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April 27, 2008

Comment: The QRA – Quandaries, Reflections & Updates

Copyright © Tony Burfield April 2008. 

QRA – A Potted History 

The Qualitative Risk Assessment (QRA) methodology was recommended as a result of progress of the COLIPA Toxicology Advisory Group and the Joint COLIPA/AISE/EFFA/IFRA Perfume Safety Group, to address dermal sensitisation risk assessment for fragrance ingredients. IFRA adopted this corporate-science derived approach for contact allergens in 2005, when we were informed it was a risk management strategy designed to combat the occurrence of consumer dermal sensitisation, via the restriction of these ingredients in fragranced cosmetic products. This exposure-based system was to be applied across a number of product types grouped into 11 product categories of products (1 to 9 being cosmetic products), setting the concentration limits of individual sensitisers to 'safe levels' for each product category. 

Thus for skin contact, dose per unit area and other considerations could be of primary importance in helping set safe levels of dermal allergens. Information on the QRA system is comprehensively set out in great detail on the IFRA website. The first QRA standards were published by IFRA in May 2006, as part of the 40th IFRA Amendment, and we were told that QRA methodology could be used to set IFRA standards for materials identified as dermal sensitisers where no standards previously existed, or to review the existing IFRA standards. For a while, the old IFRA Standard system would be maintained, whilst industry was getting used to the new QRA system, and making computer reprogramming adjustments etc. 

The first four trialed sensitisers chosen under the QRA system were citral, farnesol, phenylacetaldehyde and tea leaf absolute. EFFA submitted data to the SCCP on citral, farnesol & phenylacetaldehyde, apparently by invitation from the SCCP, who said they needed sensitivity data on IFRA restricted materials to include them in Annex III of the Cosmetics Directive. At the time IFRA restrictions for citral & phenylacetaldehyde were listed in the Inventory part II with quenching proviso’s, but un-noted by the SCCP, IFRA had quietly ditched support for the quenching phenomena (see Cropwatch Review on this topic at http://www.cropwatch.org/newslet8.pdf). Thus the limits for citral under the QRA – IFRA’s 40th Amendment become:

Category Products Limit
1 Lip Products, Toys, Insect Repellents 0.04%
2 Deodorants/Antiperspirants 0.05%
3 Hydroalcoholic Products for Shaved Skin, Eye Products, Men’s Facial Cream & Balms, Tampons 0.2%
4 Hydroalcoholic Products for Unshaved Skin, Hair Styling Aids & Sprays, Body Creams] 0.6%
5 Women’s Facial Cream/Facial Make-Up, Hand Cream, Facial masks 0.3%
6 Mouthwash, Toothpaste 1%
7 Intimate Wipes, Baby Wipes 0.1%
8 Make-up Remover, Hair Styling Aids Non-Spray, Nail Care 1.4%
9 Shampoo, Rinse-off Conditioners, Bar Soap, Feminine Hygiene Pads & Liners 5%
10 Detergents, Hard Surface Cleaners, Diapers 2.5%
11 All Non-Skin or Incidental Skin Contact Products No restriction

Citral distribution amongst some common essential oils is given in IFRA’s 40th Amendment Appendix 1 Part 1, where you will find values ranging from <90% for lemongrass oils to <0.1% for orange oil sweet (as usual with IFRA, botanical details & geographical origin details are not provided). Similarly, data is presented for farnesol distribution in some natural products.

A pity too, that before EFFA forwarded IFRA’s evidence to the SCCP, they didn’t consider the work of Sanchez-Politta et al. (2007) which indicates that there is little independent peer-reviewed evidence to actually support the classification of phenylacetaldehyde as a sensitiser. It has to be asked therefore, who’s interests are being served here? Certainly not the fragrance industry or the consumer’s. 

Taken overall, we don’t understand why the EU Commission seemingly has a vested interest in furthering the QRA approach, since not all toxicologists support its rationale, and the results from the various animal test protocols which can be used to calculate the EC3 values to predict likely sensitiser potency classifications are often conflicting, such that Dean et al. (2001) correctly surmised that the LLNA test would not correctly identify weak sensitisers or all strong irritants. Further there is very little in the way of aggregate exposure data to support the toxicology, and what there is seems to contradict the predicted classification of sensitizer potency. It is quite possible, from what we have seen so far of the workings of the Cosmetics Commission, that Commission staff themselves are largely are unaware of any other arguments on this subject. Therefore Cropwatch objected to the Regulator (see http://www.cropwatch.org/objectcitral.pdf) that this first use of the QRA methodology did not follow the correct Rules of Legal Procedure Re: Requests for SCCP Opinions in relation to Risk Assessment (C7 2004 D/370235), but we were over-ruled. We also repeated the Storrs argument (Storrs 2007) that DG-Ent/SCCP need to clearly set out & review the basis on which fragrance chemicals have previously been classified as allergens under Directive 2003/15/EC, amending Directive 76/768/EEC, before embarking on any further restrictions (e.g. for citral, farnesol & phenylacetaldehyde). Since only 5 allergens are confirmed as having been the direct cause of clinical allergy, a review of the situation seems imperative. This crucial point has been lost, but Cropwatch predicts, will come back to haunt them, as the rubber-stamping of IFRA's previous opinions on allergens by the SCCP was demonstrably unsafe, as is pretty-well universally acknowledged in the trade. 

