further public submissions on the proposed amendments to the … · 2016. 6. 7. · august 2015...

Further Public Submissions on the Proposed Amendments to the Poisons Standard Notice under subsection 42ZCZQ of the Therapeutic Goods Regulations 1990 (the Regulations)

A delegate of the Secretary to the Department of Health publishes herein all valid public submissions made in response to the invitation for further submissions on the interim decisions regarding the proposed amendments to the Poisons Standard. These submissions were considered by the chemicals scheduling and/or medicines scheduling delegates.

In accordance with the requirements of subsection 42ZCZQ of the Regulations these submissions have had confidential information removed.

Material claimed to be commercial-in-confidence was considered against the guidelines for the use and release of confidential information set out in Chapter 6 of the Scheduling Policy Framework for Medicines and Chemicals (SPF, 2015), issued by the Australian Health Ministers Advisory Council (AHMAC). The SPF is accessible at: https://www.tga.gov.au/publication/ahmac-scheduling-policy-framework-medicines-and-chemicals.

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3-isothiazolone, 2-methyl- (methylisothiazolinone)

has previously provided comments on MIT for the July 2014 meeting of the ACCS and the August 2015 joint meeting of the ACCS/ACMS. Our submissions to those meetings are provided as Attachment 1. With regard to the Delegates’ Interim Decision for;

Leave-on cosmetic preparations or therapeutic goods We have no objections to the Schedule 6 entry as proposed with a 24 month transition period to allow for reformulation of any affected products.

Rinse-off cosmetic preparations or therapeutic goods intended for topical rinse-off application

has several concerns with the proposed 0.0015% (15 ppm) exemption cut-off.

Effective concentration of MIT as a preservative At a concentration of 0.0015% or 15 ppm, MIT is not an effective preservative and will not fulfil its intended function of protecting finished product formulations from microbial contamination under normal conditions of manufacture and use. Based on reports from our members, we understand that a concentration of 0.005% (50 ppm) of MIT is the absolute minimum effective concentration in a formulation produced in pristine manufacturing settings (i.e. much better than the usual good manufacturing hygiene levels). It is usually included in formulations at 0.01% (100 ppm) as this is the dose at which it is effective against bacteria. Anecdotally, we are aware that some manufacturers have trialed the use of MIT as a preservative at a concentration of 0.0015% pre-empting the EU regulations, which notably have yet to be finalised and adopted into the Cosmetic Regulation (EC 1223/2009). The results of the trial showed that products were not adequately preserved. This is a concern as some smaller companies in Australia may believe that they can just reduce the preservative level used in their products and not replace it with another preservative. Availability and choice of preservatives – need for a broad overview As noted in our previous submissions, preservatives are chemicals intended to kill microorganisms and will therefore show some level of toxicity. However, without preservatives, products cannot be protected from microorganisms which then raises other health concerns. Removing any preservative from the currently available set of preservatives will require companies to consider whether there are other preservatives available that are as effective for all of their formulations – there is no absolute guarantee that the replacement preservative will be any better in terms of health outcomes i.e. preservative efficacy and/or significantly improved preservative toxicity profile. Research into new types of preservatives necessarily takes time, and again, there is no guarantee that there will be a better health outcome. For example, we understand that MIT is an effective replacement for parabens to preserve personal care products. Due to the focus on potential yet unproven health concerns around parabens, we understand that some companies have removed parabens from their formulations and replaced them with MIT. This leaves an interesting question for these companies if MIT cannot be used as a preservative – whether to go back to using parabens, or find some other preservative (if possible).

Attachment 1 – Previous Submissions on methylisothiazolinone (MIT)

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ACCS meeting: July 2014

3-isothiazolone, 2-methyl- (methylisothiazolone)

understands that the main reason for the proposal to schedule methylisothiazolone (MIT) arises from its sensitisation potential. There are many complex issues in scheduling consideration of MIT. We have attempted to list and explain some of these complexities below. Preservatives - Benefit vs Risk In scheduling consideration of MIT, it is necessary to consider the benefits of preservatives. MIT is one of the preservatives available on the market. When preservatives as a group are considered, it is necessary to note that they are chemicals intended to kill microorganisms and all show some level of toxicity. However, without preservatives, products cannot be protected from microorganisms which then raise other health concerns. Removing any preservative from currently available set of preservatives will require companies to consider whether there are other preservatives available that are as effective for all of their formulations – there is no absolute guarantee that the replacement preservative will be any better in terms of health outcomes i.e. preservative efficacy and/or significantly improved preservative toxicity profile. Research into new types of preservatives necessarily takes time, and again, there is no guarantee that there will be a better health outcome. For example, we understand that MIT is an effective replacement for parabens, also a preservative. Due to focus on potential yet unproven concerns around parabens, we understand that some companies have removed parabens from their formulation and replaced it with MIT. This leaves an interesting question for these companies if MIT cannot be used as a preservative – whether to go back to using parabens, or find some other preservative (if possible). Need to consider MIT as a distinct chemical for scheduling MIT is one of a family of isothiazolone preservatives. We understand from information provided to us that non-chlorinated isothiazolones are less likely to elicit sensitisation reaction. Further, cross sensitisation within the isothiazolone based preservatives does not occur i.e. MIT does not elicit an allergy response from a person sensitised to chloromethylisothiazolinone (CIT).

has been provided a summary of studies into the sensitisation potential of isothiazolinone compounds which provides further details in confidence. Having reviewed the commercial-in-confidence guidelines in Scheduling Policy Framework we are unsure whether this information can be kept confidential once provided to the ACCS. We are happy to provide the information to the ACCS if confidentiality can be retained, noting that the material was provided to us in confidence. Also, we understand that a combination of different isothiazolone preservatives can be effective while reducing the overall amount of preservatives used. An example of this is the use of benzisothiazolone (BIT) combined with MIT. It is my understanding that MIT is effective against bacteria at around 100ppm, but only effective against fungi at increased levels - up to 1000ppm. BIT however is effective against fungi at around 100ppm. Therefore combination of up to 100ppm of BIT with up to 100ppm of MIT results in a preservative effective against both bacteria and fungi.

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Given these consideration, we believe it is necessary to consider scheduling individual preservative separately, excluding salts and derivatives. Broad range and large number of available products There is a wide range and a large number of products that use CIT or MIT as a preservative. MIT is also a by-product of CIT (3:1 ratio of CIT:MIT) and the use of CIT as a preservative will necessarily include MIT in the product. From feedback received, we understand that MIT is used in:

Cosmetics including shampoos, conditioners, liquid soap, deodorants, hair fixing products, etc.,

Domestic cleaning products including floor polishes, ironing sprays, stain removers, carpet cleaners, dishwashing liquid, dish washing rinse-aid, anti-mould sprays, etc.,

Car polishes, emulsion waxes, tyre paints, etc., Paints, adhesives, sealants, patching compounds, etc., Inkjet cartridges and some marker pens, and Industrial water treatment products.

As one of our Members has summarised, basically any formulation containing water may have MIT as a preservative. We also note that MIT is on the ARTG and maybe used as a preservative in therapeutic goods. It is therefore necessary to carve out the products that are not likely to pose a concern e.g. all industrial uses and non-skin contact or no deliberate skin contact products, then have a tiered approach to scheduling for the remainder. Effective concentration vs “safe” concentration MIT is a preservative and there is a range of concentrations at which it is effective. Restricting the use of the substance to below the effective level is likely to result in the following outcome:

MIT is not likely to be used by responsible industry as the allowed levels will not be effective as a preservative, however,

MIT may be used at allowed levels by some companies which may result in microbial contamination concerns for those products.

As noted above, we understand that MIT is effective against bacteria at around 100ppm, and effective against fungus at around 1000ppm. Product concentrations reported by our Members appear to align with these concentrations - MIT is used in cosmetics at up to 100ppm and in some domestic cleaning products at up to 1000ppm.

The EU Scientific Committee on Consumer Safety (SCCS) published its opinion on MIT and sensitisation on 12 December 2013. A revised version of this report (revision date 27 March 2014) is available from the European Commission website: http://ec.europa.eu/health/scientific committees/consumer safety/docs/sccs o 145.pdf. Since the publication of the SCCS report, the US Cosmetic Ingredient Review (CIR) began evaluating the information relevant to MIT. The CIR published its Tentative Report for Public Comment (Tentative Report) on 20 June 2014. The Tentative Report is available from the CIR website: http://www.cir-safety.org/sites/default/files/mthiaz062014tent 0.pdf.

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It is important to note that there is a significant difference in opinion between the two reviews. The SCCS concluded that up to 15 ppm in rinse-off cosmetics is safe. This concentration is lower than the effective concentration of MIT. The SCCS could not establish a safe leave-on level. The CIR Tentative Report concluded that up to 100ppm in rinse-off cosmetics is safe, and non-sensitising concentration in leave-on formulations may be determined based on quantitative risk assessment (QRA). Next Steps Given the complexity of consideration, we urge the ACCS to consider the following next steps for scheduling consideration.

1. Exclude industrial and other products not intended for direct skin contact from scheduling consideration,

2. Defer the scheduling consideration for cosmetics and domestic products intended for skin contact until the finalisation of the CIR report (expected before the November 2014 meeting of the ACCS),

3. Defer the decision to a joint committee of ACCS and ACMS to ensure that therapeutic goods using MIT as a preservative are also considered,

4. Clarify that the scheduling consideration is for MIT only, and does not apply to other isothiazolone preservatives, and

5. Work with industry to reconcile the issues raised above, including the consideration of reported adverse effects locally.

ACMS/ACCS meeting: August 2015

Methylisothiazolinone (MIT) – supplementary information

The Scientific Committee on Consumer Safety (SCCS) adopted a draft opinion on MIT (sensitisation only) on 25 June 2015. The draft opinion is available from: http://ec.europa.eu/health/scientific committees/consumer safety/docs/sccs o 178.pdf. Public comment period is open until 1 September 2015.

believes that a careful consideration of both the SCCS draft opinion and the Cosmetic Ingredient Review (CIR) Safety Assessment of MIT (or MI) as used in cosmetics is necessary as the two expert bodies have reached very different conclusions. As they are both contemporary assessments of MIT, we believe that this is a case of differing opinions from two expert bodies on scientific evidence and the conclusions to be drawn from them, rather than one opinion outdating the other. For example, we have counted that there are 17 references in common i.e. cited in both the SCCS draft opinion and the CIR Safety Assessment, even though the conclusions reached are very different. The CIR Safety Assessment finalised on 8 October 2014 concluded as follows:

The CIR Expert Panel concluded that MI is safe for use in rinse-off cosmetic products at concentrations up to 100 ppm and safe in leave-on cosmetic products when they are formulated to be non-sensitizing, which may be determined based on a QRA.

