RIFM INFOX-Tokyo, Japan-18 May 2005 - Research Institute for ...

COMPREHENSIVE SCIENCE AND ADVOCACY IN THE NEW ORGANIZATION 

Ladd W. Smith, Ph.D. 

ABSTRACT 

For many years, RIFM has formed its scientific program around a core of priority materials, selected by 

chemical structure, production volume, known effects and product use. Annual budgets were prepared to 

include specific projects within testing and research categories. Over the last years, these procedures have 

been acknowledged through publication of criteria documents for both human health and environmental 

effects. Subsequently, all fragrance materials have been placed into chemical groups, as detailed in the Expert 

Panel's publication on its safety evaluation process. Further, the published linalool and related esters Group 

Summary and Fragrance Material Reviews provide the first results of the combination of these processes. 

Currently, 7 additional structural groups are in various stages of completion, beginning with preliminary 

assessment and progressing through data accumulation, RIFM Expert Panel evaluation and conclusion, and 

ending with publication in the peer-reviewed literature. 

Through a series of interactions involving the Board, RIFM staff, industry technical representatives and the 

Expert Panel, a more strategic approach developed a multiple year view and placed research and testing 

projects into functional categories. While designed as a realistic indicator of industry fragrance material safety 

needs, it retains sufficient flexibility to shift priorities over time and among technical areas. It also more 

clearly identifies specific projects within each category, for budgeting purposes and for communication of 

plans and results. 

The respiratory safety project was developed to address questions of individual susceptibility to common 

fragrance materials. Its exposure-oriented approach characterizes typical product applications as related to 

potential biological effects. The fragrance allergy category complements outreach to clinical and research 

dermatologists with projects to develop scientific data on auto-oxidation, epidemiology and elicitation 

threshold. Since methodology research is science's tool development for future use, human health projects 

address alternatives to animal testing and skin absorption prediction, while environmental projects extend 

ongoing soil fate studies to investigate similar degradation and biotransformation processes in sediment and 

marine media. Group criteria document testing provides the basis for safety evaluations through the 

identification of short term and long term hazard endpoints. Use level support testing directly addresses 

material content in product formulations and provides the scientific basis for setting IFRA Standards. 

Scientific data are most useful when collected in a planned manner, evaluated by established criteria and 

delivered to multiple audiences in various formats to be used for understanding and decision-making. To 

accomplish that, the resources of RIFM and IFRA have been combined through a global alliance of the two 

organizations. IFRA will be the umbrella name for the new organization, while RIFM will remain a separate 

legal entity and will retain its scientific independence, as will its Expert Panel. A new position of Director 

General will coordinate efforts through a Joint Executive Committee. All scientific programs will be part of 

the RIFM budget and IFRA advocacy activities will be increased substantially. The goal is to create a stronger 

industry, with a more visible compliance program, and to include more companies and more associations 

worldwide.

COMPREHENSIVE 

SCIENCE AND ADVOCACY 

IN THE NEW 

ORGANIZATION 

Ladd W. Smith, PhD, DABT 

RIFM Information Exchange 

JFFMA – Tokyo 

May 18, 2005

“Sound Science” 

William Hartmann 

“In ideal science, the glory goes not 

to the person who wins the argument 

but to the person who brings the best 

data to the table … Scientists, being 

human, do not always meet the ideal, 

but good evidence always beats 

rhetoric in the long run.” 

LWS - INFOX Tokyo, May 18, 2005

NEW ORGANIZATION 

 

• IFRA to be name of “umbrella” 

• Director General (Brussels) to coordinate 

• Joint (International) Executive Committee 

• RIFM (and IFRA) to remain separate legal 

entities 

• All scientific programs within RIFM budget 

• RIFM research and testing budget has 

increased 

• RIFM science and Expert Panel remain 

independent 


FRAGRANCE MATERIAL REVIEW 

 

Peer-reviewed publication, 

IFRA Standard 

Data become part of dossier, database 

Report reviewed by REXPAN, conclusion 

Incorporated into budget 

(group category) 

Study sponsored at 

university or laboratory 

Group evaluation 

or 

material request 

RIFM preliminary 

assessment from 

database 

REXPAN 

determination of 

specific data needs 


RIFM DATABASE 

 

100000 

80000 

60000 

40000 

20000 

0 

2001 2002 2003 2004 

References 39000 41327 43000 47178 

Studies 84549 88569 92800 97745 

Ingredients 4460 4500 4566 


GROUP SUMMARY PROGRESS 

 

Alkyl Aryl Alc. (40) 

Cyl. Terp. Alc. (46) 

Ac. Terp. Alc. (33) 

Salicylates (18) 

Ionones (34) 

Sub. Cinnam. (55) 

Cinnamyl (3) 

Linalool, Est. (11) 

1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 


RIFM PUBLICATIONS 

 

20 

15 

10 

5 

0 

1995 1997 1999 2001 2003 


www.rifm.org 

 

• Research theme 

• Revised look 

• Secure database 

access 

• Growing awareness – 

members and 

non-members are 

submitting questions 

through the web site 

• “White papers” being added as developed 

• Members Only section with technical detail 


TOTAL EXPENSE 

 

$6,000,000 

$5,000,000 

$4,000,000 

$3,000,000 

$2,000,000 

$1,000,000 

$- 

1971 1974 1977 1980 1983 1986 1989 1992 1995 1998 2001 2004 


EXPENSE/TESTING 

 

$6,000,000 

$5,000,000 

$4,000,000 

$3,000,000 

$2,000,000 

$1,000,000 

$- 

1971 1974 1977 1980 1983 1986 1989 1992 1995 1998 2001 2004 


TESTING AS % OF EXPENSE 

 

70% 

60% 

50% 

40% 

30% 

20% 

1981 1984 1987 1990 1993 1996 1999 2002 


RIFM BUDGET 

 

$7,000,000 

$6,000,000 

$5,000,000 

$4,000,000 

2003 

2004 

2005 

$3,000,000 

$2,000,000 

$1,000,000 

$0 

Income 

Operations 

Science 

Research/Testing 


IFRA 2005 SCIENCE 

 

• Consultancy with Dr. Maibach 

• Literature survey project to address the issue of 

the selection criteria of the 26 ‘allergens’ 

• Sponsorship of dermatology conferences, such as 

European SCD or International SCD 

• Support for the IVDK-German dermal database 

• All projects are intended to improve the 

relationship with the dermatological community 

to achieve a system of cooperation instead of 

confrontation in the long term 


IFRA 2005 SCIENCE 

 

• Support GREATER (Geography Referenced regional 

Exposure Assessment Tool for European Rivers) 

• R43 Limonene project with Prof. Karlberg 

Further insight into oxidation of limonene and the 

consequences for classification as a sensitizer – now 

developing adequate analytical methods 

• Shared costs for organizing the data which forms the 

basis for the EFFA/IFRA/IOFI Labeling manual – 

an important tool to ensure a harmonized approach – 

the basis for decisions taken before 2000 needs to be 

reorganized and revised 


2005 RESEARCH & TESTING 

 

Respiratory 

Fragrance Allergy 

Human Methods 

Environ. Methods 

Group Testing 

Use Levels 


COMPREHENSIVE 

 

RESEARCH PLAN 

• Respiratory Safety 

Simulated exposures, clinical study 

UNDERSTAND/MANAGE EXPOSURE 

AND EFFECTS 

• Fragrance Allergy 

Auto-oxidation, elicitation threshold, epidemiology 

REDUCE INCIDENCE OF CLINICAL 

ALLERGY 

• Human Health Methodology 

In vitro sensitization, skin absorption model 

DEVELOP ALTERNATIVE METHODS 


COMPREHENSIVE 

 

RESEARCH PLAN 

• Environmental Methodology 

Soil fate, biotransformation, marine assessments 

PREDICT/MONITOR ENVIRONMENTAL 

FATE 

• Group Testing (criteria documents) 

Human health and environmental endpoints 

EVALUATE GROUPS/INDIVIDUALS 

• Use Level Testing 

Skin sensitization, photoallergy 

SUPPORT SAFE USE 


COMPREHENSIVE 

RESEARCH PLAN ($000) 

2000 

1800 

1600 

1400 

1200 

1000 

800 

Respiratory Safety 

Fragrance Allergy 

Human Health Methods 

Environmental Methods 

Group Testing 

Use Level Testing 

600 

400 

200 

0 

2001 2002 2003 2004 2005 2006 2007 2008 2009 


THE “NEW” IFRA 

Joint Executive Committee 

Director General 

RIFM: 

Science 

Expert Panel 

IFRA: 

Advocacy 

Communication 


GLOBAL ALLIANCE 

 

Stronger industry – Suppliers and Users 

Technical Advocacy 

Visible Compliance Program 

More Regional and National Associations 

More Companies 

“ … the fragrance authority …” 


BIOGRAPHY 

LADD W. SMITH, Ph.D. 

Ladd Smith is trained as a scientist and enjoys the strategic challenges of general technical 

management. Since 1998, he has been president of the Research Institute for Fragrance Materials, Inc., 

an international organization, which evaluates the safety of fragrance ingredients. 

Previously, he was responsible for product stewardship at Occidental Chemical. Prior positions at GE 

Plastics and Dupont involved health care cost containment, regulatory affairs and laboratory research. 

During his career, he has assumed leadership roles on association boards and committees, has helped 

develop graduate and cooperative education programs and has published on subjects including health 

and environmental research, information management and risk assessment. 

Dr. Smith received his doctorate in pharmacology from the Medical College of Virginia, his masters in 

bioengineering from Clemson University and his bachelors in zoology from the University of South 

Florida. He is a diplomate of the American Board of Toxicology and currently serves as the president of 

its Board. He also serves on the Advisory Board of the Center for Alternatives to Animal Testing of the 

Bloomberg School of Public Health at Johns Hopkins University.

THE IFRA SCIENTIFIC COMMITTEE AND 

ITS ROLE IN THE FRAGRANCE INDUSTRY 

William R. Troy, Ph.D. 

