# Presentation: 927908

## BSE and Cosmetics:
FDA Risk Assessment and Management Perspectives. 
Stanley R. Milstein, Ph.D., Office of Cosmetics and Colors
CFSAN-Australian Embassy Presentation
December 7, 2006

**BSE and Cosmetics:**
**FDA Risk Assessment and Management Perspectives. **
***Stanley R. Milstein, Ph.D., Office of Cosmetics and Colors***
***CFSAN-Australian Embassy Presentation***
***December 7, 2006***

## Slide 2

## Cosmetic and Color Additive Regulatory Requirements

**Cosmetics:**
** ****No Pre-Market Approval (Products and Ingredients) **
**Color Additives:****	**
**Pre-Market Approval**

## OCAC’s Top Risk-Based Enforcement Priorities

**Safety and Security Related**
**Microbial contamination**
**Illegal color additive use**
**Bovine Spongiform Encephalopathy (BSE)**
**Bioterrorism/Counterterrorism (BT/CT)**

**Notes:**
OCAC’s top 3 risk-based enforcement priorities are microbial contamination, illegal color additive use, and BSE (that is, material from cattle as an ingredient in cosmetics and color additives).  These priorities take into account such considerations as compliance history, risk for harm, and exposure to the public.
With regard to BSE, this is more of a theoretical risk for cosmetic products, as a result of tallow, gelatin, and “exotic” ingredient use.  The skin is a robust barrier to infection when normal and intact. However, there is some concern about infection when the skin is abraded or from eye area infection. These risks are low...but non-zero...and the potential impact of an event could be high, both to the consumer and to Industry. 

## BSE and FDA Oversight of Cosmetics 

**OCAC has tracked the BSE epidemic since 1991.  **

## Cosmetics and BSE/v-CJD

**>13,500 Cosmetic Ingredients in ICID-11**
**Many Bovine Ingredients in Cosmetic Products**
**Some Ingredients Subject to Other TSEs in Cosmetics:**
***Antler Velvet, Deer Fat  (Cervidae)***
***Lanolin Derivatives (Ovidae)***
***Mink Oil, Mink Fatty Acid Derivatives (Mustela******)***

## Ingredients from the CTFA Cosmetic Ingredient Dictionary (6th edition) that are from “Bovine” or “Animal” Sources

- 8	Amniotic Fluid	Fluid surrounding the cow embryo *in utero.*
- 0	Aorta Extract		Extract derived from animal aorta.
- 0	Brain Extract		Extract of bovine and porcine brains.
- 0 	Calf Blood Extract	Extract of calf blood.
- 0 	Calfskin Extract	Extract of bovine skin.
- 0	Calfskin Hydrolysate	Hydrolysate of calfskin, derived by acid, enzyme, 				or other method of hydrolysis.
- 87	Collagen		Protein in cartilage and other connective tissue in 				animals.
- 20 	Collagen Amino Acids	The mixture of amino acids resulting from the 				complete 	hydrolysis of collagen. It is characterized 			by containing a significant level of hydroxyproline.
- 0	Colostrum		Fluid secreted by the mammary glands after the 				birth of an animal.
- 0	Colostrum Cream	The oily, yellowish portion of colostrum (q.v.).
- (No. of products containing ingredient that have been voluntarily registered with FDA)

## Ingredients from the CTFA Cosmetic Ingredient Dictionary (6th edition) that are from “Bovine” or “Animal” Sources(Continued)

- 0	Connective Tissue Extract	Extract of animal connective tissue.
- 0	Cutaneous Lysate	The end product of the controlled bacterial degradation of 			animal cutaneous tissues. It consists of a complex mixture 			of polypeptides and amino acids.
- 0	Cytochrome C		A hemoprotein found in animal cells in the mitochondrial 				protein-lipid complex.
- 10	Elastin		A fibrous protein found in the connective tissue 				of animals.
- 0	Fibronectin		A glycoprotein found in connective tissues, basement 				membranes, in plasma and other body fluids.
- 6	Glycoproteins 		Conjugated proteins which contain carbohydrate. 				groups attached covalently to the polypeptide 	chain.
- 0	Glycosaminoglycans	A mixture of mucopolysaccharides derived from various 				animal tissues.
- 6	Glycosphingolipids	Sphingolipids (q.v.) which contain a carbohydrate group 				convalently attached to the sphingolipid backbone.
- 0	Heart Extract		Extract of animal heart tissue.
- (No. of products containing ingredient that have been voluntarily registered with FDA)