In comparison, the SCCS draft Opinion adopted on 25 June 2015 concludes as follows:

1. On the basis of the data provided, does the SCCS consider Methylisothiazolinone (MI) to be safe for consumers, when used as a preservative in rinse-off products up to concentration limit of 100 ppm from the view of induction of contact allergy? The information provided does not support the safe use of MI as a preservative in rinse-off cosmetic products up to a concentration limit of 100 ppm from the view of induction of contact allergy. For rinse-off cosmetic products, a concentration of 15 ppm (0.0015%) MI is considered safe for the consumer from the point of view of induction of contact allergy. 2. On the basis of the data provided, does the SCCS consider Metylisothiazolinone (MI) to be safe for consumers, when used as a preservative in leave-on hair products up to concentration limit of 100 ppm from the view of induction of contact allergy? The information provided does not support the safe use of MI as a preservative in leave-on hair cosmetic products up to a concentration limit of 100 ppm from the point of view of induction of contact allergy. 3. Does the SCCS have any further scientific concerns with regard to the use of Methylisothiazolinone (MI) in cosmetic product

The concerns and opinions raised in SCCS Opinion SCCS/1521/13 (12 December 2013with revision 27 March 2014) remain. The results of the recent Scandinavian study do not support safety of MI in rinse-off products at either 100 ppm or at 50 ppm for elicitation or induction.

It is our understanding that the test data on MIT e.g. HRIPT studies and LLNA are very favourable, showing low likelihood of sensitisation. However, we also understand that there is an increase in the number of patients showing MIT sensitisation. It is also questionable how patients are being sensitised, noting the widespread use of MIT outside the cosmetics sector, and there is an uncertainty in the elicitation and induction doses of MIT. Given these somewhat contradictory evidence and “unknowns”, we believe a careful consideration of all available evidence is warranted for risk management of MIT. In addition to the scientific evidence provided in the CIR Safety Assessment and the SCCS draft opinion, provides the following industry factors that should be taken into consideration for risk management decisions of MIT. Effective concentration of MIT in products MIT is used as a preservative at 100 ppm because it is the dose at which it is effective against bacteria. In some products (non-cosmetic products) it is used at up to 1000 ppm, a dose at which it is effective against fungi. It is our understanding that if the manufacturing facility is pristine i.e. much better than the usual good manufacturing hygiene levels, then 50 ppm may be enough for MIT to be effective against bacteria. MIT is not an effective biocide at 15 ppm. If the SCCS draft opinion is adopted, this would mean a phase out of MIT from all cosmetic products, except as a by-product in CIT:MIT (3:1) preservative. Availability and choice of preservatives – need for a broad overview As noted in our previous submission to the July 2014 consideration of MIT, all preservatives show some level of toxicity. However, it is also recognised that preservatives play an important role in ensuring that every day products are not spoilt – spoilt products or products contaminated with bacteria and other harmful microorganisms can lead to infection and sepsis. We believe that there is a need to maintain a broad choice of preservatives for formulators of products to choose from, provided that this does not lead to an unacceptable risk. We also believe that narrowing the choice of preservatives can potentially lead to increased risk from exposure to preservatives as more consumers are exposed to products containing a narrower range of preservatives i.e. increased exposure to a single type of a preservative. In this context, removing MIT entirely from currently available range of preservatives may not be the best risk management option. However, there may be a case for limiting to use of MIT only to certain types of products and to certain concentration levels to ensure that the risk of sensitisation from contact with MIT is minimised. Timing - final review document vs draft opinion It must also be noted that the SCCS opinion is currently in draft and will not finalised until after the close of the public comment period. The final opinion is therefore unlikely to be published before the end of this year.

One of the options available to the Committees and the Delegates is to defer the final decision on MIT until the SCCS draft opinion is finalised. However, noting the wide spread use of MIT in all types of use i.e. industrial, consumer and cosmetic, we believe it may be prudent to consult on a detailed proposal for scheduling of MIT prior to finalisation of any decisions. Transition time for any scheduling decisions Once again noting the wide spread use of MIT, any scheduling decision on MIT should allow a 24 months transition. Where it is likely that reformulation is required, industry would need minimum 24 months to reformulate their products and phase out existing products.

Attachment 2 – ASEAN Cosmetics Associations presentation on Quantitative Risk Assessment of MIT

Methylisothiazolinone

The presentation is based on Cosmetics Europe data

Sensitisation Assessment Factors (SAF)

Apply of NESIL to extrapolate from controlled experimental situation to real life exposure scenarios (Ref: Felter et al 2002)

Three areas of extrapolation/SAF’s• Inter-individual susceptibility• Matrix effects• Use considerations

Product specific:• For a shower gel a SAF of 100 is applied

Derivation of Acceptable exposure level (AEL)• 15μg/cm2 / 100• for shower gel is 0.15µg/cm2

Inter-individual Variability(Age, Gender, Ethnicity, Inherent Dermal Barrier and Genetic

Effects)

Vehicle or Product Matrix Effects(e.g. presence of irritants, penetration enhancer)

Use Considerations(Site of Contact, Barrier Function, Occlusion)

10

1 103

1 103

6

10

3

3

QRA for representative cosmetic products

• Used the QRA to rank the risk of Induction of skin allergy in consumers for a wide range of cosmetic products

• Exposure data has been taken from SCCS notes of guidance, Hall et al 2006, or QRA guidance document for fragrance allergens.

– Where data have not been available internal data from member companies has been used or suitable surrogates identified

• Representative product portfolio assessed included the major product / exposure scenarios.

• The NESIL was derived from publically available data from SCCS opinion 2004

– NOEL = 15μg/cm2

• Safety assessment factors were applied in consistency with the QRA technical guidance document for fragrance allergens

Methylisothiazolinone (MIT)

QRA DATA FROM CE (Cosmetics Europe) defending 100 ppm in Rinse off products

NESIL is determined to be 15 μg/cm2 by WoE approach based on data from HRIPT

Methylisothiazolinone (MIT)

QRA Outcome from 100 ppm

Attachment 3 – Correspondence from the ASEAN Cosmetics Associations

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recommendations1 allow for a cut-off in rinse-off preparations of 0.01% (100 ppm), as do the current EU regulations2, adopted in 2014.

As a result, the key global regulators are currently aligned on a cut-off of 0.01% and a move to a cut-off of 0.0015% currently represents a unique Australian requirement, not aligned with the rest of the world.

notes the recent opinion of the EU Scientific Committee on Consumer Safety (SCCS)3, which has concluded that a concentration of 0.0015% (15 ppm) is safe in rinse-off topical products. However, this opinion has not yet been adopted into European legislation. It does however highlight the ongoing safety concerns around skin sensitization.

MIT is not an effective preservative / biocide at 15 ppm (0.0015%). The proposed cut-off of 0.015% (15 ppm) therefore is below the level at which the preservative is effective.

In effect, this means that the vast majority, if not all, topical products that contain MIT will require reformulation.

Although some products are being re-formulated to remove MIT, there are still many products that contain MIT at levels below 0.01%, but over 0.0015% and these products will require re-formulation.

Noting the above points, it is clear that many Australian companies, particularly those which import US or European products containing MIT, will be required to make significant product changes if Australia cannot accept products that can be supplied in the rest of the world. Although many sponsors will have started looking at alternative preservative systems as a result of the EU SCCS opinion4, sponsors cannot be certain that this will be done within the stricter timeframes proposed by the Australian regulator compared to the rest of the world. This highlights the importance of Australian decisions that align with the recommendations and timings of the other key regulators. The proposed cut-off of 0.0015% in rinse off topical products will have a significant industry impact as Australia will be out of alignment with US and European legislation. Should a new scheduling entry for MIT result, then requests that the Delegate allow at least 24 months and preferably 30 months transition period so as to give affected manufacturers sufficient time to investigate alternative preservative systems, develop new formulations, perform the required testing to ascertain the optimal formulation and preservative systems, manufacture test batches and perform the associated stability / quality control on test batches before going to market. Please contact me should you require any further clarification relating to this submission. Yours sincerely,

1 http://www.cir-safety.org/sites/default/files/mthiaz062014tent 0.pdf 2 http://eur-lex.europa.eu/legal-content/EN/TXT/HTML/?uri=CELEX:32014R1003&from=EN 3 http://ec.europa.eu/health/scientific committees/consumer safety/docs/sccs o 178.pdf 4 http://ec.europa.eu/health/scientific committees/consumer safety/docs/sccs o 178.pdf

The Secretary 15 October 2015 Scheduling Secretariat GPO Box 9848 CANBERRA ACT 2601 Dear Sir/Madam, RE: Response to the interim decisions & reasons for decisions by Delegate’s of the Secretary to the Department of Health from the August 2015 joint meeting of the Advisory Committee on Chemicals Scheduling and the Advisory Committee on Medicines Scheduling (ACCS/ACMS #11)

would like to provide comments to the Delegate’s interim decisions relating to the scheduling proposals which were referred to the joint meeting of the Advisory Committee on Chemicals Scheduling and the Advisory Committee of Medicines Scheduling (ACCS/ACMS) in August 2015. Methylisothiazolinone (MIT)

supports the interim decision to include MIT contained in leave on products in Schedule 6 of the SUSMP with an implementation date of 01 October 2017. However, does not agree that an exemption cut off of .0015% (15ppm) for MIT is appropriate for rinse off cosmetic preparations or topical therapeutic goods for the following reasons:

- MIT is not an effective preservative/biocide at 15ppm. - Globally, MIT is currently used in readily available leave-on and rinse off cosmetics

and topical therapeutic goods at concentrations up to 0.01% (100 ppm). - Further work is currently being conducted in Europe by industry (IFRA) in

partnership with the Joint Research Centre (JRC) - the European Commission's in-house science service which employs scientists to carry out research in order to provide independent scientific advice and support to EU policy. The focus of this work is to further improve on the QRA methodology under the IDEA project1 (International Dialogue for the Evaluation of Allergens), which will facilitate a more robust safety assessment for the use of MIT in rinse-off products. An outcome is expected in 2016.

Based on the above, proposes two options for scheduling of MIT in rinse off cosmetic preparations and topical therapeutic goods:

1. To further defer the final decision on MIT in rinse off cosmetics and topical therapeutic goods until the SCCS draft opinion is finalised, and further results from the improved QRA is available. This approach has been used in the past by the NDPSC with the up-scheduling proposal of codeine in analgesics and cold and flu products. OR

2. Implement an exemption cut off of .01% (100ppm) for rinse off cosmetic preparations and topical therapeutic goods with a transition period of 24 months. In this time we would expect to have more information available on the safety of MIT in rinse off products, which could be used to review the appropriateness of the 100ppm cut off.