ABSTRACT 

The IFRA Scientific Committee is charged by the Board of IFRA with assuring the safe use of 

fragrances by the membership and by the user community. To achieve this objective, a group of 

technical experts, chosen for their differing spheres of expertise, meet three times per year to 

address issues pertaining to fragrance safety. There is a close working relationship with RIFM 

staff, and a formalized interaction with the RIFM Expert Panel (REXPAN) as regards the 

development of IFRA Standards. The IFRA Scientific Committee, and REXPAN—together with 

the staffs of IFRA and RIFM—constitute the “science arm” of the new, global fragrance 

organization.

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THE IFRA SCIENTIFIC COMMITTEE 

AND ITS ROLE IN THE FRAGRANCE 

INDUSTRY 

RIFM INFOX – 18 May 2005 

William Troy, Ph.D. 

Chairman, IFRA 

Scientific Committee

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Mission 

• Mission: To monitor the safety 

evaluation activities of IFRA with the 

objective of assuring the continued safe 

use of fragrances by the membership 

and by the user community 

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Activities 

• To develop and implement procedures as 

necessary to achieve the primary mission 

• To evaluate, communicate and implement 

product safety information 

• To act in concert with RIFM concerning safety 

evaluation and to assist in the implementation 

of recommendations arising from RIFM’s 

activities 

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Activities (cont’d) 

• To document the Standards to be adopted by IFRA 

based on the scientific conclusions of the REXPAN 

• To monitor and publish on a regular basis the usage 

of and exposure to fragrance ingredients within 

specified geographical areas from which priorities for 

evaluating and/or testing raw materials can be 

established 

• To safeguard the uncompromising independence and 

integrity of RIFM, through adherence to a defined 

protocol for operation and communication 

4

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IFRA Scientific Committee 

• Membership limited to 10-12 12 technical 

representatives from fragrance supplier 

companies 

• Areas of expertise represented: 

Toxicology 

Chemistry 

Environmental science 

Perfumery 

Regulatory affairs 

5

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SC Members 

• Toru Asakoshi 

 

T. Hasegawa 

• Gunda Bertram 

 

Symrise 

• Veronique Epstein 

 

Givaudan 

• Robert Fellous 

 

IFF 

• Antoine Gaillard 

 

Givaudan 

• Matsuo Hiroyuki 

 

Takasago 

• John Middleton 

Quest 

• Philippe Racine 

Robertet 

• Kevin Renskers 

Takasago 

• Ken Schrankel 

IFF 

• Bill Troy (Chairman) 

Firmenich 

6

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Association Staff Liaison 

• IFRA 

Matthias Vey 

IFRA Scientific 

Director 

Audrey Martin 

Scientific 

Information 

Specialist 

• RIFM 

Ladd Smith 

RIFM President 

Anne Marie Api 

RIFM Scientific 

Director 

7

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• Meetings held 3X per year 

U.S. 

Europe 

Japan (March 2004) 

• Agenda is such that 2 days required for 

the meeting 

8

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• SC can identify issues for REXPAN to 

address 

• SC gathers information for REXPAN to 

review 

• SC responsible for the IFRA Standards 

process 

• SC responsible for recommending 

changes to the Code 

9

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SC Agenda Topics 

• Non-skin contact restrictions 

Cinnamic aldehyde, Eugenol 

• Classification of complex natural 

materials 

DPD, customers 

Industry impact 

10

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SC Agenda Topics (cont’d) 

• Fragrance material quality 

Hydroperoxides – limonene, linalool 

Atranol/chloroatranol 

– the mosses 

Benzene, toluene, etc., residues 

Polyaromatic hydrocarbons (PAH) in 

wood tar derivatives – cade, , birch 

11

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SC Agenda Topics (cont’d) 

• Interaction of fragrance ingredients 

Additivity? 

Synergism? 

Quenching? 

12

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IFRA Code - Annex 1 

• Annex 1 contains the Safety Standards 

for Fragrance Ingredients 

• “Fragrance ingredients should be used 

only after satisfactory evaluation” 

ref. Human health criteria publication 

• Consideration of skin effects – irritation, 

sensitization, photo effects 

13

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IFRA Code - Annex 1 

• Systemic toxicity relative to exposure 

• Environmental effects 

• Data for ingredient evaluation may 

come from published literature, 

structure-activity review, health and 

safety legislation 

• If inadequate data exists, a testing 

program is constructed 

14

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IFRA Code of Practice & Standards 

38th Amendment was issued March 2004 

Currently: 

• > 100 Standards for fragrance ingredients 

• 36 Standards prohibiting the use of certain 

fragrance ingredients* 

• 50 ingredients are limited for their use in 

fragrance compounds 

• 14 raw materials: special purity criteria 

* plus 24 ‘other materials’ banned due to insufficient data 

15

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Process for the IFRA Standards 

• Basis for the IFRA-Standards is a safety 

evaluation (risk assessment) of the safety 

data for a fragrance ingredients by REXPAN 

(RIFM Expert Panel), an independent panel 

of experts consisting of toxicologists, 

dermatologists and pharmacologists as well 

as an associated group of specialists in 

areas like environmental protection 

• The final decision on the content (impact) of 

the IFRA Standards is solely in the hands of 

REXPAN, not IFRA 

16

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The Future 

• An even closer working relationship for 

IFRA Scientific Committee and RIFM 

scientists/REXPAN 

• Implementation of an advocacy arm of 

IFRA will make maximum use of 

industry science in promoting our 

program 

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ARIGATO GOZAIMASU! 

18

BIOGRAPHY 

William R. Troy, Ph.D. 

Dr. William R. Troy, Vice President, General Manager, Product Safety & Regulatory Affairs, has direct 

responsibility for all aspects of the safety and legislative compliance of flavors, fragrances and aromachemicals for 

Firmenich North America, and indirect responsibility for the same in Latin America and Asia/Pacific. He oversees 

the safety testing and U.S. registration of all new aromachemicals, and is the primary customer contact at Firmenich 

North America for all issues relating to product safety and legislation. 

Dr. Troy began his career with Revlon, in their Research Center, where he undertook a special program that focused 

on the examination of aging in the skin. He gradually progressed into a role in the toxicology group there, where he 

developed an inhalation safety program for testing the company’s aerosol products. After 5 years at Revlon he 

moved on to Avon Products, Research & Development group, as an Inhalation Toxicologist with responsibility for 

design and construction of a state-of-the-art inhalation toxicology laboratory. He held various management positions 

in the Toxicology Department over the next 10 years, eventually assuming responsibility for the Regulatory Affairs 

group as well. In 1985 he moved from Toxicology and Regulatory Affairs to Product Development as Manager of 

Fragrance Products R&D category. In 1987 he became R&D Product Development Director for Fragrance Products, 

with responsibility for development of all new fragrances and fragranced products as well. After 20 years at Avon, 

he accepted his current position at Firmenich. 

Dr. Troy holds undergraduate and graduate degrees in Biology, as well as a Ph.D. in Experimental Pharmacology 

from St. Johns University, Jamaica, New York. 

Dr. Troy holds positions in many of the professional organizations within the fragrance industry including Board 

member, of the Fragrance Materials Association and Chairman, of the Fragrance Materials Association Scientific 

Affairs Committee; the Flavor and Fragrance High Production Volume Chemicals Consortium; the Flavor Extract 

Manufacturers Association International Regulatory Affairs Committee; and the International Fragrance Association 

Scientific Committee. He is a Delegate of the U.S. Flavor Industry to the International Organization of Flavor 

Industries Technical Experts Committee and is also a Member of the International Fragrance Association 

Communications Working Group, the Joint Fragrance Materials Association/Flavor Extract Manufacturers 

Association Environmental Subcommittee and the Joint CTFA/FMA SAC Liaison Committee 

Dr. Troy has authored a number of publications on the fragrance industry, its operation and the safety evaluation of 

fragrance materials.

MMDHA: ASSAYS OF DERMAL ABSORPTION AND 

SYSTEMIC & DEVELOPMENTAL TOXICITY 

Adrianne E. Rogers, M.D. 

Boston University School of Medicine 

ABSTRACT 

MMDHCA is a commercially available fragrance ingredient. World-wide annual use is greater than100 

metric tons. Human exposure occurs primarily via the skin. Maximum average dermal exposure 

(hydroalcoholics) is 2.9%. Systemic exposure is calculated to be 0.12 mg/kg/day. Three studies have been 

performed by RIFM. In vitro skin absorption studies showed that 42% of the applied dose was absorbed 

at 24 hours and 50% at 48 hours. In a 13-week study in rats of MMDHA toxicity by dermal application 

(150-600 mg/kg/day), there was no mortality or effect on body weight, feed consumption, organ weights 

or gross appearance, sperm counts and morphology or estrous cycles in any group. The skin showed 

erythema, edema, desquamation, atonia, fissuring, erosion, ulceration, hyperkeratinization and 

inflammation in all groups, with severity related to dose. The changes resolved after 4 weeks except for 

slight dermal fibrosis. The NOAEL and NOEL were 0.05 g/kg/day based on toxicity in the skin 

(inflammation, erosion). The NOEL was greater than 0.3 g/kg based on systemic toxicity. In a study in 

rats of MMDHA maternal & developmental toxicity, the maternal NOAEL was 125 mg/kg/day, and the 

developmental NOAEL was greater than 250 mg/kg/day.

DERMAL ABSORPTION AND SUBCHRONIC TOXICITY 

OF Α-METHYL-1,3-BENZODIOXOLE-5- 

PROPIONALDEHYDE 

ANNE MARIE API, AURELIA LAPCZYNSKI, DANIEL A. ISOLA 

AND I. GLENN SIPES 

ORAL (GAVAGE) DEVELOPMENTAL TOXICITY STUDY OF 

αMETHYL-3,4-METHYLENE-DIOXYHYDROXINNAMIC ALDEHYDE IN RATS 

CHARLES RIVER LABORATORY, ARGUS DIVISION 

FINAL REPORT 

FEBRUARY 18, 2005 

1

O 

O 

O 

Figure 1. Structure of α-Methyl-1,3-benzodioxole-5-propionaldehyde (MMDHCA) 

2

MMDHCA is a commercially available 

fragrance ingredient widely used in fine 

fragrances, cosmetics, household 

cleaners, and detergents. World-wide 

annual use is >100 metric tons. 