## Ingredients from the CTFA Cosmetic Ingredient Dictionary (6th edition) that are from “Bovine” or “Animal” Sources(Continued)

- 0 	Hydrolized Calf Ligaments/Liver/Skin 	Hydrolysate of young bovine liver and skin derived by 				acid, enzyme or other method of hydrolysis.
- 0	Hydrolized Calf Skin		Hydrolysate of calf skin, derived by acid, enzyme or 				other method of hydrolysis.
- 0	Hydrolized Spinal Protein		Hydrolysate of animal spinal cord protein, derived by 				acid, enzyme or other method of hydrolysis.
- 11	Keratin			Protein derived from hair, wool, horn, nail, or other 				similar tissues in animals.
- 0	Liver Extract			Extract of bovine livers.
- 0	Liver Hydrolysate		Hydrolysate of animal liver, derived by acid, enzyme or 				other method of hydrolysis.
- 0	Mammalian Hydrolysate		Hydrolysate of animal mammalian tissue, derived by 				acid, enzyme or other method of hydrolysis.
- 0	Mammary Extract		Extract of bovine mammary tissue.
- 0	Marrow Extract			Extract of bovine bone marrow.
- 0	Muscle Extract			Extract of bovine muscle.
- 0	Neural Extract			Extract of bovine neural tissue.
- (No. of products containing ingredient that have been voluntarily registered with FDA)

## Ingredients from the CTFA Cosmetic Ingredient Dictionary (6th edition) that are from “Bovine” or “Animal” Sources(Continued)

- 0	Omental Lipids		Lipids obtained from bovine omentum.
- 0	Ovarian Extract		Extract derived from bovine ovaries.
- 7	Placental Enzymes	A mixture of enzymes obtained from an aqueous extract 				of animal placentas.
- 31 	Placental Extract	Extract of animal placentas.
- 0	Placental Lipids		A mixture of lipids from animal placentas.
- 0 	Placental Proteins	A mixture of proteins derived from animal placentas.
- 0	Soluble Proteoglycan	Solubilized glycoproteins having a very high carbohydrate 				content.
- 0	Spinal Cord Extract	An extract obtained from animal spinal cords.
- 0	Spinal Lipid Extract	An extract of animal spinal lipids.
- 5	Spleen Extract		An extract of bovine spleens.
- 0	Testicular Extract	An extract of bovine testicular tissue.
- 0	Thymus Extract		An extract of animal thymus.
- (No. of products containing ingredient that have been voluntarily registered with FDA)

## BSE

**Issues for Cosmetics**
_**Possible**_** vehicle for infection**
**Abraded skin, eye area, mucous membranes**
**Identification of ingredient sources**** **
**Risk Assessment:  tissue, country of origin **
**“****Safe-sourcing” from non-BSE countries; non-BSE herds in BSE or BSE-suspect countries**
**Avoid “Co-mingling” and “cross-contamination” **
**Use of SRMs and other “BSE-Risk Materials”**
**Tallow and Tallow Derivatives**
**Gelatin and Gelatin Derivatives**

## Specified Risk Materials (SRMs)

**What are specified risk materials?**
- Specified risk materials, from cattle 30 months and older, are the:
**brain **
**skull **
**eyes **
**trigeminal ganglia **
**spinal cord **
**vertebral column (excluding the vertebrae of the tail, the transverse processes of the thoracic and lumbar vertebrae, and the wings of the sacrum) **
**dorsal root ganglia. **
- Specified risk materials from cattle of any age are the:
**tonsils and **
**distal ileum of the small intestine. **

