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Directorate-General for Health and Food Safety
1. Terms of Reference
Background
Annex II of the Cosmetic Directive 76/768/EEC (List of substances which must not form part of the composition of cosmetic products) prohibits the use of cells, tissues or products of human origin from use in cosmetic products marketed in the EU. These materials are listed under entry 416 of Annex II. Such materials were prohibited from use in cosmetic products due to the potential risk of transmission of Creutzfeldt-Jakob disease, human spongiform encephalopathy and viral diseases.
Current Status
This prohibition has excluded the use of materials derived from human hair in cosmetic products, such as amino acids. COLIPA – The European Cosmetic Toiletry and Perfumery Association - have requested that the entry is modified in order to allow the use of some materials derived from human hair and have produced a safety rationale to support this proposal.
The proposed modification to entry 416 :
Cells, tissues or products of human origin. However, amino acids obtained by hydrolysis of human hair may be used provided that the following method has been used and certified by the producer :
- Hydrolysis with HCl (> 20% throughout the whole process) for at least 6 hours at 100°C.
2. Mandate
It is requested that the SCCNFP review the received submission and respond to the following :
* Does the information contained in the safety dossier support the modification of entry 416 of Annex II to reflect the COLIPA proposal given above?
* Does the SCCNFP recommend alternative conditions/restrictions?
3. Opinion
3.1. The product, object of this evaluation
The product, object of this evaluation is a mixture of amino acids obtained from human hair hydrolysates after hydrolysis with concentrated HCl (>20%), 6 hours at 100ºC combined with subsequent activated carbon filtration and crystallisation and drying according to an appropriate industrial process.
3.2. Regulations and SSC / SCC opinions
- According to Annex II, number 416, of the Cosmetics Directive (18th Commission Directive of 10 July 1995) Cells, tissues or products of human origin must not form part of the composition of cosmetic products for the reason that they "are liable to transmit the CJD, human spongiform encephalopathy, and certain virus diseases";
- The position of the SCC (Scientific Committee on Cosmetology), as stated on the 4 October 1994, is to prohibit the use of human tissues and extracts in cosmetics. This position led to the precedent Commission Directive.
- According the opinions, adopted by the SSC (Scientific Steering Committee) the 26-27 March 1998 and 21-22 January 1999, the inactivation factor of 102.84 (for the referred infectious agents) for industrial gelatine process, is safe.
- According to the opinion on the safety of amino acids from human hair hydrolysate used in cosmetic products for topical application, with regard to Transmissible Spongiform Encephalopathy risk, adopted by the Scientific Steering Committee (SSC) at its meeting of 25-26 May 2000, it may be concluded that the risk resulting from the use of human hair to provide amino acids for incorporation into human hair- and skin-care products would appear to be negligible.
3.3. Terms of Reference
The question raised by COLIPA is that following recent opinions of SSC, SCC and latest scientific data, it seems justified to re-evaluate these measures with regard to amino acids derived from human hair hydrolysates.
3.4. Context of the problem
In recent years the spread of Bovine Spongiform Encephalopathy (BSE) has created considerable public concern, which was exacerbated from 1996 when a new variant (nv) of the sporadic Creutzfeld-Jakob disease (CJD) was described. Current concerns are :
1) The same infectious agent probably causes BSE and nvCJD.
2) nvCJD was probably caused by the ingestion of bovine products containing the infectious agent of BSE in cattle.
3) The transmission of CJD from one individual to another occurred by certain human tissues or products derived from them.
4) All nvCJD cases have occurred in young adults (below 50), in contrast with CJD that occurs in aged/old people (a peak at 70).
5) Prions are highly resistant to physical and chemical treatments that normally destroy bacteria and viruses (including proteases treatments, autoclaving at 121 ºC and 1 bar, radiation and disinfectants).
These situations led to precautionary measures and studies with respect to the use of medicinal products and food in order to prevent CJD, nvCJD and other human transmissible spongiform encephalopaties (hTSE). These diseases led inevitably (no remission or recovery) to the death after incubation periods ranging from 2 to 104 weeks. A protein called "prion" that experimentally causes the disease by intracerebral inoculation causes these diseases. Two types of prions are known: PrPC and PrPSc. PrPSc cause the disease and it is a protease-resistant isoform of the PrPC. PrPC is a normal host cellular protein, present at high levels in neurons, astrocytes, peripheral tissues and lymphocytes and it is believed to play a role in basic cell functions.