Human exposure occurs primarily via the 

skin. Maximum average dermal exposure 

(hydroalcoholics) is 2.9%. Systemic 

exposure is calculated to be 0.12 

mg/kg/day. 

3

ORAL LD 50 IN RATS = 3.6 G/KG (CI 3.25 -3.9) 

DERMAL LD 50 IN RABBITS = >2 G/KG 

IN VIVO IP MOUSE MICRONUCLEUS ASSAYS = 

NEGATIVE UP TO 725 MG/KG 

AMES ASSAYS = NEGATIVE 

IN VITRO CHROMOSOME ABERRATION ASSAY 

IN CHO CELLS = POSITIVE 

4

Human skin epidermal membrane preparations 

(breast or abdomen) mounted in diffusion cells with 

stratum corneum facing the donor chamber 

Diffusion area approximately 1cm 2 

Donor chamber: 20 μl of 1% benzyl - 14 c-mmdhca 

Reception chamber: 50/50 ethanol/water 

Samples 2, 8, 24, 36, 48 hours from receptor chamber 

Residual samples: membrane wipes and 10 tape 

strips, digested membrane, donor chamber 

Evaporative loss at 24, 48 hours 

5

24 HOURS: 42% OF APPLIED DOSE 

48 HOURS: 50% OF APPLIED DOSE 

RESIDUAL SAMPLES: 17% 

EVAPORATIVE LOSS: 19% 

RECOVERY: 86% OF APPLIED DOSE 

6

90 

80 

70 

% Applied Dose 

60 

50 

40 

30 

20 

10 

0 

2 8 24 36 48 

Time (hours) 

Receptor phase Remaining epidermis Evaporative loss 

Surface wipe Tape strips Donor chamber 

Figure 2. Percutaneous absorption of MMDHCA following application to 

human skin. 14 C-MMDHCA was applied to human skin epidermal membranes 

and its penetration into the receptor phase was determined over time. Results 

are presented as the percent of applied dose. 

7

Dose range finding study 

Crl: (sd) rats, 5/sex/dose 

MMDHCA, 96.8% pure applied neat to intact clipped dorsal skin, 

0, 0.3, 0.6, 1.0 g/kg/day x 17 days 

13-week study, 15 rats/sex/dose 

0.05, 0.15, 0.3 g/kg/day (0.043-0.259 ml/kg/day or reverse 

osmosis water, 0.259 ml/kg/day with semioccusive dressing for 

6-7 hours. 

Clinical, laboratory, necropsy observation. 

8

Dose range finding study (0.3, 0.6, 1.0 g kg/day) 

No mortality or effect on body weight, feed consumption. 

SKIN: Erosion, Ulceration, Acanthosis, Hyperkeratosis, 

Parakeratosis, Dermal Inflammation: All Doses 

LABORATORY: ↑ Neutrophils: All Doses 

↑ Eosinophils: M, 0.6 and 1.0 g/kg/day 

↓ Albumin: F, 1.0 g/kg/day 

↑ Cholesterol: F, 1.0 G/KG/DAY 

CONCLUSION: Use 0.05, 0.15, 0.3, g/kg/day for 13-week 

study 

9

― 

13 WEEK STUDY 

No mortality or effect on body weight, feed consumption, organ 

weights or gross appearance, sperm counts and morphology, 

estrous cycles in any group 

SKIN: Dermal irritation (erythema, edema, desquamation, 

atonia, fissuring, erosion, ulceration, hyperkeratinization, 

inflammation) in all groups, severity related to dose. Resolved 

after 4 weeks except slight dermal fibrosis 

LABORATORY: ↑ Neutrophils 

↑ Globulin 

All Groups 

10

Dermal Effect 

(Moderate Severity) a 

Number of Rats Affected 

(N=15/ group) 

Erythema 

Edema 

Atonia 

Desquamation 

Fissuring 

50 

1 

1 

1 

- 

- 

Male Dose 

(mg/kg/day) 

150 

2 

1 

1 b 

- 

- 

300 

4 

4 

2 

4 

2 

Female dose 

Dose (mg/kg/day) 

50 

4 

2 

2 

3 

1 

150 

3 

2 

1 

1 

1 

300 

5 

3 

3 

4 

5 C 

a. Animals in all dose groups showed mild effects 

b. This animal graded marked 

c. One of the 5 graded marked 

11

NOEL (13 WEEKS) < 0.05 G/KG/DAY 

BASED ON DERMAL TOXICITY 

NOEL (13 WKS) > 0.3 G/KG BASED 

ON SYSTEMIC TOXICITY 

12

― 

Pregnant CRL: CD Rats, 25/Group 

MMDHCA 62, 125, OR 250 mg/kg/day in corn 

oil, 10 ml/kg, or corn oil alone 

Gastric Gavage 1/Day, Gestation Days 7-17 

Caesarean Sectioning, Examination at Day 21 

13

Dosage Period 

a. Fetal evaluations (all fetuses: external examination; one-half the 

fetuses in each litter, soft tissue or skeletal examinations). 

b. Maternal evaluations (body weight, feed intake, clinical appearance, 

litter parameters, gross necropsy) 

14

15

Maternal weight gain and feed 

consumption: ↓ 250 mg/kg/day 

Pigment excretion around nose, mouth, 

vagina: 250 mg/kg 

Fetal Parameters: NO ABNORMALITIES 

Maternal NOAEL 125 mg/kg/day 

Developmental NOAEL >250 mg/kg/day 

16

BIOGRAPHY 

Dr. Adrianne E. Rogers 

Dr. Adrianne E. Rogers is the Professor & Associate Chair of Pathology and Director of the Office of 

Medical Education at Boston University. Her research focuses on breast cancer and the goals of her 

Medical Education programs at B.U. are Cancer Prevention and Control Education for Medical 

Students 

Dr. Rogers received her Bachelors degree, magna cum laude, in Biochemistry at Radcliffe College, 

Cambridge, Mass., her Doctor of Medicine, cum laude, at Harvard Medical School, Boston, Mass. and 

served as a Research Fellow in Pathology at the Mallory Institute and Harvard Medical School, Boston, 

Mass. 

She has been a member of the Research Institute for Fragrance Materials; Inc.; Expert Panel, since 1996 

and is on the Editorial Boards: J. of Nutritional Biochemistry; Nutrition & Cancer; Toxicology; Natural 

Standard (an online EBM-based review of herbals and other alternative therapies) 

Dr. Rogers has published numerous articles on her research.

QUANTITATAVE RISK ASSESSMENT FOR SENSITIZING FRAGRANCE MATERIALS 

Anne Marie Api, PhD 

ABSTRACT 

Many of the chemicals in common use today possess, to some degree, the potential to cause contact allergy. 

However, the fact that a chemical is a contact allergen does not mean it cannot be formulated into a consumer 

product at safe levels. Based on the chemical, cellular and molecular understanding of contact allergy, it is 

possible to conduct an exposure-based risk assessment to determine safe levels in consumer products. 

Key steps of the risk assessment process are hazard identification, dose-response assessment, exposure 

assessment and risk characterization. These key elements have also been applied to induction of skin 

sensitization for fragrance ingredients. Using the principles of quantitative risk assessment, it is possible to 

determine acceptable exposure levels for fragrance materials in a variety of consumer products. 

No-effect sensitization induction levels (NESILs) for induction of sensitization for a group of fragrance 

allergens, were based on a weight of evidence approach, which considers all data including guinea pig, mice 

(LLNA) and human predictive tests. In addition, sensitization assessment factors (SAFs) specific for fragrance 

materials in the Research Institute for Fragrance Materials, Inc., (RIFM) scientific program, were determined 

in different product types and supported by scientific data. Exposure data are critical to any risk assessment 

and it is important to use the most robust data available as well as published human parameters data. 

Consumer exposure through normal product use can be calculated using these data. Using all these 

parameters, an acceptable exposure level (AEL) can be calculated and compared with the consumer exposure 

level (CEL). The ratio of the AEL to CEL must be favorable to support the safe use of the contact allergen. 

An example will be presented using the fragrance ingredient, cinnamic aldehyde, in three consumer product 

types (hydroalcoholic used on unshaved skin, deodorant/antiperspirant and shampoo). This new approach will 

be used by the International Fragrance Association (IFRA) as the basis to establish limits for Standards on 

sensitizing fragrance materials. Since the current IFRA Standards are limited to only two product categories 

(skin contact and non-skin contact products), this would be a significant enhancement to a more well-defined 

basis for such limits.

QUANTITATIVE RISK 

ASSESSMENT (QRA) FOR 

SENSITIZING FRAGRANCE 

MATERIALS 

Anne Marie Api, Ph.D. 

Scientific Director 

RIFM INFOX 

MAY 18, 2005 

AM API RIFM INFOX MAY 2005 

1

DERMAL SENSITIZATION OF FMs 

Current Practice 

Based on qualitative 

scientific principles 

TWO Product Categories 

‣ Skin Contact = NOEL/10 

‣ Non-Skin Contact = NOEL 

QRA Approach 

Based on general 

(quantitative) exposure- 

based RA 

Weight of Evidence 

approach to NESIL setting 

Limits for different 

product categories 

‣ Some more restrictive 

than before 

‣ Some less restrictive 

than before 


2

PRIMARY VS. SECONDARY 

PREVENTION 

Prevention 

Primary Prevent 

Secondary 

Prevent ion 

• Induction 

• Acquire 

Sensitization 

• Premise of RIFM 

testing and the 

basis for IFRA 

Standards on 

sensitization 

• Elicitation 

• Manifestation 

Sensitization in 

patients with allergic 

contact dermatitis 

• Concern from 

dermatologists 


3

Contact Dermatitis, 2001, 45, 333-340 

Understanding fragrance 

allergy using an exposure-based 

risk assessment approach 

G. FRANK GERBERICK, 

MICHAEL K. ROBINSON, 

SUSAN P. FELTER, IAN R. WHITE 

AND DAVID A. BASKETTER 

Based on induction of sensitization 


4

EXPOSURE-BASED 

RISK ASSESSMENT 

Apply the general principles, 

used in general (systemic) 

toxicology, to dermal 

sensitization 


5

RISK ASSESSMENT PROCESS 

• Hazard identification 

Inherent ability of a material to cause an effect 

• Dose-response assessment 

Addresses the derivation of a NOEL 

Establishes the relationship between the level 

of exposure and probability that an adverse 

event will occur 

• Exposure assessment 

Uses habits and practices data and established 

human parameters data 

• Risk Characterization 

Where identified hazard is placed in the 

contact of the human experience 


6

QRA FOR DERMAL SENSITIZATION 

Application to induction of skin sensitization - also 

a threshold phenomenon 

• Determine potential (hazard) to induce sensitization 

 

