM</strong> <strong>INFOX</strong> MAY <strong>2005</strong><br />
10
SENSITIZATION ASSESSMENT<br />
FACTORS<br />
Developed <strong>for</strong> products:<br />
• Intended use<br />
• Foreseeable use<br />
• Accidental exposure (not really<br />
applicable with sensitization)<br />
• NOT product misuse!<br />
• Not an average value, but a<br />
conservative factor<br />
• Determined <strong>for</strong> FMs only<br />
AM API <strong>RIFM</strong> <strong>INFOX</strong> MAY <strong>2005</strong><br />
11
SAF FOR A<br />
DEODORANT/ANTIPERSPIRANT<br />
SAF = 300<br />
Inter-individual susceptibility = 10<br />
Matrix = 3<br />
Matrix <strong>for</strong> the product may have irritating<br />
(active) ingredients or may be designed to<br />
enhance penetration<br />
Use = 10<br />
The area is the underarm 3 ; the skin is<br />
easily irritated 4 , highly follicular 3 and an<br />
area that is shaved 5 . Type of occlusion is<br />
similar to that of the experimental test<br />
conditions 6 .<br />
AM API <strong>RIFM</strong> <strong>INFOX</strong> MAY <strong>2005</strong><br />
12
SOME SAF VALUES<br />
Deodorants/antiperspirants = 300<br />
Eye, Body Lotions, Shaving Creams And<br />
Men’s s Facial Products = 300<br />
Depilatory = 300<br />
Lip Products = 300<br />
Hydroalcoholics Applied To Recently Shaved Skin = 300<br />
Hydroalcoholics Applied To Unshaved Skin = 100<br />
Nail Enamel/polish Remover, Women’s s Facial,<br />
Make-up Remover, Hair Sprays And Styling Aids,<br />
Leave-in Hair Conditioner Products = 100<br />
Rinse Off Products (Shampoo, Body Wash/gels,<br />
Conditioner, Bar Soaps, Face Wash/gel/scrubs,<br />
Bath Gels Etc., ) = 100<br />
Toothpaste, Mouthwash, Denture Adhesive = 300<br />
Non-skin/unintentional Use = 10<br />
AM API <strong>RIFM</strong> <strong>INFOX</strong> MAY <strong>2005</strong><br />
13
EXPOSURE DATA (DOSE/AREA)<br />
Product Type<br />
Deo/AP<br />
Hydroalcoholic, Unshaved<br />
Women’s Facial Cream<br />
Women’s Facial Make-up<br />
Eye Product<br />
Body Cream<br />
Men’s Facial<br />
Hair Sprays<br />
Hair Styling Aids<br />
Shampoo<br />
Body Wash/Gels<br />
SCCNFP<br />
Exposure<br />
mg/cm 2 /day<br />
2.5<br />
5.2*<br />
2.9<br />
ND<br />
0.8<br />
0.3<br />
2.1<br />
1.0<br />
1.0<br />
0.06<br />
0.01<br />
CTFA Exposure<br />
Mean<br />
mg/cm 2 /day<br />
4.0<br />
1.5*<br />
3.7<br />
1.2<br />
In Progress<br />
0.6<br />
0.6<br />
ND<br />
0.1<br />
0.01<br />
95 %ile<br />
mg/cm 2 /day<br />
11.6<br />
2.2*<br />
7.2<br />
3.9<br />
In Progress<br />
1.1<br />
1.8<br />
ND<br />
0.2<br />
0.02<br />
AM API <strong>RIFM</strong> <strong>INFOX</strong> MAY <strong>2005</strong><br />
*Cano & Rich data<br />
14
EXPOSURE DATA (DOSE/AREA)<br />
Product Type<br />
Conditioner, rinse-off<br />
Shaving Cream<br />
Depilatory<br />
Lip Products<br />
Make-up Remover<br />
Nail Care<br />
Bar Soaps<br />
Face Washes, Gels, Scrubs<br />
Bath Gels, Foams, Mousses<br />
Toothpaste<br />
Mouthwash<br />
SCCNFP<br />
Exposure<br />
mg/cm 2 /day<br />
0.1<br />
0.07<br />
0.004<br />
8.3<br />
0.9<br />
1.0<br />
0.06<br />
0.03<br />
0.1<br />
0.1<br />
1.4<br />
Mean<br />
mg/cm 2 /day<br />
In Progress<br />
ND<br />
ND<br />
5.0<br />
ND<br />
ND<br />
ND<br />
In Progress<br />
CTFA Exposure<br />
ND<br />
ND<br />
ND<br />
95 %ile<br />
mg/cm 2 /day<br />
In Progress<br />
ND<br />
ND<br />
<strong>18</strong>.1<br />
ND<br />
ND<br />
ND<br />
In Progress<br />
ND<br />
ND<br />
ND<br />
AM API <strong>RIFM</strong> <strong>INFOX</strong> MAY <strong>2005</strong><br />
15
RISK CHARACTERIZATION<br />
• Calculation of Maximum Acceptable<br />
Exposure Level<br />
Maximum Acceptable<br />
Exposure Level (AEL)<br />
WoE NESIL<br />
=<br />
Sensitization Assessment<br />
Factor (SAF)<br />
• Comparison of Acceptable Exposure<br />
Level (AEL) to calculated Consumer<br />
Exposure Level (CEL)<br />
AEL/CEL >1 to be Acceptable<br />
AM API <strong>RIFM</strong> <strong>INFOX</strong> MAY <strong>2005</strong><br />
16
RISK ASSESSMENT–<br />
SKIN SENSITIZATION<br />
Practical Examples
QRA DERMAL SENSITIZATION<br />
CINNAMIC ALDEHYDE<br />
Weight of Evidence NESIL<br />
•Guinea-pig data – moderate sensitizer<br />
•Local Lymph Node Assay<br />
EC 3 = 280 µg/cm<br />
2<br />
•Human data<br />
HRIPT NOEL = 591 µg/cm<br />
2<br />
•Weight of Evidence NESIL = 590 µg/cm<br />
2<br />
SAF<br />
•Considerations<br />
Inter-individual variability<br />
Product matrix differences<br />
Variations in use patterns<br />
•Hydroalcoholic UF is 100<br />
•Deo/AP UF is 300<br />
•Shampoo UF is 100<br />
Exposure<br />
•Calculation <strong>for</strong> Daily<br />
Exposure to 0.05% CA (IFRA<br />
Standard):<br />
= [Amount of CA in<br />
product x Amount product<br />
applied (mg)]/Surface(<br />
area<br />
exposed (cm 2 )<br />
•Consumer exposure<br />
Hydroalcoholic (unshaved<br />
skin) = 0.05 % x 2.2<br />
mg/cm<br />
2 = 1.1 µg/cm<br />
2<br />
Deo/AP=0.05% x 11.6<br />
mg/cm<br />
2 = 5.8 µg/cm<br />
2<br />
Shampoo = 0.05 % x 0.2<br />
mg/cm<br />
2 = 0.1 µg/cm<br />
2<br />
AM API <strong>RIFM</strong> <strong>INFOX</strong> MAY <strong>2005</strong><br />
<strong>18</strong>
QRA DERMAL SENSITIZATION CINNAMIC<br />
ALDEHYDE IN HYDROALCOHOLICS –<br />
UNSHAVED SKIN INDUCTION<br />
0.05%<br />
1.1 μg/cm<br />
2<br />
CEL<br />
5.5<br />
μg/cm<br />
2<br />
AEL<br />
(1999 1%<br />
22 μg/cm<br />
2 )<br />
550<br />
μg/cm<br />
2<br />
WoE NESIL<br />
AEL/CEL = 5<br />
Acceptable >1<br />
SAF = 100<br />
0.001 0. 01 0.1 1.0 10 100 1000<br />
Cinnamic Aldehyde Level - log μg/cm<br />
2<br />
AM API <strong>RIFM</strong> <strong>INFOX</strong> MAY <strong>2005</strong><br />
19
QRA DERMAL SENSITIZATION CINNAMIC<br />
ALDEHYDE IN DEO/AP - INDUCTION<br />
2.0<br />
μg/cm<br />
2<br />
AEL<br />
0.05%<br />
5.8 μg/cm<br />
2<br />
CEL<br />
590 μg/cm<br />
2<br />
Woe NESIL<br />
SAF = 300<br />
AEL/CEL =0.3<br />
Unacceptable<br />
0.001 0. 01 0.1 1.0 10 100 1000<br />
Cinnamic Aldehyde Level - log μg/cm<br />
2<br />
AM API <strong>RIFM</strong> <strong>INFOX</strong> MAY <strong>2005</strong><br />
20
QRA DERMAL SENSITIZATION CINNAMIC<br />
ALDEHYDE IN SHAMPOOS - INDUCTION<br />
0.05%<br />
0.1 μg/cm<br />
2<br />
CEL<br />
2.0% =<br />
4.0 μg/cm<br />
2<br />
Potential<br />
Consumer<br />
exposure<br />
5.5<br />
μg/cm<br />
2<br />
AEL<br />
550<br />
μg/cm<br />
2<br />
WoE NESIL<br />
AEL/CEL = 55<br />
Acceptable >1<br />
SAF = 100<br />
0.001 0. 01 0.1 1.0 10 100 1000<br />
Cinnamic Aldehyde Level - log μg/cm<br />
2<br />
AM API <strong>RIFM</strong> <strong>INFOX</strong> MAY <strong>2005</strong><br />
21
REFINEMENT RISK ASSESSMENT-<br />
SKIN SENSITIZATION<br />
RA<br />
Clinical<br />
Reports<br />
Risk<br />
Mgmt<br />
AM API <strong>RIFM</strong> <strong>INFOX</strong> MAY <strong>2005</strong><br />
22
BUCKLEY et al., 2000<br />
Br. J. Derm., 142: 279-283<br />
• Cinnamic aldehyde clinical data<br />
1980-1996<br />
1996<br />
25,545 patients<br />
“..striking reduction in the<br />
frequency of sensitivity to CA<br />
(by <strong>18</strong>% yearly; P
FUTURE FOCUS<br />
• Application of the Quantitative Risk<br />
Assessment Model<br />
SCCNFP Requests — Citral, Farnesol,<br />
Phenylacetaldehyde<br />
SCCNFP Requests Outstanding—<br />
HMPCC, Chloroatranol/Atranol<br />
Fragrance Mix II—Coumarin,<br />
α-Amyl<br />
cinnamic aldehyde<br />
Prospectively, new IFRA Standards<br />
Retrospectively, existing IFRA Standards<br />
Compliance with IFRA Standards (REXPAN(<br />
REXPAN)<br />
AM API <strong>RIFM</strong> <strong>INFOX</strong> MAY <strong>2005</strong><br />
24
SUMMARY<br />
QRA SENSITIZATION APPROACH<br />
• Major change from current approach<br />
• Based on quantitative, not<br />
qualitative, scientific principles<br />
• Is an exposure-based risk<br />
assessment<br />
• Uses a Weight of Evidence approach<br />
to NESIL setting<br />
AM API <strong>RIFM</strong> <strong>INFOX</strong> MAY <strong>2005</strong><br />
25
SUMMARY<br />
QRA SENSITIZATION APPROACH<br />
• What is going to be the impact to you<br />
as a user of the Standards?<br />
A potential change in the way you do<br />
internal safety evaluations,<br />
<strong>May</strong> necessitate changes in your<br />
electronic systems <strong>for</strong> managing the<br />
compliance check of <strong>for</strong>mulations.<br />
• Establishes limits <strong>for</strong> as many as 10<br />
product categories (not only 2<br />
product categories)<br />
Some more restrictive than be<strong>for</strong>e<br />