Sheep can be infected experimentally by the oral route with less than 1 g of BSE brain. Immune protection does not take place because the immune system recognises prions as "self" proteins. CJD are reported in many countries, at a prevalence of 1 out of 1 million humans. One of the main concerns about prions is their high resistance to conditions and agents that destroy micro-organisms or hydrolyse proteins.
How prions arise in animals or humans (apart from the horizontal transmission by ingestion or medical procedures) is still unknown. The current hypothesis proposes a somatic mutation of the PrPC gene into PrPSc gene or a spontaneous conversion of protein PrPC into protein PrPSc. PrPC is encoded by a gene on the short arm of chromosome 20 in humans and it is transmitted as a Mendelian dominant trait. In fact about 25% of the CJD are hereditary. However, many questions and uncertainties remain unanswered due to experimental difficulties and insufficient knowledge on prion proteins.
3.5. Situations of risk
There is conclusive evidence showing that humans might be infected by prions in the following ways :
- Hereditary transmission (Mendelian by an autosomal and dominant trait)
- Oral ingestion of a contaminated specific risk material (brain, spinal cord, bone marrow, organs and viscera)
- Contamination through medical procedures such as surgery or medicinal products (intracerebral, intravenous, intraperitoneal, subcutaneous and intramuscular administration).
3.6. Conclusion
Whereas :
1) At present, prions associated with TSE have not been detected in hair and thus are not considered as a specific risk material according to the SSC opinion (ref. 3, 13).
2) In a study of risk assessment (ref. 7, 8) the industrial process to obtain the evaluated product reduces the number of infectious units to an inactivation factor of 1011.6 which is safer than the EU adopted inactivation factor in the industrial production of gelatine which is 102.84. These inactivation factors have been determined using the same bioassay which evaluate TSE by assessing the presence and infectivity of PrPSc of infectious Syrian hamster scrapie agent. In environmental public health microbiology, an inactivation factor of 104 is usually considered to be safe. An additional consideration is that gelatine is obtained from animal bones, including bone marrow, which is a material with a high risk of CJD transmission.
3). Cosmetic uses of these hydrolysates are for topical application only, which completely excludes the known routes of transmission for human TSE.
4) At present, neither PrPC or PrPSc have been detected in human hair and there is no evidence indicating that TSE may be transmitted by topical application. The only reason to analyse the potential transmissible risk of CJD by prions from human hair are the two recent papers (ref. 5, 6) that describe the presence of PrPC (not PrPSc) in skin.
5) The vigorous conditions of the hydrolysis' method (>20% HCl, >6h, >100°C) in combination with compulsory control testing for absence of peptides, may guarantee the exclusion of transmissible PrPSc.
3.7. Opinion
The SCCNFP is of the opinion that amino acids obtained by hydrolysis of human hair can be considered safe as long as they are not contaminated with risk material.
The opinion is based on current knowledge on TSE and on the fact that amino acids can not transmit TSE.
3.8. Answers to the questions asked by DG ENTR :
- Does the information contained in the safety dossier support the modification of entry 416 of Annex II to reflect the COLIPA proposal given above?
Answer of the SCCNFP : the current scientific knowledge fully support the modification of entry 416 of Annex II to reflect the COLIPA proposal (see page 2).
- Does the SCCNFP recommend alternative conditions/restrictions?
Answer of the SCCNFP : the SCCNFP does not recommend alternative conditions nor restrictions.
4. References
1. COLIPA, 1999. Submission I. Concerned substances: Cells, tissues or products of human origin. Amino Acids from Human Hair Hydrolysed. January 2000.
2. COLIPA, 2000. Submission II. Concerned substances: Cells, tissues or products of human origin. AminoAcids from Human Hair Hydrolysed. January 2000.
3. E.C. (European Commission), 1998. Listing of specified risk materials: a scheme for assessing relative risks to man. Opinion of the Scientific Steering Committee. Adopted on 9 December 1997, re-edited on 22-23 January 1998.
4. E.C. (European Commission), 1998. Risk quantification for CJD transmission via substances of human origin. Opinion of the Scientific Committee on Medicinal Products and Medical Devices. Adopted on 21 October 1998.