## Tallow – Cosmetic Functions

- Definition: “Tallow is the fat derived from the fatty tissue of sheep or cattle.  It consists primarily of fatty acid glycerides”
- Skin conditioning agent-occlusive
- Bath soaps and detergents

## FREQENCY OF USE BY CHEMICAL NAME

- 30 	Tallow
- 11 	Tallow Fatty Acid
- 4 	Potassium Tallowate
- 103 	Sodium Tallowate
- 18 	Tallow Glyceride
- 9 	Tallow Glycerides
- 120 	Hydrogenated Tallow
- 25 	Hydrogenated Tallow Glyceride
- 10 	Hydrogenated Tallow Glycerides
- 18	Hydrogenated Tallow-60 Myristyl Glycol
- 3	Aluminum Hydrogenated Tallow Glutamate
- 14 	Dihydroxyethyl Tallow Glycinate
- 12	Ditallowdimonium
- 13 	Hydrogenated Ditallowamine

- 6	MEA-Tallowate
- 21	PEG-15 Tallow Polyamine
- 19	PEG-2 Hydrogenated Tallow Amine
- 122	PEG-2 Tallow Amine
- 29	PEG-5 Tallow Amine
- 87	PEG-50 Tallow Amide
- 45	PEG-8 Hydrogenated Tallow Amine
- 24	PEG-8 Tallow Amine
- 4	Tallowdimonium Propyltrimonium Dichloride
- 5	Talloweth-60 Myristyl Glycol
- 143	Tallowtrimethylammonium Chloride
- 2592	Glycerin
- 2210 	Glyceryl Derivitives

## Animal (Potential BSE) Ingredients FoU Update:  2002 vs. 2004

## Animal (Potential BSE) Ingredients FoU Update:  2002 vs. 2004

## Animal (Potential BSE) Ingredients FoU Update:  2002 vs. 2004

## Gelatin – Cosmetic Functions

- Definition: “Gelatin is a product obtained by the partial hydrolysis of collagen derived from the skin, white connective tissue, and bones of animals...”
- Binder
- Lytic Agent
- Oral Health Care Drug
- Skin Conditioning Agent
- Hair Conditioning Agent
- Viscosity Increasing Agent - Aqueous

## Gelatin – 57 Cosmetic Product Registrations {FDA VCRP Data, 21 CFR 720.4; May 2003}

- Bath Preparations            6
- Hair Preparations      (Non-Coloring)               15
- Makeup Preparations    (Not Eye)                          5

- Manicuring Preparations             10
- Shaving Preparations      1
- Skincare Preparations                   20

## Gelatin – Cosmetic Ingredients

- Gelatin     (57)*
- Gelatin Keratin Amino Acid/Lysine Hydroxypropyltrimonium Chloride    (18)*
- Gelatin/Lysine/Polyacrylamide Hydroxypropyltrimonium Chloride     (0)*
***   FDA  Cosmetic Product Registrations  (21 CFR 720.4,  May 2003)**

## Lytic Agent 

*“**Lytic Agents are substances which help break down lipids, proteins, and polysaccharides usually by enzymatic or other actions”*   (CTFA, ICID-9)

## Oral Health Care Drugs(CTFA, ICID-9)

*“**Oral Health Care Drugs are active ingredients used in oral health care products....”*
*“**In the EU and other countries, oral health care products are considered to be cosmetics and are controlled under cosmetic regulations...”*
*“**The listing...includes those ingredients reported to be safe and effective for use in U.S. over-the-counter (OTC) drug products.  These ingredients may also have a cosmetic purpose in cosmetic formulations.”*

## Regulatory Coverage of Ruminant Tissues and Tissue Derived Ingredients 

- Import Alert #17-04
- 1994, 1996 “Letter to Manufacturers and Marketers of Dietary Supplements and Cosmetics’
- Importers of cosmetic products should have procedures to assure that ruminant tissue and tissue-derived ingredients do not come from cattle in countries where BSE occurs