1 IDEA Project http://www.ideaproject.info/

International status and ongoing safety assessments The SCCS and CIR panels used the Quantitative Risk Assessment to rank the risk of skin allergy induction in consumers for a wide range of cosmetic products. The QRA plays a role in a weight of evidence to prevent induction of new sensitisations. Europe The EU SCCS opinion on MIT is currently in draft, with the public comment period having closed on 1 September 2015. The latest draft opinion from the SCCS was in July 2015. Industry stakeholders in Europe provided considerable information to inform the SCCS opinion during the comment period, including a Quantitative Risk Assessment (QRA) of MIT when used at a concentration of 0.001% (100ppm) in rinse-off cosmetics. The SCCS has acknowledged that further work to refine the QRA methodology is needed before it can be accepted and applied to specific ingredients. Please refer to the submission in response to the Delegate’s interim decision for further details on the information provided to the SCCS in July 2015. As discussed above further work is currently being conducted to further improve the QRA methodology under the IDEA project. This work will facilitate a more robust safety assessment for the use of MIT in rinse-off products. An outcome is expected in 2016. Additionally the European commission has not as yet implemented changes to their legislation with respect to MIT and its use in cosmetic products. The recommendations are currently under public consultation. On the basis of the information provided to the EU Commission, they propose to proceed in two steps:

1. Banning MIT in leave-on products while the SCCS conducts an additional risk assessment for rinse-off and hair leave-on products based on new data. This measure should already have a positive effect on the incidence of allergies;

2. Wait for the final SCCS opinion on rinse-off and hair leave-on products, before reducing the concentration from 100ppm to 15ppm.

There are two reasons why the European Commission has agreed to wait on implementing the changes. They feel recently submitted data needs to be assessed and that the cosmetic industry considers that a concentration of 15ppm would not be an effective preservative, which is concerning due to recent challenges to cosmetic product preservation.2 If the Delegate decided to include MIT in Schedule 6 of the SUSMP with a cut off of 15ppm for rinse off products, it will be the first regulator globally to have made this a legislated change. ___________________________ 2 Public consultation on Methylisothiazolinone (MI) - Regulation (EC) No. 1223/2009 on cosmetic. http://ec.europa.eu/growth/tools-databases/newsroom/cf/itemdetail.cfm?item_id=8372

USA In June 2015, The CIR Expert Panel was provided with the SCCS opinion on Methylisothiazolinone (MIT). The expert panel considered the same information as the SCCS but came to a different conclusion. In September 2014, "the CIR Expert Panel concluded that MIT is safe for use in rinse-off cosmetic products at concentrations up to .01% (100 ppm) and safe in leave-on cosmetic products when they are formulated to be non-sensitizing, which may be determined based on a Quantitative Risk Assessment." In September 2015, the CIR Expert Panel voted not to open the report on MIT. They have indicated they will be monitoring reports of sensitization rates on this preservative.3

Summary

Based on the above request the Delegate to consider one of the two options below:

1. To further defer the final decision on MIT in rinse off cosmetics and topical therapeutic goods until the SCCS draft opinion is finalised, and further results from the improved QRA is available OR

2. Implement an exemption cut off of .01% (100ppm) for rinse off cosmetic products and topical therapeutic goods with a transition period of 24 months. In this time we would expect to have more information available on the safety of MIT in rinse off products, which could be used to review the appropriateness of the 100ppm cut off.

A careful consideration of all available evidence is warranted for risk management of MIT in rinse off products. METHYLCHLOROISOTHIAZOLINONE (MCI)

supports the interim decision to include Methylchloroisothiazolinone in schedule 6 except in rinse off cosmetic preparations or therapeutic goods intended for topical rinse off application containing 0.0015 per cent or less of methylchloroisothiazolinone and methylisothiazolinone in total; or other preparations that are not for human use containing 0.0015 per cent or less of methylchloroisothiazolinone and methylisothiazolinone in total. Yours faithfully,

________________________

3 Cosmetic Ingredient Review Expert Panel 136th Meeting- Findings. September 25, 2015

ACMS/ACCS meeting: August 2015

Methylisothiazolinone (MIT) – supplementary information

The Scientific Committee on Consumer Safety (SCCS) adopted a draft opinion on MIT (sensitisation only) on 25 June 2015. The draft opinion is available from: http://ec.europa.eu/health/scientific committees/consumer safety/docs/sccs o 178.pdf. Public comment period is open until 1 September 2015.

believes that a careful consideration of both the SCCS draft opinion and the Cosmetic Ingredient Review (CIR) Safety Assessment of MIT (or MI) as used in cosmetics is necessary as the two expert bodies have reached very different conclusions. As they are both contemporary assessments of MIT, we believe that this is a case of differing opinions from two expert bodies on scientific evidence and the conclusions to be drawn from them, rather than one opinion outdating the other. For example, we have counted that there are 17 references in common i.e. cited in both the SCCS draft opinion and the CIR Safety Assessment, even though the conclusions reached are very different. The CIR Safety Assessment finalised on 8 October 2014 concluded as follows:

The CIR Expert Panel concluded that MI is safe for use in rinse-off cosmetic products at concentrations up to 100 ppm and safe in leave-on cosmetic products when they are formulated to be non-sensitizing, which may be determined based on a QRA.

In comparison, the SCCS draft Opinion adopted on 25 June 2015 concludes as follows:

1. On the basis of the data provided, does the SCCS consider Methylisothiazolinone (MI) to be safe for consumers, when used as a preservative in rinse-off products up to concentration limit of 100 ppm from the view of induction of contact allergy? The information provided does not support the safe use of MI as a preservative in rinse-off cosmetic products up to a concentration limit of 100 ppm from the view of induction of contact allergy. For rinse-off cosmetic products, a concentration of 15 ppm (0.0015%) MI is considered safe for the consumer from the point of view of induction of contact allergy. 2. On the basis of the data provided, does the SCCS consider Metylisothiazolinone (MI) to be safe for consumers, when used as a preservative in leave-on hair products up to concentration limit of 100 ppm from the view of induction of contact allergy? The information provided does not support the safe use of MI as a preservative in leave-on hair cosmetic products up to a concentration limit of 100 ppm from the point of view of induction of contact allergy. 3. Does the SCCS have any further scientific concerns with regard to the use of Methylisothiazolinone (MI) in cosmetic product

The concerns and opinions raised in SCCS Opinion SCCS/1521/13 (12 December 2013with revision 27 March 2014) remain. The results of the recent Scandinavian study do not support safety of MI in rinse-off products at either 100 ppm or at 50 ppm for elicitation or induction.

It is our understanding that the test data on MIT e.g. HRIPT studies and LLNA are very favourable, showing low likelihood of sensitisation. However, we also understand that there is an increase in the number of patients showing MIT sensitisation. It is also questionable how patients are being sensitised, noting the widespread use of MIT outside the cosmetics sector, and there is an uncertainty in the elicitation and induction doses of MIT. Given these somewhat contradictory evidence and “unknowns”, we believe a careful consideration of all available evidence is warranted for risk management of MIT. In addition to the scientific evidence provided in the CIR Safety Assessment and the SCCS draft opinion, provides the following industry factors that should be taken into consideration for risk management decisions of MIT. Effective concentration of MIT in products MIT is used as a preservative at 100 ppm because it is the dose at which it is effective against bacteria. In some products (non-cosmetic products) it is used at up to 1000 ppm, a dose at which it is effective against fungi. It is our understanding that if the manufacturing facility is pristine i.e. much better than the usual good manufacturing hygiene levels, then 50 ppm may be enough for MIT to be effective against bacteria. MIT is not an effective biocide at 15 ppm. If the SCCS draft opinion is adopted, this would mean a phase out of MIT from all cosmetic products, except as a by-product in CIT:MIT (3:1) preservative. Availability and choice of preservatives – need for a broad overview As noted in our previous submission to the July 2014 consideration of MIT, all preservatives show some level of toxicity. However, it is also recognised that preservatives play an important role in ensuring that every day products are not spoilt – spoilt products or products contaminated with bacteria and other harmful microorganisms can lead to infection and sepsis. We believe that there is a need to maintain a broad choice of preservatives for formulators of products to choose from, provided that this does not lead to an unacceptable risk. We also believe that narrowing the choice of preservatives can potentially lead to increased risk from exposure to preservatives as more consumers are exposed to products containing a narrower range of preservatives i.e. increased exposure to a single type of a preservative. In this context, removing MIT entirely from currently available range of preservatives may not be the best risk management option. However, there may be a case for limiting to use of MIT only to certain types of products and to certain concentration levels to ensure that the risk of sensitisation from contact with MIT is minimised. Timing - final review document vs draft opinion It must also be noted that the SCCS opinion is currently in draft and will not finalised until after the close of the public comment period. The final opinion is therefore unlikely to be published before the end of this year.

One of the options available to the Committees and the Delegates is to defer the final decision on MIT until the SCCS draft opinion is finalised. However, noting the wide spread use of MIT in all types of use i.e. industrial, consumer and cosmetic, we believe it may be prudent to consult on a detailed proposal for scheduling of MIT prior to finalisation of any decisions. Transition time for any scheduling decisions Once again noting the wide spread use of MIT, any scheduling decision on MIT should allow a 24 months transition. Where it is likely that reformulation is required, industry would need minimum 24 months to reformulate their products and phase out existing products.