5. Lemaire-Vieille, C., Schulze, T., Podevin-Mimster, V., Follet, J., Bailly, Y., Blanquet-Grossard, F., Decavel, J-P., Heinen, E., Cesbron, J-Y., (2000). Epithelial and endothelial expression of the green fluorescent protein gene under the control of bovine prion protein (PrP) gene regulatory sequences in transgenic mice. PNAS, 97 (10): 5422-5427.
6. Pammer, J., Weninger, W. and Tschachler, E. (1998) Human keratinocytes express cellular prion-related proteins in vitro and during inflammatory skin disease. American Journal of Pathology 153, 1353-1358.
7. Riesner D. and T. Appel. 1998. Risk assessment for L-Cystine, L-cisteine and derived products from keratin (human hair). (Two reports) Institute of Physical Biology, Heinrich Heine Universität Düsseldorf.
8. Riesner D. and T. Appel. 1999. Risk assessment for L-Cystine, L-cisteine and derived products from keratin (human hair). Part IV. Bioassay results: removal of TSE infectivity by HCl treatment and filtration.. Institute of Physical Biology, Heinrich Heine Universität Düsseldorf.
9. E.C. (European Commission), 1998.Safety of hydrolysed proteins produced from bovine hides. Opinion of the Scientific Steering Committee. Adopted on 22-23 October.
10. E.C. (European Commission), 1998. Opinion of the Scientific Steering Committee on the Safety of Gelatine. Adopted on 26-27 March 1998.
11. E.C. (European Commission), 1999. Evaluation of the "133º/20'/3 bars/pressure conditions" for the production of gelatine regarding its equivalency with commonly used industrial gelatine production processes in terms of its capacity of inactivating/eliminating possible TSE infectivity in the raw material. Report and Opinion of the Scientific Steering Committee- Adopted on 21-22 January 1999.
12. E.C. (European Commission), 1996. Opinion of the Scientific Committee on Cosmetology concerning Bovine Spongiform Encephalopathy. Adopted on 4 October 1996.
13. E.C. (European Commission), 2000. Considerations on the safety of amino acids from human hair hydrolysate used in cosmetic products for topical application, with regard to transmissible Spongiform Encephalopathy risks. Opinion of the Scientific Steering Committee. Adopted on 25-26 May 2000.
Background
Annex II of the Cosmetic Directive 76/768/EEC (List of substances which must not form part of the composition of cosmetic products) prohibits the use of cells, tissues or products of human origin from use in cosmetic products marketed in the EU. These materials are listed under entry 416 of Annex II. Such materials were prohibited from use in cosmetic products due to the potential risk of transmission of Creutzfeldt-Jakob disease, human spongiform encephalopathy and viral diseases.
Current Status
This prohibition has excluded the use of materials derived from human hair in cosmetic products, such as amino acids. COLIPA – The European Cosmetic Toiletry and Perfumery Association - have requested that the entry is modified in order to allow the use of some materials derived from human hair and have produced a safety rationale to support this proposal.
The proposed modification to entry 416 :
Cells, tissues or products of human origin. However, amino acids obtained by hydrolysis of human hair may be used provided that the following method has been used and certified by the producer :
- Hydrolysis with HCl (> 20% throughout the whole process) for at least 6 hours at 100°C.
2. Mandate
It is requested that the SCCNFP review the received submission and respond to the following :
* Does the information contained in the safety dossier support the modification of entry 416 of Annex II to reflect the COLIPA proposal given above?
* Does the SCCNFP recommend alternative conditions/restrictions?
3. Opinion
3.1. The product, object of this evaluation
The product, object of this evaluation is a mixture of amino acids obtained from human hair hydrolysates after hydrolysis with concentrated HCl (>20%), 6 hours at 100ºC combined with subsequent activated carbon filtration and crystallisation and drying according to an appropriate industrial process.
3.2. Regulations and SSC / SCC opinions
- According to Annex II, number 416, of the Cosmetics Directive (18th Commission Directive of 10 July 1995) Cells, tissues or products of human origin must not form part of the composition of cosmetic products for the reason that they "are liable to transmit the CJD, human spongiform encephalopathy, and certain virus diseases";
- The position of the SCC (Scientific Committee on Cosmetology), as stated on the 4 October 1994, is to prohibit the use of human tissues and extracts in cosmetics. This position led to the precedent Commission Directive.
