Dermal Sensitization QRA Approach for Fragrance Ingredient

QUANTITATIVE RISK 

ASSESSMENT (QRA) FOR 

INDUCTION OF THE DERMAL 

SENSITIZATION FOR FRAGRANCE 

INGREDIENTS: ITS PRACTICAL 

APPLICATION 

Anne Marie Api, PhD 

Research Institute for Fragrance Materials, Inc. 

Vice President, Human Health Sciences 

QRA Implementation Workshop 

January 23, 2007

Contact Dermatitis, 2001, 45, 

333-340 

Dermal Sensitization Quantitative Risk Assessment (QRA) 

For Fragrance Ingredients 

Technical Dossier 

March 15, 2006 

Revised May 26, 2006 

The group recommended an 

exposure-based QRA methodology 

for fragrance ingredients …now 

implemented 

Api QRA Worksop Jan 2007 

Revised June 22,2006 

QRA Expert Group 

Anne Marie Api (RIFM), David A. Basketter (SEAC, Unilever), 

Peter A. Cadby (Firmenich), Marie-France Cano (LVMH), 

Graham Ellis (Givaudan), G. Frank Gerberick (Procter & 

Gamble), Peter Griem (Clariant Produkte GmbH), Pauline M. 

McNamee (Procter & Gamble), Cindy A. Ryan (Procter & 

Gamble) and Bob Safford (SEAC, Unilever)

QRA IMPLEMENTATION STATUS 

• Technical dossier published on RIFM website 

www.rifm.org/pub/publications.asp 

• Informational booklet issued May 2006 on RIFM 

website 

www.rifm.org/pub/publications.asp 

• 40 th Amendment May 2006 - Citral, Farnesol, 

Phenylacetaldehyde, Tea Leaf Absolute 

• Publications in peer reviewed journals - in 

preparation 

• Publications in trade press – in preparation 

• Implementation guidance - users & customers - 

ongoing 

Api QRA Worksop Jan 2007

QRA FOR DERMAL SENSITIZATION 

FRAGRANCE INGREDIENTS 

Application to induction of skin sensitization - a threshold 

phenomenon 

• Determine potential (hazard) to induce sensitization: 

• Pre-clinical studies e.g. Guinea-Pig Test, LLNA 

• Human data (historical) 

• Structure based predictive approach 

• Dose response: 

• Determine the No-Expected-Sensitization Induction-Level (NESIL) 

based on the Weight of Evidence (WoE) 

• Calculate Sensitization Assessment Factor (SAF) 

• Exposure: 

• Dose metric: expressed in Dose/Area 

• Understand consumer exposure expressed as product 

categories 

• How consumers are exposed: amount, duration and frequency 

• Risk characterization: 

Acceptable Exposure Level = WoE NESIL 

(AEL) 

(SAF) 


QRA FOR DERMAL SENSITIZATION 

FRAGRANCE INGREDIENTS: WHAT’S S NEW 

• NESIL - No Expected 

Sensitization 

Induction 

Level 

• Establishment of scientifically sound NESILs is key 

• Weight of evidence approach to use of data 

• Identifies studies inappropriate for consideration 

• Can be derived from animal and human data 

• SAF – Sensitization Assessment Factor 

• Greater understanding of different elements comprising 

overall SAF 

• Extrapolation from controlled experimental situation to 

real life exposure scenarios 

• Detailed scientific rationale for SAF determination 

• Exposure 

• Consistent use of the same dose metric (μg/cm 2 ) 

• Sources of exposure data in calculation of exposure to 

fragrance ingredients in consumer products 


CITRAL 

• Hazard Identification 

• Guinea pig data - weak sensitizer [14] 

• Local Lymph Node Assay 

• EC 3 = 1414 µg/cm 2 [11] 