Some less restrictive than be<strong>for</strong>e<br />
AM API <strong>RIFM</strong> <strong>INFOX</strong> MAY <strong>2005</strong><br />
26
BIOGRAPHY<br />
Anne Marie Api, Ph.D.<br />
Anne Marie Api is the Scientific Director of The <strong>Research</strong> <strong>Institute</strong> <strong>for</strong> Fragrance Materials, Inc.<br />
(<strong>RIFM</strong>). <strong>RIFM</strong> is an independent international scientific organization, which tests and evaluates the safety<br />
of fragrance materials. The <strong>Institute</strong> represents more than seventy member companies on a worldwide<br />
basis. Dr. Api is responsible <strong>for</strong> overseeing the planning, conduct and completion of the research and<br />
testing program at <strong>RIFM</strong>.<br />
Dr. Api started with <strong>RIFM</strong> in 1984 as a Scientific Assistant and has progressed through Toxicologist and<br />
then Manager be<strong>for</strong>e her current position. Be<strong>for</strong>e joining <strong>RIFM</strong>, she worked at Unilever <strong>Research</strong> in<br />
Edgewater, NJ where she worked in the safety assurance section.<br />
Dr. Api holds a Bachelor of Science degree in biochemistry from Manhattan College and a Masters of<br />
Science degree in toxicology from St. John's University. Dr. Api earned a Doctor of Philosophy from<br />
Aston University in Birmingham, England.<br />
In April 2004, she was appointed Adjunct Assistant Professor, University of Medicine and Dentistry of<br />
New Jersey, School of Health Related Professions, Departments of Clinical Laboratory Sciences in<br />
Newark, NJ.<br />
Among her professional affiliations, she is a member of the American Chemical Society, American<br />
Contact Dermatitis Society, American Society <strong>for</strong> Photobiology, European Society Contact Dermatitis,<br />
Mid-Atlantic Chapter of the Society of Toxicology, Society of Investigative Dermatology, Society of<br />
Toxicology and the Women in Flavor & Fragrance Commerce (Board of Director 1997-present). She also<br />
is a member of the Dermal Clinical Evaluation Society and served on the DCES Board of Directors from<br />
1991-1997. She has authored over 85 scientific publications and presentations.
<strong>RIFM</strong>'S ELICITATION THRESHOLD STUDY: OBJECTIVES AND DESIGN<br />
Valerie T. Politano, Ph.D.<br />
ABSTRACT<br />
The objective of this study is to determine the threshold <strong>for</strong> elicitation of allergy and<br />
irritation of eugenol using two methods – patch testing and repeated open application. On<br />
hundred eugenol-sensitive subjects will be recruited from approximately ten facilities<br />
distributed in the USA, Europe, and <strong>Japan</strong>. An additional 100 control subjects, with a prior<br />
history of allergic contact dermatitis (or any dermatitis) but without hypersensitivity to<br />
perfumes, eugenol, balsam of Peru and/or fragrance mix, will be recruited from the same<br />
facilities. The method involves two phases, in Phase I will be a patch test and a repeated open<br />
application test (ROAT) started concomitantly. This will be followed by a rest period and then<br />
Phase II, consisting of only a patch test. The endpoints evaluated will be: 1) the number of<br />
applications and amount of test solution used until a visible reaction appeared; 2) the<br />
relationship between exposure time and use concentration in ROAT; 3) the threshold<br />
concentration, determined by the patch testing, defined as the weakest concentration giving at<br />
least a visible reaction (1+) in a nearly continuous line of patch test reactions starting from the<br />
highest test concentration, with the overall threshold concentrations <strong>for</strong> the group reported as<br />
the minimum elicitation threshold <strong>for</strong> 5% and 10% of the population; and 4) determination if<br />
the ROAT influences patch test results in Phase II, is there a boosting effect?
<strong>RIFM</strong>'S ELICITATION THRESHOLD STUDY:<br />
Objectives and Design<br />
Valerie T. Politano, Ph.D.<br />
Human Health Scientist<br />
<strong>Research</strong> <strong>Institute</strong> <strong>for</strong> Fragrance Materials, Inc.<br />
Woodcliff Lake, NJ<br />
<strong>RIFM</strong> <strong>INFOX</strong> – <strong>18</strong> <strong>May</strong> <strong>2005</strong> – <strong>Tokyo</strong>, <strong>Japan</strong>
OBJECTIVE<br />
To determine the threshold <strong>for</strong><br />
elicitation of allergy and<br />
irritation of eugenol using two<br />
methods<br />
Patch testing<br />
Repeated open application<br />
testing (ROAT)<br />
2
TEST MATERIAL- EUGENOL<br />
CAS<br />
Number<br />
Worldwide Volume of<br />
Use (2000)<br />
Metric Tons<br />
Average Maximum<br />
Skin Level in<br />
Hydroalcoholics<br />
Dermal Systemic<br />
Exposure in Cosmetic<br />
Products<br />
97-53-0 100-1000 2.54% 0.08 (mg/kg/day)<br />
O<br />
OH<br />
3
RECRUITMENT<br />
Pilot study- one test site, 5-10<br />
eugenol-sensitive subjects<br />
Confirm appropriateness of the<br />
concentrations selected<br />
Subjects recruited from<br />
approximately 10 study sites<br />
distributed in the United States,<br />
Europe, and <strong>Japan</strong><br />
USA sites recommended by<br />
ASCD/NACDG<br />
Europe sites recommended by ESCD<br />
<strong>Japan</strong> sites recommended by <strong>Japan</strong><br />
Society of Contact Dermatitis<br />
4
SUBJECTS- INCLUSION CRITERIA<br />
100 Test subjects<br />
Eugenol-sensitive<br />
Positive (≥1) patch test reaction to<br />
1% or 2% eugenol in petrolatum<br />
within past 5 years<br />
100 Control subjects<br />
History of allergic contact dermatitis<br />
No hypersensitivity to eugenol,<br />
perfumes, balsam of Peru, and/or<br />
fragrance mix<br />
5
SUBJECTS- EXCLUSION CRITERIA<br />
Less than <strong>18</strong> years old<br />
Women who are pregnant, actively planning<br />
a pregnancy, or nursing<br />
Active dermatitis at study sites (arms, back)<br />
and/or over >10% of the body surface area<br />
Use within two weeks prior to start of study<br />
of phototherapy, or oral/topical therapies<br />
known to have an effect on allergic contact<br />
dermatitis<br />
Any significant medical condition(s) known<br />
to compromise immune responsiveness<br />
Inability to provide in<strong>for</strong>med consent, follow<br />
instructions, and return to clinic <strong>for</strong> study<br />
visits<br />
6
EXPERIMENTAL DESIGN<br />
Phase I- 4 weeks<br />
Patch test<br />
ROAT<br />
Rest period- 3 weeks<br />
Phase II- 1 week<br />
Patch test<br />
8 week study, 10 required visits<br />
Two separate investigators<br />
7
EXPERIMENTAL DESIGN<br />
Wk<br />
Monday<br />
Tue<br />
Wednesday<br />
Th<br />
Friday<br />
Sat<br />
Sun<br />
1<br />
PHASE I<br />
-Patch application(Day 0)<br />
-Distribute ROAT samples<br />
-Remove patch(Day 2)<br />
-Patch reading<br />
-Evaluate ROAT sites<br />
-Patch reading(Day 4)<br />
-Evaluate ROAT sites<br />
2<br />
-Patch reading(Day 7)<br />
-Evaluate ROAT sites<br />
-Weigh ROAT samples<br />
-Distribute ROAT samples<br />
3<br />
-Evaluate ROAT sites(Day 14)<br />
-Weigh ROAT samples<br />
-Distribute ROAT samples<br />
4<br />
-Evaluate ROAT sites(Day 21)<br />
-Weigh ROAT samples<br />
REST<br />
5<br />
PERIOD<br />
6<br />
7<br />
8<br />
PHASE II<br />
-Patch application(Day 49)<br />
-Remove Patch(Day 51)<br />
-Patch reading<br />
-Patch reading(Day 53)<br />
9<br />
-Patch reading(Day 56)<br />
8
PATCH TEST<br />
8 mm Finn Chambers ® on Scanpor ®<br />
tape<br />
15 μl of test material, applied<br />
immediately to upper back, patches<br />
removed after 48 hours<br />
Phase I- apply day 0, read day 2, 4, 7<br />
Phase II- apply day 49, read day 51,<br />
53, 56<br />
Applied randomly, investigator<br />
blinded to concentrations<br />
9
20 patches<br />
PATCH TEST<br />
3 Vehicle control patches<br />
3:1 DEP:EtOH, DEP, EtOH<br />
17 Eugenol% patches in 3:1 DEP:EtOH<br />
2.0 0.125 0.008 0.0005<br />
1.32 0.063 0.004 0.00025<br />
1.0 0.031 0.002 0.00012<br />
0.5 0.016 0.001 0.00006<br />
0.25<br />
10
ROAT<br />
Beginning on day 0, applied twice a<br />
day <strong>for</strong> 21 days<br />
2 drops of solution distributed over<br />
a 3x3 cm 2 area on lower arm<br />
Solutions color coded and<br />
randomized, 2 solutions per arm<br />
Investigator blinded, read sites on<br />
days 2, 4, 7, 14, 21, more if needed<br />
11
ROAT<br />
4 solutions<br />
1 Vehicle control<br />
3:1 DEP:EtOH<br />
3 Eugenol% in 3:1 DEP:EtOH<br />