- According the opinions, adopted by the SSC (Scientific Steering Committee) the 26-27 March 1998 and 21-22 January 1999, the inactivation factor of 102.84 (for the referred infectious agents) for industrial gelatine process, is safe.
- According to the opinion on the safety of amino acids from human hair hydrolysate used in cosmetic products for topical application, with regard to Transmissible Spongiform Encephalopathy risk, adopted by the Scientific Steering Committee (SSC) at its meeting of 25-26 May 2000, it may be concluded that the risk resulting from the use of human hair to provide amino acids for incorporation into human hair- and skin-care products would appear to be negligible.
3.3. Terms of Reference
The question raised by COLIPA is that following recent opinions of SSC, SCC and latest scientific data, it seems justified to re-evaluate these measures with regard to amino acids derived from human hair hydrolysates.
3.4. Context of the problem
In recent years the spread of Bovine Spongiform Encephalopathy (BSE) has created considerable public concern, which was exacerbated from 1996 when a new variant (nv) of the sporadic Creutzfeld-Jakob disease (CJD) was described. Current concerns are :
1) The same infectious agent probably causes BSE and nvCJD.
2) nvCJD was probably caused by the ingestion of bovine products containing the infectious agent of BSE in cattle.
3) The transmission of CJD from one individual to another occurred by certain human tissues or products derived from them.
4) All nvCJD cases have occurred in young adults (below 50), in contrast with CJD that occurs in aged/old people (a peak at 70).
5) Prions are highly resistant to physical and chemical treatments that normally destroy bacteria and viruses (including proteases treatments, autoclaving at 121 ºC and 1 bar, radiation and disinfectants).
These situations led to precautionary measures and studies with respect to the use of medicinal products and food in order to prevent CJD, nvCJD and other human transmissible spongiform encephalopaties (hTSE). These diseases led inevitably (no remission or recovery) to the death after incubation periods ranging from 2 to 104 weeks. A protein called "prion" that experimentally causes the disease by intracerebral inoculation causes these diseases. Two types of prions are known: PrPC and PrPSc. PrPSc cause the disease and it is a protease-resistant isoform of the PrPC. PrPC is a normal host cellular protein, present at high levels in neurons, astrocytes, peripheral tissues and lymphocytes and it is believed to play a role in basic cell functions.
Sheep can be infected experimentally by the oral route with less than 1 g of BSE brain. Immune protection does not take place because the immune system recognises prions as "self" proteins. CJD are reported in many countries, at a prevalence of 1 out of 1 million humans. One of the main concerns about prions is their high resistance to conditions and agents that destroy micro-organisms or hydrolyse proteins.
How prions arise in animals or humans (apart from the horizontal transmission by ingestion or medical procedures) is still unknown. The current hypothesis proposes a somatic mutation of the PrPC gene into PrPSc gene or a spontaneous conversion of protein PrPC into protein PrPSc. PrPC is encoded by a gene on the short arm of chromosome 20 in humans and it is transmitted as a Mendelian dominant trait. In fact about 25% of the CJD are hereditary. However, many questions and uncertainties remain unanswered due to experimental difficulties and insufficient knowledge on prion proteins.
3.5. Situations of risk
There is conclusive evidence showing that humans might be infected by prions in the following ways :
- Hereditary transmission (Mendelian by an autosomal and dominant trait)
- Oral ingestion of a contaminated specific risk material (brain, spinal cord, bone marrow, organs and viscera)
- Contamination through medical procedures such as surgery or medicinal products (intracerebral, intravenous, intraperitoneal, subcutaneous and intramuscular administration).
3.6. Conclusion
Whereas :
1) At present, prions associated with TSE have not been detected in hair and thus are not considered as a specific risk material according to the SSC opinion (ref. 3, 13).
2) In a study of risk assessment (ref. 7, 8) the industrial process to obtain the evaluated product reduces the number of infectious units to an inactivation factor of 1011.6 which is safer than the EU adopted inactivation factor in the industrial production of gelatine which is 102.84. These inactivation factors have been determined using the same bioassay which evaluate TSE by assessing the presence and infectivity of PrPSc of infectious Syrian hamster scrapie agent. In environmental public health microbiology, an inactivation factor of 104 is usually considered to be safe. An additional consideration is that gelatine is obtained from animal bones, including bone marrow, which is a material with a high risk of CJD transmission.
