Alternative Methods in the Safety Assessment of Fragrance Ingredients

Alternative Methods in 

the Safety Assessment of 

Fragrance Ingredients 

Flavors & Fragrance Competitiveness Cluster 

May 26, 2008 

Jon Lalko, Senior Test Program Specialist 

Research Institute for Fragrance Materials, Inc. 

Woodcliff Lake, NJ USA

RIFM VISION and MISSION 

To be the International Scientific Authority for 

the Safe Use of Fragrance Materials 

1. Engage in research and evaluation of fragrance 

materials through an independent Expert Panel 

2. Determine safety in use 

3. Gather, analyze and publish scientific information 

4. Distribute scientific data and safety assessment 

judgments to RIFM members, industry associations 

and other interested parties 

5. Maintain an active dialogue with official 

international agencies 

J Lalko - May 26 2008

Fragrance Product Safety 

Member 

Companies 

Code of 

Practice & 

Standards 

I 

F 

R 

A 

R 

I 

F 

M 

Research 

& Testing 

J Lalko - May 26 2008 

REXPAN 

Safety 

Evaluations

RIFM Safety Assessment Process 

 

Loss of Database key in vivo tools 

Move to Alternatives: 

Priorities 

Need to evaluate replacements 

Integrate new in vitro methodologies into the process 

Exposure Assessment 

Testing 

REXPAN Safety Assessment 

Communications 

IFRA Standard 

Publications 

RIFM Expert Panel Safety Evaluation Process Reg. Tox. & Pharm., 37 (2), 218-273, 2003 


The shift to alternatives – 

Impact and challenges to risk assessment 

• There continues to be significant challenges to the 

fragrance industry to defend the safe use of materials 

 

Legislation (REACH, California) 

 

 

Scientific community y( (Publications) 

NGOs 

• Validated and accepted experimental tests are 

essential to answering these challenges 

• Loss of key tools in the risk assessment process 

complicate our ability to successfully address 

questions 

‣ Result – A pressing need to identify suitable 

alternatives and determine how best to 

integrate them into the process 


The shift to alternatives – 

What are the specific consideration for 

fragrance materials? 

• Will the test system be compatible/adaptable to our 

materials? 

Often concerns with solubility or volatility 

• Will the test system be relevant to fragrance 

exposure? 

Dermal and inhalation 

• Will the test system be useful for complex mixtures? 

Essential oils 


The RIFM Program – 

Alternatives Methodology Development in 

Three Areas 


Local Lymph Node Assay (LLNA 

LLNA) 

Since 2000, RIFM has used the LLNA almost exclusively for 

hazard and potency assessment of potential dermal sensitizers 

• Focused on continued Refining of the assay…. 

Development of the B220 endpoint 

(distinguish irritant vs. sensitization in the LLNA) 

Dr. Anne Marie Api – ICCVAM Review Panel 

• Using the LLNA as a bridge to develop Replacements …. 

Incorporating RIFM data into publications providing a 

standardized dataset 

‣ Benefits – Work in this area will allow us to benchmark 

new methodologies for skin sensitization 


Johns Hopkins University –Center for 

Alternatives to Animal Testing (CAAT) 

• Dr. Ladd W. Smith - Industrial advisory board 

Review of proposals related to Replacement, Reduction and 

Refinement technologies (3Rs) 

• Support grants through CAAT: 

Gerberick et al. (P&G) ‘Gene expression changes as they relate 

to the skin sensitization potential of chemicals’ 

Walker et al. (Iowa State University) ‘microfluidics 

assay’ 

Svensson et al. (University of Iowa) ‘Skin explants for 

assessment of cutaneous reactions to xenobiotics’ 

Benefits: 1) Steering alternatives research relevant to 

fragrance materials 

2) Collaborative interaction with 

‘thought leaders’ 


Skin Absorption - 

Experimental Studies 

• Historically, RIFM has utilized in vivo methodologies 

to investigate i the percutaneous penetration of 

fragrance materials 

• RIFM has fully transitioned to human in vitro studies 

• A growing g in vitro dataset (recently published) has 

developed for key fragrance materials that will… 

1. Allow for comparative analysis based on structure and 

vehicle of administration (important for group risk 

assessments) 