 

 

Pre-clinical studies e.g. Guinea-Pig Test, Local Lymph Node 

Assay (LLNA) 

Human data (historical) 

Structure based predictive approach 

• Dose Response 

 

 

 

Determine the No-Expected 

Expected-Sensitization Induction-Level 

(NESIL) based on the Weight of Evidence (WoE) 

Dose metrics: expressed in Dose/Area 

Calculate Sensitization Assessment Factor (SAF) 

• Exposure 

 

 

Understand consumer exposure in different product 

categories 

How consumer are exposed to a material in terms of 

amount, duration and frequency 

• Risk assessment conclusions 


7

INFLUENCE OF AREA EXPOSED 

ON SENSITIZATION 

62.5μg g DNCB 

62.5μg g DNCB 

1.8 cm 2 Site 

Sensitization Rate 

85% 

8% 


7.1 cm 2 Site 

Reviewed in Contact Dermatitis 1992, 27:281-286 

286 

8

SENSITIZATION ASSESSMENT 

FACTORS 

• Inter-individual Variability – genetic 

effects, sensitive populations, 

inherent barrier function, , age, 

gender and race 

• Vehicle or Product Matrix Effects – 

consideration of vehicle in the 

experimental situation to the 

product formulation (irritants, 

penetration enhancers 

• Use Considerations – site of contact, 

skin integrity, occlusion 


9


FACTORS 

Inter-individual Variability 

10 

1 3 

10 

Vehicle or Product Matrix Effects 

1 3 

10 

Use Considerations 

Felter et al. . 2002 Contact Dermatitis 47: 257-266 

266 


10


FACTORS 

Developed for products: 

• Intended use 

• Foreseeable use 

• Accidental exposure (not really 

applicable with sensitization) 

• NOT product misuse! 

• Not an average value, but a 

conservative factor 

• Determined for FMs only 


11

SAF FOR A 

DEODORANT/ANTIPERSPIRANT 

SAF = 300 

Inter-individual susceptibility = 10 

Matrix = 3 

Matrix for the product may have irritating 

(active) ingredients or may be designed to 

enhance penetration 

Use = 10 

The area is the underarm 3 ; the skin is 

easily irritated 4 , highly follicular 3 and an 

area that is shaved 5 . Type of occlusion is 

similar to that of the experimental test 

conditions 6 . 


12

SOME SAF VALUES 

Deodorants/antiperspirants = 300 

Eye, Body Lotions, Shaving Creams And 

Men’s s Facial Products = 300 

Depilatory = 300 

Lip Products = 300 

Hydroalcoholics Applied To Recently Shaved Skin = 300 

Hydroalcoholics Applied To Unshaved Skin = 100 

Nail Enamel/polish Remover, Women’s s Facial, 

Make-up Remover, Hair Sprays And Styling Aids, 

Leave-in Hair Conditioner Products = 100 

Rinse Off Products (Shampoo, Body Wash/gels, 

Conditioner, Bar Soaps, Face Wash/gel/scrubs, 

Bath Gels Etc., ) = 100 

Toothpaste, Mouthwash, Denture Adhesive = 300 

Non-skin/unintentional Use = 10 


13

EXPOSURE DATA (DOSE/AREA) 

Product Type 

Deo/AP 

Hydroalcoholic, Unshaved 

Women’s Facial Cream 

Women’s Facial Make-up 

Eye Product 

Body Cream 

Men’s Facial 

Hair Sprays 

Hair Styling Aids 

Shampoo 

Body Wash/Gels 

SCCNFP 

Exposure 

mg/cm 2 /day 

2.5 

5.2* 

2.9 

ND 

0.8 

0.3 

2.1 

1.0 

1.0 

0.06 

0.01 

CTFA Exposure 

Mean 

mg/cm 2 /day 

4.0 

1.5* 

3.7 

1.2 

In Progress 

0.6 

0.6 

ND 

0.1 

0.01 

95 %ile 

mg/cm 2 /day 

11.6 

2.2* 

7.2 

3.9 

In Progress 

1.1 

1.8 

ND 

0.2 

0.02 


*Cano & Rich data 

14

EXPOSURE DATA (DOSE/AREA) 

Product Type 

Conditioner, rinse-off 

Shaving Cream 

Depilatory 

Lip Products 

Make-up Remover 

Nail Care 

Bar Soaps 

Face Washes, Gels, Scrubs 

Bath Gels, Foams, Mousses 

Toothpaste 

Mouthwash 

SCCNFP 

Exposure 

mg/cm 2 /day 

0.1 

0.07 

0.004 

8.3 

0.9 

1.0 

0.06 

0.03 

0.1 

0.1 

1.4 

Mean 

mg/cm 2 /day 

In Progress 

ND 

ND 

5.0 

ND 

ND 

ND 

In Progress 

CTFA Exposure 

ND 

ND 

ND 

95 %ile 

mg/cm 2 /day 

In Progress 

ND 

ND 

18.1 

ND 

ND 

ND 

In Progress 

ND 

ND 

ND 


15

RISK CHARACTERIZATION 

• Calculation of Maximum Acceptable 

Exposure Level 

Maximum Acceptable 

Exposure Level (AEL) 

WoE NESIL 

= 

Sensitization Assessment 

Factor (SAF) 

• Comparison of Acceptable Exposure 

Level (AEL) to calculated Consumer 

Exposure Level (CEL) 

AEL/CEL >1 to be Acceptable 


16

RISK ASSESSMENT– 

SKIN SENSITIZATION 

Practical Examples

QRA DERMAL SENSITIZATION 

CINNAMIC ALDEHYDE 

Weight of Evidence NESIL 

•Guinea-pig data – moderate sensitizer 

•Local Lymph Node Assay 

EC 3 = 280 µg/cm 

2 

•Human data 

HRIPT NOEL = 591 µg/cm 

2 

•Weight of Evidence NESIL = 590 µg/cm 

2 

SAF 

•Considerations 

Inter-individual variability 

Product matrix differences 

Variations in use patterns 

•Hydroalcoholic UF is 100 

•Deo/AP UF is 300 

•Shampoo UF is 100 

Exposure 

•Calculation for Daily 

Exposure to 0.05% CA (IFRA 

Standard): 

= [Amount of CA in 

product x Amount product 

applied (mg)]/Surface( 

area 

exposed (cm 2 ) 

•Consumer exposure 

Hydroalcoholic (unshaved 

skin) = 0.05 % x 2.2 

mg/cm 

2 = 1.1 µg/cm 

2 

Deo/AP=0.05% x 11.6 

mg/cm 

2 = 5.8 µg/cm 

2 

Shampoo = 0.05 % x 0.2 

mg/cm 

2 = 0.1 µg/cm 

2 


18

QRA DERMAL SENSITIZATION CINNAMIC 

ALDEHYDE IN HYDROALCOHOLICS – 

UNSHAVED SKIN INDUCTION 

0.05% 

1.1 μg/cm 

2 

CEL 

5.5 

μg/cm 

2 

AEL 

(1999 1% 

22 μg/cm 

2 ) 

550 

μg/cm 

2 

WoE NESIL 

AEL/CEL = 5 

Acceptable >1 

SAF = 100 

0.001 0. 01 0.1 1.0 10 100 1000 

Cinnamic Aldehyde Level - log μg/cm 

2 


19


ALDEHYDE IN DEO/AP - INDUCTION 

2.0 

μg/cm 

2 

AEL 

0.05% 

5.8 μg/cm 

2 

CEL 

590 μg/cm 

2 

Woe NESIL 

SAF = 300 

AEL/CEL =0.3 

Unacceptable 

0.001 0. 01 0.1 1.0 10 100 1000 


2 


20


ALDEHYDE IN SHAMPOOS - INDUCTION 

0.05% 

0.1 μg/cm 

2 

CEL 

2.0% = 

4.0 μg/cm 

2 

Potential 

Consumer 

exposure 

5.5 

μg/cm 

2 

AEL 

550 

μg/cm 

2 

WoE NESIL 

AEL/CEL = 55 

Acceptable >1 

SAF = 100 

0.001 0. 01 0.1 1.0 10 100 1000 


2 


21

REFINEMENT RISK ASSESSMENT- 

SKIN SENSITIZATION 

RA 

Clinical 

Reports 

Risk 

Mgmt 


22

BUCKLEY et al., 2000 

Br. J. Derm., 142: 279-283 

• Cinnamic aldehyde clinical data 

1980-1996 

1996 

25,545 patients 

“..striking reduction in the 

frequency of sensitivity to CA 

(by 18% yearly; P

FUTURE FOCUS 

• Application of the Quantitative Risk 

Assessment Model 

SCCNFP Requests — Citral, Farnesol, 

Phenylacetaldehyde 

SCCNFP Requests Outstanding— 

HMPCC, Chloroatranol/Atranol 

Fragrance Mix II—Coumarin, 

α-Amyl 

cinnamic aldehyde 

Prospectively, new IFRA Standards 

Retrospectively, existing IFRA Standards 

Compliance with IFRA Standards (REXPAN( 

REXPAN) 


24

SUMMARY 

QRA SENSITIZATION APPROACH 

• Major change from current approach 

• Based on quantitative, not 

qualitative, scientific principles 

• Is an exposure-based risk 

assessment 

• Uses a Weight of Evidence approach 

to NESIL setting 


25

SUMMARY 

QRA SENSITIZATION APPROACH 

• What is going to be the impact to you 

as a user of the Standards? 

A potential change in the way you do 

internal safety evaluations, 

May necessitate changes in your 

electronic systems for managing the 

compliance check of formulations. 

• Establishes limits for as many as 10 

product categories (not only 2 

product categories) 

Some more restrictive than before 

Some less restrictive than before 


26

BIOGRAPHY 

Anne Marie Api, Ph.D. 

