here - Research Institute for Fragrance Materials

Skin Absorption Modeling: 

Practical Applications 

Valerie T. Politano, Ph.D. 

Human Health Scientist 

Research Institute for Fragrance Materials, Inc. 

Woodcliff Lake, NJ 

13 November 2007 American College of Toxicology

Research Institute for Fragrance 

• RIFM VISION Statement 

Materials, Inc. 

• To be the International Scientific Authority for the Safe Use 

of Fragrance Materials 

• RIFM MISSION Statement 

• Engage in research and evaluation of fragrance materials 

through an independent Expert Panel 

• Determine safety in use 

• Gather, analyze and publish scientific information 

• Distribute scientific data and safety assessment judgments 

to RIFM members, industry associations and other 

interested parties 

• Maintain an active dialogue with official international 

agencies 

13 November 2007 American College of Toxicology 2



• Non-profit corporation, created in 1966 

• Membership open to all companies that 

manufacture, sell, distribute or engage in 

business related to the fragrance industry 

• Maintain database of greater than 4500 

fragrance and flavor ingredients 

• RIFM sponsored studies 

• Member company data 

• Scientific literature 




• RIFM's Panel of Experts (REXPAN) 

• Independent and international group of 

dermatologists, pathologists, environmental 

scientists and toxicologists 

• No commercial ties to fragrance industry 

• REXPAN advises RIFM on its strategic 

approach, reviews protocols and evaluates all 

scientific findings* 

• REXPAN's conclusions form the basis for the 

Standards set by the International Fragrance 

Association (IFRA) 

* Bickers et al. (2003) Reg. Toxicol. Pharmacol. 37:218-273. 


Group Approach 

• Used by many groups for quite some time 

• OECD process 

• US EPA 

• Joint FAO/WHO Expert Committee on Food 

Additives (JECFA) 

• FEMA Expert Panel (flavors) 

• RIFM Expert Panel (fragrances) 

• Successful example in the OECD process 

• Solvents propyl acetate and butyl acetate 

• easily metabolized by esterases to the corresponding acid 

and alcohol, which are the ultimate active molecules 


Group Approach 

• Chemical structure helps to predict 

• Transdermal absorption 

• Metabolism 

• Disposition 

• Functional groups that can influence toxicity 

• Group safety evaluations can demonstrate 

that within a congeneric group similar 

biochemical fate and toxicological potential 

can be exhibited 

• It can be shown that the group is efficiently 

detoxified to yield the same or similar 

metabolites 


RIFM Fragrance Structure- 

Activity Group Approach 

• 88% fragrances are structurally simple 

• Low molecular weight 

• Predominantly semi-volatile substances 

• Consisting of carbon, hydrogen and oxygen 

• Majority can be assigned to several homologous groups 

of structurally-related related materials 

• ~ 2,100 chemically defined fragrance ingredients 

• 23 Structurally-related related groups (e.g. Acids, Acetals, , Alcohols) 

• > 150 Subgroups (e.g. Straight chain saturated, straight chain 

unsaturated etc.) 

• These structure-activity groups form the basis of the 

REXPAN Group Summaries, which contain 20-30 

materials 

• Though a material is included in a single structure-activity group 

it may be part of several REXPAN summaries 


Ketones 

10% 

RIFM Groupings for Fragrance 

Volume of Use 

Hydrocarbons 

4% 

Musks 

6% 

Aldehydes 

15% 

Other 

8% 

Ingredients 

Alcohols 

23% 

Esters 

34% 

Number of 

Materials 

Esters 

33% 

Hydrocarbons 

4% 

Alcohols 

16% 

Aldehydes 

10% 

Musks 

0.3% 

Other 

26% 

Ketones 

12% 


RIFM Group Approach 

• Form basis for REXPAN Group Summaries 

• Can reasonably predict some degree of consistency 

of metabolism and toxicity 

• For most, it can be shown that the group is 

efficiently detoxified to yield the innocuous 

metabolites 

• Low systemic exposure levels (many below 

thresholds of toxicological concern) 