2. Assist the development and refinement of 

mathematical models 


Skin Absorption - 

Mathematical Modeling 

• Collaborative work with Dr. Richard Guy (University 

of Bath, UK) to refine models of percutaneous 

penetration for fragrance materials 

• Modeling skin absorption provides for… 

Further alternatives to in vivo testing 

Ability to generate information for an entire group of 

materials 

Ability to identify materials that may require closer 

inspection 

‣ Benefits : 1) Methodology already integrated into risk assessment 

2) In vitro/modeled skin absorption data can 

guide exposure based development of other 

alternatives 


In Silico Approaches 

• International QSAR Foundation 

• TIMES (Tissue Metabolism Simulator – Skin 

Sensitization) 

• MultiCase 

• In Silico approaches… 

Assist in building groups for risk assessment (justification 

for inclusion i and exclusion of molecules) 

l Help to identify relevant materials to test 

Will not be used in place of experimental tests for REACH 

‣ Benefits: 1) Rapid Screening – in practice we have done 

much of this ‘by hand’ 


2) Supporting evidence for decision making

Respiratory Program – 

5 Year Strategy 

IMMEDIATE 

GOALS 

(6 months) 

Conduct a 

comprehensive 

review of the 

database for 

inhalation data 

Develop 

inhalation 

screening 

criteria for new 

and existing 

materials 


INTERMEDIATE 

GOALS 

~3 years 

Facet #1: Establish 

deposition/dosimetry 

profiles 

Facet #2: Replicate 

deposition/dosimetry 

profiles in vivo 

Facet #3: Conduct 

in vitro studies on 

isolated cell types 

LONG TERM 

GOALS 

3+ years 

Respiratory 

sensitization 

mechanism 

and method 

development 

Reaction 

chemistry and 

indoor air 

quality

Respiratory Program – 

In Vitro Methodology Development 

• In vitro respiratory model system development 

Pilot program at Austrian Research Centers (ARC) 

• In vitro analysis of effects in lung cell lines 

University of Medicine and Dentistry of New Jersey (UMDNJ) 

• Peptide Reactivty and Dendritic Cell Activation – 

Dermal vs. Respiratory Sensitizers 

University of Manchester and P&G 

‣ Benefits: 1) D l t d i d t ifi ll dd th 

Benefits: 1) Development designed to specifically address the 

needs of fragrance ingredients 

2) Program will address the pressing need to 

fill data gaps 


Environmental Program – 

In Vitro Methodology Issues 

• Regulatory pressure to avoid/eliminate 

i vertebrate testing, including fish tests 

• This would affect both risk assessment (fish 

acute and chronic studies) and hazard 

assessment (bioaccumulation testing) 

• Presently, unclear if fish studies are banned 

under the deadlines established in the 

Cosmetics Directive (7th Amendment) 


• Research: 

Environmental Program – 

In Vitro Methodology Issues 

HESI Bioaccumulation Project 

OECD Toolbox 

• Interactions: 

Dr. Daniel Salvito - SETAC Bioaccumulation 

Science Advisory Group 

Active in SETAC’s advisory group on animal 

alternatives 

‣ Benefits: Similar to those we have discussed previously… 


- Development relevant to fragrance materials 

- Data will address need to fill data gaps 

- Provide industry a ‘Voice at the Table’


Timeline -

Challenges Ahead 

• Selecting the relevant methodologies 

• Developing , Evaluating and Optimizing those assays 

for use with fragrance materials 

• Assuring gg 

general consensus in the scientific and 

regulatory community (Not just a RIFM Problem, 

significant hurdle) 

• Integration of resulting assays into a uniform risk 

assessment process 

‣ There will need to be significant ifi collaboration with 

those both inside and outside of the fragrance 

industry to be successful 


Conclusion and Perspective – 

• New in vitro methods can provide an 

advantage over those they replace 

More relevant (Human based cells and biology) 

More efficient (Higher throughput) 

More cost effective (Employee time, raw materials, 

physical plant) 


MORE INFORMATION 

Research Institute for 

Fragrance Materials, Inc. 

Tel.: +1 201-689 

689-80898089 

jlalko@rifm.org 

RIFM: www.rifm.org 

IFRA: www.ifraorg.org

Alternative Methods in the Safety Assessment of Fragrance Ingredients

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