SCCS/1557/15

Scientific Committee on Consumer Safety

SCCS

OPINION ON

Methylisothiazolinone (MI) (P94)

Submission III

(Sensitisation only)

The SCCS adopted this opinion at its 10th plenary meeting

on 25 June 2015

SCCS/1557/15

Opinion on Methylisothiazolinone (MI) (P94), submission III, sensitisation only

3

ACKNOWLEDGMENTS

SCCS Members

Dr. U. Bernauer Dr. Q. Chaudhry

Prof. P.J. Coenraads Prof. G. Degen (chairperson)

Dr. M. Dusinska

Dr. W. Lilienblum Dr. E. Nielsen

Prof. T. Platzek Dr. S. Ch. Rastogi

Dr. Ch. Rousselle Dr. J. van Benthem

External experts

Prof. A. Bernard

Prof. J. Duus-Johansen Dr. J. Ezendam

Prof. A. M. Giménez-Arnau (rapporteur) Dr. E. Mikova

Dr. E. Panteri Prof. T. Vanhaecke

Keywords: SCCS, scientific opinion, Methylisothiazolinone (MI) (P94), sensitisation,

Regulation 1223/2009, CAS 2682-20-4, EC 220-239-6

Opinion to be cited as: SCCS (Scientific Committee on Consumer Safety), Opinion on

Methylisothiazolinone (MI) (P94) sensitisation only, 25 June 2015, SCCS/1557/15

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TABLE OF CONTENTS

ACKNOWLEDGMENTS ........................................................................................... 3

TABLE OF CONTENTS ............................................................................................ 4

1. BACKGROUND ............................................................................................. 5

2. TERMS OF REFERENCE .................................................................................. 6

3. OPINION ..................................................................................................... 7

3.1 Chemical and Physical Specifications ....................................................... 7

3.2 Epidemiology of contact allergy to methylisothiazolinone updated ............... 7

3.3 (SCCS/1521/13) opinion on Methylisothiazolinone (P94) and rinse-off products

9

3.4 New submission ................................................................................... 9

3.5 Resubmission of comments from CE for re-consideration ......................... 10

3.6 Submission of new data from CE .......................................................... 11

3.7 Use test with rinse-off products in MI sensitised consumers. ................... 15

3.8 Compilation of cosmetovigilance data related to cosmetic products containing

Methylisothiazolinone (MI) ................................................................................ 15

3.9 DISCUSSION ..................................................................................... 17

4. CONCLUSION ............................................................................................ 19

5. REFERENCES ............................................................................................. 20

ANNEX I ........................................................................................................... 22

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1. BACKGROUND

The Scientific Committee on Cosmetic Products and Non-Food Products (SCCNFP) adopted

two opinions on "Methylisothiazolinone" respectively in March 2003 (SCCNFP/0625/02) and in April 2004 (SCCNFP/0805/04).

The SCCNFP (March 2003 - SCCNFP/0625/02) concluded that the information submitted was insufficient at that time to allow an adequate risk assessment of Methylisothiazolinone

to be carried out. The SCCNFP required: more detailed information concerning the physico-chemical properties of Methylisothiazolinone (e.g. LCMS analysis, pH, stability and

degradation products); information on the material used in the tests (batch numbers, purity and impurities); an in vitro percutaneous absorption study and relevant and adequate

genotoxicity/mutagenicity studies.

In response to the opinion of the SCCNFP concerning Methylisothiazolinone, adopted during

the 23rd plenary meeting of 18 March 2003 (doc. n° SCCNFP/0625/02), additional information on the physico-chemical properties of the substance, an in vitro percutaneous

absorption study and two studies on mutagenicity/genotoxicity were submitted to the SCCNFP for evaluation. In April 2004 the SCCNFP (SCCNFP/0805/04) concluded that the

requested data were complete. Methylisothiazolinone was considered non genotoxic/mutagenic.

Methylisothiazolinone (MI) was listed in Annex V/57 of Regulation (EC) No 1223/2009 to be

used as preservative at maximum concentration of 0.01% (100 ppm) in cosmetics products.

According to several Member States and a good number of published papers, the

sensitisation to MI is becoming an increasing problem all over Europe. In light of this information, the Commission requested to the Scientific Committee (SCCS) a reassessment

of the safety of MI when it is used as preservative in cosmetics products at maximum concentration of 100 ppm. The scientific opinion of the SCCS (SCCS/1521/13) on

Methylisothiazolinone (P94) Submission II (Sensitisation only) was delivered in March 2014 with the following conclusions:

Current clinical data indicate that 100 ppm MI in cosmetic products is not safe for the consumer. For leave-on cosmetic products (including 'wet wipes'), no safe concentrations of

MI for induction of contact allergy or elicitation have been adequately demonstrated. For rinse-off cosmetic products, a concentration of 15 ppm (0.0015%) MI is considered safe for

the consumer from the view of induction of contact allergy. However, no information is available on elicitation.

Recently, the SCCS received a new mandate in order to assess safety of 100 ppm of MI

included in rinse off and hair leave on products. Data from Cosmetics Europe concerning the

safety of MI in rinse-off and hair leave on products were received in June 2014, new cosmetovigilance data in February 2015 and data on aggregate exposures to rinse-off

products in May 2015. The concentration limit of MI to 15 ppm proposed by the SCCS for rinse off products is based on the data available related to the mixture MCI/MI

(SCCS/1238/09). New data are submitted trying to demonstrate that 100 ppm included in rinse-off and in leave-on hair cosmetics products is safe for the consumers. The SCCS is

requested to give an opinion about the safety of MI at 100 ppm in rinse-off and leave-on hair cosmetic products.

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2. TERMS OF REFERENCE

1. On the basis of the data provided, does the SCCS consider Methylisothiazolinone (MI) to

be safe for consumers, when used as a preservative in rinse-off products up to concentration limit of 100 ppm from the view of induction of contact allergy?

2. On the basis of the data provided, does the SCCS consider Methylisothiazolinone (MI) to be safe for consumers, when used as a preservative in leave-on hair products up to

concentration limit of 100 ppm from the view of induction of contact allergy?

3. Does the SCCS have any further scientific concerns with regard to the use of Methylisothiazolinone (MI) in cosmetic products?

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3. OPINION

3.1 Chemical and Physical Specifications

3.1.1 Chemical identity

3.1.1.1 Primary name and/or INCI name

INCI methylisothiazolinone

3.1.1.2 Chemical names

Methylisothiazolinone

IUPAC: 2-Methylisothiazol-3(2H)-one Other: 2-Methyl-4-isothiazolin-3-one

3.1.1.3 Trade names and abbreviations

3.1.1.4 CAS / EC number

CAS no. 2682-20-4

EC 220-239-6

3.1.1.5 Structural formula

3.1.1.6 Empirical formula

C4H5NOS

3.2 Epidemiology of contact allergy to methylisothiazolinone updated

The SCCS Opinion on Methylisothiazolinone published 27 March 2014 includes a complete review of the literature published about Methylisothiazolinone (MI) contact allergy up to that

date. The most important data introduced in the 2014 report are the following:

MI alone (without MCI) was introduced as a preservative in industrial products in the early 2000s, and in 2005 it was allowed as a preservative in both leave-on and rinse-off

cosmetics at a maximum concentration of 100 ppm (0.01%) (Annex V/57 of the Cosmetic

Regulation 1223/2009/ECC; Cosmetic Directive 2005/42/EC).

The first report on contact allergy from MI was published in 1987 (1). After 2000, MI was introduced in industrial products (e.g. paints, adhesives, varnishes and cooling fluids), and

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due to its weaker preservative effect was used at higher concentrations than in MCI/MI.

Allergic contact dermatitis from MI in occupational settings was reported in 2004 (2) mainly due to exposure to paints (3, 4).

The first reports from MI contact allergy caused by cosmetics originate from 2010 (5)

mainly due to wet wipes for hygiene (baby wipes, moist tissues, moist toilet paper), hair cosmetics (shampoos), facial cosmetics (6, 7), deodorants (8) and sunscreens (9).

Air exposure to MI induced severe cases of airborne allergic contact dermatitis and systemic

contact dermatitis, particularly from recently painted walls (10, 11), including a case in a

four-year-old child most probably sensitised to MI through baby wipes. Airborne exposures and allergic contact dermatitis from toilet cleaners have also been reported (12).

MI has only recently been tested as a single allergen, separate from MCI/MI in the European

baseline series and in the local baseline series in several countries. In the European baseline patch test series, MI is tested at 2000 ppm (0.2%) (17). Reactivity in patients who were

patch tested was around 1.5% until 2008 in Denmark (7) but values increased from 0.9% in 2006 to 1.8% in 2008 in Finland (13) and very high prevalences were demonstrated in

2011/12 in Leeds (4.6%) (14), London (6%), Coimbra (4.5%) and Leuven, (5.8%), with a

very high percentage of reactions found to be actually relevant because the source of the exposure was demonstrated (15).

In Germany, although in selected patients with suspected cosmetic or occupational

exposure, MI sensitisation rose from 1.9% in 2009 to 4.4% in 2011, particularly in female patients (188% increase) and in patients with facial dermatitis (200% increase), suggesting

that increase in prevalence is most probably related to cosmetic exposure (16). In the US, a similar situation seems to have occurred as MI was considered the allergen of the year 2013

(9).

Contact allergy to MI has been reported in consecutively tested dermatitis patients in

Sweden, Denmark, Germany, Finland and the UK. The contact allergy rates reported vary between 0.5% and 6% in 2012. The rates from the UK where noticed in Leeds from 0.6% in

2009 to 4.6% in 2012 (14). In Denmark, an increase from 1.4% in 2009 to 3.1% in 2011 was recorded (11).

Other European countries have recently published their own experiences showing an

increased prevalence of contact sensitisation to MI (Figure 1). In Belgium, where in 2012, the sensitisation rate to MCI/MI had increased to 4.5% and that for MI to 6.0%, the latter

showed a further increase to 7.2% in 2013. (18) The MCI/MI sensitisation rate increased in the South of Gran Canaria from 3.6% in 2007 to 17.3% in 2012, and when MI was patch

tested alone at either 0.05% or 0.2%, the representative sample of this area showed a prevalence of 8.2% (19). The French data from the REVIDAL-GERDA network, with sixteen

centres and 7874 patients tested, showed a significant increase in the proportion of MI-positive tests in 2012 and 2011 as compared to 2010 (5.6%, 3.3%, and 1.5%, respectively;

p<0.001) when patch testing MI at 200 ppm aq. (20). In Finland a clearly increasing

incidence of MI contact allergy was found in all clinics providing data (21). It was regarded

as an epidemic of contact allergy to MI (see also Figure 1). (22)

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Figure 1. Data from recently published scientific literature concerning changes over time in MI contact allergy

among patch-tested patients in different countries, based on refs: 18, 20-23, 29, 30

3.3 (SCCS/1521/13) Opinion on Methylisothiazolinone (P94) and rinse-

off products

In the Opinion on MI from March 2014 (SCCS/1521/13), it was concluded that current clinical data indicate that 100 ppm MI in cosmetic products is not safe for the consumer. For

leave-on cosmetic products (including ‘wet wipes’), no safe concentrations of MI for induction of contact allergy or elicitation have been adequately demonstrated. For rinse-off

cosmetic products, a concentration of 15 ppm (0.0015) MI is considered safe for the consumer from the view of induction of contact allergy. However, no information is available

on elicitation.