• LOEL 

• HRIPT: 3876 µg/cm 2 in EtOH 5/8 

• HMT: 2759 µg/cm 2 in pet. 29/150 

• Other Data 

• 1240 µg/cm 2 in pet. 0/50 

• 775 µg/cm 2 in EtOH 0/41 

• 338 µg/cm 2 in EtOH 0/40 

• Confirmatory HRIPT - NOEL 

• 1400 µg/cm 2 in 3:1 DEP:EtOH 0/101 


EXPOSURE DATA (DOSE/AREA) 

Product Type 

Source 

Exposure 

mg/cm 2 /day 

Deo/AP Solid 

CTFA 

8.5 

Hydroalcoholic, Unshaved 

Women’s Facial Cream 

Cano & Rich* 

Colipa 

2.2 

0.2 

Shaving Cream SCCP 0.07 

Eye Product 

Body Cream 

Lip Products 

Hair Sprays 

Toothpaste 

CTFA 

Colipa 

Colipa 

CTFA 

Colipa 

2.17 

0.5 

11.7 

2.2 

0.13 

Mouthwash SCCP 1.4 

Shampoo 

Body Wash/Gels 

CTFA 

SCCP 

0.2 

0.01 


*Cano & Rich, 2001; Tozer et al., 2004

CONSUMER EXPOSURE LEVEL 

Exposure assessment for shampoos: 

• Calculated exposure = 23,630 mg/day 

(CTFA) 

• Area = 1430 cm 2 (EPA, 1997; area hands + 

½ head) 

• Retention Factor = 1% or 0.01 (SCCNFP, 

2003) 

Exposure = 23,630 mg/day * 0.01 ÷ 1430 cm 2 

= 0.2 mg/cm 2 /day 


RISK CHARACTERIZATION FOR 

FRAGRANCE INGREDIENTS 

• Acceptable Exposure Levels (AELs) to 

fragrance ingredients that are dermal 

sensitizers can be determined in specific real 

life consumer product types 

Acceptable 

Exposure Level (AEL) Sensitization 

Assessment Factor 

(SAF) 

• Comparison of Acceptable Exposure Levels 

(AEL) to calculated Consumer Exposure 

Level (CEL) 


= 

WoE NESIL 

AEL > CEL to be Acceptable

QRA DERMAL SENSITIZATION 

CITRAL 

Weight of Evidence NESIL 

•Guinea-pig data – weak sensitizer 

•Local Lymph Node Assay 

EC 3 

= 1414 µg/cm 2 [11] 

•Human data 

HRIPT NOEL = 1400 µg/cm 2 

•Weight of Evidence NESIL = 1400 µg/cm 2 

Sensitization Assessment 

Factors 

•Considerations 

Inter-individual variability 

Product matrix differences 

Variations in use patterns 

•Hydroalcoholic Unshaved SAF is 100 

•Deo/AP SAF is 300 


Exposure 

•Consumer exposure 

Hydroalcoholic (unshaved 

skin) = 2.2 mg/cm 2 

AEL = 1400/100 

= 14.0 µg/cm 2 

AEL/CEL 

(14.0 ug/cm 2 X 0.001 

mg/µg) ÷ 2.2 mg/cm 2 /day 

= 0.0064 

AEL≥CEL ≤ 0.64% 


DEO/AP = 8.5mg/cm 2 

AEL = 1400/300 

= 4.7 µg/cm2 

AEL/CEL = 0.0005 

AEL≥CEL ≤ 0.05%


CITRAL IN A HYDROALCOHOLIC 

UNSHAVED SKIN - INDUCTION 

0.6% 

13 μg/cm 2 1.7% 

CEL 37 μg/cm 2 

CEL 

14 

μg/cm 2 

AEL 

1400 

μg/cm 2 

WoE NESIL 

AEL/CEL Acceptable 

SAF = 100 

AEL/CEL 

Unacceptable 

0.01 0. 1 1.0 10 100 1000 10,000 

Citral Level - log μg/cm 2 



CITRAL IN SOLID AP - INDUCTION 

0.05% 

4.3 μg/cm 2 

CEL 

4.7 

μg/cm 2 

AEL 

1400 

μg/cm 2 

Woe NESIL 


SAF = 300 

0.01 0. 1 1.0 10 100 1000 10,000 

Citral Level - log μg/cm 2 



CINNAMIC ALDEHYDE 

Weight of Evidence NESIL 

•Guinea-pig data – moderate sensitizer 

•Local Lymph Node Assay 

EC 3 = 280 µg/cm 2 [23] 

