Exposure Data: RIFM’s Human Health Safety Assessment

Anne Marie Api, PhD Vice President, Human Health Sciences

RIFM Exposure Webinar May 8, 2013

General Safety Assessment Principles Hazard identification

Inherent ability of a material to cause an adverse effect Dose-response assessment

Addresses derivation of a NOEL Establishes relationship between 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 Placement of identified hazard in context of human

experience

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Safety Assessment using Margin Of Exposure (MOE )

MOE compares the magnitude of NOAEL (No Observed Adverse Effect Level) with that of Human Exposure

MOE needs to be compared with product of Uncertainty Factors (UF)

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If MOE ≤ UFs Risk If MOE > UFs No Risk

Why Exposure Data?

A safety assessment cannot be conducted unless the exposure is

known

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Systemic Exposure to Fragrance Materials

Current Method*: Cumulative dermal exposure from 10 cosmetic products

Modify the current method to include Oral exposure (toothpaste/mouthwash) Inhalation from air care products Indirect oral and inhalation exposure (e.g. oral

exposure from dishwashing products; inhalation exposure from cleaners)

Household and functional care product types Aggregate exposure

*Cadby et al., 2002. Reg. Tox. & Pharm., 36, 246-252.

*Ford et al., 2000. Reg. Tox. & Pharm., 31, 166-181.

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RIFM Aggregate Exposure Model To develop a standard approach that can be used

widely for industry where total systemic exposure includes: Estimate for entire population (preferably World Wide

but initially for Europe and North America) From all exposure pathways – dermal, oral and

inhalation From all key products in which fragrance ingredients

are used The data will also be made available in a software

model which can be used to perform assessments in the future

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RIFM Aggregate Exposure Model – Products Included

Phase I Body Lotion (prestige vs.

mass market) Deodorant/antiperspirants Face cream/Moisturizers Shampoo/Conditioners Hair Styling Products

(excluding hair spray) Hand Cream Hydroalcoholics Lipstick Liquid/Makeup Foundation Mouthwash Shower Gel Toothpaste

Phase II Bar Soap Liquid Hand Soap Body Spray Inhalation

Air Fresheners Candles Hair Spray, Perfume,

Deodorant Spray Combined Food &

Cosmetics exposure

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These products cover the major exposure contribution to fragrance ingredients

RIFM Aggregate Exposure Model

The RIFM Creme model includes detailed usage data for over 36,000 consumers representing the European and US populations. This robust population sample allows us to generate accurate and realistic exposure results.

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RIFM Requests for Concentration Data RIFM will be requesting concentration data for

most of the fragrance materials in use today and will use the concentration data to calculate the total systemic exposure needed for a safety assessment.

The concentration data will remain confidential. RIFM’s first request issued on May 2.

Concentration Survey 001 is RIFM’s first request for data on 60 fragrance ingredients.

Each organization has a separate upload site. Please complete and return this survey by May

31, 2013.

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RIFM Requests for Concentration Data Anticipated that each month there will be

another request for data; this may be scaled up such in a more expedited

manner. The data will be entered into the model and

sources of the data will not be made available.

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RIFM Concentration Survey 001

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RIFM Concentration Survey 001 Request for Concentration Data on 60 Fragrance Ingredients

RIFM is evolving its safety evaluation process to more rapidly incorporate advances in in vitro and in silico methodologies. The focus of the evaluation is now on the individual fragrance material. This will allow RIFM to take of advantage of advances in the science of safety evaluations, as well as meet the increasingly stringent requirements from regulatory bodies and the increased expectations of fragrance users. Exposure data are essential for the completion of a safety assessment for all human health endpoints. RIFM, with member company representatives and Creme Global (a well-established partner to Industry in modeling exposure for cosmetics and foods, and their methodology is used and accepted by regulators), developed a probabilistic aggregate exposure model to calculate total systemic exposure, with distributions used to model various parameters. The new model will enable the measurement of real life consumer exposure to a fragrance material. RIFM will be requesting concentration data for most of the fragrance materials in use today and will use the concentration data to calculate the total systemic exposure needed for a safety assessment. The concentration data will remain confidential. This Concentration Survey is RIFM’s first request for data on 60 fragrance ingredients. The link below will provide information on registration for transferring survey data and on completing the survey:

https://cremeglobal.com/rifmfiletransfer/register.php Once registration is complete, Creme Global will provide login details and the responder will be able to download the Excel spreadsheet and upload responses for each fragrance ingredient. Each organization has a separate upload site. Please complete and return this survey by May 31, 2013. A RIFM Webinar will be held on Wednesday May 8, 2013 to explain in detail how this survey should be completed. More information on the Webinar is available in the Member area of the RIFM website at www.rifm.org. RIFM will issue a new survey each month. The concentration data will be entered into the model but the sources of the data will not be made available. The information must be provided from fragrance compounders (companies that blend fragrance ingredients) for marketed fragrance mixtures only. Please do not enter exposures that are not currently in use. RIFM will follow due diligence to obtain exposure information. Materials for which usage concentration data are not provided will be eliminated from the RIFM evaluation process. At that time, RIFM will inform IFRA that due to lack of data a safety evaluation cannot be completed. The material will then be reviewed by IFRA for possible risk management actions which may include removal from the IFRA Transparency List and/or a ban due to insufficient data. For more information, please contact Dr. Anne Marie Api, amapi@rifm.org.

Research Institute for Fragrance Materials, Inc. 50 Tice Boulevard • Woodcliff Lake, NJ 07677

Phone: 201.689.8089 • Fax: 201.689.8090 www.rifm.org rifm@rifm.org

RIFM Concentration Survey 001 Request for Concentration Data on 60 Fragrance Ingredients

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CAS Number EINECS Principal Name Synonyms 1 100-52-7 202-860-4 Benzaldehyde Artificial almond oil; Benzene carboxaldehyde;

Benzenecarbonal; Benzenecarboxaldehyde; Benzenemethylal; Benzoic aldehyde; Bitter almond oil, synthetic; Phenylformaldehyde; Phenylmethanol aldehyde

2 101-86-0 202-983-3 alpha-Hexylcinnamaldehyde 2-Benzylideneoctanal; alpha-n-Hexyl-beta-phenylacrolein; alpha-n-Hexylcinnamic aldehyde; H.C.A.; Hexyl cinnamal; Hexyl cinnamic aldehyde; Hexyl cinnamyl; Jasmonal H.; Octanal, 2-(phenylmethylene)-

3 104-20-1 203-184-2 4-(p-Methoxyphenyl)-2-butanone 2-Butanone, 4-(4-methoxyphenyl)-; 4-(4-Methoxyphenyl)butan-2-one; 4-(p-Methoxyphenyl)butan-2-one; Anisylacetone; Methyl oxanone; p-Methoxybenzylacetone; Raspberry ketone methyl ether

4 104-54-1 203-212-3 Cinnamyl alcohol 2-Propen-1-ol, 3-phenyl-; 3-Phenyl-2-propen-1-ol; 3-Phenylallyl alcohol; 3-Phenylprop-2-en-1-ol; Cinnamic alcohol; Styrone; Styryl alcohol; Styryl carbinol; Zimtalcohol

5 104-55-2 203-213-9 Cinnamaldehyde 2-Propenal, 3-phenyl-; 3-Phenyl-2-propen-1-al; 3-Phenyl-2-propenal; 3-Phenylacrylaldehyde; 3-Phenylpropenal; Cinnamal; Cinnamic aldehyde; Phenylacrolein

6 115-95-7 204-116-4 Linalyl acetate 1,5-Dimethyl-1-vinylhex-4-en-1-yl acetate; 1,6-Octadien-3-ol, 3,7-dimethyl-, acetate; 3,7-Dimethyl-1,6-octadien-3-ol acetate; 3,7-Dimethyl-1,6-octadien-3-yl acetate; Bergamol; Linalool acetate

7 117-98-6 204-225-7 Vetiveryl acetate 2-Isopropylidene-4,8-dimethyl-1,2,3,3a,4,5,6,8a-octahydroazulen-6-yl acetate; 6-Azulenol, 1,2,3,3a,4,5,6,8a-octahydro-4,8-dimethyl-2-(1-methylethylidene)-, acetate; 6-Azulenol, 1,2,3,3a,4,5,6,8a-octahydro-4,8-dimethyl-2-(methylethylidene)-, acetate; Vetiver acetate; Vetivert Acetate; Vetivert acetate (Haiti); Vetyvenyl acetate