3.4 New submission

The dossier of data submitted consists of a submission letter entitled 'Industry submission

concerning safety of methylisothiazolinone (MI) in rinse-off and leave-on products', dated

12 June 2014, and eight other documents, some of which were submitted later (see below):

Resubmission of comments and data Re-submission of the comments made by Cosmetics Europe to the draft 2013 Opinion,

consisting of: a. Cosmetic Europe's response to the SCCS Opinion on Methylisothiazolinone,

adopted 12 December 2013 (dated 14 February 2014)

b. Hazard characterisation data for Methylisothiazolinone (MI) and

Methylisothiazolinone / Chloromethylisothiazolinone (MCI/MI)(Annex I)

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c. The Efficacy of Methylisothiazolinone (MI) and Methylchloroisothiazolinone/

Methylisothiazolinone (CMI/MI) and the Microbiological Safety of Cosmetic Products (Annex II)

Submission of new data Submissions of new data were accepted in 3 rounds, June 2014, February 2015 and May

2015. Data received were:

a. Summary of the data reviewed by the SCCNFP in its opinions on MI from 2003

to 2004.

b. Skin allergy assessment and the Quantitative Risk Assessment.

c. Methylisothiazolinone and the mixture of chlorinated CMI/MI (3:1 ratio) are two different preservatives with different safety and efficacy profiles (dated 26.

May 2014)

d. Compilation of cosmeto-vigilance data related to cosmetic products

containingMI (submitted February 2015).

e. Assessment of impact on the risk of induction of skin sensitisation from aggregated exposure arising from use of rinse-off cosmetic products

containing 100ppm methylisothiazolinone (MI) (submitted May 2015).

3.5 Resubmission of comments from CE for re-consideration

Cosmetics Europe re-submitted a dossier with their previous response to the Opinion of

SCCS dated 12 December 2013 consisting of the 3 documents mentioned above.

In the submission letter (dated 12Th June 2014, CE justifies this re-submission with the fact that they do not feel their comments were adequately addressed in the final SCCS Opinion,

especially concerning the following points:

Clinical data in isolation is insufficient to establish safe induction levels for MI.

MCI is at least one order of magnitude more potent than MI. The animal data and data from Human Repeated Insult Patch Tests are given in the re-submission (annex I) and it

is concluded that ‘applying identical specific concentration limits to both MCI/MI and MI is not justified based on the available hazard characterization data.'

SCCS comment

The use of MI in cosmetic has caused an unprecedented high rate of sensitised individuals in Europe as reflected by the patch test data from dermatology clinics mentioned above.

Clinical data have established that current uses of MI at 100 ppm are unsafe. The risk assessment based on predictive assays using the methods available at the time (SCCS

opinion 2004) and later has failed to protect the consumer with regard to induction of contact allergy to MI and allergic contact dermatitis.

Data from humans who have developed contact sensitisation and allergic contact dermatitis

through the use of consumer products are highly relevant for risk assessment and should

never be disregarded, especially not when risk assessment based on predictive assays has failed. Below, the SCCS comments further on some of these data.

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Concerning the difference in potency between MCI and MI, the prediction of potency is

based on experimental studies in animals and sometimes humans. These are models that may or may not accurately reflect the true difference between substances. MI has been

used since its inclusion in cosmetics in up to 8.8 times higher concentrations (100 ppm) than MCI (11.25 ppm in the mixture MCI/MI 3:1 at 15 ppm). According to the submission,

the difference in potency is at least one order of magnitude: the NESIL derived from HRIPTs MCI is 18 times more potent than MI (NESIL MCI: 0.83µg/cm2 and MI: 15µg/cm2).

Nevertheless, the use of MI in up to 8.8 times higher concentrations than MCI for the past 10 years in cosmetic products has led to the current situation of exceptionally high rates of

contact allergy to MI in consumers.

The SCCS also replied to these comments by Cosmetics Europe following the consultation

concerning the SCCS Opinion (SCCS/1521/13). In this Opinion it is suggested that MI at 15 ppm in rinse-off products should be safe for the consumer. There is, at present, no data to

indicate that a higher level is ‘safe’ for either induction or elicitation. Therefore, 15 ppm was chosen for safety reasons, as clearly discussed in the Opinion.

3.6 Submission of new data from CE

3.6.1 Quantitative Risk Assessment applied to Methylisothiazolinone in rinse of products and leave-on hair cosmetics

In the submission, Cosmetics Europe applied the Quantitative Risk Assessment (QRA)

methodology (24, 25) to predict maximum safe exposure levels, i.e. exposure levels that

are assumed not to cause induction of skin sensitisation.

3.6.1.1 QRA methodology

According to the submission, the QRA approach for allergens in consumer products follows the same four fundamental steps as identified for general toxicology risk assessment: a)

hazard identification b) dose-response assessment or hazard quantification c) exposure assessment and d) risk characterisation. The induction of skin sensitisation is a threshold-

based event; the metric for risk assessment for this toxicological endpoint is accepted to be

dose per unit area of skin (or g/cm2). The key steps of the QRA process are determination of known safe benchmarks, application of sensitisation assessment factors, and calculation

of consumer exposure through normal products use. With these parameters, an acceptable exposure level (AEL) can be calculated and compared with the consumer exposure level

(CEL). When the AEL exceeds the CEL, it is predicted that induction of skin sensitisation is unlikely to occur.

SCCS comment

The SCCP adopted an Opinion concerning Dermal Sensitisation Quantitative Risk

Assessment (Citral, Farnesol and Phenylacetaldehyde) on 24 June 2008 (SCCP/1153/08).

The QRA model mentioned and applied in the new submission is identical with the QRA model assessed in the Opinion (SCCP/1153/08), leading to the following conclusion, as

stated in that Opinion:

The dermal sensitisation QRA model is based primarily on data from experimental sensitisation tests in humans e.g. Human Repeated Insult Patch Tests (HRIPT).

There is a lack of in-depth method description, and the experience with this test,

its validity, sensitivity and reliability is sparse outside industry. Performing this type of experimental sensitisation tests on humans is considered unethical.

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Epidemiological and experimental data, providing information on

sensitisation/elicitation reactions in consumers by the substance evaluated (e.g preservative or fragrance) in marketed products, are not integrated in the dermal

sensitisation QRA model. It is of concern that the model operates with multiple product categories without considering risk from aggregated exposures and that

scientific consensus has not been achieved concerning the choice of safety factors. Occupational exposures are not considered although they have been

identified as an important area of development of the dermal sensitisation QRA.

The data provided shows that the application of the dermal sensitisation QRA

approach would allow increased exposures to allergens, already known to cause allergic contact dermatitis in consumers. The model has not been validated and

no strategy of validation has been suggested. There is no degree of certainty that the levels of skin sensitisers identified by the dermal sensitisation QRA are safe

for the consumer.

Identification of safe levels of exposure to existing substances known to cause allergic contact dermatitis in the consumer should be based on clinical data

and/or elicitation low effect levels. Currently these are the only methods that

have proven efficient in reducing/preventing existing problems of sensitisation/allergic contact dermatitis in the consumer.

The QRA model in the new submission from June 2014 has not been updated or modified concerning any of the points raised above. In the additional submission dated 25 May 2015

the effect of aggregate exposures to MI in rinse–off products on risk of induction of sensitisation by QRA was addressed. See below.

3.6.1.2 Application of quantitative risk assessment to MI

In the submission by CE, the QRA methodology was applied to MI in cosmetic products according to the principles explained above. As stated above, the SCCS has no faith in the

model in its current form (SCCP/1153/08), but has nevertheless chosen to comment on substance specific data in this section used in the QRA, as these comments may have

relevance for further development of the model and future quantitative risk assessment of MI.

The maximum permitted amount of MI in cosmetic products is 100 ppm. The consumer exposure to 100 ppm (0.01%) MI is calculated by multiplying the amount of product used

per day by 0.01% and is expressed as dose/surface area (i.e. µg/cm2). The range of products for which suitable exposure data have been identified, along with the amount of

product used, is listed in Table 1 (Annex I of this Opinion).

According to the submission, No Expected Skin Sensitisation Level (NESIL) is a benchmark that is derived from animal and human data through the application of a Weight of Evidence

(WoE) approach using all relevant data.

For the determination of a WoE NESIL for MI, the data from 5 Human Repeat Insult Patch

Tests (HRIPT) and 4 local lymph node assays (LLNA) were considered. In the HRIPTs, no positive responses were observed up to an exposure level of 15 µg/cm2 MI in water.

Sensitisation was induced at exposures of 20 and 25 µg/cm2. Based on these data, CE concludes that MI can be considered to be a strong sensitiser.

In the LLNA, MI had EC3 values between 0.4% (100µg/cm2) and 11% (2750µg/cm2)

depending on the vehicle used. The EC3 values indicate that MI is a strong sensitiser.

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Taking all of the data together, since the HRIPT threshold is the lowest no observed effect

level (NOEL) available, it shall, according to the submission, take precedence in deriving the NESIL for use in the QRA. Therefore, the WoE NESIL for MI is 15µg/cm2. A summary of the

considered HRIPT studies (26) conducted on MI is given in the submission as table 2 and reproduced below:

Vehicle, Dose Volume, Patch Size

Induction Concentration (ug/cm2)

Challenge Concentration

Positive Responses

Water; 0.2ml, 4 cm2 200ppm (10 µg/cm2) 200ppm 0 / 100




Water; 0.2mL,4 cm2 600ppm (30 µg/cm2) 600ppm 0 / 214

Table 2: Summary of the HRIPT studies conducted on MI (from the submission)

SCCS comment

In the submission, the NESIL is determined to be 15 µg/cm2 by WoE approach based on

data from HRIPT given above and as table 2 in the submission.

The sensitivity and predictivity of the HRIPT does not only depend on the choice of concentration for induction, but also the choice of challenge concentration.

It can be seen from table 2 above (from the submission) that not only the induction

concentrations varied between experiments, but also the challenge concentration of MI. The high dose induction group has been challenged with a high dose (max 600 ppm) and the

low dose induction group with a low dose (min 200 ppm). It is a general principle in patch

testing that the maximal concentration that can be tolerated without causing skin irritation should be used for demonstrations of sensitisation (27).

This means that the lower levels in these experiments, which seemingly cause no induction,

are not put to a sufficient test at challenge and that induction may have occurred but may

not have been revealed. The NESIL for MI may be lower than 15 µg/cm2, as the

experiments have not been performed in a way so that conclusions on no-effect levels can

be made. The SCCS also has comments regarding AEL/CEL ratio and predicted risk from rinse-off

products and stay-on hair cosmetics.