Anne Marie Api is the Scientific Director of The Research Institute for Fragrance Materials, Inc. 

(RIFM). RIFM is an independent international scientific organization, which tests and evaluates the safety 

of fragrance materials. The Institute represents more than seventy member companies on a worldwide 

basis. Dr. Api is responsible for overseeing the planning, conduct and completion of the research and 

testing program at RIFM. 

Dr. Api started with RIFM in 1984 as a Scientific Assistant and has progressed through Toxicologist and 

then Manager before her current position. Before joining RIFM, she worked at Unilever Research in 

Edgewater, NJ where she worked in the safety assurance section. 

Dr. Api holds a Bachelor of Science degree in biochemistry from Manhattan College and a Masters of 

Science degree in toxicology from St. John's University. Dr. Api earned a Doctor of Philosophy from 

Aston University in Birmingham, England. 

In April 2004, she was appointed Adjunct Assistant Professor, University of Medicine and Dentistry of 

New Jersey, School of Health Related Professions, Departments of Clinical Laboratory Sciences in 

Newark, NJ. 

Among her professional affiliations, she is a member of the American Chemical Society, American 

Contact Dermatitis Society, American Society for Photobiology, European Society Contact Dermatitis, 

Mid-Atlantic Chapter of the Society of Toxicology, Society of Investigative Dermatology, Society of 

Toxicology and the Women in Flavor & Fragrance Commerce (Board of Director 1997-present). She also 

is a member of the Dermal Clinical Evaluation Society and served on the DCES Board of Directors from 

1991-1997. She has authored over 85 scientific publications and presentations.

RIFM'S ELICITATION THRESHOLD STUDY: OBJECTIVES AND DESIGN 

Valerie T. Politano, Ph.D. 

ABSTRACT 

The objective of this study is to determine the threshold for elicitation of allergy and 

irritation of eugenol using two methods – patch testing and repeated open application. On 

hundred eugenol-sensitive subjects will be recruited from approximately ten facilities 

distributed in the USA, Europe, and Japan. An additional 100 control subjects, with a prior 

history of allergic contact dermatitis (or any dermatitis) but without hypersensitivity to 

perfumes, eugenol, balsam of Peru and/or fragrance mix, will be recruited from the same 

facilities. The method involves two phases, in Phase I will be a patch test and a repeated open 

application test (ROAT) started concomitantly. This will be followed by a rest period and then 

Phase II, consisting of only a patch test. The endpoints evaluated will be: 1) the number of 

applications and amount of test solution used until a visible reaction appeared; 2) the 

relationship between exposure time and use concentration in ROAT; 3) the threshold 

concentration, determined by the patch testing, defined as the weakest concentration giving at 

least a visible reaction (1+) in a nearly continuous line of patch test reactions starting from the 

highest test concentration, with the overall threshold concentrations for the group reported as 

the minimum elicitation threshold for 5% and 10% of the population; and 4) determination if 

the ROAT influences patch test results in Phase II, is there a boosting effect?

RIFM'S ELICITATION THRESHOLD STUDY: 

Objectives and Design 


Human Health Scientist 

Research Institute for Fragrance Materials, Inc. 

Woodcliff Lake, NJ 

RIFM INFOX – 18 May 2005 – Tokyo, Japan

OBJECTIVE 

To determine the threshold for 

elicitation of allergy and 

irritation of eugenol using two 

methods 

Patch testing 

Repeated open application 

testing (ROAT) 

2

TEST MATERIAL- EUGENOL 

CAS 

Number 

Worldwide Volume of 

Use (2000) 

Metric Tons 

Average Maximum 

Skin Level in 

Hydroalcoholics 

Dermal Systemic 

Exposure in Cosmetic 

Products 

97-53-0 100-1000 2.54% 0.08 (mg/kg/day) 

O 

OH 

3

RECRUITMENT 

Pilot study- one test site, 5-10 

eugenol-sensitive subjects 

Confirm appropriateness of the 

concentrations selected 

Subjects recruited from 

approximately 10 study sites 

distributed in the United States, 

Europe, and Japan 

USA sites recommended by 

ASCD/NACDG 

Europe sites recommended by ESCD 

Japan sites recommended by Japan 

Society of Contact Dermatitis 

4

SUBJECTS- INCLUSION CRITERIA 

100 Test subjects 

Eugenol-sensitive 

Positive (≥1) patch test reaction to 

1% or 2% eugenol in petrolatum 

within past 5 years 

100 Control subjects 

History of allergic contact dermatitis 

No hypersensitivity to eugenol, 

perfumes, balsam of Peru, and/or 

fragrance mix 

5

SUBJECTS- EXCLUSION CRITERIA 

Less than 18 years old 

Women who are pregnant, actively planning 

a pregnancy, or nursing 

Active dermatitis at study sites (arms, back) 

and/or over >10% of the body surface area 

Use within two weeks prior to start of study 

of phototherapy, or oral/topical therapies 

known to have an effect on allergic contact 

dermatitis 

Any significant medical condition(s) known 

to compromise immune responsiveness 

Inability to provide informed consent, follow 

instructions, and return to clinic for study 

visits 

6

EXPERIMENTAL DESIGN 

Phase I- 4 weeks 

Patch test 

ROAT 

Rest period- 3 weeks 

Phase II- 1 week 

Patch test 

8 week study, 10 required visits 

Two separate investigators 

7

EXPERIMENTAL DESIGN 

Wk 

Monday 

Tue 

Wednesday 

Th 

Friday 

Sat 

Sun 

1 

PHASE I 

-Patch application(Day 0) 

-Distribute ROAT samples 

-Remove patch(Day 2) 

-Patch reading 

-Evaluate ROAT sites 

-Patch reading(Day 4) 


2 



-Weigh ROAT samples 


3 

-Evaluate ROAT sites(Day 14) 



4 

-Evaluate ROAT sites(Day 21) 


REST 

5 

PERIOD 

6 

7 

8 

PHASE II 

-Patch application(Day 49) 

-Remove Patch(Day 51) 

-Patch reading 


9 


8

PATCH TEST 

8 mm Finn Chambers ® on Scanpor ® 

tape 

15 μl of test material, applied 

immediately to upper back, patches 

removed after 48 hours 

Phase I- apply day 0, read day 2, 4, 7 

Phase II- apply day 49, read day 51, 

53, 56 

Applied randomly, investigator 

blinded to concentrations 

9

20 patches 

PATCH TEST 

3 Vehicle control patches 

3:1 DEP:EtOH, DEP, EtOH 

17 Eugenol% patches in 3:1 DEP:EtOH 

2.0 0.125 0.008 0.0005 

1.32 0.063 0.004 0.00025 

1.0 0.031 0.002 0.00012 

0.5 0.016 0.001 0.00006 

0.25 

10

ROAT 

Beginning on day 0, applied twice a 

day for 21 days 

2 drops of solution distributed over 

a 3x3 cm 2 area on lower arm 

Solutions color coded and 

randomized, 2 solutions per arm 

Investigator blinded, read sites on 

days 2, 4, 7, 14, 21, more if needed 

11

ROAT 

4 solutions 

1 Vehicle control 

3:1 DEP:EtOH 

3 Eugenol% in 3:1 DEP:EtOH 

0.5 

0.05 

0.005 

12

ROAT 

Subjects supplied with new bottles each 

week, used bottles returned and weighed 

Subjects keep daily log of applications, 

reactions, etc. 

Sites evaluated for erythema, infiltration, 

papules, vesicles, scaling 

Subjects continue use until positive reaction 

confirmed by investigator or day 21 

Clearly visible and indurated erythema in 

25% of application site 

Stop application of that solution 

13

END POINTS 

1. Number of applications and amount of test 

solution used until a visible reaction appeared 

2. Relationship between exposure time and use 

concentration in ROAT 

3. The threshold concentration will be 

determined by the patch testing 

 

defined as the weakest concentration giving at 

least a visible reaction (1+) in a nearly 

continuous line of patch test reactions starting 

from the highest test concentration 

overall threshold concentrations for the group 

will be reported as the minimum elicitation 

threshold for 5% and 10% of the population 

4. Determine if ROAT influences patch test 

results 

Is there a boosting effect? 

14

BIOGRAPHY 


Valerie T. Politano, Ph.D, Human Health Scientist, serves as project officer/sponsor to laboratories 

conducting studies for RIFM, including sensitization, reproductive/developmental, and elicitation 

threshold studies. Her responsibilities include developing protocols, monitoring studies, evaluating 

reports, and writing and/or presenting scientific data to various audiences. 

Dr. Politano earned her B.A. in Chemistry from DePauw University, Greencastle, Indiana and her 

Ph.D. in Toxicology from Rutgers University, New Brunswick, New Jersey and the University of 

Medicine and Dentistry of New Jersey, Newark, New Jersey. 

She has authored several publications on estradiol-induced mammary carcinogenesis and also on 

enzyme activities.

THE RIFM PROGRAM ON FRAGRANCE MATERIALS 

IN THE ENVIRONMENT 

Daniel T. Salvito, Ph.D. 

ABSTRACT 

RIFM has established a program to comprehensively assess the risks potentially posed by fragrance 

materials in various environmental media. The RIFM Framework forms the basis for this program. In 

addition to the testing necessary to refine fragrance material risk assessments, RIFM has supported 

research to better determine the fate and persistence of fragrance materials in wastewater, soils, and 

presently sediments. Components of the RIFM environmental program are presented at international 

conferences and workshops and published in the peer reviewed literature.

THE RIFM PROGRAM 

ON FRAGRANCE MATERIALS 

IN THE ENVIRONMENT 

Daniel Salvito, Ph.D. 