• Review existing information for a group 

• May need to submit a fragrance ingredient to full 

toxicological testing OR 

• May be necessary to test one or more particular 

members of a group to obtain more robust data to 

solidify assessment of the class as a whole 


Group Summaries 

• Perform safety evaluations on groups of 

structurally-related related fragrance materials 

• Systematic review of all human health and 

environmental data for the group 

• Review for data gaps, conduct studies if 

necessary 

• Conduct studies on high-volume material to 

support group 

• Published together in peer-reviewed reviewed scientific 

journal 

• Group Summary authored by REXPAN 

• Fragrance Material Review on each member of 

the group, authored by RIFM staff 


Skin Absorption 

• Major route of human exposure to fragrance 

materials occurs through skin contact 

• Exposures can vary widely with different 

product types, ranging from fine perfumes 

and lotions to household cleaners 

• In risk assessments, currently assume 100% 

absorption when no data exists 

• Conservative assumption 

• Few fragrance materials have data 

• Narrow margin of safety 


Skin Absorption 

• Several factors relevant to fragrance 

exposures, including but not limited to 

• Volume applied 

• Area of exposure 

• Time of contact 

• Barrier status 

• Vehicle 


Limited Experimental Data 

• Have experimental data on few 

fragrance materials, from a variety of 

structure-activity groups 

• RIFM has conducted in vivo and/or in vitro 

studies on approximately 35 fragrance 

materials 

• Few other materials have data from 

member companies or scientific literature 


Criteria Document* Directs Test 

Program and Group Selection 

• Linalool and Related Ester Group 

Linalool 

Linalyl acetate 

Linalyl benzoate 

Linalyl butyrate 

Linalyl cinnamate 

Linalyl formate 

Linalyl hexanoate 

Linalyl isobutyrate 

Linalyl isovalerate 

Linalyl phenylacetate 

Linalyl propionate 

• Expeditious 

• Greatly reducing animal testing 

• Cost Saving 

• Low volume materials will not need the same amount of test data 

• Evaluation of linalool will support linalool and related ester group g 

(11) AND non-cyclic 

terpene alcohol group (32) 

*Ford et al. (2000) Reg. Toxicol. Pharmacol. 31:166-181. 


Example Fragrance Material: 

Linalool 

• Estimated exposure* to linalool from 

multiple cosmetic products: 0.3 

mg/kg/day 

• NOAEL from rat oral subchronic 

toxicity study**: 50 mg/kg/day 

• Margin Of Safety = 50 / 0.3 = 167 

*Cadby et al. (2002) Reg. Toxicol. Pharmacol. 36:246-252. 

**Bickers et al. (2003) Food Chem. Toxicol. 41:919-942. 


Example Fragrance Material: 

Linalool 

• Estimated exposure: 0.3 mg/kg/day 

• In vitro human skin absorption* 

(occluded): 14.4% 

• Revised exposure: 0.3 x 0.144 = 0.04 

• NOAEL from rat oral subchronic 

toxicity study: 50 mg/kg/day 

• Margin Of Safety = 50 / 0.04 = 1250 

*Lalko et al. ACT Poster # 32 


Theoretical Prediction 

Modeling 

• Alternative to animal testing 

• Sometimes difficult to obtain viable human 

skin samples for in vitro 

• Lower cost 

• Provide modeled data on low-volume 

materials within a group that do not have 

experimental data 

• Group Summary of 32 materials 

• Higher throughput than experimental testing 

• 2100 fragrance materials 


Theoretical Prediction 

• Current Status 

Modeling 

• Dr. Richard Guy – have prediction data 

with a comparison to experimental data for 

approximately 20 fragrance materials 

• Publish report of comparison in peer- 

reviewed literature 

• Continue to perform experimental work on 

lead materials in a group 

• Use theoretical prediction model to predict 

skin absorption of remaining materials

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