•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 

•Deo/AP SAF is 300 

•Conditioners SAF 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 ) 


Deo/AP=0.05% x 8.5 

mg/cm 2 = 4.3 µg/cm 2 

Conditioners = 0.05 % x 

0.2 mg/cm 2 = 0.1 µg/cm 2 


QRA DERMAL SENSITIZATION CINNAMIC 

ALDEHYDE IN SOLID AP - INDUCTION 

2.0 μg/cm 

2 

AEL 

0.02% 

1.7 μg/cm 

2 

CEL 

0.05% 

4.3 μg/cm 

2 

CEL 

590 μg/cm 

2 

WoE NESIL 


SAF = 300 

AEL/CEL 

Unacceptable 

0.001 0. 01 0.1 1.0 10 100 1000 

Cinnamic Aldehyde Level - log μg/cm 

2 


QRA DERMAL SENSITIZATION CINNAMIC 

ALDEHYDE IN CONDITIONERS - INDUCTION 

0.05% 

0.1 μg/cm 2 

CEL 

3.0% = 

5.8 μg/cm 2 

Potential 

Consumer 

exposure 

5.9 

μg/cm 2 

AEL 

590 μg/cm 2 

WoE NESIL 

AEL/CEL 

Acceptable 

SAF = 100 

0.001 0. 01 0.1 1.0 10 100 1000 

Cinnamic Aldehyde Level - log μg/cm 

2 


REFINEMENT RISK ASSESSMENT- 

SKIN SENSITIZATION 

RA 

Risk 

Mgmt 

Clinical 

Reports 


PATCH TEST DATABASE 

Fragrance 

Ingredient 

U. HOSPITAL LEUVEN 

2000-2005 

2005 

Product 

Type 

Positive Patch 

Test Reactions 

Cinnamic Deodorant 2 

Aldehyde 

Aftershave 1 

Isoeugenol 

Deodorant 1 

Hair Dye 1 

Hydroalcoholic 5 

Citral Hydroalcoholic 6 

303/3323 (9.1%) Positive to Fragrance Mix; 133/303 Positive to Own 

Cosmetic; 66/133 fragrance-related contact allergic reactions 


IFRA PRODUCT CATEGORIES 

IFRA Category 

Category 1 

Category 2 

Category 3 

Category 4 

Category 5 

Category 6 

Category 7 

Category 8 

Category 9 

Category 10 

Category 11 

BASED ON QRA 

Examples of Products 

Lip Products, Toys, Insect Repellents 

Deodorants/Antiperspirants 

Hydroalcoholic Products for Shaved Skin, Eye Products, 

Men’s Facial Cream & Balms, Tampons 

Hydroalcoholic Products for Unshaved Skin, Hair Styling 

Aids & Sprays, Body Creams 

Women’s Facial Cream/Facial Make-up, Hand Cream, Facial 

Masks, Wipes/Refreshing Tissue for Hands, Face, Neck, Body 

Mouthwash, Toothpaste 

Intimate Wipes, Baby Wipes 

Make-up Remover, Hair Styling Aids Non-Spray, Nail Care 

Shampoo, Rinse-Off Conditioners, Bar Soap, Feminine 

Hygiene Pads & Liners 

Detergents, Hard Surface Cleaners, Diapers 

All Non-Skin or incidental skin contact products 


IFRA PRODUCT CATEGORY 11 

All non-skin contact or incidental skin 

contact. Including: 

Candles 

Air Fresheners and Fragrancing of all types (plug-ins, solid 

substrate, membrane delivery, ambient, electrical, pot 

pourri, powders, fragrancing sachets, incense, etc.) 