In the submission table 3 (reproduced in Annex 1), 20 products categories are green: ranging from an AEL/CEL of 1.0 (body lotion and after-sun cream) to 140.6 (shower gel).

According to the submission product, categories with an AEL/CEL >1 are unlikely to cause induction. This would also mean that body lotion and after-sun cream lotion with an

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AEL/CEL of 1 should have been coloured red in the table 3 as these products are likely to

induce sensitisation.

According to the submission 100 ppm is safe for use concerning induction of sensitisation in rinse-off products and stay-on cosmetics as the AEL/CEL is above 1.

The AEL/CEL is calculated in the following way with data used for shower gels:

AEL= NESIL (15 µg/cm2) /SAF (100)= 0.15 µg/cm2

CEL= 0.0011 µg/cm2 (table 2- Annex 1)

AEL/CEL= 0.15 µg/cm2/0.0011 µg/cm2 = 136 (incorrectly given as 140.6 in the

submission (table 3-Annex 1).

A product with an AEL/CEL of 1.1 is in theory unlikely to cause induction. This means that the QRA model predicts that not only 100 ppm (0.01%) in a shower gel is unlikely to cause

induction but also 1.2% MI (12000 ppm). For shampoos 0.18% (1800 ppm) is the predicted maximum concentrations unlikely to induce sensitisation and for hairstyling products 0.03%

(300 ppm) given an AEL/CEL ratio of 1.1.

The data provided show that the application of the dermal sensitisation QRA approach to

rinse-off products would allow increased exposures to MI, a strong allergen already known to cause many cases of allergic contact dermatitis in consumers. This alone makes it difficult

to have confidence in the model in its current version.

The comments above also apply to stay-on hair cosmetic products. Furthermore, it is not clear if the QRA model for stay-on hair cosmetics in the original submission (June 2014)

also takes exposure to the hands into account. Hands are bound to be exposed to the hair products either during application or by touching the hair unintentionally.

3.6.1.3 Assessment of aggregate exposure in the QRA

In the new submission by CE (May 2015), aggregate exposures to a number of rinse-off products such as shower gels and shampoos are calculated. Aggregate exposure is

calculated using an interim/pragmatic approach in which the CEL is calculated for different body parts relevant for MI exposure by rinse-off products, e.g. hands, face, scalp and the

rest of the body. Aggregate exposure is the sum of the exposure level estimated for the individual products used on the respective body part. In all cases concerning aggregate

exposures to rinse-off cosmetic products yields an AEL:CEL ratio greater than 1. The

following AEL:CEL ratios were reported: Hands = 2.1

Face = 1.8 (females) and 5.3 (males) Scalp = 8.8

Rest of the body = 140.

CE considers it an interim assessment of impact of aggregate exposures and concludes that the risk of induction from aggregate exposure to rinse-off products is very low.

SCCS comment The SCCS assessed the QRA in 2008 and pointed to several shortcomings in the model

including the lack of considerations of aggregate exposures. The SCCS is aware that updating of the QRA model is currently ongoing in industry. The QRA presented by CE is

using the same approach, except the aggregate exposure assessments, as defined in the initial QRA approach. Hence, the criticism raised previously by the SCCS (SCCP1153/08) is

the same. Furthermore, the aggregate exposure assessment, which is presented as an interim approach, needs to be evaluated and accepted by the SCCS before it can be applied

to specific substances.

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3.7 Use test with rinse-off products in MI sensitised consumers.

In the submission letter (dated 12 June 2014), a paragraph is devoted to the subject of

performing a use test study – also called ROAT study - in sensitised consumers.

A negative use test study with a rinse-off product would confirm safety concerning not only elicitation, but also induction. CE states that: 'The cosmetics industry is studying different

possibilities to further confirm the safety of MI-preserved rinse-off products in MI-patch test

positive consumers’.

SCCS comment In the meantime a use test study in MI sensitised consumers has been performed and

published in February 2015 (28). Here 19 MI-allergic subjects and 19 controls without MI allergy applied 2 liquid hand soaps five times per day on areas of 5*10 cm on the ventral

side of their forearms. One soap contained 100 ppm MI, the maximum allowed concentration in cosmetics, and was used by 10 allergic subjects and all controls. Another

liquid soap with 50 ppm MI was used by 9 allergic subjects. As the negative control, all

subjects used a similar soap that did not contain MI. The repeated open applications (ROAT) proceeded for up to 21 days or until a positive reaction occurred. The study was conducted

in a randomised and blinded fashion. Ten (10) out of 10 MI-allergic subjects developed positive reactions to the soap with 100 ppm and 7 out of 9 reacted to the 50 ppm soap,

while none of the 19 controls had a positive reaction during 21 days of application (p=0.0001). The authors concluded that rinse-off products preserved with 50 ppm MI or

more are not safe for consumers. A no-effect level was not determined (28).

The results of this study do not support safety of MI in rinse-off products at either 100 ppm

or at 50 ppm for elicitation or induction.

3.8 Compilation of cosmetovigilance data related to cosmetic products containing Methylisothiazolinone (MI)

Five major manufacturers of cosmetic products from the Cosmetics Europe MI Task Force collated all reported undesirable events associated with products containing MI and products

from the same categories without MI for a period of five years and 6 months (1 January

2009 – 30 June 2014). The categories for which data were identified were: rinse-off products (face wash, shampoo, conditioner, and shower products), hair leave-on products

(hair styling products), skin leave-on products (face wipes, deodorants, face care, baby wipes, after-shave products).

The causal relationship of each reported event to the product was assessed using a 5-level

scale and was assigned to one of the following categories: “very likely”, “likely”, “not clearly attributable”, “unlikely” and “excluded”, in accordance with the causality assessment

method recommended by the European Commission. Undesirable events given a causality assessment “likely” and “very likely” were considered as undesirable effects; they were

further assessed by a qualified assessor and those which were compatible with the symptoms and chronology of allergic contact dermatitis and skin irritation were given the

respective designation.

Reporting rates were calculated as the number of undesirable events (separately for MI-

containing and non-MI-containing products) per millions of units sold for the time period considered. Overall ‘industry rates’ were calculated by dividing the sum of all reported

undesirable events by the sum of all units sold by the five companies during the five years

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and six months (in millions). The results are reported separately for leave-on skin products,

rinse-off skin and hair products and leave-on hair products.

Once leave-on products were assessed there was an approximately 5-fold difference in confirmed undesirable effects (allergic contact dermatitis and skin irritation) between leave-

on skin products containing MI and leave-on skin products without MI. There was no increase in reporting rates for rinse-off products containing MI (0.71) as compared to rinse-

off products without MI (2.0). No increase in reporting rates for leave-on hair products containing MI (0.09) was observed as compared to leave-on hair products without MI

(0.15). It is concluded in the report that the reporting rates are generally low for both MI-

containing and non-MI-containing products.

SCCS comment

The submission does not provide detailed information about methodology or data concerning numbers and types of the adverse events, the number of products in each

category from each company or the number of adverse events disregarded. It only provides end results as given above. It is therefore not possible to assess the data.

A number of recent peer-reviewed scientific papers from different countries address the same question as the cosmetovigilance study by CE concerning product types involved in

allergic contact dermatitis to MI (18, 20, 30). They all show that rinse-off products play a role in allergic reactions in consumers diagnosed with MI contact allergy.

A restropective, nationwide and multicentre French report-based study (20) involved an

analysis of all cases reported by French doctors belonging to the REVIDAL-GERDA group and performing patch tests from 2010 to 2012. Sixteen centers participated in the study

and 7874 patients were tested. MI-positive tests rose from 1.5% in 2010 to 5.5% in 2012.

Tests were clinically relevant in 80.2% to 90.3% of cases. Information about the products used was available for 83.7% (247/295) of MI-positive patients. Cosmetics accounted for

73.1% of causative products. Among the cosmetics that were specified, the majority were rinse-off, mainly soaps, particularly industrial soaps, toilet products, and hair products (20).

A study from Belgium (18) reviewed the medical charts of patients who were investigated

between 2010 and 2012 by members of the Belgian Contact and Environmental Dermatitis Group for MCI/MI and MI allergy. All together 8680 patients were patch tested for MCI/MI

allergy and 5979 with MI alone, and 373 (4.3%) and 324 (5.4%), respectively, turned out

positive. The youngest patient was 2 years of age. Cosmetics were allergen sources for MI and or MCI/MI in 53.7% to 61.3% of cases. Although the exact cosmetic was reported only

for a subgroup of patients, some specific leave-on products were mentioned including wet wipes and deodorants. Also a considerable number of rinse-off products were involved (e.g.

shampoos), but the specific number was not given (18).

In Germany (30), contact allergy surveillance data collected by the Information Network of Departments of Dermatology in the years 2009–2012 were analysed. For 602 MI-positive

patients, their own products had been patch tested (altogether, 4933 different products

causing a total of 372 positive patch test reactions). In particular, leave-on products caused a high proportion of positive patch test reactions to the tested products. In total 5.6% out

of the MI positive patients without fragrance allergy was positive to liquid soaps/shower gels and 3.9% to shampoo. In comparison 7.5% were positive to face cream and 17.5% to

moisturisers. Patch tests with rinse-off products may be quite non-sensitive for detecting sensitisation to any of their ingredients including MI, as the product is diluted before testing

(30).

These studies differ from the CE cosmetovigilance study in methodology as the consumer (patient) with an adverse reaction to a cosmetic product has been seen by a dermatologist

SCCS/1557/15


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and also patch tested. This means that a diagnosis can be made and a causal relationship to

product types established. The studies do not offer a comparison with other preservatives.

In addition to these studies RIVM in the Netherlands took a multi-stakeholder approach entailing spontaneous reports from consumers, general practitioners and dermatologists

regarding undesirable effects to cosmetic products. The four most frequently reported cosmetic products involved in undesirable reactions were moisturisers, make-up, hair care

products and soaps. Dermatologists reported more cases than consumers of undesirable effects of hair care products (predominately shampoos, constituting 82% of the products)

and soaps (bath and shower products). The most commonly reported allergens in the

patients were isothiazolinones (23%), whereof almost half were found have a causal link between the undesirable effect and the cosmetic product, however no direct link was made

between the specific allergens and product types in the report (31).

3.9 DISCUSSION

In the previous Opinion on MI from March 2014 (SCCS/1521/13), it was concluded that no

safe concentrations of MI for induction of contact allergy or elicitation have been adequately demonstrated for leave-on cosmetic products. For rinse-off cosmetic products, a

concentration of 15 ppm (0.0015 %) MI was considered safe for the consumer from the view of induction of contact allergy, while no data were available concerning elicitation.