8 118-58-1 204-262-9 Benzyl salicylate 2-Hydroxybenzoic acid, benzyl ester; Benzoic acid, 2-hydroxy-, phenylmethyl ester; Benzyl 2-hydroxybenzoate; Benzyl o-hydroxybenzoate; Phenylmethyl 2-hydroxybenzoate; Salicylic acid, benzyl ester

9 119-61-9 204-337-6 Benzophenone alpha-Oxodiphenylmethane; alpha-Oxoditane; Benzene, benzoyl-; Benzophenon krist; Benzoylbenzene; Diphenyl ketone; Diphenylmethanone; Methanone, diphenyl-; Phenyl ketone

10 121-32-4 204-464-7 Ethyl vanillin 3-Ethoxy-4-hydroxybenzaldehyde; 3-Ethoxyprotocatechualdehyde; Benzaldehyde, 3-ethoxy-4-hydroxy-; Bourbonal; Ethyl protal; Ethylprotocatechualdehyde-3-ethyl ether

RIFM Requests for Concentration Data

The information must be provided from fragrance compounders (companies that blend fragrance ingredients) for marketed fragrance mixtures only.

Please do not enter exposures that are not currently in use Data Needed from Fragrance Compounders

Report data on materials used as such only. RIFM will follow due diligence in order to

obtain exposure information.

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RIFM Requests for Concentration Data

Materials for which exposure is not provided will be eliminated from the RIFM evaluation process

At that time, RIFM will inform IFRA that due to lack of data a safety evaluation cannot be completed. The material will then be reviewed by IFRA for possible risk management actions which may include removal from the IFRA Transparency List and/or a ban due to insufficient data.

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Examples

How do I enter data? Need to register for transferring survey data

and on completing the survey:

https://cremeglobal.com/rifmfiletransfer/register.php

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Fragrance Ingredient A

Extract & gather data for Fragrance Ingredient

2 year sold formulae? All data points Clean-up data Remove chemical sales, bases etc. (Need final

concentration in marketed formulae) Translate internal classifications to RIFM

product types Fill-in template

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?

Fragrance Ingredient A Formula Name Application Sector % Conc.

Formula 1 Air Freshener - Electrical Home Care 0.5333 Formula 2 Skin Care/Face Body Care 0.05 Formula 3 Body Deo Cream/Stick/Solid Body Care 0.125 Formula 4 Perfume/Edp/Edt/Col (FW) Fine Fragrance 0.0014 Formula 5 AntiP/Deo (FW) Fine Fragrance 0.0003 Formula 6 Soap Bar Body Care 0.0487 Formula 7 Skin Care/Face Body Care 0.1 Formula 8 All Purpose Cleaner Home Care 0.0645 Ingredient Chemicals Chemicals 100 Formula 10 Perfume/Edp/Edt/Col (FW) Fine Fragrance 0.017 Formula 11 Shampoo Body Care 0.0006 Formula 12 Hand Liquid Soap Body Care 0.0031 Formula 13 Laundry Rinse/Condit. Home Care 0.0667 Formula 14 Shower Product (BC) Body Care 0.0045 Formula 15 Skin Care/Hand & Body Body Care 0.0005 Formula 16 AntiP/Deo (FW) Fine Fragrance 0.0012 Formula 17 Soap (FM) Fine Fragrance 0.0029 Formula 18 Hair Rinse/Conditioner Body Care 0.0008 Formula 19 Body Deo Spray/Aer./Pump Body Care 0.001 Formula 20 Liquid Detergent Home Care 6.6667 Formula 21 Men Deocol/Splash (BC) Body Care 0.0758 Base Body AntiP Spray/Aer./Pump Body Care 71.4286 Formula 23 All Purpose Cleaner Home Care 0.4 Formula 25 Shower Product (BC) Body Care 0.0032

Fragrance Ingredient B

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Formula Name Application Sector % Conc. Formula 1, 2, 3, 4, 5 Air Freshener - Electrical Home Care 0.5333Formula 5, 16 AntiP/Deo (FW) Fine Fragrance 0.0003 - .0012Formula 3, 19 Body Deo Cream/Stick/Solid Body Care 0.001- 0.125Formula 18 Hair Rinse/Conditioner Body Care 0.0008Formula 12 Hand Liquid Soap Body Care 0.0031Formula 13 Laundry Rinse/Condit. Home Care 0.0667Formula 21 Men Deocol/Splash (BC) Body Care 0.0758Formula 4, 10 Perfume/Edp/Edt/Col (FW) Fine Fragrance 0.0014-0.0017Formula 11 Shampoo Body Care 0.0006Formula 14, 25 Shower Product (BC) Body Care 0.0032-0.0045Formula 15 Skin Care/Face Body Care 0.0005-0.01Formula 2,7 Skin Care/Face Body Care 0.01-0.1Formula 17, 6 Soap (FM) Fine Fragrance 0.0029-0.0487