Deodorizers/Maskers Not Intended For Skin Contact (e.g. 

fabric drying machine deodorizers, carpet powders) 

Insecticides (e.g. mosquito coil, paper, electrical, etc.) 

Toilet Blocks; Joss Sticks; Shoe Polishes 

Machine Dishwash Detergent and Deodorizers 

Machine Only Laundry Detergent (e.g. liquitabs) 

Plastic articles (excluding toys) 

Fuels; Paints; Cat litter; Animal Sprays 

Treated Textiles (e.g. starch sprays, fabric treated with 

fragrances after wash, deodorizers for textiles or fabrics, 

tights with moisturizers) 

Odored Distilled Water (that can be added to steam irons) 

Floor wax 


Pragmatic 

Level 

These 

products 

result in 

negligible 

skin contact. 

The approach 

for a 

pragmatic 

concentration 

of fragrance 

ingredient in 

this category 

is explained 

in IFRA RIFM 

Booklet

IFRA PRODUCT CATEGORY 5 

SAF 

Product Type 

Consumer 

Exposure 

Level 

mg/cm 2 /day 

100 Facial Cream/Make-up 3.17 

100 Hand Cream 4.2 

IFRA 

Category 5 

Consumer 

Exposure 

4.2 


IFRA PRODUCT CATEGORIES 

BASED ON QRA 

IFRA 

Category 

SAF 

Category Consumer Exposure 

mg/cm 2 /day 

Product Type Designating 

IFRA Category 

Category 1 

Category 2 

Category 3 

Category 4 

300 11.7 Lipstick 

300 8.5 Solid Antiperspirant 

300 2.2 Aftershave 

100 2.2 Perfume 

Category 5 

Category 6 

Category 7 

Category 8 

Category 9 

Category 10 

Category 11 

100 

100 

300 

100 

100 

100 

10 

4.2 

1.4 

4.4 

1.0 

0.2 

0.1 

0.00033 

Hand Cream 

Toothpaste 

Intimate Wipes 

Hair Styling Aids 

Conditioners, Rinse-Off 

Hard Surface Cleaners 

Candles 


IFRA STANDARD LIMITS FOR 

CITRAL BASED ON QRA 

IFRA 

Cat. 

Examples of Product Type 

Citral 

QRA 

1 Lip Products 0.04% 

2 Deodorant/Antiperspirant 0.05% 

3 Hydroalc., Shaved Skin 0.2% 

4 Hydroalc., Unshaved Skin 0.6% 

5 Women Facial Cream 0.3% 

6 Mouthwash 1.0% 

7 Intimate Wipes 0.1% 

8 Hair Styling Aids Non-Spray 1.4% 

9 Conditioners, Rinse-off 5.0% 

10 Hard Surface Cleaners 2.5% 

11 Candle (Non-Skin/Incidental Skin) Limited 


QRA IMPLEMENTATION 

FUTURE FOCUS 

• 42 nd Amendment (2007) – about 40 

fragrance ingredients (new and existing) 

based on volume of use 

• 43 rd Amendment (2008) about 40 

fragrance ingredients (new and existing) 

• Key goal: to review by 2011 all chemically 

defined fragrance ingredients that have 

structural alerts for dermal sensitization 

that are used at greater than 1 metric ton 

per year on a worldwide basis. 

• Compliance with IFRA Standards (REXPAN( 

REXPAN) 


FUTURE QRA MEETINGS 

• Developments in Exposure-Based 

Quantitative Risk Assessment (QRA) for 

Induction of Dermal Sensitization for 

Fragrance Ingredients Symposium- 

Wednesday March 28, 2007 1:30 PM. 

The Society of Toxicology Meeting, 

Charlotte, North Carolina, USA, March 

25-29, 2007. 

• 9 th Contact Dermatitis State-of-the-Art 

Issues, Fragrance Mini-Symposium 

Friday July 13, 2007, July 12-14, 2007, 

Hershey PA

Dermal Sensitization QRA Approach for Fragrance Ingredient

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