0.5<br />
0.05<br />
0.005<br />
12
ROAT<br />
Subjects supplied with new bottles each<br />
week, used bottles returned and weighed<br />
Subjects keep daily log of applications,<br />
reactions, etc.<br />
Sites evaluated <strong>for</strong> erythema, infiltration,<br />
papules, vesicles, scaling<br />
Subjects continue use until positive reaction<br />
confirmed by investigator or day 21<br />
Clearly visible and indurated erythema in<br />
25% of application site<br />
Stop application of that solution<br />
13
END POINTS<br />
1. Number of applications and amount of test<br />
solution used until a visible reaction appeared<br />
2. Relationship between exposure time and use<br />
concentration in ROAT<br />
3. The threshold concentration will be<br />
determined by the patch testing<br />
<br />
defined as the weakest concentration giving at<br />
least a visible reaction (1+) in a nearly<br />
continuous line of patch test reactions starting<br />
from the highest test concentration<br />
overall threshold concentrations <strong>for</strong> the group<br />
will be reported as the minimum elicitation<br />
threshold <strong>for</strong> 5% and 10% of the population<br />
4. Determine if ROAT influences patch test<br />
results<br />
Is there a boosting effect?<br />
14
BIOGRAPHY<br />
Valerie T. Politano, Ph.D.<br />
Valerie T. Politano, Ph.D, Human Health Scientist, serves as project officer/sponsor to laboratories<br />
conducting studies <strong>for</strong> <strong>RIFM</strong>, including sensitization, reproductive/developmental, and elicitation<br />
threshold studies. Her responsibilities include developing protocols, monitoring studies, evaluating<br />
reports, and writing and/or presenting scientific data to various audiences.<br />
Dr. Politano earned her B.A. in Chemistry from DePauw University, Greencastle, Indiana and her<br />
Ph.D. in Toxicology from Rutgers University, New Brunswick, New Jersey and the University of<br />
Medicine and Dentistry of New Jersey, Newark, New Jersey.<br />
She has authored several publications on estradiol-induced mammary carcinogenesis and also on<br />
enzyme activities.
THE <strong>RIFM</strong> PROGRAM ON FRAGRANCE MATERIALS<br />
IN THE ENVIRONMENT<br />
Daniel T. Salvito, Ph.D.<br />
ABSTRACT<br />
<strong>RIFM</strong> has established a program to comprehensively assess the risks potentially posed by fragrance<br />
materials in various environmental media. The <strong>RIFM</strong> Framework <strong>for</strong>ms the basis <strong>for</strong> this program. In<br />
addition to the testing necessary to refine fragrance material risk assessments, <strong>RIFM</strong> has supported<br />
research to better determine the fate and persistence of fragrance materials in wastewater, soils, and<br />
presently sediments. Components of the <strong>RIFM</strong> environmental program are presented at international<br />
conferences and workshops and published in the peer reviewed literature.
THE <strong>RIFM</strong> PROGRAM<br />
ON FRAGRANCE MATERIALS<br />
IN THE ENVIRONMENT<br />
Daniel Salvito, Ph.D.<br />
Manager – Environmental Program<br />
<strong>Research</strong> <strong>Institute</strong> <strong>for</strong> Fragrance Materials
Fragrance Industry Approach to<br />
Environmental Issues<br />
Risk based approach<br />
‣ Publication of human health and<br />
environmental approach in 4 research papers<br />
Voluntary exposure surveys<br />
‣ Conducted by international trade association<br />
Program transparency<br />
‣ Peer reviewed publications and presentations<br />
at scientific meetings<br />
Establishment of an external advisory panel<br />
Provide scientific advocacy
ENVIRONMENTAL PATHWAYS<br />
Atmosphere<br />
Septic<br />
Sewer<br />
TREATMENT<br />
PLANT<br />
SURFACE<br />
WATERS<br />
SOIL<br />
SEDIMENTS<br />
GROUND<br />
WATER
IFRA Environmental Task Force<br />
Membership<br />
‣ Ron Senna, IFF, Chair<br />
‣ Tom Federle, P&G<br />
‣ Patrick Guiney, SCJ<br />
‣ Pierre Meurice, L’Oreal<br />
‣ Jacques Rudio, Givaudan<br />
‣ Ian Malcomber, Unilever<br />
‣ Colin McIntosh, Firmenich<br />
‣ Gunda Bertram, Symrise<br />
‣ Arielle Gard, Rhodia<br />
In their advisory capacity, the ETF has been<br />
instrumental in the development and<br />
implementation of the Environmental<br />
Framework
Regulatory Activities<br />
EU – 3 rd and 4 th Priority Lists<br />
EU Chemicals Policy – REACH<br />
Environment Canada DSL<br />
OSPAR DIFF Risk Assessments<br />
OSPAR DYNAMEC List<br />
Monitored <strong>for</strong> in Germany,<br />
Netherlands, et al.<br />
USGS<br />
USEPA PPCPs
<strong>RIFM</strong> Framework:<br />
Problem Formulation<br />
The <strong>RIFM</strong>/FEMA Database of Materials<br />
consists of over 2100 chemically defined<br />
organic compounds<br />
Testing all 2100 materials is neither<br />
practical nor cost effective<br />
A screening tool is needed to assess if a<br />
potential <strong>for</strong> environmental risk from these<br />
materials exists and to effectively allocate<br />
resources on higher priority materials
Application To<br />
Fragrance Materials<br />
First Tier: Using only volume of use,<br />
molecular weight, and log Kow,<br />
PEC/PNEC ratios are determined<br />
Second Tier: For all those materials with<br />
PEC/PNEC >1<br />
‣ ECOSAR was used as an alternate QSAR<br />
‣ PEC/PNEC ratio re-determined
Exposure Characterization<br />
Calculate per<br />
capita usage and<br />
wastewater<br />
concentration<br />
Estimate<br />
removal in<br />
treatment<br />
Apply<br />
dilution<br />
factor<br />
Calculate<br />
PEC
Exposure Characterization:<br />
PEC<br />
Model assumptions:<br />
‣ All the fragrance usage volume is<br />
discharged down the drain<br />
‣ No volatilization occurs<br />
‣ Both 1° 1 and 2° 2 treatment occurs<br />
‣ Material removal during treatment is<br />
only the result of sorption (no<br />
biodegradation or biotrans<strong>for</strong>mation)<br />
‣ Minimal dilution (a factor of 3) occurs at<br />
the mixing zone
Ecological Effects<br />
Characterization: PNEC<br />
Assumption: All the fragrance is<br />
considered bioavailable<br />
QSAR Equation (Könemann(<br />
nemann, , 1981):<br />
log 1/LC50 = 0.871 log Kow – 4.8<br />
Assessment Factor of 10 6 used
Data Refinement<br />
PEC<br />
‣ Model allows <strong>for</strong> the use of<br />
biodegradation data<br />
‣ Input of measured WTP or<br />
in-stream<br />
data<br />
PNEC<br />
‣ Use of alternate QSARS<br />
‣ Collection of ecotoxicity data
Initial Framework Results<br />
In the First Tier screening, 73% of the<br />
materials had PEC/PNEC ratios
<strong>Research</strong> Initiatives<br />
Goal: Fill data gaps identified by priority<br />
setting process<br />
Program areas to date<br />
‣ Biotrans<strong>for</strong>mation of poorly degraded<br />
materials (collaboration with P&G)<br />
‣ Fate in the terrestrial compartment<br />
(University of Delaware)
Biotrans<strong>for</strong>mation of<br />
Fragrance Materials (P&G)<br />
Fate in Activated Sludge and in Sewage Effluents<br />
discharged into River Water<br />
‣ AHTN, Acetyl Cedrene, and HHCB<br />
Work at Realistic Concentrations (
Biotrans<strong>for</strong>mation Results<br />
In activated sludge, AHTN, acetyl<br />
cedrene, and HHCB are biotrans<strong>for</strong>med to<br />
lower K ow more polar metabolites<br />
Acetyl cedrene and HHCB also are<br />
biotrans<strong>for</strong>med in river water containing<br />
sewage effluent.<br />
Based upon K ow , metabolites are predicted<br />
to be less toxic and bioaccumulative than<br />
the parent compounds
Terrestrial Fate<br />
Limited understanding of dissipation of<br />
fragrance materials in sludge-amended soils<br />
<strong>Research</strong> conducted to evaluate the fate<br />
processes which control the dissipation of<br />
fragrance materials (FMs(<br />
FMs) ) in soil<br />
Establish property-activity relationships to<br />
predict the fate and concentrations of other<br />
FM compounds in soil
O<br />
O<br />
O<br />
O<br />
O<br />
o<br />
O<br />
Acetyl Cedrene<br />
AH TN<br />
Benzyl<br />
Acetate<br />
p-t-Bucinal<br />
Diphenyl Ether<br />
DPMI<br />
O<br />
OH<br />
O<br />
O<br />
OH<br />
O<br />
O<br />
O<br />
O<br />
Eugenol<br />
Hexyl Salicylate<br />
Hexylcinnamaldehyde<br />
HHCB<br />
Isob ornyl A cetate<br />
OH<br />
O<br />
O<br />
O<br />
O<br />
OH<br />
d-Limonene<br />
Linalool<br />
O<br />
M ethyl Dihydrojasm onate<br />
γ -MethylIonone<br />
Methyl<br />
Salicylate<br />
O<br />