The present SCCS Opinion addresses safety concerns regarding the use of MI at 100 ppm in

rinse-off and leave-on hair cosmetic products. The arguments to defend this concentration

used by Cosmetic Europe are based on the results of a QRA including new data on aggregate exposures and the information obtained from the cosmetovigilance system.

According to the QRA methodology, rinse-off and leave-on hair cosmetic products are considered safe with a low risk of inducing contact sensitisation. The data obtained from the

cosmetovigilance system established by Industry do not show an excess of adverse events due to MI in rinse–off and leave-on hair cosmetic products compared to products without

MI.

Nevertheless, the most recently published peer-reviewed literature shows an increase in

contact allergy to methylisothiazolinone in Europe. New data from Belgium, Gran Canaria, France, Germany, Finland and the United Kingdom demonstrate an extraordinary increase

and high rate of contact allergy to MI. In some countries, the increase has more than tripled in just a few years and has reached epidemic proportions. New cases are also seen in very

young children of 1-2 years of age, which is unusual for contact allergy.

The QRA for induction of contact sensitisation has previously been evaluated by the Scientific Committee (SCCP1153/08), which amongst others concluded that: ‘The model has

not been validated and no strategy of validation was suggested. There is no confidence that

the levels of skin sensitizers identified by the dermal sensitisation QRA are safe for the consumer.’ The QRA model used in this new submission about MI in rinse-off and leave-on

hair cosmetic products is similar to the QRA previously evaluated by the SCCP.

The QRA data provided specifically on MI in the current submission predict that 100 ppm (0.01%) MI is unlikely to induce sensitisation in rinse-off products and stay-on hair

cosmetics. However, this QRA approach does predict that even higher concentrations of MI - up to 12.000 ppm (1.2%) - in such products would be unlikely to induce sensitisation. The

fact that the QRA model permits such high levels of a strong sensitiser in rinse-off products seriously questions its predictions and makes it difficult to have confidence in the presented

QRA model, as also highlighted in the Opinion SCCP1153/08. Aggregate exposure is not

considered in the first submission of QRA data from June 2014, but in an additional

SCCS/1557/15


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submission from Cosmetics Europe from May 2015, QRA interim data considering aggregate

exposures to rinse-off products were provided.

The SCCS is aware that the QRA model is currently being updated. All the criticism raised in Opinion SCCP1153/08 needs to be addressed and the new model needs to be assessed and

scientifically accepted before it can be applied to specific substances. The aggregate exposure model also needs to be evaluated and accepted by the SCCS before it can be

applied to specific substances.

Predictive models are important to avoid adverse health effects in humans from cosmetic

ingredients. However in situations where the adverse health effects have already occurred in humans, it is appropriate to consider the epidemiological data as these represent the

relevant end-point at which preventive actions are to be directed. Such data exist from dermatology clinics and as cosmetovigilance data, either as spontaneous reports or active

surveillance.

The cosmetovigilance system established by industry is based on spontaneous reports primarily from consumers and rarely supported by dermatological assessment or allergy

testing, which makes the causality assessment difficult and subject to variation among

companies. Such cosmetovigilance data may be useful in indicating a problem with certain ingredients or specific products, but is in general of limited value in establishing safety or

disproving a problem. The data submitted by Cosmetics Europe lacked details in reporting, such as numbers of adverse reaction to different product types, and could thus not be

assessed.

Cosmetovigilance data have recently been published from several countries (2014-2015). A multi-stakeholder approach was taken by The Netherlands entailing spontaneous reports

from consumers, general practitioners and dermatologists. Dermatologists reported more

cases than consumers of undesirable effects of hair care products (predominately shampoos) and soaps (bath and shower products). The most commonly reported allergens

in the patients were isothiazolinones, but this study did not allow to causally link the specific allergens to certain product types.

In Belgium and France, all data on MI contact allergic patients from multiple dermatological

centers were reviewed. In the Belgium study it was concluded that although the exact cosmetic was reported only for a subgroup of patients, a considerable number of rinse-off

cosmetics (e.g. shampoos) were involved. No distinction was made between MI and/or

MCI/MI. In the French study concerning MI allergy, the majority of causative products were rinse-off, mainly soaps, particularly industrial soaps, toilet products, and hair products. In a

German multi-centre study patients had been tested with their own cosmetic products. Stay-on cosmetic products were clearly more often positive in MI allergic patients than

rinse-off products. Nevertheless, rinse-off products also gave reactions. Testing of rinse-off products requires dilution and may make the test less sensitive in picking up allergies.

These data represent consumers who have been exposed sufficiently to develop the disease allergic contact dermatitis. This may be caused by one product or multiple products

simultaneously or in sequence.

There is no doubt from the clinical data as presented in the previous and present Opinion

that stay-on cosmetic products, especially wet wipes, are important causes of MI allergy. This is also acknowledged by CE in their submission and they have advised their members

to discontinue the use of MI in such products. Rinse-off cosmetic products also play a significant role in allergic contact dermatitis to MI according to recent epidemiological

studies. This is supported by a new use test study performed in patients sensitised to MI, where a soap preserved with 100 ppm or 50 ppm MI used five times a day elicited allergic

reactions in all or almost all sensitised patients and not in controls. This study may not directly show that rinse-off products are implicated in induction of contact allergy to MI, but

may indicate a role. It is generally accepted that concentrations/doses of allergens, which

SCCS/1557/15


19

do not elicit reactions, would also be safe for induction in the majority of individuals e.g.

The Nickel Directive (Nickel Directive (76/769/EEC - now 94/27/EEC)) and the recent REACH regulation of chromium VI in leather (regulation EU 301/2014, which adds a

Chromium VI restriction to Annex XVII of regulation 1907/2006 (REACH)) are based on this principle. Thus as almost all the participants in the use test study developed allergic contact

dermatitis to a soap with 100 ppm or 50 ppm, the result of this study do not support safety of MI at current use concentrations in terms of induction.

In the scientific Opinion (SCCS/1521/13) on methylisothiazolinone (MI), the conclusion

concerning safe use of MI in rinse-off products at 15 ppm was based on bench-marking to

the experience with the use of the mixture MCI/MI at 15 ppm for the past 30 years. In the new submission, industry submits that MCI and MI are very different in their sensitising

potency and therefore imposing identical concentration limits is not warranted.

In the current Opinion it is highlighted that MI has been used in up to 8.8 times higher concentrations than MCI for the past 10 years in cosmetic products, which has led to the

current situation of high rates of contact allergy to MI in consumers. There are, at present, no convincing data to indicate that a higher level is ‘safe’ for either induction or elicitation.

Therefore, 15 ppm was chosen for safety reasons given in the previous Opinion

(SCCS/1521/13).

4. CONCLUSION

1. On the basis of the data provided, does the SCCS consider Methylisothiazolinone

(MI) to be safe for consumers, when used as a preservative in rinse-off products up to concentration limit of 100 ppm from the view of induction of contact allergy?

The information provided does not support the safe use of MI as a preservative in rinse-off

cosmetic products up to a concentration limit of 100 ppm from the view of induction of contact allergy.

For rinse-off cosmetic products, a concentration of 15 ppm (0.0015%) MI is considered safe for the consumer from the point of view of induction of contact allergy.

2. On the basis of the data provided, does the SCCS consider Methylisothiazolinone (MI) to be safe for consumers, when used as a preservative in leave-on hair

products up to concentration limit of 100 ppm from the view of induction of contact allergy?

The information provided does not support the safe use of MI as a preservative in leave-on hair cosmetic products up to a concentration limit of 100 ppm from the point of view of

induction of contact allergy.

3. Does the SCCS have any further scientific concerns with regard to the use of Methylisothiazolinone (MI) in cosmetic product

The concerns and opinions raised in SCCS Opinion SCCS/1521/13 (12 December 2013 with

revision 27 March 2014) remain. The results of the recent Scandinavian study do not

support safety of MI in rinse-off products at either 100 ppm or at 50 ppm for elicitation or induction.

SCCS/1557/15


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5. REFERENCES

1. Bruze M, Dahlquist I, Fregert S, Gruvberger B, Persson K. Contact allergy to the active ingredients of Kathon CG. Contact Dermatitis. 1987 ;16(4):183-8.

2. Gruvberger B, Bruze M. Occupational contact allergy and dermatitis from

methylisothiazolinone after contact with wallcovering glue and after a chemical burn from a

biocide. Dermatitis. 2004;15(4):201-5.

3. Thyssen JP, Sederberg-Olsen N, Thomsen JF, Menné T. Contact dermatitis from methylisothiazolinone in a paint factory. Contact Dermatitis. 2006; 54(6):322-4.

4. Mose AP, Lundov MD, Zachariae C, Menné T, Veien NK, Laurberg G, Kaaber K, Avnstorp

C, Andersen KE, Paulsen E, Gotthard Mortz C, Sommerlund M, Danielsen A, Thormann J, Kristensen O, Kristensen B, Andersen BL, Vissing S, Nielsen NH, Johansen JD. Occupational

contact dermatitis in painters: an analysis of patch test data from the Danish Contact

Dermatitis Group. Contact Dermatitis. 2012; 67(5):293-7.

5. García-Gavín J1, Vansina S, Kerre S, Naert A, Goossens A. García-Gavín J1, Vansina S, Kerre S, Naert A, Goossens A. Methylisothiazolinone, an emerging allergen in cosmetics?

Contact Dermatitis. 2010;63(2):96-101.

6. Lundov MD1, Thyssen JP, Zachariae C, Johansen JD Prevalence and cause of methylisothiazolinone contact allergy. Contact Dermatitis. 2010;63(3):164-7.

7. Lundov MD, Krongaard T, Menné TL, Johansen JD Methylisothiazolinone contact allergy: a review.Br J Dermatol. 2011;165(6):1178-82.

8. Amaro C, Santos R, Cardoso J. Contact allergy to methylisothiazolinone in a deodorant.

Contact Dermatitis. 2011;64(5):298-9.

9. Castanedo-Tardana MP1, Zug KA Methylisothiazolinone. Dermatitis. 2013; 24(1):2-6.

10. Aerts O, Cattaert N, Lambert J, Goossens A Airborne and systemic dermatitis, mimicking

atopic dermatitis, caused by methylisothiazolinone in a young child. Contact Dermatitis. 2013; 68(4):250-1.

11. Lundov MD, Zachariae C, Menné T, Johansen JD. Airborne exposure to preservative

methylisothiazolinone causes severe allergic reactions. BMJ. 2012; 4:345

12. Lundov MD, Menné T. Airborne exposure to methylchloroisothiazolinone and methylisothiazolinone from a toilet cleaner. Contact Dermatitis. 2013; 68(4):252-3.