Manager – Environmental Program 

Research Institute for Fragrance Materials

Fragrance Industry Approach to 

Environmental Issues 

Risk based approach 

‣ Publication of human health and 

environmental approach in 4 research papers 

Voluntary exposure surveys 

‣ Conducted by international trade association 

Program transparency 

‣ Peer reviewed publications and presentations 

at scientific meetings 

Establishment of an external advisory panel 

Provide scientific advocacy

ENVIRONMENTAL PATHWAYS 

Atmosphere 

Septic 

Sewer 

TREATMENT 

PLANT 

SURFACE 

WATERS 

SOIL 

SEDIMENTS 

GROUND 

WATER

IFRA Environmental Task Force 

Membership 

‣ Ron Senna, IFF, Chair 

‣ Tom Federle, P&G 

‣ Patrick Guiney, SCJ 

‣ Pierre Meurice, L’Oreal 

‣ Jacques Rudio, Givaudan 

‣ Ian Malcomber, Unilever 

‣ Colin McIntosh, Firmenich 

‣ Gunda Bertram, Symrise 

‣ Arielle Gard, Rhodia 

In their advisory capacity, the ETF has been 

instrumental in the development and 

implementation of the Environmental 

Framework

Regulatory Activities 

EU – 3 rd and 4 th Priority Lists 

EU Chemicals Policy – REACH 

Environment Canada DSL 

OSPAR DIFF Risk Assessments 

OSPAR DYNAMEC List 

Monitored for in Germany, 

Netherlands, et al. 

USGS 

USEPA PPCPs

RIFM Framework: 

Problem Formulation 

The RIFM/FEMA Database of Materials 

consists of over 2100 chemically defined 

organic compounds 

Testing all 2100 materials is neither 

practical nor cost effective 

A screening tool is needed to assess if a 

potential for environmental risk from these 

materials exists and to effectively allocate 

resources on higher priority materials

Application To 

Fragrance Materials 

First Tier: Using only volume of use, 

molecular weight, and log Kow, 

PEC/PNEC ratios are determined 

Second Tier: For all those materials with 

PEC/PNEC >1 

‣ ECOSAR was used as an alternate QSAR 

‣ PEC/PNEC ratio re-determined

Exposure Characterization 

Calculate per 

capita usage and 

wastewater 

concentration 

Estimate 

removal in 

treatment 

Apply 

dilution 

factor 

Calculate 

PEC

Exposure Characterization: 

PEC 

Model assumptions: 

‣ All the fragrance usage volume is 

discharged down the drain 

‣ No volatilization occurs 

‣ Both 1° 1 and 2° 2 treatment occurs 

‣ Material removal during treatment is 

only the result of sorption (no 

biodegradation or biotransformation) 

‣ Minimal dilution (a factor of 3) occurs at 

the mixing zone

Ecological Effects 

Characterization: PNEC 

Assumption: All the fragrance is 

considered bioavailable 

QSAR Equation (Könemann( 

nemann, , 1981): 

log 1/LC50 = 0.871 log Kow – 4.8 

Assessment Factor of 10 6 used

Data Refinement 

PEC 

‣ Model allows for the use of 

biodegradation data 

‣ Input of measured WTP or 

in-stream 

data 

PNEC 

‣ Use of alternate QSARS 

‣ Collection of ecotoxicity data

Initial Framework Results 

In the First Tier screening, 73% of the 

materials had PEC/PNEC ratios

Research Initiatives 

Goal: Fill data gaps identified by priority 

setting process 

Program areas to date 

‣ Biotransformation of poorly degraded 

materials (collaboration with P&G) 

‣ Fate in the terrestrial compartment 

(University of Delaware)

Biotransformation of 

Fragrance Materials (P&G) 

Fate in Activated Sludge and in Sewage Effluents 

discharged into River Water 

‣ AHTN, Acetyl Cedrene, and HHCB 

Work at Realistic Concentrations (

Biotransformation Results 

In activated sludge, AHTN, acetyl 

cedrene, and HHCB are biotransformed to 

lower K ow more polar metabolites 

Acetyl cedrene and HHCB also are 

biotransformed in river water containing 

sewage effluent. 

Based upon K ow , metabolites are predicted 

to be less toxic and bioaccumulative than 

the parent compounds

Terrestrial Fate 

Limited understanding of dissipation of 

fragrance materials in sludge-amended soils 

Research conducted to evaluate the fate 

processes which control the dissipation of 

fragrance materials (FMs( 

FMs) ) in soil 

Establish property-activity relationships to 

predict the fate and concentrations of other 

FM compounds in soil

O 

O 

O 

O 

O 

o 

O 

Acetyl Cedrene 

AH TN 

Benzyl 

Acetate 

p-t-Bucinal 

Diphenyl Ether 

DPMI 

O 

OH 

O 

O 

OH 

O 

O 

O 

O 

Eugenol 

Hexyl Salicylate 

Hexylcinnamaldehyde 

HHCB 

Isob ornyl A cetate 

OH 

O 

O 

O 

O 

OH 

d-Limonene 

Linalool 

O 

M ethyl Dihydrojasm onate 

γ -MethylIonone 

Methyl 

Salicylate 

O 

NO 2 

O 

HO 

O 2 

N 

NO 2 

Musk Ketone 

O 2 

N 

Musk Xylene 

NO 2 

OTNE 

P henyl Ethyl Alcohol 

β-Pinene 

OH 

Terpineol

Soil Fate Study - Findings 

Study has only been able to report on 11 of 22 

materials in soil and 9 of 22 in leachate: 

‣ AHTN, HHCB, MX, MK, DPMI, OTNE, acetyl 

cedrene, diphenyl ether, methyl ionone, hexyl sal, 

hexyl cinnamaldehyde in soil (1 st 9 in leachate) 

Only 6 are likely to be found in sludge-amended soils 

(AHTN, HHCB, musk ketone, musk xylene, acetyl 

cedrene, and OTNE). 

Leaching (to aquifer) is probably insignificant. 

Soil organic matter content greatly influences the 

retention of FMs in soil (e.g., AHTN, musk ketone). 

Different FMs dissipate at very different rates 

and through different mechanisms.

Testing Program 

Goal: Publish material risk assessments in 

the peer-reviewed reviewed literature and have data 

available for regulatory inquiries 

Materials are risk ranked based on RIFM 

Environmental Framework 

Testing performed to refine risk assessments 

Materials are further broken down into 

structure-activity groups

2005 Program Review 

Testing 

‣ Biotransformation Technology Transfer 

Research 

‣ Sediment Fate Program 

• Sediments identified as important media 

for study of high Kow compounds 

• University of Delaware developing 

program built upon the successes of the 

soil fate program 

• SC Johnson provided co-funding

Biotransformation Technology 

Transfer 

Program supported by Procter&Gamble (T.Federle, 

N.Itrich, D.Lee) ) and IFF (M.Fukayama( 

M.Fukayama, T.Levorse, 

P.Ribeiro, R.Senna, C.Smith,) 

HHCB activated sludge and river water die-away 

validations complete 

OTNE river water die-away underway 

Continuous Activated Sludge protocol in 

development 

‣ HHCB and OTNE materials selected for study 

HPLC measurement of log Kow of metabolites 

added to program

FMs and Sediments 

In Europe and the US nitromusk and polycyclic 

musks have been measured in freshwater and 

estuarine sediments 

Analytical and fate program at University of 

Delaware complemented by ecotoxicology 

studies underway at Roskilde University in 

Denmark 

Ecotoxicology studies are developing methods 

and measuring effects in sediment dwellers 

(poster in preparation for SETAC Europe)

Sediment Fate Study 

Removal, Biological Exposure, and Uptake of 

Fragrance Materials in Soil and Sediment 

Objectives 

‣ To determine the importance of sorption to 

sediment as a removal mechanism for FMs in 

streams 

‣ To determine dissipation rates of FMs in streams 

and sediments and and their steady-state 

state 

concentrations 

1st year of study to focus on analytical method 

development, material selection and overall 

study design

PBT Activities 

IFRA Information Letter 

EFFA comments on EU Chemicals Policy 

Response to on-going questions from 

Environment Canada 

Database Assessment 

PBT Training 

ECETOC Task Force

USEPA’s PBT Profiler 

Assessment Tool 

PBT Training (with Christen Sachse-Vasquez) 

‣ The Hazard Assessment of Fragrance 

Materials Using the USEPA’s PBT Profiler 

‣ US Session – 19 July/European Session 29 

September (2004) 

‣ Japanese Session – 18 April 2005 

‣ Other sessions held at individual member 

locations in US and Europe

ECETOC Task Force 

ECB request to examine how risk assessment 

applies to PBTs and vPvBs 

Lead on “Effects” chapter 

‣ Food chain effects/secondary poisoning 

considered important endpoint for PBTs and 

vPvBs 

‣ Long-term studies thought necessary for 

verified PBTs and vPvBs

STEP Workshop 

Joint TNO/Wildlife International Workshop 

at the request of RIVM 

RIFM co-sponsorship 

For potential input into REACH 

development 

EU, US, and Canadian regulators attending 

RIFM participating on advisory board and 

co-chair chair for metabolites session 

Final report in preparation

PBT Program 

PBT list refined 

‣ PBT Profiler output forms the basis 

‣ Include international criteria 

‣ Reviewing database for P,B, and T data 

• Data Gap Analysis to prepare for REACH 

requested by IFRA ETF 

‣ Establish scope of PBT issue for FMs 

Biotransformtion Technology Transfer (P) 

Soil Fate and Sediment Fate Programs (P) 

Wildlife International Proposal (B)

Interactions 

Environment Canada 

UmweltBundesAmt/GREAT 

/GREAT-ERER 

USGS/NJDEP 

USEPA 

San Francisco Estuary Institute 

SETAC North American Meeting 

SETAC European Meeting

Communications 

Provides transparency to the program 

Participation in international scientific 

conferences 

‣ SETAC 

‣ ACS Meeting 

‣ EAWAG 

‣ Gordon Research Conference 

All research, testing and risk 

assessments published in the peer 

reviewed literature

Papers and Presentations 

Papers 

‣ Fragrance materials and their environmental impact: 

Salvito, Senna, Vey (published FFJ) 

‣ Dissipation of Fragrance Materials in Sludge-Amended 

Soils: DiFrancesco, Chiu, Standley, , Allen, Salvito 

(published ES&T) 

‣ Recent Studies conducted by the Research Institute 

for Fragrance Materials (RIFM) in Support of the 

Environmental Risk Assessment Process: Balk, 

Salvito, Blok 

Presentations 

‣ SETAC North American and European Meeting: 

Limitations of Commonly Used Ecotoxicity QSARs 

Poster 

‣ American Chemical Society: Removal Mechanisms 

for Fragrance Materials in Sludge-Amended Soils

Summary 

RIFM environmental program provides a 

risk based approach to assessing the impact 

of fragrance materials to the environment 

Research and testing are focused on high 

priority areas 

Program is designed to be transparent to 

industry, regulatory authorities, academic 

scientists and the public

BIOGRAPHY 

Daniel Salvito, Ph.D. 