**Notes:**
Should the issue of human tissue being used in cosmetics go here?

## Use of Material Derived from Cattle in Cosmetics(69 FR 42256, at 42274, July 14, 2004)

- Cosmetics shall not contain “prohibited cattle material”
- SRMs, MS (beef), Non-Ambulatory Disabled Cattle, Cattle not inspected and passed (USDA)
- Exemptions for Tallow (_<_0.15% “hexane-insolubles) and Tallow Derivatives

## BSE/ v-CJD:  OCAC Role In Process of BSE Risk Analysis- I

- 1992 – Education and Outreach
-  Intra-Agency OCAC-sponsored Seminar by CVM
- Guidance to Industry
- 1994,1996 – “Letters to Manufacturers of FDA-Regulated Products (Dietary Supplements and Cosmetics)”
- FDA TSE Advisory Committee (TSEAC)
- OCAC Participation in FDA Inter-Center TSE Working Group on Tallow (mid 1990s)
- OCAC Presentation on Tallow to FDA-TSEAC (April 1998)

## BSE/ v-CJD:  OCAC Role In Process of BSE Risk Analysis- II

- Import Alert # 17-04 and Cosmetic Compliance Program (CPG 7829.001/ 7829.002) in Cosmetics “BSE-Firewall”
- Incorporate USDA/APHIS restrictions at 9 CFR 94.18 and
- 	9 CFR 95.4  (1998 et. seq.)
- Bovine Ingredients Usage Establishment Inspection  (EI) Questionnaire
- 2001–2004:  OCAC Representation on FDA-CFSAN Regulatory BSE Initiatives
- CFSAN BSE Coordinating Committee
- Regulation and Guidance Development Teams
- BSE Emergency Response Plan (ERP)
- BSE “Prohibited Cattle Materials” Proposal, Interim Final Rule (IFR), and Recordkeeping Proposal

## Industry Initiatives

- CTFA Board Policy Statement on ‘*Mad Cow Disease*’ (April 20, 2001)
- Cosmetic products must not contain BSE-risk raw materials, as identified by WHO as SRMs.
-  Suppliers to certify bovine-derived ingredients  free of risk materials
- Tallow derivatives to be processed by methods that assure they are safe.

## BSE/ v-CJD:  OCAC Role In Process of BSE Risk Analysis- III

- 2001-2003:  OCAC Support to FDA Field
- Bovine Stem Cell Imports for ‘Cosmetic’ Use
- LOS-DO, CBER
- 2001-2004: OCAC International Outreach
- Health Canada Risk Assessment (Focal Point Research)
- Guidance on BSE Risk Management
-  KFDA (Korea)
-  MHLW (Japan)

## Bovine Spongiform Encephalopathy (BSE)

- FDA BSE Emergency Response Plan Summary (12/24/03)
- FDA press release – “FDA Strengthens Existing Multiple Firewalls Against BSE or ‘Mad Cow’ Disease” (1/26/04)
- Cosmetic Compliance Program (CPG 7829.001/ 7829.002)
- Bovine Ingredients Usage Questionnaire During Establishment Inspections (EI)
- USDA/APHIS regulations at 9 CFR 94.18 and 9 CFR 95.4
- USDA/APHIS list of “BSE Countries” (http://www.aphis.usda.gov)

**Notes:**
The first case of mad cow was discovered in Washington on 1/23.  Following this FDA announced immediate elimination of several exemptions to existing regulations prohibiting the feed of ruminant remains (cows, sheep, and goats) to other ruminants.  In addition, blood could no longer be fed to ruminants, and poultry litter and restaurant waste may not be used as a feed ingredient.  Feed plants using protein for other animals that is banned in ruminant feed must now use separate production lines to prevent contamination.  