In May 2007, the 42nd IFRA Amendment was introduced, to enable the QRA system to be used as a basis to review & redefine IFRA standards set on the basis of dermal sensitisation (16 standards) plus 14 new standards. These were said to cover most of the chemicals currently involved in allergen labeling. Further, as some of these new IFRA standards include ingredients that are present in essential oils and extracts, so these ingredients will also be affected. 

Cropwatch Responds To Bullying

The level of bureaucracy required to enact the QRA approach required that unless perfumes were designed hand-in-hand with software package (such as Formpack), perfumers & formulators would be unable to keep up with the level of calculations required to determine the allowable levels of sensitizers. In early 2007 (15th Jan) Cropwatch started a petition against & announced a boycott of the IFRA 40th Amendment, pointing out that the QRA was creating a hostile environment for the aroma trade, and that the effects of the QRA approach would effectively favour synthetics at the expense of natural aromatics. Cropwatch also alleged discrimination against SME's, since the implementation of this complex approach would make enormously demands on the scarce resources of both small- & micro-organisations. To date, the petition mentioned above has been signed by more than 950, perfumers, natural perfumers, soap-makers, essential oil producers, distributors & users (see http://www.ipetitions.com/petition/ifra40/signatures-20.html), and the petition was eventually presented to IFRA in mid-2007. IFRA did not even have the courtesy to acknowledge receipt of the petition, or to respond in any way, reflecting (in my opinion) the contempt it holds for those who disagree with them. 

Before this, P&F now had started to run a web-poll for votes for and against the QRA issue (see http://www.perfumerflavorist.com/newsletter/5326381.html), and Cropwatch with its massive support from the natural perfumery, essential-oil-using-, soap-making & crafting sectors quickly overwhelmed the poll. Because IFRA was losing heavily (85.1%-14.9%), Jean-Paul Henri, IFRA Director-General, called foul and publicly rapped Jeb Gleason (P&F editor) over the knuckles, so that a grovelling note from Gleason subsequently appeared together with  an accompanying  mail  from Houri (see http://www.perfumerflavorist.com/newsletter/5957641.html). Poll results disappeared from the website & Cropwatch was not invited to put their side of the story - thus history was re-written. In spite of Cropwatch's considerable influence in the perfumery sector, P&F have never printed a single word about Cropwatch activities since (so much for the notion of a free aroma trade press). Louise Prance ran an article on 2nd Mar 2007 for Cosmetics-Design Europe, independently taking the Cropwatch theme that IFRA (exclusively) promotes synthetic ingredients in fragrances, which was hastily taken down, re-written and put-up again, following an objection by Jean-Pierre Houri (Cropwatch has both versions of the article on file). Private correspondence between Houri & Prance has since been circulated amongst aroma trade organisation members (Cropwatch also has a copy of this on file). By the time that Prance had left Cosmetics-Design Europe, Cropwatch was being pilloried on the IFRA website over its opposition to the QRA system (we think this has subsequently been taken down, after Cropwatch claimed that the piece had given us a lot of positive publicity, although there remains a brief mention in IFRA Newsletter Jan 2007). Basenotes invited Burfield and Houri to put their different cases, Burfield bringing up a number of issues at http://www.basenotes.net/columnists/20070223cropwatchvsifra.html. In contrast Houri (not a scientist) chose to give a short propaganda piece about IFRA's policy, its connectivity, its power & importance, not answering any of the specific issues raised (see http://www.basenotes.net/columnists/20070223cropwatchvsifra.html). 