NO 2<br />
O<br />
HO<br />
O 2<br />
N<br />
NO 2<br />
Musk Ketone<br />
O 2<br />
N<br />
Musk Xylene<br />
NO 2<br />
OTNE<br />
P henyl Ethyl Alcohol<br />
β-Pinene<br />
OH<br />
Terpineol
Soil Fate Study - Findings<br />
Study has only been able to report on 11 of 22<br />
materials in soil and 9 of 22 in leachate:<br />
‣ AHTN, HHCB, MX, MK, DPMI, OTNE, acetyl<br />
cedrene, diphenyl ether, methyl ionone, hexyl sal,<br />
hexyl cinnamaldehyde in soil (1 st 9 in leachate)<br />
Only 6 are likely to be found in sludge-amended soils<br />
(AHTN, HHCB, musk ketone, musk xylene, acetyl<br />
cedrene, and OTNE).<br />
Leaching (to aquifer) is probably insignificant.<br />
Soil organic matter content greatly influences the<br />
retention of FMs in soil (e.g., AHTN, musk ketone).<br />
Different FMs dissipate at very different rates<br />
and through different mechanisms.
Testing Program<br />
Goal: Publish material risk assessments in<br />
the peer-reviewed reviewed literature and have data<br />
available <strong>for</strong> regulatory inquiries<br />
Materials are risk ranked based on <strong>RIFM</strong><br />
Environmental Framework<br />
Testing per<strong>for</strong>med to refine risk assessments<br />
Materials are further broken down into<br />
structure-activity groups
<strong>2005</strong> Program Review<br />
Testing<br />
‣ Biotrans<strong>for</strong>mation Technology Transfer<br />
<strong>Research</strong><br />
‣ Sediment Fate Program<br />
• Sediments identified as important media<br />
<strong>for</strong> study of high Kow compounds<br />
• University of Delaware developing<br />
program built upon the successes of the<br />
soil fate program<br />
• SC Johnson provided co-funding
Biotrans<strong>for</strong>mation Technology<br />
Transfer<br />
Program supported by Procter&Gamble (T.Federle,<br />
N.Itrich, D.Lee) ) and IFF (M.Fukayama(<br />
M.Fukayama, T.Levorse,<br />
P.Ribeiro, R.Senna, C.Smith,)<br />
HHCB activated sludge and river water die-away<br />
validations complete<br />
OTNE river water die-away underway<br />
Continuous Activated Sludge protocol in<br />
development<br />
‣ HHCB and OTNE materials selected <strong>for</strong> study<br />
HPLC measurement of log Kow of metabolites<br />
added to program
FMs and Sediments<br />
In Europe and the US nitromusk and polycyclic<br />
musks have been measured in freshwater and<br />
estuarine sediments<br />
Analytical and fate program at University of<br />
Delaware complemented by ecotoxicology<br />
studies underway at Roskilde University in<br />
Denmark<br />
Ecotoxicology studies are developing methods<br />
and measuring effects in sediment dwellers<br />
(poster in preparation <strong>for</strong> SETAC Europe)
Sediment Fate Study<br />
Removal, Biological Exposure, and Uptake of<br />
Fragrance Materials in Soil and Sediment<br />
Objectives<br />
‣ To determine the importance of sorption to<br />
sediment as a removal mechanism <strong>for</strong> FMs in<br />
streams<br />
‣ To determine dissipation rates of FMs in streams<br />
and sediments and and their steady-state<br />
state<br />
concentrations<br />
1st year of study to focus on analytical method<br />
development, material selection and overall<br />
study design
PBT Activities<br />
IFRA In<strong>for</strong>mation Letter<br />
EFFA comments on EU Chemicals Policy<br />
Response to on-going questions from<br />
Environment Canada<br />
Database Assessment<br />
PBT Training<br />
ECETOC Task Force
USEPA’s PBT Profiler<br />
Assessment Tool<br />
PBT Training (with Christen Sachse-Vasquez)<br />
‣ The Hazard Assessment of Fragrance<br />
Materials Using the USEPA’s PBT Profiler<br />
‣ US Session – 19 July/European Session 29<br />
September (2004)<br />
‣ <strong>Japan</strong>ese Session – <strong>18</strong> April <strong>2005</strong><br />
‣ Other sessions held at individual member<br />
locations in US and Europe
ECETOC Task Force<br />
ECB request to examine how risk assessment<br />
applies to PBTs and vPvBs<br />
Lead on “Effects” chapter<br />
‣ Food chain effects/secondary poisoning<br />
considered important endpoint <strong>for</strong> PBTs and<br />
vPvBs<br />
‣ Long-term studies thought necessary <strong>for</strong><br />
verified PBTs and vPvBs
STEP Workshop<br />
Joint TNO/Wildlife International Workshop<br />
at the request of RIVM<br />
<strong>RIFM</strong> co-sponsorship<br />
For potential input into REACH<br />
development<br />
EU, US, and Canadian regulators attending<br />
<strong>RIFM</strong> participating on advisory board and<br />
co-chair chair <strong>for</strong> metabolites session<br />
Final report in preparation
PBT Program<br />
PBT list refined<br />
‣ PBT Profiler output <strong>for</strong>ms the basis<br />
‣ Include international criteria<br />
‣ Reviewing database <strong>for</strong> P,B, and T data<br />
• Data Gap Analysis to prepare <strong>for</strong> REACH<br />
requested by IFRA ETF<br />
‣ Establish scope of PBT issue <strong>for</strong> FMs<br />
Biotrans<strong>for</strong>mtion Technology Transfer (P)<br />
Soil Fate and Sediment Fate Programs (P)<br />
Wildlife International Proposal (B)
Interactions<br />
Environment Canada<br />
UmweltBundesAmt/GREAT<br />
/GREAT-ERER<br />
USGS/NJDEP<br />
USEPA<br />
San Francisco Estuary <strong>Institute</strong><br />
SETAC North American Meeting<br />
SETAC European Meeting
Communications<br />
Provides transparency to the program<br />
Participation in international scientific<br />
conferences<br />
‣ SETAC<br />
‣ ACS Meeting<br />
‣ EAWAG<br />
‣ Gordon <strong>Research</strong> Conference<br />
All research, testing and risk<br />
assessments published in the peer<br />
reviewed literature
Papers and Presentations<br />
Papers<br />
‣ Fragrance materials and their environmental impact:<br />
Salvito, Senna, Vey (published FFJ)<br />
‣ Dissipation of Fragrance Materials in Sludge-Amended<br />
Soils: DiFrancesco, Chiu, Standley, , Allen, Salvito<br />
(published ES&T)<br />
‣ Recent Studies conducted by the <strong>Research</strong> <strong>Institute</strong><br />
<strong>for</strong> Fragrance Materials (<strong>RIFM</strong>) in Support of the<br />
Environmental Risk Assessment Process: Balk,<br />
Salvito, Blok<br />
Presentations<br />
‣ SETAC North American and European Meeting:<br />
Limitations of Commonly Used Ecotoxicity QSARs<br />
Poster<br />
‣ American Chemical Society: Removal Mechanisms<br />
<strong>for</strong> Fragrance Materials in Sludge-Amended Soils
Summary<br />
<strong>RIFM</strong> environmental program provides a<br />
risk based approach to assessing the impact<br />
of fragrance materials to the environment<br />
<strong>Research</strong> and testing are focused on high<br />
priority areas<br />
Program is designed to be transparent to<br />
industry, regulatory authorities, academic<br />
scientists and the public
BIOGRAPHY<br />
Daniel Salvito, Ph.D.<br />
Daniel Salvito is the Manager of the Environmental Program <strong>for</strong> The <strong>Research</strong> <strong>Institute</strong> <strong>for</strong> Fragrance<br />
Materials, Inc. (<strong>RIFM</strong>). <strong>RIFM</strong> is an independent scientific organization, which tests and evaluates the<br />
safety of fragrance materials. The <strong>Institute</strong> represents more than seventy member companies on a<br />
worldwide basis. Dr. Salvito is responsible <strong>for</strong> overseeing the planning, conduct and completion of the<br />
environmental research and testing program at <strong>RIFM</strong>.<br />
Dr. Salvito started with <strong>RIFM</strong> in 1999. Be<strong>for</strong>e joining <strong>RIFM</strong>, he worked at Public Service Electric and<br />
Gas Co., of Newark, NJ where he worked in Environmental Affairs and supervised the corporate<br />
analytical laboratory.<br />
Dr. Salvito holds a Bachelor of Science degree in chemistry from Adelphi University and a Masters of<br />
Science degree in chemistry from the State University of New York at Stony Brook. Dr. Salvito<br />
received his Doctor of Philosophy in environmental science from Rutgers University. His current<br />
research interests include aquatic and terrestrial fate of organic chemicals.<br />
Among his professional affiliations, Dr. Salvito is a member of the American Chemical Society, the<br />
Society of Environmental Toxicology and Chemistry, and the American Association <strong>for</strong> the<br />
Advancement of Science. He has authored over 20 scientific publications and presentations.