3). Cosmetic uses of these hydrolysates are for topical application only, which completely excludes the known routes of transmission for human TSE.
4) At present, neither PrPC or PrPSc have been detected in human hair and there is no evidence indicating that TSE may be transmitted by topical application. The only reason to analyse the potential transmissible risk of CJD by prions from human hair are the two recent papers (ref. 5, 6) that describe the presence of PrPC (not PrPSc) in skin.
5) The vigorous conditions of the hydrolysis' method (>20% HCl, >6h, >100°C) in combination with compulsory control testing for absence of peptides, may guarantee the exclusion of transmissible PrPSc.
3.7. Opinion
The SCCNFP is of the opinion that amino acids obtained by hydrolysis of human hair can be considered safe as long as they are not contaminated with risk material.
The opinion is based on current knowledge on TSE and on the fact that amino acids can not transmit TSE.
3.8. Answers to the questions asked by DG ENTR :
- Does the information contained in the safety dossier support the modification of entry 416 of Annex II to reflect the COLIPA proposal given above?
Answer of the SCCNFP : the current scientific knowledge fully support the modification of entry 416 of Annex II to reflect the COLIPA proposal (see page 2).
- Does the SCCNFP recommend alternative conditions/restrictions?
Answer of the SCCNFP : the SCCNFP does not recommend alternative conditions nor restrictions.
4. References
1. COLIPA, 1999. Submission I. Concerned substances: Cells, tissues or products of human origin. Amino Acids from Human Hair Hydrolysed. January 2000.
2. COLIPA, 2000. Submission II. Concerned substances: Cells, tissues or products of human origin. AminoAcids from Human Hair Hydrolysed. January 2000.
3. E.C. (European Commission), 1998. Listing of specified risk materials: a scheme for assessing relative risks to man. Opinion of the Scientific Steering Committee. Adopted on 9 December 1997, re-edited on 22-23 January 1998.
4. E.C. (European Commission), 1998. Risk quantification for CJD transmission via substances of human origin. Opinion of the Scientific Committee on Medicinal Products and Medical Devices. Adopted on 21 October 1998.
5. Lemaire-Vieille, C., Schulze, T., Podevin-Mimster, V., Follet, J., Bailly, Y., Blanquet-Grossard, F., Decavel, J-P., Heinen, E., Cesbron, J-Y., (2000). Epithelial and endothelial expression of the green fluorescent protein gene under the control of bovine prion protein (PrP) gene regulatory sequences in transgenic mice. PNAS, 97 (10): 5422-5427.
6. Pammer, J., Weninger, W. and Tschachler, E. (1998) Human keratinocytes express cellular prion-related proteins in vitro and during inflammatory skin disease. American Journal of Pathology 153, 1353-1358.
7. Riesner D. and T. Appel. 1998. Risk assessment for L-Cystine, L-cisteine and derived products from keratin (human hair). (Two reports) Institute of Physical Biology, Heinrich Heine Universität Düsseldorf.
8. Riesner D. and T. Appel. 1999. Risk assessment for L-Cystine, L-cisteine and derived products from keratin (human hair). Part IV. Bioassay results: removal of TSE infectivity by HCl treatment and filtration.. Institute of Physical Biology, Heinrich Heine Universität Düsseldorf.
9. E.C. (European Commission), 1998.Safety of hydrolysed proteins produced from bovine hides. Opinion of the Scientific Steering Committee. Adopted on 22-23 October.
10. E.C. (European Commission), 1998. Opinion of the Scientific Steering Committee on the Safety of Gelatine. Adopted on 26-27 March 1998.
11. E.C. (European Commission), 1999. Evaluation of the "133º/20'/3 bars/pressure conditions" for the production of gelatine regarding its equivalency with commonly used industrial gelatine production processes in terms of its capacity of inactivating/eliminating possible TSE infectivity in the raw material. Report and Opinion of the Scientific Steering Committee- Adopted on 21-22 January 1999.
12. E.C. (European Commission), 1996. Opinion of the Scientific Committee on Cosmetology concerning Bovine Spongiform Encephalopathy. Adopted on 4 October 1996.
13. E.C. (European Commission), 2000. Considerations on the safety of amino acids from human hair hydrolysate used in cosmetic products for topical application, with regard to transmissible Spongiform Encephalopathy risks. Opinion of the Scientific Steering Committee. Adopted on 25-26 May 2000.