13. Ackermann L, Aalto-Korte K, Alanko K, Hasan T, Jolanki R, Lammintausta K,Lauerma A, Laukkanen A, Liippo J, Riekki R, Vuorela AM, Rantanen T. Contact sensitisation to

methylisothiazolinone in Finland--a multicentrestudy. Contact Dermatitis 2011; 64; 49-53

14. Urwin R & Wilkinson M. Methylchloroisothiazolinone and methylisothiazolinone contact allergy: a new “epidemic”. Contact Dermatitis 2013; 68: 253–5

15. Gonçalo M, Goossens A. Whilst Rome Burns: The Epidemic of Contact Allergy to

Methylisothiazolinone. Contact Dermatitis 2013; 68: 257-258

16. Geier J, Lessmann H, Schnuch A, Uter W. Recent increase in allergic reactions to

methylchloroisothiazolinone/methylisothiazolinone: is methylisothiazolinone the culprit? Contact Dermatitis 2012; 67: 334-41

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17. Bruze M, Engfeldt M, Gonçalo M and Goossens A. Recommendation to include

methylisothiazolinone in the European baseline patch test series. (On behalf of the European Society of Contact Dermatitis (ESCD) and the European Environmental and

Contact Dermatitis Research Group (EECDRG)). Contact Dermatitis 2013; 69: 263-271

18. Aerts O, Baeck M, Constandt L, Dezfoulian B, Jacobs MC, Kerre S, Lapeere H, Pierret L, Wouters K, Goossens A. The dramatic increase in the rate of methylisothiazolinone contact

allergy in Belgium: a multicenter study. Contact Dermatitis 2014; 71: 41-48

19. Liuti F, Hernandez Hernandez Z, Borrego Hernando L. Increased sensitisation to Kathon

CG (methylchloroisothiazolinone plus methylisothiazolinone) in the South of Gran Canaria, Spain. Actas Dermosifiliogr 2014; 105:882-883

20. Hosteing S, Meyer N, Waton J, Barbaud A, Bourrain JL, Raison-Peyron N et al. Outbreak

of contact sensitisation to methylisothiazolinone:an analysis of French data from the REVIDAL-GERDA network. Contact Dermatitis 2014; 70: 262-269

21. Lammintausta K, Aalto-Korte K, Ackerman L, Alanko K, Berry P, Hasan T et al. An

epidemic of contact allergy to methylisotiazolinone in Finland. Contact Dermatitis 2014; 70:

184-185

22. Lundov MD, Opstrup MS, Johansen JD. Methylisothiazolinone contact allergy- a growing epidemic. Contact Dermatitis. 2013;69:271-5.

23. Madsen JT, Andersen KE. Further evidence of the methylisothiazolinone epidemic.

Contact Dermatitis. 2014; 70: 246-247

24. Basketter DA, Clapp CJ, Safford BJ, Jowsey IR, McNamee P, Ryan CA, Gerberick GF.

Preservatives and skin sensitisation quantitative risk assessment. Dermatitis. 2008 Jan-Feb;19(1):20-7.

25. QRA Technical Guidance Dossier 2006 and updated information booklets can be found

on the RIFM website. http://www.rifm.org/publications

26. Politano VT, Api AM. The Research Institute for Fragances Materials´human repeated insult patch test protocol. Regulatory Toxicology and Pharmacology 2008; 52:35-38

27. Bruze M, Svedman C, Andersen KE, Bruynzeel D, Goossens A, Duus Johansen J, Matura M, Orton D, Vigan M on behalf of the ESCD. Contact Dermatitis 2012; 66:131-136

28. Yazar K, Lundov MD, Faurschou A, Matura M, Boman A, Johansen JD, Liden C.

Methylisothiazolinone in rinse-off products causes allergic contact dermatitis: A Repeated Open Application study. Br J Dermatol 2015: Accepted

29. Johnston GA, contributing members of the British Society for Cutaneous A. The rise in

prevalence of contact allergy to methylisothiazolinone in the British Isles. Contact Dermatitis

2014:70(4):238-40

30. Uter W, Geier J, Bauer A, Schnuch A. Risk factors associated with methylisothiazolinone contact sensitisation. Contact Dermatitis 2013 69, 231–238

31. Salverda JG, Braqt PJ, de Wit-Bos L et al. Results of cosmetovigilance survey in The

Netherlands. Contact Dermatitis 2013: 68:139-14842

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ANNEX I

Table 1: Summary of source consumer exposure data to product and product containing

100 ppm MI for use in quantitative risk assessment.

The following hierarchy of exposure data was used:

a) SCCS notes of Guidance b) QRA Technical Guidance dossier for fragrance ingredients (IFRA)

c) Where no exposure data was available, surrogate data was derived from the technical expertise of the Cosmetics Europe companies:

c1) surrogate exposure: face cream with 10% retention factor applied. c2) surrogate exposure: styling aids

c3) surrogate exposure: foundation c4) surrogate exposure: face cream

c5) surrogate exposure: non-spray deodorant

c6) surrogate exposure: deposition from film of liquid

Product type

Product

exposure

(g per day)

Product

surface area

(cm2)

Product exposure

data

(µg/cm2)

Exposure

data source

Consumer

exposure level

(μg/cm2)

Shower gel 18.67 17500 0 011 a 0.0011

Facial wash (liquid) 1.6 565 0 028 a 0.0028

Hand wash soap - bar 4.8 840 0 057 b 0.0057

Shaving products (male) 2 305 0 066 b 0.0066

Shampoo 10.46 1440 0 073 a 0.0073

Hair conditioner rinse off 14 1440 0 097 b 0.0097

Hand wash soap - liquid 20 840 0 238 a 0.0238

Facial cleaning lotion 1 54 565 0 273 c1 0.0273

Facial toning lotion 1 54 565 0 273 c1 0.0273

Face mask (PVA) 1 54 565 0 273 c1 0.0273

Face mask (non-PVA) 1 54 565 0 273 c1 0.0273

Hair conditioner leave on 4 1440 0 278 c2 0.0278

Hair styling products 4 1010 0 396 a 0.0396

Body lotion 7 82 15670 0.499 a 0.0499

After sun cream lotion 7 82 15670 0.50 a 0.0499

Eye shadow 0 02 24 0.83 a 0.0833

Make-up remover 5 565 0.88 a 0.0885

Liquid foundation 0 51 565 0.90 a 0.0903

concealer 0 51 565 0.90 c3 0.0903

Mouthwash 21.62 216.8 1.00 a 0.0997

Sunscreen lotion/cream/trigger 18 17500 1.03 a 0.1029

Toothpaste 2.7 216.8 1.25 a 0.1245

Eyeliner 0.005 3.2 1.56 a 0.1563

After shaving cream 1.6 775 2 065 c1 0.2065

Men's facial care 1.6 775 2 065 b 0.2065

baby nappy area Cleansing lotion 0 55 220 2.50 b 0.2500

Hand cream 2.16 860 2 512 a 0.2512

Face cream (women) 1 54 565 2.726 a 0.2726

Face mask (overnight treatment) 1 54 565 2.726 c4 0.2726

Deodorant aerosol spray (excluding propellant) 0 69 200 3.45 a 0.3450

nappy area protection cream 1 32 220 6.00 b 0.6000

Semi-permanent hair dyes (and lotions) 35 580 6 034 a 0.6034

Deodorant body spray (ethanolic) 1.43 200 7.15 a 0.7150

Deodorant non-spray 1 51 200 7.55 a 0.7550

Deodorant cosmetic pump spray 1 51 200 7.55 c5 0.7550

Lipstick, lip salve 0.057 4.8 11 88 a 1.1875

Diaper rash cream 2 64 220 12 00 b 1.2000

Facial wipes NA NA 13 00 c6 1.3000

Moist toilet tissue, NA NA 13 00 c6 1.3000

Mascara 0.025 1.6 15 63 a 1.5625

Baby wipes NA NA 21 00 c6 2.1000

Nail varnish product 0 25 11 22.73 b 2.2727

SCCS/1557/15


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Table 3: The QRA outcome for 100 ppm MI in a range of cosmetic products

Product type

Consumer exposure

level to MI (μg/cm2)

Product

specific SAF AEL / CEL ratio

Shower gel 0.0011 100 140.6

Facial wash (liquid) 0.0028 100 53.0

Hand wash soap - bar 0.0057 100 26.3

Shaving products (male) 0.0066 300 7.6

Shampoo 0.0073 100 20.7

Hair conditioner rinse off 0.0097 100 15.4

Hand wash soap - liquid 0.0238 100 6.3

Facial cleaning lotion 0.0273 100 5.5

Facial toning lotion 0.0273 100 5.5

Face mask (PVA) 0.0273 300 1.8

Face mask (non-PVA) 0.0273 100 5.5

Hair conditioner leave on 0.0278 100 5.4

Hair styling products 0.0396 100 3.8

Body lotion 0.0499 300 1.0

After sun cream lotion 0.0499 300 1.0

Eye shadow 0.0833 300 0.6

Make-up remover 0.0885 100 1.7

Liquid foundation 0.0903 100 1.7

concealer 0.0903 100 1.7

Mouthwash 0.0997 100 1.5

Sunscreen lotion/cream/trigger 0.1029 300 0.5

Toothpaste 0.1245 100 1.2

Eyeliner 0.1563 300 0.3

After shaving cream 0.2065 300 0.2

Men's facial care 0.2065 300 0.2

baby nappy area Cleansing lotion 0.2500 300 0.20

Hand cream 0.2512 100 0.6

Face cream (women) 0.2726 100 0.6

Face mask (overnight treatment) 0.2726 100 0.6

Deodorant aerosol spray (excl. propellant) 0.3450 300 0.1

nappy area protection cream 0.6000 300 0.08

Semi-permanent hair dyes (and lotions) 0.6034 100 0.2

Deodorant body spray (ethanolic) 0.7150 300 0.1

Deodorant non-spray 0.7550 300 0.1

Deodorant cosmetic pump spray 0.7550 300 0.1

Lipstick, lip salve 1.1875 300 0.04

Diaper rash cream 1.2000 300 0.04

Facial wipes 1.3000 100 0.1

Moist toilet tissue, 1.3000 300 0.04

Mascara 1.5625 300 0.03

Baby wipes 2.1000 300 0.02

Nail varnish product 2.2727 100 0.1

further public submissions on the proposed amendments to the … · 2016. 6. 7. · august 2015...

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