Daniel Salvito is the Manager of the Environmental Program for The Research Institute for Fragrance 

Materials, Inc. (RIFM). RIFM is an independent scientific organization, which tests and evaluates the 

safety of fragrance materials. The Institute represents more than seventy member companies on a 

worldwide basis. Dr. Salvito is responsible for overseeing the planning, conduct and completion of the 

environmental research and testing program at RIFM. 

Dr. Salvito started with RIFM in 1999. Before joining RIFM, he worked at Public Service Electric and 

Gas Co., of Newark, NJ where he worked in Environmental Affairs and supervised the corporate 

analytical laboratory. 

Dr. Salvito holds a Bachelor of Science degree in chemistry from Adelphi University and a Masters of 

Science degree in chemistry from the State University of New York at Stony Brook. Dr. Salvito 

received his Doctor of Philosophy in environmental science from Rutgers University. His current 

research interests include aquatic and terrestrial fate of organic chemicals. 

Among his professional affiliations, Dr. Salvito is a member of the American Chemical Society, the 

Society of Environmental Toxicology and Chemistry, and the American Association for the 

Advancement of Science. He has authored over 20 scientific publications and presentations.

RESPIRATORY SAFETY PROGRAM 

Daniel Isola 

ABSTRACT 

Consumer exposure to inhaled fragrances is not well characterized and has raised concerns 

about asthma, allergy, neurological and other effects. To address those concerns, RIFM instituted its 

Respiratory Safety Program in 2000. A series of simulated exposure studies using 3 different surrogate 

product forms containing 9 key fragrance materials were planned and conducted. The studies presented 

here describe the exposures to the surrogates and were designed to assess consumer exposure to these 

products during intended use. The surrogate product forms were a pressurized aerosol air freshener, a 

heated oil plug-in air freshener, and a fine fragrance. Each surrogate contained, in addition to 

excipients, benzyl acetate (BA), eugenol (EU), hexylcinnamaldehyde (HCA), 1,3,4,6,7,8-hexahydro- 

4,6,6,7,8,8-hexamethylcyclopenta-γ-benzopyran (HHCB), hydroxy- citronellal (HO-C), β-ionone (β-I), 

d-limonene (d-L), linalool (LL), and methyl dihydrojasmonate (MDJ) - at 0.06% each for the aerosol, 

8.89% each for the plug-in, and 2.2% each for the fine fragrance. The materials were chosen based on 

volatility, chemical structure, toxicity, and volume of use. Results of the aerosol study indicated the 

peak air concentration of total fragrance at the adult breathing height (5 ft.) was 2165 µg/m 3 and 1753 

µg/m 3 at the child breathing height (1.5 ft.). The peaks occurred at different times. After 2 hrs, the 

concentrations ranged from 105 to 64 µg/m 3 at the adult and child hts, respectively. The Mean 

Aerodynamic Diameter (MAD) of the airborne particles was approximately 1.5 µm. Plug-in study 

results showed peak total concentration were 557 µg/m 3 at 1 hr. and declined to 78 µg/m 3 after 701 hrs. 

NB: These figures were corrected for room size. Fine fragrance study results showed peak total 

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 

both breathing hts., the concentrations decreased to


Daniel Isola 

ABSTRACT 






















Daniel Isola 

ABSTRACT 






















Daniel Isola 

ABSTRACT 






















Daniel Isola 

ABSTRACT 






















Daniel Isola 

ABSTRACT 





















ββ 

 

 

 

γ

2002 2003 2004 


2Q 3Q 4Q 2Q 3Q 4Q 2Q 3Q 4Q 2Q 3Q 4Q 

2006 

Aerosol 

Plug-In Fine Fragrance

2002 2003 2004 


2Q 3Q 4Q 2Q 3Q 4Q 2Q 3Q 4Q 2Q 3Q 4Q 

2006 

Aerosol 

Plug-In Fine Fragrance

Airborne Fragrance Concentrations (μg/m 3 ) 

Fragrances 

Adult Breathing Zone 

Child Breathing Zone 

Max Min Max Min 

BA 380.5 15.2 241.5 7.8 

Eugenol 410.4 7.5 266.6 5.2 

HCA 125.1 3.9 192.9 3.1 

HHCB 122.6 4.3 201.7 3.0 

HO-C 299.3 13.3 250.5 11.4 

Ionone 273.9 10.1 196.1 6.3 

d-Limonene 396.4 27.9 297.7 15.2 

Linalool 414.2 20.0 243.5 10.4 

MDJ 127.6 3.4 176.9 3.2


Fragrances 




BA 380.5 15.2 241.5 7.8 

Eugenol 410.4 7.5 266.6 5.2 

HCA 125.1 3.9 192.9 3.1 

HHCB 122.6 4.3 201.7 3.0 

HO-C 299.3 13.3 250.5 11.4 

Ionone 273.9 10.1 196.1 6.3 

d-Limonene 396.4 27.9 297.7 15.2 

Linalool 414.2 20.0 243.5 10.4 

MDJ 127.6 3.4 176.9 3.2


Fragrances 




BA 380.5 15.2 241.5 7.8 

Eugenol 410.4 7.5 266.6 5.2 

HCA 125.1 3.9 192.9 3.1 

HHCB 122.6 4.3 201.7 3.0 

HO-C 299.3 13.3 250.5 11.4 

Ionone 273.9 10.1 196.1 6.3 

d-Limonene 396.4 27.9 297.7 15.2 

Linalool 414.2 20.0 243.5 10.4 

MDJ 127.6 3.4 176.9 3.2


Fragrances 




BA 380.5 15.2 241.5 7.8 

Eugenol 410.4 7.5 266.6 5.2 

HCA 125.1 3.9 192.9 3.1 

HHCB 122.6 4.3 201.7 3.0 

HO-C 299.3 13.3 250.5 11.4 

Ionone 273.9 10.1 196.1 6.3 

d-Limonene 396.4 27.9 297.7 15.2 

Linalool 414.2 20.0 243.5 10.4 

MDJ 127.6 3.4 176.9 3.2

Airborne Concentration at 1.5' Height and 0' Distance 

160 

Airborne Concentration (ug/m3) 

140 

120 

100 

80 

60 

40 

20 

0 

0 50 100 150 200 250 300 350 

Time (min) 

D-limonene Linalool Benzyl Acetate HOC Eugenol Ionone MDJ HCA HHCB

Airborne Concentration at 1.5' Height and 0' Distance 

160 

Airborne Concentration (ug/m3) 

140 

120 

100 

80 

60 

40 

20 

0 

0 50 100 150 200 250 300 350 

Time (min) 

D-limonene Linalool Benzyl Acetate HOC Eugenol Ionone MDJ HCA HHCB

Chamber: 1759 at 1 hr 

Room: 557 at 1 hr 

956 at 3 hr 

Adult: 2165 at 1 min 

Child: 1753 at 6 min 

Adult: 1030 at 10 min, 0 ft 

1042 at 5 min, 1.5 ft 

881 at 10 min, 5 ft 

Child: 711 at 5 min, 0 ft 

2065 at 5 min, 1.5 ft 

681 at 10 min, 5 ft

Chamber: 1759 at 1 hr 

Room: 557 at 1 hr 

956 at 3 hr 

Adult: 2165 at 1 min 

Child: 1753 at 6 min 

Adult: 1030 at 10 min, 0 ft 

1042 at 5 min, 1.5 ft 

881 at 10 min, 5 ft 

Child: 711 at 5 min, 0 ft 

2065 at 5 min, 1.5 ft 

681 at 10 min, 5 ft

Allergen 

Nose 

Rhinitis 

Allergic Reaction 

Lung 

Asthma

Allergen 

Nose 

Rhinitis 


Lung 

Asthma

Allergen 

Nose 

Rhinitis 


Lung 

Asthma

Allergen 

Nose 

Rhinitis 


Lung 

Asthma

Allergen 

Nose 

Rhinitis 


Lung 

Asthma

Allergen 

Nose 

Rhinitis 


Lung 

Asthma

Allergen 

Nose 

Rhinitis 


Lung 

Asthma

BIOGRAPHY 

Daniel Isola 

Daniel Isola is the Respiratory Safety Program Manager at RIFM. His responsibilities include 

determining human exposures to inhaled fragrance materials through the use of simulated exposures 

based on intended product use. Further responsibilities include the design and conduct of clinical 

studies using classical and state of the art biochemical and sensory techniques to assess the potential 

physiological and psychological effects of inhaled fragrance materials, determining the respiratory 

sensitization potential for fragrance materials, and identifying the systemic effects of inhaled fragrance 

materials. Previously at RIFM, he supported the human health testing program and other programs of 

interest and importance to the fragrance industry. His broad career experience includes research in 

academia as well as research and health assessments in the pharmaceutical/consumer products industry 

(Bristol-Myers) and the petrochemical industry (Texaco) 

Mr. Isola earned his graduate degree in Biology from New York University through a joint 

program between the Post-Graduate School of Medicine and the Graduate School of Arts and Sciences. 

His area of study was industrial/environmental hygiene and toxicology. His thesis research, conducted 

at NYU Medical Center, was in inhalation toxicology and carcinogenesis. A second Master's Degree in 

Toxicology was acquired from St. John's University in New York City. Additionally, he studied 

ecology for several years in the Graduate Ecology Program at Fordham University in New York City. 

Mr. Isola has authored numerous publications. He interacts with various agencies in the United 

States and elsewhere and actively participates and presents at professional meetings and trade 

associations.

FRAGRANCE MATERIAL REVIEWS 

GROUP SUMMARY DEVELOPMENT 

FFIDS 

Charlene S. Letizia 

ABSTRACT 

The safety evaluation review process now includes a Group Summary authored by the Expert Panel, 

which is accompanied by individual Fragrance Material Reviews on each fragrance ingredient in the 

Group. Both the Group Summary and the Fragrance Materials Reviews will be published together in a 

peer-reviewed scientific journal. 