RESPIRATORY SAFETY PROGRAM<br />
Daniel Isola<br />
ABSTRACT<br />
Consumer exposure to inhaled fragrances is not well characterized and has raised concerns<br />
about asthma, allergy, neurological and other effects. To address those concerns, <strong>RIFM</strong> instituted its<br />
Respiratory Safety Program in 2000. A series of simulated exposure studies using 3 different surrogate<br />
product <strong>for</strong>ms containing 9 key fragrance materials were planned and conducted. The studies presented<br />
here describe the exposures to the surrogates and were designed to assess consumer exposure to these<br />
products during intended use. The surrogate product <strong>for</strong>ms were a pressurized aerosol air freshener, a<br />
heated oil plug-in air freshener, and a fine fragrance. Each surrogate contained, in addition to<br />
excipients, benzyl acetate (BA), eugenol (EU), hexylcinnamaldehyde (HCA), 1,3,4,6,7,8-hexahydro-<br />
4,6,6,7,8,8-hexamethylcyclopenta-γ-benzopyran (HHCB), hydroxy- citronellal (HO-C), β-ionone (β-I),<br />
d-limonene (d-L), linalool (LL), and methyl dihydrojasmonate (MDJ) - at 0.06% each <strong>for</strong> the aerosol,<br />
8.89% each <strong>for</strong> the plug-in, and 2.2% each <strong>for</strong> the fine fragrance. The materials were chosen based on<br />
volatility, chemical structure, toxicity, and volume of use. Results of the aerosol study indicated the<br />
peak air concentration of total fragrance at the adult breathing height (5 ft.) was 2165 µg/m 3 and 1753<br />
µg/m 3 at the child breathing height (1.5 ft.). The peaks occurred at different times. After 2 hrs, the<br />
concentrations ranged from 105 to 64 µg/m 3 at the adult and child hts, respectively. The Mean<br />
Aerodynamic Diameter (MAD) of the airborne particles was approximately 1.5 µm. Plug-in study<br />
results showed peak total concentration were 557 µg/m 3 at 1 hr. and declined to 78 µg/m 3 after 701 hrs.<br />
NB: These figures were corrected <strong>for</strong> room size. Fine fragrance study results showed peak total<br />
concentrations of 1042 μg/m 3 at 5 min (adult ht.) and 2065 μg/m 3 at 5 min (child ht.). After 5 hrs, at<br />
both breathing hts., the concentrations decreased to
RESPIRATORY SAFETY PROGRAM<br />
Daniel Isola<br />
ABSTRACT<br />
Consumer exposure to inhaled fragrances is not well characterized and has raised concerns<br />
about asthma, allergy, neurological and other effects. To address those concerns, <strong>RIFM</strong> instituted its<br />
Respiratory Safety Program in 2000. A series of simulated exposure studies using 3 different surrogate<br />
product <strong>for</strong>ms containing 9 key fragrance materials were planned and conducted. The studies presented<br />
here describe the exposures to the surrogates and were designed to assess consumer exposure to these<br />
products during intended use. The surrogate product <strong>for</strong>ms were a pressurized aerosol air freshener, a<br />
heated oil plug-in air freshener, and a fine fragrance. Each surrogate contained, in addition to<br />
excipients, benzyl acetate (BA), eugenol (EU), hexylcinnamaldehyde (HCA), 1,3,4,6,7,8-hexahydro-<br />
4,6,6,7,8,8-hexamethylcyclopenta-γ-benzopyran (HHCB), hydroxy- citronellal (HO-C), β-ionone (β-I),<br />
d-limonene (d-L), linalool (LL), and methyl dihydrojasmonate (MDJ) - at 0.06% each <strong>for</strong> the aerosol,<br />
8.89% each <strong>for</strong> the plug-in, and 2.2% each <strong>for</strong> the fine fragrance. The materials were chosen based on<br />
volatility, chemical structure, toxicity, and volume of use. Results of the aerosol study indicated the<br />
peak air concentration of total fragrance at the adult breathing height (5 ft.) was 2165 µg/m 3 and 1753<br />
µg/m 3 at the child breathing height (1.5 ft.). The peaks occurred at different times. After 2 hrs, the<br />
concentrations ranged from 105 to 64 µg/m 3 at the adult and child hts, respectively. The Mean<br />
Aerodynamic Diameter (MAD) of the airborne particles was approximately 1.5 µm. Plug-in study<br />
results showed peak total concentration were 557 µg/m 3 at 1 hr. and declined to 78 µg/m 3 after 701 hrs.<br />
NB: These figures were corrected <strong>for</strong> room size. Fine fragrance study results showed peak total<br />
concentrations of 1042 μg/m 3 at 5 min (adult ht.) and 2065 μg/m 3 at 5 min (child ht.). After 5 hrs, at<br />
both breathing hts., the concentrations decreased to
RESPIRATORY SAFETY PROGRAM<br />
Daniel Isola<br />
ABSTRACT<br />
Consumer exposure to inhaled fragrances is not well characterized and has raised concerns<br />
about asthma, allergy, neurological and other effects. To address those concerns, <strong>RIFM</strong> instituted its<br />
Respiratory Safety Program in 2000. A series of simulated exposure studies using 3 different surrogate<br />
product <strong>for</strong>ms containing 9 key fragrance materials were planned and conducted. The studies presented<br />
here describe the exposures to the surrogates and were designed to assess consumer exposure to these<br />
products during intended use. The surrogate product <strong>for</strong>ms were a pressurized aerosol air freshener, a<br />
heated oil plug-in air freshener, and a fine fragrance. Each surrogate contained, in addition to<br />
excipients, benzyl acetate (BA), eugenol (EU), hexylcinnamaldehyde (HCA), 1,3,4,6,7,8-hexahydro-<br />
4,6,6,7,8,8-hexamethylcyclopenta-γ-benzopyran (HHCB), hydroxy- citronellal (HO-C), β-ionone (β-I),<br />
d-limonene (d-L), linalool (LL), and methyl dihydrojasmonate (MDJ) - at 0.06% each <strong>for</strong> the aerosol,<br />
8.89% each <strong>for</strong> the plug-in, and 2.2% each <strong>for</strong> the fine fragrance. The materials were chosen based on<br />
volatility, chemical structure, toxicity, and volume of use. Results of the aerosol study indicated the<br />
peak air concentration of total fragrance at the adult breathing height (5 ft.) was 2165 µg/m 3 and 1753<br />
µg/m 3 at the child breathing height (1.5 ft.). The peaks occurred at different times. After 2 hrs, the<br />
concentrations ranged from 105 to 64 µg/m 3 at the adult and child hts, respectively. The Mean<br />
Aerodynamic Diameter (MAD) of the airborne particles was approximately 1.5 µm. Plug-in study<br />
results showed peak total concentration were 557 µg/m 3 at 1 hr. and declined to 78 µg/m 3 after 701 hrs.<br />
NB: These figures were corrected <strong>for</strong> room size. Fine fragrance study results showed peak total<br />
concentrations of 1042 μg/m 3 at 5 min (adult ht.) and 2065 μg/m 3 at 5 min (child ht.). After 5 hrs, at<br />
both breathing hts., the concentrations decreased to
RESPIRATORY SAFETY PROGRAM<br />
Daniel Isola<br />
ABSTRACT<br />
Consumer exposure to inhaled fragrances is not well characterized and has raised concerns<br />
about asthma, allergy, neurological and other effects. To address those concerns, <strong>RIFM</strong> instituted its<br />