New Developments

In a curious out-of-character move, EFFA have suddenly presented the Schnuch opinions to DG-Enterprise, for labeling requirements for 10 allergens of the notorious ‘26 allergens’ to be reconsidered, on the grounds that in trials, these ingredients rarely present as allergens and in three cases, have not presented at all (Schnuch et al. 2007, Schnuch 2005). This is hardly new; Cropwatch have been imploring the EU Commissioners to look at the Schnuch findings from July 2004 (pub. 2005) for 4 years. These misclassified ingredients are identified (Schnuch et al. 2007) as benzyl alcohol, benzyl benzoate, methyl heptine carbonate, hexyl cinnamal, anisyl alcohol, linalol, benzyl salicylate, amyl cinnamal, limonene & a-methyl ionone (see http://www.cropwatch.org/Cropwatch Claims Victory Over 26 Allergens.pdf). Let’s further consider the implications of this strange move by EFFA. Does it mean that EFFA are (at last) at variance with IFRA policy over the 26 alleged allergen situation? Where does the Schnuch evidence leave the QRA approach? (wrecked!). Does this also mean that EFFA are now pressing DG-Enterprise to consider adverse end-user data present in the Schnuch evidence? - this outcome was, of course, previously ruled as inadmissible to Cropwatch by the Regulator in a Brussels meeting in 2007. Or do different rules now apply for EFFA safety evidence submissions, as opposed to Cropwatch submissions? 

The Oko-test results of Schunch et. al (2004) also identified citral and farnesol in the "rarely found as allergens" category, although in a previous paper Schnuch et al. (2004) had found that farnesol was an important allergen. Nevertheless, as mentioned above, EFFA had previously presented evidence to the SCCP that citral & farnesol should be considered allergens under the QRA system. So (considering the less ambiguous citral case) are EFFA supporting some parts of the Schnuch evidence, but not other parts? It’s all very confusing. EFFA have also taken up the several Cropwatch references from the work of Hostynek & Maibach which broadly suggests that the evidence used to classify anisyl alcohol, amylcinnamic aldehyde, linalol, geraniol, citronellol, alpha-methyl-iso-ionone & methyl heptine carbonate as allergens is not sufficiently scientifically robust on which to base legislation. Again this would seem to potentially undermine the position of the QRA, so we have no idea of EFFA’s motives. It also reflects on the undue haste with which the EU Cosmetics Commission is acting these days, pushing industry for results & policies when the science isn’t sufficiently developed & mature to oblige them. 

IFRA in its Information Letter 801 (02.08.2008), are to introduce yet another costly QRA U-turn for industry, under the forthcoming 43rd IFRA Amendment. Having sold (as a benefit) the fact that under the QRA approach, higher use levels could be introduced for some materials than the current IFRA Standards allow, in the next breath they change their minds, as “increased exposure due to elevated use levels presents a theoretical possibility that certain pre-sensitised individuals might experience an allergic contact dermatitis where previously they had not.” This gets the 2008 Cropwatch Prize for a Statement of the Bleedin’ Obvious, but we are so pleased that IFRA have caught up their thinking with everyone else on this matter. Unfortunately the financial penalty for industry is the re-writing of formulae & the re-programming of computers to re-align to the downwards exposure limits for the 14 new Standards already introduced under the IFRA 42nd Amendment. 

Conclusions

The general realisation that excessive regulation from IFRA/RIFM, EFFA & the EU is killing aroma industry prospects is leading to increasing technical support for Cropwatch from within the industry itself, & from aroma ingredient end-users. Blinding people with science or using high-tech. methodology such as the QRA for safety testing belies the fact that there are fundamental weaknesses in this safety strategy, and no amount of arrogance & posturing by safety officials can obliterate this. The fact that IFRA are unable to defend the use of key aroma ingredients on a risk/benefits basis, and that the EU Commissioners have allowed excessive precautionary principled policies to dominate their agenda, means that the time is right for a new independent safety authority to come along and sweep these people away. 

References 

Dean J.H., Twerdok L.E., Tice R.R., Sailstad D.M., Hattan D.G. & Stokes W.S. (2001) “OCCVAM evaluation of the murine local lymph node assay. II Conclusions & recommendations of an independent scientific peer review panel.” Regulatory Toxicology & Pharmacology 34(3), 258-273. 

Sanchez-Politta S., Campanelli A., Pashe-Koo F., Saurat J.H. & Piletta P. (2007) "Allergic contact dermatitis to phenylacetaldehyde: a forgotten allergen?" Contact Dermatitis 56(3),171-2. 

Schnuch A., Uter W., Geier J., Lessmann H. & Frosch PJ. (2004) "Contact allergy to farnesol in 2021 consecutively patch tested patients. Results of the IVDK." Contact Dermatitis. 50(3), 117-21. Schnuch A. (2005) Öko-Test, No. 7 (July) 2004, 55 

Schnuch A., Uter W., Geier J., Lessmann H. & Frosch P.J. (2007) “Sensitization to 26 fragrances to be labelled according to current European regulation. Results of the IVDK and review of the literature.” Contact Dermatitis. 57(1),1-10. 

Storrs F.J. (2007) “Allergen of the year: fragrance.” Dermatitis 18(1), 3-7.   

Posted by Tony Burfield on April 27, 2008 in Perfumery, Regulatory Issues, Safety/Toxicity | Permalink

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