The Group Summaries are a toxicologic and dermatologic assessment of the relevant data selected from 

the large bibliography of studies and reports on the individual materials in the group. Whereas our 

earlier published monographs on fragrance raw materials simply reported the data on individual 

materials, the Group Summary encompasses a new format that includes the Expert Panels conclusions 

on the safety of the group under specified conditions of use. Each Fragrance Material Review is a 

comprehensive summary of all the toxicological data on an individual ingredient in the group. 

RIFM also disseminates safety data through our Fragrance and Flavor Ingredient Data Sheets which are 

RIFM’s version of Material Safety Data Sheets (MSDS). 

RIFM originally developed Flavor and Fragrance Ingredient Data Sheets in response to the U.S. OSHA 

Hazard Communication Standard, which required manufacturers to provide material safety data sheets 

(MSDS) to employees. Today, the Flavor and Fragrance Ingredient Data Sheets are prepared to be 

internationally compliant. Since 1985 RIFM has issued approximately 1800 Flavor and Fragrance 

Ingredient Data Sheets.


GROUP SUMMARY DEVELOPMENT 

FFIDS 

Charlene Letizia 

Project Manager, Technical Writing 

Tokyo INFOX 

May 18, 2005

THE RIFM DATABASE 

RIFM has a repository of information 

on the safety of fragrance raw 

ingredients 

Data is used to prepare safety 

evaluations 

Data for these evaluations comes 

from various sources: 

 

 

 

 

Studies conducted by RIFM 

Studies conducted by our member 

companies 

Government studies such as those from 

the National Toxicology Program 

Published literature 

2

SAFETY EVALUATION 

RESULTS 

How does RIFM 

communicate 

the results of 

their Safety 

Evaluations 

Previously 

through our 

Monographs on 

Fragrance Raw 

Materials 

3

THE PANEL’S S CONCLUSION 

Group Summaries are 

toxicologic and 

dermatologic 

assessments 

Each Group Summary is 

an evaluation of 

relevant data 

Group Summaries are 

authored by the RIFM 

Expert Panel 

They contain the Panel’s 

conclusion about the 

safety of the materials 

as fragrance ingredients 

4


(FMRs) 

Fragrance Material 

Reviews (FMRs) are 

authored by RIFM 

staff 

They are a 

comprehensive 

summary of all the 

toxicological data 

Individual 

ingredients in the 

group 

5

MATERIAL SELECTION 

How does RIFM select which materials to 

review first. 

Chemically defined fragrance ingredients 

were placed into 23 basic structurally related 

groups and approximately 150 subgroups 

The human health criteria document 

prioritizes fragrance materials for review 

(Ford et al., 2000. Criteria for development 

of a database for safety evaluation of 

fragrance ingredients. Regulatory Toxicology 

and Pharmacology 31, 166) 

It is from this priority list that the groups of 

structurally related materials are selected for 

evaluation. 

6

MATERIAL GROUPS 

These are homologous groups of 

structurally related materials 

Some degree of consistency of 

metabolism and toxicity can be 

predicted 

Safety issues are considered within 

the context of the information that 

exists for the structural group as a 

whole 

Existing information may eliminate 

the need to submit each material to 

full toxicological testing 

7

THE LINALOOL GROUP 

Linalool and Linalyl acetate were 

among the high priority list of 

materials 

Group Summary and 11 FMRs 

first to be reviewed and 

published 

Food and Chemical Toxicology 

(2003) Volume 41(7), pages 919- 

1033. 

8

THE CINNAMYL GROUP 

Cinnamyl alcohol, Cinnamaldehyde 

and Cinnamic acid also among the 

high priority materials 

 

Second group to be reviewed and 

was recently published 

Food and Chemical Toxicology (2005) 

Volume 43(6), pages 837-943. 

These 3 materials will serve as the 

basis for the whole cinnamyl group 

which contains approximately 60 

materials 

9

FUTURE GROUPS 

Ionones 

 

 

 

 

Contains 35 materials 

Group Summary has been presented to 

the Panel 

FMRs have been reviewed by the Panel 

Targeted for submission to Food and 

Chemical Toxicology by the end of 2005 

Salicylates 

 

 

 

 

Contains 18 materials 

Group Summary is in preparation for 

submission to the Panel 

FMRs have been reviewed by the Panel 

Targeted for submission to Food and 

Chemical Toxicology by the end of 2005 

10

FUTURE GROUPS 

Substituted Cinnamaldehydes 

 

 

 

Contains 19 materials 

Group Summary is in preparation for submission 

to the Panel 

FMRs have been completed and will be sent to 

the Panel for their review 

Non-Cyclic Terpene Alcohols 

 

Comprehensive toxicity table submitted to the 

Panel 

Cyclic Terpene Alcohol Group 

 

Comprehensive toxicity table submitted to the 

Panel 

Aryl Alkyl Alcohols 

 

Comprehensive literature searches are being 

conducted 

11

NEW GROUPS 

Six New Groups have been 

selected 

Aryl Aldehydes 

Alcohol Branched Chain 

Ketones Cyclopentanones 

Esters Acetates Aryl Alkyl 

Esters Acetates Cyclic 

Esters Acetates Terpenes Cyclic 

12

FFIDS 

Another way that RIFM 

disseminates safety data is 

through our Flavor and 

Fragrance Ingredient Data 

Sheets (FFIDS) 

FFIDS are the RIFM equivalent 

of Material Safety Data Sheets 

(MSDS) 

13

FFIDS DEVELOPMENT 

FFIDS originally developed in response to 

the OSHA Hazard Communication Standard 

(29 CFR 1910.1200) which stated: 

Chemical Manufacturers and Importers 

Shall Obtain or Develop A Material Safety 

Data Sheet for Each Hazardous Chemical 

They Produce or Import 

OSHA began requiring MSDS’s s for 

hazardous materials effective May 26, 1986 

To insure compliance with the OSHA 

Standard, an external regulatory review is 

conducted by RIFM member companies 

technical representatives 

Responsible for assigning U.S. Health 

Hazard Statements according to the OSHA 

Hazardous Communication Standard 

14

RISK & SAFETY PHRASES 

Risk and Safety Phrases were added in 

response to Dangerous Substances Directive 

European Dangerous Substances Directive 

(DSD) 98/24/EC of 7 April 1998 on the 

protection of the health and safety of 

workers from the risks related to chemical 

agents at work (fourteenth individual 

Directive within the meaning of Article 16(1) 

of Directive 89/391/EEC 

Another review is conducted by the 

EFFA/IFRA/IOFI Hazard Communication 

Working Group 

Responsible for assigning Risk and Safety 

Phrases (R and S Phrases) according to the 

Dangerous Substances Directive 

15

ISSUING A FFIDS 

After the R and S Phrases are 

confirmed, the materials are 

entered into the EFFA/IFRA/IOFI 

Labeling Manual 

The FFIDS are issued after each 

group makes their formal review 

and assigns hazard statements or 

R & S phrases and the materials 

have been entered into the 

Labeling Manual 

16

FFIDS CONTINUE 

In 1985 RIFM initially issued 

9 volumes of FFIDS 

RIFM has continued to issue 

updates since September 26, 

1986 

Approximately 1800 new or 

revised FFIDS have been 

issued over the last 20 years 

17

FFIDS INFORMATION 

Information in a FFIDS includes: 

Chemical identity 

Physical properties 

Physical hazards 

Toxicology data 

Occupational exposures 

18

EUROPEAN 

RISK & SAFETY PHRASES 

IX. CLASSIFICATION AND LABELING AS 

PRESCRIBED IN ANNEX I TO THE 

DANGEROUS SUBSTANCES DIRECTIVE 

67/548/EEC OR IN ANNEX VI OF THIS 

DIRECTIVE AS DETERMINED BY THE 

IFRA/IOFI/EFFA WORKGROUP 

S61 

Avoid release to the 

environment. Refer to 

special instructions/Safety 

data sheets. 

R50/53 Very toxic to aquatic 

organisms, may cause longterm 

adverse effects in the 

aquatic environment. 

R38 

Irritating to skin. 

N – Dangerous for the 

environment 

Xi - Irritant 

19

TOXICOLOGICAL DATA 

V. LABORATORY ANIMAL TOXICOLOGICAL DATA 

1. LD50 Data 

Oral: The acute oral LD50 in rats was 

reported to exceed 5 g/kg, based on 

0/2 deaths at that dose (RIFM, 1987b). 

The acute oral LD50 in rats was 

reported to exceed 5 ml/kg, based on 

2/10 deaths at that dose (RIFM, 1981e). 

The acute oral LD50 in rats was 

reported to exceed 2 g/kg, based on 

0/10 deaths at that dose (RIFM, 1991a). 

Inhalation: Not Found 

Dermal: The acute dermal LD50 in rats 

was reported to exceed 5 ml/kg, based 

on 0/10 deaths at that dose (RIFM, 

1981f). 

20

U.S. HEALTH HAZARD 

STATEMENTS 

VIII. STATEMENTS RELEVANT 

TO MAKING A HEALTH 

HAZARD DETERMINATION 

Irritant 

Sensitizer 

Liquid may be 

irritating to skin 

and eyes. 

Repeated contact 

may cause 

allergic 

dermatitis. 

21

RIFM MEMBERS BENEFIT 

RIFM members receive copies of 

the Group Summaries and the 

Fragrance Material Reviews as 

soon as they are published 

FFIDS continue to be updated 

and are available through e-maile 

They are also available on the 

RIFM database for RIFM 

members who subscribe 

22

BIOGRAPHY 

CHARLENE LETIZIA 

Charlene Letizia is a long time staff member of the Research Institute for Fragrance Materials, Inc. She 

has been involved in many projects at RIFM and has recently been appointed the Project Manager, 

Technical Writing. Her group has direct responsibility for the FFIDS program and for the development, 

preparation and publication of Group Summaries and Fragrance Material Reviews 

Ms. Letizia earned her bachelor’s degree in Chemistry from Fairleigh Dickinson University in Teaneck, 

New Jersey. She has co-authored many of RIFM’s monographs and all of the Fragrance Material 

Reviews.

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