Respiratory Safety Program in 2000. A series of simulated exposure studies using 3 different surrogate<br />
product <strong>for</strong>ms containing 9 key fragrance materials were planned and conducted. The studies presented<br />
here describe the exposures to the surrogates and were designed to assess consumer exposure to these<br />
products during intended use. The surrogate product <strong>for</strong>ms were a pressurized aerosol air freshener, a<br />
heated oil plug-in air freshener, and a fine fragrance. Each surrogate contained, in addition to<br />
excipients, benzyl acetate (BA), eugenol (EU), hexylcinnamaldehyde (HCA), 1,3,4,6,7,8-hexahydro-<br />
4,6,6,7,8,8-hexamethylcyclopenta-γ-benzopyran (HHCB), hydroxy- citronellal (HO-C), β-ionone (β-I),<br />
d-limonene (d-L), linalool (LL), and methyl dihydrojasmonate (MDJ) - at 0.06% each <strong>for</strong> the aerosol,<br />
8.89% each <strong>for</strong> the plug-in, and 2.2% each <strong>for</strong> the fine fragrance. The materials were chosen based on<br />
volatility, chemical structure, toxicity, and volume of use. Results of the aerosol study indicated the<br />
peak air concentration of total fragrance at the adult breathing height (5 ft.) was 2165 µg/m 3 and 1753<br />
µg/m 3 at the child breathing height (1.5 ft.). The peaks occurred at different times. After 2 hrs, the<br />
concentrations ranged from 105 to 64 µg/m 3 at the adult and child hts, respectively. The Mean<br />
Aerodynamic Diameter (MAD) of the airborne particles was approximately 1.5 µm. Plug-in study<br />
results showed peak total concentration were 557 µg/m 3 at 1 hr. and declined to 78 µg/m 3 after 701 hrs.<br />
NB: These figures were corrected <strong>for</strong> room size. Fine fragrance study results showed peak total<br />
concentrations of 1042 μg/m 3 at 5 min (adult ht.) and 2065 μg/m 3 at 5 min (child ht.). After 5 hrs, at<br />
both breathing hts., the concentrations decreased to
RESPIRATORY SAFETY PROGRAM<br />
Daniel Isola<br />
ABSTRACT<br />
Consumer exposure to inhaled fragrances is not well characterized and has raised concerns<br />
about asthma, allergy, neurological and other effects. To address those concerns, <strong>RIFM</strong> instituted its<br />
Respiratory Safety Program in 2000. A series of simulated exposure studies using 3 different surrogate<br />
product <strong>for</strong>ms containing 9 key fragrance materials were planned and conducted. The studies presented<br />
here describe the exposures to the surrogates and were designed to assess consumer exposure to these<br />
products during intended use. The surrogate product <strong>for</strong>ms were a pressurized aerosol air freshener, a<br />
heated oil plug-in air freshener, and a fine fragrance. Each surrogate contained, in addition to<br />
excipients, benzyl acetate (BA), eugenol (EU), hexylcinnamaldehyde (HCA), 1,3,4,6,7,8-hexahydro-<br />
4,6,6,7,8,8-hexamethylcyclopenta-γ-benzopyran (HHCB), hydroxy- citronellal (HO-C), β-ionone (β-I),<br />
d-limonene (d-L), linalool (LL), and methyl dihydrojasmonate (MDJ) - at 0.06% each <strong>for</strong> the aerosol,<br />
8.89% each <strong>for</strong> the plug-in, and 2.2% each <strong>for</strong> the fine fragrance. The materials were chosen based on<br />
volatility, chemical structure, toxicity, and volume of use. Results of the aerosol study indicated the<br />
peak air concentration of total fragrance at the adult breathing height (5 ft.) was 2165 µg/m 3 and 1753<br />
µg/m 3 at the child breathing height (1.5 ft.). The peaks occurred at different times. After 2 hrs, the<br />
concentrations ranged from 105 to 64 µg/m 3 at the adult and child hts, respectively. The Mean<br />
Aerodynamic Diameter (MAD) of the airborne particles was approximately 1.5 µm. Plug-in study<br />
results showed peak total concentration were 557 µg/m 3 at 1 hr. and declined to 78 µg/m 3 after 701 hrs.<br />
NB: These figures were corrected <strong>for</strong> room size. Fine fragrance study results showed peak total<br />
concentrations of 1042 μg/m 3 at 5 min (adult ht.) and 2065 μg/m 3 at 5 min (child ht.). After 5 hrs, at<br />
both breathing hts., the concentrations decreased to
RESPIRATORY SAFETY PROGRAM<br />
Daniel Isola<br />
ABSTRACT<br />
Consumer exposure to inhaled fragrances is not well characterized and has raised concerns<br />
about asthma, allergy, neurological and other effects. To address those concerns, <strong>RIFM</strong> instituted its<br />
Respiratory Safety Program in 2000. A series of simulated exposure studies using 3 different surrogate<br />
product <strong>for</strong>ms containing 9 key fragrance materials were planned and conducted. The studies presented<br />
here describe the exposures to the surrogates and were designed to assess consumer exposure to these<br />
products during intended use. The surrogate product <strong>for</strong>ms were a pressurized aerosol air freshener, a<br />
heated oil plug-in air freshener, and a fine fragrance. Each surrogate contained, in addition to<br />
excipients, benzyl acetate (BA), eugenol (EU), hexylcinnamaldehyde (HCA), 1,3,4,6,7,8-hexahydro-<br />
4,6,6,7,8,8-hexamethylcyclopenta-γ-benzopyran (HHCB), hydroxy- citronellal (HO-C), β-ionone (β-I),<br />
d-limonene (d-L), linalool (LL), and methyl dihydrojasmonate (MDJ) - at 0.06% each <strong>for</strong> the aerosol,<br />
8.89% each <strong>for</strong> the plug-in, and 2.2% each <strong>for</strong> the fine fragrance. The materials were chosen based on<br />
volatility, chemical structure, toxicity, and volume of use. Results of the aerosol study indicated the<br />
peak air concentration of total fragrance at the adult breathing height (5 ft.) was 2165 µg/m 3 and 1753<br />
µg/m 3 at the child breathing height (1.5 ft.). The peaks occurred at different times. After 2 hrs, the<br />
concentrations ranged from 105 to 64 µg/m 3 at the adult and child hts, respectively. The Mean<br />
Aerodynamic Diameter (MAD) of the airborne particles was approximately 1.5 µm. Plug-in study<br />
results showed peak total concentration were 557 µg/m 3 at 1 hr. and declined to 78 µg/m 3 after 701 hrs.<br />
NB: These figures were corrected <strong>for</strong> room size. Fine fragrance study results showed peak total<br />
concentrations of 1042 μg/m 3 at 5 min (adult ht.) and 2065 μg/m 3 at 5 min (child ht.). After 5 hrs, at<br />
both breathing hts., the concentrations decreased to
ββ<br />
<br />
<br />
<br />
γ
2002 2003 2004<br />
<strong>2005</strong><br />
2Q 3Q 4Q 2Q 3Q 4Q 2Q 3Q 4Q 2Q 3Q 4Q<br />
2006<br />
Aerosol<br />
Plug-In Fine Fragrance
2002 2003 2004<br />
<strong>2005</strong><br />
2Q 3Q 4Q 2Q 3Q 4Q 2Q 3Q 4Q 2Q 3Q 4Q<br />
2006<br />
Aerosol<br />
Plug-In Fine Fragrance
Airborne Fragrance Concentrations (μg/m 3 )<br />
Fragrances<br />
Adult Breathing Zone<br />
Child Breathing Zone<br />
Max Min Max Min<br />
BA 380.5 15.2 241.5 7.8<br />
Eugenol 410.4 7.5 266.6 5.2<br />
HCA 125.1 3.9 192.9 3.1<br />