Fragrance Ingredient C

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Formula Name Application Sector Min % Conc Max %

Conc Typical % Conc

Formula 1, 2, 3, 4, 5 Air Freshener - Electrical Home Care 0.01 0.0533 0.03

Formula 5, 16 AntiP/Deo (FW) Fine Fragrance 0.0003 0.0012 0.0005

Formula 3, 19 Body Deo Cream/Stick/Solid Body Care 0.001 0.00125 0.0011

Formula 18-20 Hair Rinse/Conditioner Body Care 0.0008 0.001 0.0005

Formula 12-13 Hand Liquid Soap Body Care 0.0031 0.0667 0.005

Formula 21-30 Men Deocol/Splash (BC) Body Care 0.0758 0.1 0.08

Formula 35-30 Perfume/Edp/Edt/Col (FW) Fine Fragrance 0.0014 0.0017 0.0015

Formula 11 Shampoo Body Care 0.0006 0.001 0.007

Formula 14, 25 Shower Product (BC) Body Care 0.0032 0.0045 0.004

Formula 2,7,15 Skin Care/Face Body Care 0.0005 0.01 0.0008

Formula 17, 6 Soap (FM) Fine Fragrance 0.0029 0.0487 0.003

Cronan McNamara, CEO

E.J. Daly, CTO 15th May 2013

RIFM Webinar – Data Collection Expert Models for Decision Makers TM

G L O B A L

Creme Global - Overview

RIFM – Creme Global – Partnership: Project Commenced in 2010 – 3 Work Packages over Two Phases

RIFM Creme Model – Aggregate Exposure Assessment – Fragrances and Flavorings – Dermal, Inhalation, Oral and Ingestion

Creme Global - Services

High Performance Cloud Software

Technical Services & Projects

Data Validation &

Curation

EXPOSURE MODEL RIFM Aggregate Exposure Project

Calculating Exposure

Exposure per unit body weight (mg/kg/day) = 𝐹𝐹𝐹𝐹𝐹𝐹𝐹𝐹𝐹 × 𝐴𝐴𝐴𝐹𝐹𝐴 × 𝐶𝐴𝐹𝐹𝐹𝐹𝐴𝐹𝐶𝐴𝐶𝐴𝐹 × 𝑅𝐹𝐹𝐴𝐹𝐹𝐴𝐶𝐴𝐹 × 𝑃𝐹𝐹𝐹𝐴𝐹𝐶𝐴𝐶𝐴𝐹

𝐵𝐴𝐵𝐹 𝑊𝐹𝐶𝑊𝑊𝐴

Dermal Exposure (mg/cm2/day) =

𝐹𝐹𝐹𝐹𝐹𝐹𝐹𝐹𝐹 × 𝐴𝐴𝐴𝐹𝐹𝐴 × 𝐶𝐴𝐹𝐹𝐹𝐹𝐴𝐹𝐶𝐴𝐶𝐴𝐹 × 𝑅𝐹𝐹𝐴𝐹𝐹𝐴𝐶𝐴𝐹𝑆𝐹𝐹𝑆𝐶𝐹𝐹 𝐴𝐹𝐹𝐶

Calculation repeated for: Each subject Each product Each body part

Exposure Algorithm

1. Choose fragrance of interest

3. Find all usage events in the diary involving those products

4. Determine the exposure to the fragrance at each usage event

5. Determine the aggregate exposure to the fragrance for each subject

2. Find all products that contains that fragrance

6. Collate exposures for each subject to give the distribution of exposure in the population

Concentration Data Collection

MORE INFORMATION

20 Api PCPC SRTC June 2011

Research Institute for Fragrance Materials, Inc.Tel.: +1-201-689-8089

amapi@rifm.orgwww.rifm.orgrifm@rifm.org

https://cremeglobal.com/rifmfiletransfer/register.php

http://www.cremeglobal.com/products/cremerifm/Data%20Collection/