The new rules will ban certain bovine materials for FDA-regulated human food, supplements and cosmetics.  These include:
Materials from “downers,” cattle that cannot walk.  
Material from cattle that died before they reached slaughter.
Brains, skull, eyes and spinal cords of cattle 30 months and older
The small intestine and tonsils

## Use of Material Derived From Cattle in Cosmetics

- Federal Register, Vol. 69, No. 134, pgs. 42255-42274, July 14, 2004
- Cosmetics shall not contain** ****“prohibited cattle material”**
- SRMs, MS(Beef), ‘Non-Ambulatory Disabled Cattle”, Cattle not Inspected and Passed (USDA)
- Exemptions for Tallow (≤0.15% “hexane-insolubles) and Tallow Derivatives

**Notes:**
As I’m sure you know, an interim final rule published on July 14, 2004 that bans PROHIBITED cattle material...not ALL cattle material... from cosmetics. As the definition is essentially a list, I won’t get into all the details.  
A new codified section at 21 CFR 700.27 will contain the details concerning the definition of prohibited cattle material, as does the FR notice.  
The interim final rule includes exceptions for protein-free tallow and more highly processed tallow derivatives.
Manufacturers are also required to keep records under this rule.

## 2005 Amendments to BSE Interim Final Rule (IFR)

**Federal Register, Vol. 70, No. 172, pgs. 53063-53069, September 7, 2005**
- _Not_ considered ‘prohibited cattle material’ :
- Bovine Small Intestine – Distal Ileum;
- Bovine hide or hide-derivatives, milk or milk products, and tallow derivatives;
- AOCS (or equivalent) method OK to measure insoluble impurities in tallow
-  FCC method originally specified in IFR.

**Notes:**
Most recently, FDA responded to Public Comments to the IFR in September 2005 by publishing an Amendment to the IFR.  This Amendment specifies that bovine small intestine, from which the distal ileum , or at least 80 inches of the uncoiled and trimmed small intestine as measured from the caeco-colic junction & proceeding proximally toward the jejunum, has been removed, is not considered an infectious ‘prohibited cattle material’.  

The Amendment also clarifies that bovine hide, milk, and tallow derivatives are similarly not considered ‘prohibited cattle material’ (if no cross-contamination during processing occurs).  

Finally, the amendment also allows the use of the less costly AOCS method... or any other method that will produce equivalent results...  for demonstrating compliance with the IFR’s performance standard for essentially protein-free tallow.   

## Proposed Record-Keeping for Cosmetics With Cattle Material 

- Federal Register, Vol. 69, No. 134, pgs. 42275-42285, July 14, 2004
- Manufacturers must keep records and make them available to FDA
- Importers to electronically affirm at time of entry that those cosmetics with cattle material do not contain prohibited material

**Notes:**
The BSE record-keeping proposal also published on July 14, 2004.  In the proposal, the agency stated that its electronic entry system will be modified to include a field for importers to affirm compliance, and that records will also have to be made available upon request.

## Record-Keeping

**Effective  -  January 9, 2007**
- 	(71 FR 59653, October 11, 2006)
- 		**21 CFR 700.27(c)**
- Manufacturers must keep records and make them available to FDA
- Importers to electronically affirm at time of entry that those cosmetics with cattle material do not contain prohibited material

## FDA Export Certificates

- CTFA, ICMAD designated by FDA as “competent authority” for issuance of “BSE-free” certifications for industry firms

**Notes:**
See attachments.

## BSE Export Certificates

- Cosmetics Guidance http://www.cfsan.fda.gov/~lrd/certific.html
- CTFA and ICMAD designated as “Competent Authority” by FDA

**Notes:**
As for BSE Certification, due to our budget constraints, FDA re-delegated the authority to issue such certificates to 2 trade associations designated as “Competent Authorities”:
The Cosmetic, Toiletry, and Fragrance Association or CFTA
The Independent Cosmetic Manufacturers and Distributors (ICMAD) Association
The Certificate of Export indicates that the product is regulated by the FDA and that it is not the subject of enforcement action by the FDA at this time. The certificate is no guarantee of the product's safety or quality. It is issued at the request of a domestic company.
The procedure for certification appears online at the URL on this slide.