HHCB 122.6 4.3 201.7 3.0<br />
HO-C 299.3 13.3 250.5 11.4<br />
Ionone 273.9 10.1 196.1 6.3<br />
d-Limonene 396.4 27.9 297.7 15.2<br />
Linalool 414.2 20.0 243.5 10.4<br />
MDJ 127.6 3.4 176.9 3.2
Airborne Fragrance Concentrations (μg/m 3 )<br />
Fragrances<br />
Adult Breathing Zone<br />
Child Breathing Zone<br />
Max Min Max Min<br />
BA 380.5 15.2 241.5 7.8<br />
Eugenol 410.4 7.5 266.6 5.2<br />
HCA 125.1 3.9 192.9 3.1<br />
HHCB 122.6 4.3 201.7 3.0<br />
HO-C 299.3 13.3 250.5 11.4<br />
Ionone 273.9 10.1 196.1 6.3<br />
d-Limonene 396.4 27.9 297.7 15.2<br />
Linalool 414.2 20.0 243.5 10.4<br />
MDJ 127.6 3.4 176.9 3.2
Airborne Fragrance Concentrations (μg/m 3 )<br />
Fragrances<br />
Adult Breathing Zone<br />
Child Breathing Zone<br />
Max Min Max Min<br />
BA 380.5 15.2 241.5 7.8<br />
Eugenol 410.4 7.5 266.6 5.2<br />
HCA 125.1 3.9 192.9 3.1<br />
HHCB 122.6 4.3 201.7 3.0<br />
HO-C 299.3 13.3 250.5 11.4<br />
Ionone 273.9 10.1 196.1 6.3<br />
d-Limonene 396.4 27.9 297.7 15.2<br />
Linalool 414.2 20.0 243.5 10.4<br />
MDJ 127.6 3.4 176.9 3.2
Airborne Fragrance Concentrations (μg/m 3 )<br />
Fragrances<br />
Adult Breathing Zone<br />
Child Breathing Zone<br />
Max Min Max Min<br />
BA 380.5 15.2 241.5 7.8<br />
Eugenol 410.4 7.5 266.6 5.2<br />
HCA 125.1 3.9 192.9 3.1<br />
HHCB 122.6 4.3 201.7 3.0<br />
HO-C 299.3 13.3 250.5 11.4<br />
Ionone 273.9 10.1 196.1 6.3<br />
d-Limonene 396.4 27.9 297.7 15.2<br />
Linalool 414.2 20.0 243.5 10.4<br />
MDJ 127.6 3.4 176.9 3.2
Airborne Concentration at 1.5' Height and 0' Distance<br />
160<br />
Airborne Concentration (ug/m3)<br />
140<br />
120<br />
100<br />
80<br />
60<br />
40<br />
20<br />
0<br />
0 50 100 150 200 250 300 350<br />
Time (min)<br />
D-limonene Linalool Benzyl Acetate HOC Eugenol Ionone MDJ HCA HHCB
Airborne Concentration at 1.5' Height and 0' Distance<br />
160<br />
Airborne Concentration (ug/m3)<br />
140<br />
120<br />
100<br />
80<br />
60<br />
40<br />
20<br />
0<br />
0 50 100 150 200 250 300 350<br />
Time (min)<br />
D-limonene Linalool Benzyl Acetate HOC Eugenol Ionone MDJ HCA HHCB
Chamber: 1759 at 1 hr<br />
Room: 557 at 1 hr<br />
956 at 3 hr<br />
Adult: 2165 at 1 min<br />
Child: 1753 at 6 min<br />
Adult: 1030 at 10 min, 0 ft<br />
1042 at 5 min, 1.5 ft<br />
881 at 10 min, 5 ft<br />
Child: 711 at 5 min, 0 ft<br />
2065 at 5 min, 1.5 ft<br />
681 at 10 min, 5 ft
Chamber: 1759 at 1 hr<br />
Room: 557 at 1 hr<br />
956 at 3 hr<br />
Adult: 2165 at 1 min<br />
Child: 1753 at 6 min<br />
Adult: 1030 at 10 min, 0 ft<br />
1042 at 5 min, 1.5 ft<br />
881 at 10 min, 5 ft<br />
Child: 711 at 5 min, 0 ft<br />
2065 at 5 min, 1.5 ft<br />
681 at 10 min, 5 ft
Allergen<br />
Nose<br />
Rhinitis<br />
Allergic Reaction<br />
Lung<br />
Asthma
Allergen<br />
Nose<br />
Rhinitis<br />
Allergic Reaction<br />
Lung<br />
Asthma
Allergen<br />
Nose<br />
Rhinitis<br />
Allergic Reaction<br />
Lung<br />
Asthma
Allergen<br />
Nose<br />
Rhinitis<br />
Allergic Reaction<br />
Lung<br />
Asthma
Allergen<br />
Nose<br />
Rhinitis<br />
Allergic Reaction<br />
Lung<br />
Asthma
Allergen<br />
Nose<br />
Rhinitis<br />
Allergic Reaction<br />
Lung<br />
Asthma
Allergen<br />
Nose<br />
Rhinitis<br />
Allergic Reaction<br />
Lung<br />
Asthma
BIOGRAPHY<br />
Daniel Isola<br />
Daniel Isola is the Respiratory Safety Program Manager at <strong>RIFM</strong>. His responsibilities include<br />
determining human exposures to inhaled fragrance materials through the use of simulated exposures<br />
based on intended product use. Further responsibilities include the design and conduct of clinical<br />
studies using classical and state of the art biochemical and sensory techniques to assess the potential<br />
physiological and psychological effects of inhaled fragrance materials, determining the respiratory<br />
sensitization potential <strong>for</strong> fragrance materials, and identifying the systemic effects of inhaled fragrance<br />
materials. Previously at <strong>RIFM</strong>, he supported the human health testing program and other programs of<br />
interest and importance to the fragrance industry. His broad career experience includes research in<br />
academia as well as research and health assessments in the pharmaceutical/consumer products industry<br />
(Bristol-Myers) and the petrochemical industry (Texaco)<br />
Mr. Isola earned his graduate degree in Biology from New York University through a joint<br />
program between the Post-Graduate School of Medicine and the Graduate School of Arts and Sciences.<br />
His area of study was industrial/environmental hygiene and toxicology. His thesis research, conducted<br />
at NYU Medical Center, was in inhalation toxicology and carcinogenesis. A second Master's Degree in<br />
Toxicology was acquired from St. John's University in New York City. Additionally, he studied<br />
ecology <strong>for</strong> several years in the Graduate Ecology Program at Fordham University in New York City.<br />
Mr. Isola has authored numerous publications. He interacts with various agencies in the United<br />
States and elsewhere and actively participates and presents at professional meetings and trade<br />
associations.
FRAGRANCE MATERIAL REVIEWS<br />
GROUP SUMMARY DEVELOPMENT<br />
FFIDS<br />
Charlene S. Letizia<br />
ABSTRACT<br />
The safety evaluation review process now includes a Group Summary authored by the Expert Panel,<br />
which is accompanied by individual Fragrance Material Reviews on each fragrance ingredient in the<br />
Group. Both the Group Summary and the Fragrance Materials Reviews will be published together in a<br />
peer-reviewed scientific journal.<br />
The Group Summaries are a toxicologic and dermatologic assessment of the relevant data selected from<br />
the large bibliography of studies and reports on the individual materials in the group. Whereas our<br />
earlier published monographs on fragrance raw materials simply reported the data on individual<br />
materials, the Group Summary encompasses a new <strong>for</strong>mat that includes the Expert Panels conclusions<br />
on the safety of the group under specified conditions of use. Each Fragrance Material Review is a<br />
comprehensive summary of all the toxicological data on an individual ingredient in the group.<br />
<strong>RIFM</strong> also disseminates safety data through our Fragrance and Flavor Ingredient Data Sheets which are<br />
<strong>RIFM</strong>’s version of Material Safety Data Sheets (MSDS).<br />
<strong>RIFM</strong> originally developed Flavor and Fragrance Ingredient Data Sheets in response to the U.S. OSHA<br />
Hazard Communication Standard, which required manufacturers to provide material safety data sheets<br />
(MSDS) to employees. Today, the Flavor and Fragrance Ingredient Data Sheets are prepared to be<br />
internationally compliant. Since 1985 <strong>RIFM</strong> has issued approximately <strong>18</strong>00 Flavor and Fragrance<br />
Ingredient Data Sheets.