## BSE Risk Assessment

- Published by FDA-CFSAN as a notification to WTO/TBT on July 14, 2004
- Transparency
- Public posting to FDA-CFSAN Website
- 	http://www.cfsan.fda.gov/~comm/bse-ra.html
- Qualitative Risk Assessment
- Follows generally accepted framework endorsed by Codex Alimentarius Commission,  the U.S. National Academy of Sciences, and others

## BSE Risk Assessment: Framework

- Hazard Identification
- Exposure Assessment
- Hazard Characterization
- Dose/ Response Assessment
- Risk Characterization

## BSE Risk Assessment

- Hazard Identification: vCJD
- Exposure Assessment (Cosmetics)
- BSE in the United States :
- Washington State, 1 non-native born adult Holstein cow (bovine), December 23, 2003 (USDA)
- Use of Cattle Protein in Cosmetics
- Some protein ingredients but mostly tallow derivatives
- Absorption of ‘Prions’ from Cosmetics
- Eye area, shampoo
- Shaving or other skincare (abraded skin)
- Peroral ingestion-prone (lipcare, mouthwash, dentifrice)

## BSE Risk Assessment-1

- Hazard Characterization
- asymptomatic lag period (6 mo. – 4 yr.)
- Associative PrPc → PrPres  conversion in CNS tissue (exponential concentration increase)
- Dose/Response experimental infectivity in cattle
- Species Barrier in Humans of 101-104 needed to cause illness compared with cattle

## BSE Risk Assessment-2

- Risk Characterization
- Qualitative Risk Assessment
- Considerable “uncertainty” in premises, risk estimate,  exposure assessment, and cost-benefit analysis (CBA)
** **

## BSE Risk Assessment

**Conclusions**
**vCJD**** – **may be caused by BSE “prions”
**Primary source of exposure**** ****– **Ingestion of infected beef
**Secondary routes of exposure**** ****– **Topical (abraded skin), Ocular, or Oral/Buccal potentially possible, even if unlikely
**Dose/Response (cattle)**** ****- **Small doses still infectious but require longer incubation periods
**Species Barrier ****- **Human  = ca. 101 – 104 (cattle)
**Quantitative Risk Assessment ****- **difficult due to much  “Uncertainty”  in assumptions and available data
**Risk Management**
** **Effectiveness of cosmetic manufacturing proceses for inactivating BSE prions is unknown
-  Best control of risk through cosmetics is to avoid and control exposure to high-risk cattle raw materials used in the manufacture of cosmetics.

## Recent BSE Cases in North America:  January 23, 2006; March 13, 2006

**Dairy cow, 6-7 yrs old,  Alberta, Canada **
**Beef cow, > 10 yrs old, **
**     ****State of Alabama                  **
**FDA and USDA Notified by CFIA (Canadian Cow)**
**No part of either infected cow entered human food or animal feed chain**
**FDA evaluating any ‘next steps’ through ORA and CVM.**

## v-CJD Cases in the U.S.

- Tracked by CDC and FDA
- Few in number, generally non-resident or resident-alien
- 200 cases worldwide;  3 cases in U.S.
- November 28, 2006 - Latest case reported by CDC is young Saudi Arabian adult, resident in U.S. resident since late 2005, living in Virginia.
- Other cases:  UK (164), France (21), Republic of Ireland (4), the Netherlands (2), Canada (1), Italy (1), Japan (1), Portugal (1), Saudi Arabia (1), and Spain (1).

## FDA Export Certificates

- Guidance
- Cosmetics _[http://www.cfsan.fda.gov/~lrd/certific.html](http://www.cfsan.fda.gov/~lrd/certific.html)_
- CTFA, ICMAD designated by FDA as “competent authority”

**Notes:**
See attachments.

## CFSAN-OCAC Address Information

- How To Find Us:
- OCAC Management:
- CFSAN (HFS-100, 101)
- University Station (CPK2)
- 4300 River Road, College Park MD 20740
- Phone:  301 436-1130
- Fax:      301 436-2975
- E-Mail:   **stanley.milstein@fda.hhs.gov**
- Additional Locators:  CFSAN Website:
- http://www.cfsan.fda.gov/~dms/cos-toc.html