FRAGRANCE MATERIAL REVIEWS<br />
GROUP SUMMARY DEVELOPMENT<br />
FFIDS<br />
Charlene Letizia<br />
Project Manager, Technical Writing<br />
<strong>Tokyo</strong> <strong>INFOX</strong><br />
<strong>May</strong> <strong>18</strong>, <strong>2005</strong>
THE <strong>RIFM</strong> DATABASE<br />
<strong>RIFM</strong> has a repository of in<strong>for</strong>mation<br />
on the safety of fragrance raw<br />
ingredients<br />
Data is used to prepare safety<br />
evaluations<br />
Data <strong>for</strong> these evaluations comes<br />
from various sources:<br />
<br />
<br />
<br />
<br />
Studies conducted by <strong>RIFM</strong><br />
Studies conducted by our member<br />
companies<br />
Government studies such as those from<br />
the National Toxicology Program<br />
Published literature<br />
2
SAFETY EVALUATION<br />
RESULTS<br />
How does <strong>RIFM</strong><br />
communicate<br />
the results of<br />
their Safety<br />
Evaluations<br />
Previously<br />
through our<br />
Monographs on<br />
Fragrance Raw<br />
Materials<br />
3
THE PANEL’S S CONCLUSION<br />
Group Summaries are<br />
toxicologic and<br />
dermatologic<br />
assessments<br />
Each Group Summary is<br />
an evaluation of<br />
relevant data<br />
Group Summaries are<br />
authored by the <strong>RIFM</strong><br />
Expert Panel<br />
They contain the Panel’s<br />
conclusion about the<br />
safety of the materials<br />
as fragrance ingredients<br />
4
FRAGRANCE MATERIAL REVIEWS<br />
(FMRs)<br />
Fragrance Material<br />
Reviews (FMRs) are<br />
authored by <strong>RIFM</strong><br />
staff<br />
They are a<br />
comprehensive<br />
summary of all the<br />
toxicological data<br />
Individual<br />
ingredients in the<br />
group<br />
5
MATERIAL SELECTION<br />
How does <strong>RIFM</strong> select which materials to<br />
review first.<br />
Chemically defined fragrance ingredients<br />
were placed into 23 basic structurally related<br />
groups and approximately 150 subgroups<br />
The human health criteria document<br />
prioritizes fragrance materials <strong>for</strong> review<br />
(Ford et al., 2000. Criteria <strong>for</strong> development<br />
of a database <strong>for</strong> safety evaluation of<br />
fragrance ingredients. Regulatory Toxicology<br />
and Pharmacology 31, 166)<br />
It is from this priority list that the groups of<br />
structurally related materials are selected <strong>for</strong><br />
evaluation.<br />
6
MATERIAL GROUPS<br />
These are homologous groups of<br />
structurally related materials<br />
Some degree of consistency of<br />
metabolism and toxicity can be<br />
predicted<br />
Safety issues are considered within<br />
the context of the in<strong>for</strong>mation that<br />
exists <strong>for</strong> the structural group as a<br />
whole<br />
Existing in<strong>for</strong>mation may eliminate<br />
the need to submit each material to<br />
full toxicological testing<br />
7
THE LINALOOL GROUP<br />
Linalool and Linalyl acetate were<br />
among the high priority list of<br />
materials<br />
Group Summary and 11 FMRs<br />
first to be reviewed and<br />
published<br />
Food and Chemical Toxicology<br />
(2003) Volume 41(7), pages 919-<br />
1033.<br />
8
THE CINNAMYL GROUP<br />
Cinnamyl alcohol, Cinnamaldehyde<br />
and Cinnamic acid also among the<br />
high priority materials<br />
<br />
Second group to be reviewed and<br />
was recently published<br />
Food and Chemical Toxicology (<strong>2005</strong>)<br />
Volume 43(6), pages 837-943.<br />
These 3 materials will serve as the<br />
basis <strong>for</strong> the whole cinnamyl group<br />
which contains approximately 60<br />
materials<br />
9
FUTURE GROUPS<br />
Ionones<br />
<br />
<br />
<br />
<br />
Contains 35 materials<br />
Group Summary has been presented to<br />
the Panel<br />
FMRs have been reviewed by the Panel<br />
Targeted <strong>for</strong> submission to Food and<br />
Chemical Toxicology by the end of <strong>2005</strong><br />
Salicylates<br />
<br />
<br />
<br />
<br />
Contains <strong>18</strong> materials<br />
Group Summary is in preparation <strong>for</strong><br />
submission to the Panel<br />
FMRs have been reviewed by the Panel<br />
Targeted <strong>for</strong> submission to Food and<br />
Chemical Toxicology by the end of <strong>2005</strong><br />
10
FUTURE GROUPS<br />
Substituted Cinnamaldehydes<br />
<br />
<br />
<br />
Contains 19 materials<br />
Group Summary is in preparation <strong>for</strong> submission<br />
to the Panel<br />
FMRs have been completed and will be sent to<br />
the Panel <strong>for</strong> their review<br />
Non-Cyclic Terpene Alcohols<br />
<br />
Comprehensive toxicity table submitted to the<br />
Panel<br />
Cyclic Terpene Alcohol Group<br />
<br />
Comprehensive toxicity table submitted to the<br />
Panel<br />
Aryl Alkyl Alcohols<br />
<br />
Comprehensive literature searches are being<br />
conducted<br />
11
NEW GROUPS<br />
Six New Groups have been<br />
selected<br />
Aryl Aldehydes<br />
Alcohol Branched Chain<br />
Ketones Cyclopentanones<br />
Esters Acetates Aryl Alkyl<br />
Esters Acetates Cyclic<br />
Esters Acetates Terpenes Cyclic<br />
12
FFIDS<br />
Another way that <strong>RIFM</strong><br />
disseminates safety data is<br />
through our Flavor and<br />
Fragrance Ingredient Data<br />
Sheets (FFIDS)<br />
FFIDS are the <strong>RIFM</strong> equivalent<br />
of Material Safety Data Sheets<br />
(MSDS)<br />
13
FFIDS DEVELOPMENT<br />
FFIDS originally developed in response to<br />
the OSHA Hazard Communication Standard<br />
(29 CFR 1910.1200) which stated:<br />
Chemical Manufacturers and Importers<br />
Shall Obtain or Develop A Material Safety<br />
Data Sheet <strong>for</strong> Each Hazardous Chemical<br />
They Produce or Import<br />
OSHA began requiring MSDS’s s <strong>for</strong><br />
hazardous materials effective <strong>May</strong> 26, 1986<br />
To insure compliance with the OSHA<br />
Standard, an external regulatory review is<br />
conducted by <strong>RIFM</strong> member companies<br />
technical representatives<br />
Responsible <strong>for</strong> assigning U.S. Health<br />
Hazard Statements according to the OSHA<br />
Hazardous Communication Standard<br />
14
RISK & SAFETY PHRASES<br />
Risk and Safety Phrases were added in<br />
response to Dangerous Substances Directive<br />
European Dangerous Substances Directive<br />
(DSD) 98/24/EC of 7 April 1998 on the<br />
protection of the health and safety of<br />
workers from the risks related to chemical<br />
agents at work (fourteenth individual<br />
Directive within the meaning of Article 16(1)<br />
of Directive 89/391/EEC<br />
Another review is conducted by the<br />
EFFA/IFRA/IOFI Hazard Communication<br />
Working Group<br />
Responsible <strong>for</strong> assigning Risk and Safety<br />
Phrases (R and S Phrases) according to the<br />
Dangerous Substances Directive<br />
15
ISSUING A FFIDS<br />
After the R and S Phrases are<br />
confirmed, the materials are<br />
entered into the EFFA/IFRA/IOFI<br />
Labeling Manual<br />
The FFIDS are issued after each<br />
group makes their <strong>for</strong>mal review<br />
and assigns hazard statements or<br />
R & S phrases and the materials<br />
have been entered into the<br />
Labeling Manual<br />
16
FFIDS CONTINUE<br />
In 1985 <strong>RIFM</strong> initially issued<br />
9 volumes of FFIDS<br />
<strong>RIFM</strong> has continued to issue<br />
updates since September 26,<br />
1986<br />
Approximately <strong>18</strong>00 new or<br />
revised FFIDS have been<br />
issued over the last 20 years<br />
17
FFIDS INFORMATION<br />
In<strong>for</strong>mation in a FFIDS includes:<br />
Chemical identity<br />
Physical properties<br />
Physical hazards<br />
Toxicology data<br />
Occupational exposures<br />
<strong>18</strong>
EUROPEAN<br />
RISK & SAFETY PHRASES<br />
IX. CLASSIFICATION AND LABELING AS<br />
PRESCRIBED IN ANNEX I TO THE<br />
DANGEROUS SUBSTANCES DIRECTIVE<br />
67/548/EEC OR IN ANNEX VI OF THIS<br />
DIRECTIVE AS DETERMINED BY THE<br />
IFRA/IOFI/EFFA WORKGROUP<br />
S61<br />
Avoid release to the<br />
environment. Refer to<br />
special instructions/Safety<br />
data sheets.<br />
R50/53 Very toxic to aquatic<br />
organisms, may cause longterm<br />
adverse effects in the<br />
aquatic environment.<br />
R38<br />
Irritating to skin.<br />
N – Dangerous <strong>for</strong> the<br />
environment<br />
Xi - Irritant<br />
19
TOXICOLOGICAL DATA<br />
V. LABORATORY ANIMAL TOXICOLOGICAL DATA<br />
1. LD50 Data<br />
Oral: The acute oral LD50 in rats was<br />
reported to exceed 5 g/kg, based on<br />
0/2 deaths at that dose (<strong>RIFM</strong>, 1987b).<br />
The acute oral LD50 in rats was<br />
reported to exceed 5 ml/kg, based on<br />
2/10 deaths at that dose (<strong>RIFM</strong>, 1981e).<br />
The acute oral LD50 in rats was<br />
reported to exceed 2 g/kg, based on<br />
0/10 deaths at that dose (<strong>RIFM</strong>, 1991a).<br />
Inhalation: Not Found<br />
Dermal: The acute dermal LD50 in rats<br />
was reported to exceed 5 ml/kg, based<br />
on 0/10 deaths at that dose (<strong>RIFM</strong>,<br />
1981f).<br />
20
U.S. HEALTH HAZARD<br />
STATEMENTS<br />
VIII. STATEMENTS RELEVANT<br />
TO MAKING A HEALTH<br />
HAZARD DETERMINATION<br />
Irritant<br />
Sensitizer<br />
Liquid may be<br />
irritating to skin<br />
and eyes.<br />
Repeated contact<br />
may cause<br />
allergic<br />
dermatitis.<br />
21
<strong>RIFM</strong> MEMBERS BENEFIT<br />
<strong>RIFM</strong> members receive copies of<br />
the Group Summaries and the<br />
Fragrance Material Reviews as<br />
soon as they are published<br />
FFIDS continue to be updated<br />
and are available through e-maile<br />
They are also available on the<br />
<strong>RIFM</strong> database <strong>for</strong> <strong>RIFM</strong><br />
members who subscribe<br />
22
BIOGRAPHY<br />
CHARLENE LETIZIA<br />
Charlene Letizia is a long time staff member of the <strong>Research</strong> <strong>Institute</strong> <strong>for</strong> Fragrance Materials, Inc. She<br />
has been involved in many projects at <strong>RIFM</strong> and has recently been appointed the Project Manager,<br />
Technical Writing. Her group has direct responsibility <strong>for</strong> the FFIDS program and <strong>for</strong> the development,<br />
preparation and publication of Group Summaries and Fragrance Material Reviews<br />
Ms. Letizia earned her bachelor’s degree in Chemistry from Fairleigh Dickinson University in Teaneck,<br />
New Jersey. She has co-authored many of <strong>RIFM</strong>’s monographs and all of the Fragrance Material<br />
Reviews.