The questions and responses

1. How is the EC3 value considered when it comes to skin sensitization?

How does MEPPD's EC3 value compare to PPD and how does this translate in terms of likelihood to induce an allergic reaction?

The EC3 value is a derived measure of allergen potency from a murine local lymph node
assay (LLNA) (2). Expressed as a percentage, the smaller the value, the more potent the allergen, with values for known skin contact allergens covering several orders of magnitude (approximately 0.001% to 100%). PPD is the strongest of the hair dye allergens, with an EC3 value about 0.11% (10 determinations; range 0.06% - 0.18%) (2). By comparison, ME-PPD has an EC3 value of 4.3%, approximately 40-fold higher (3). It should be borne in mind that EC3 values are not absolute - they are biological
determinations; typically repeated determinations of a value will vary by around of factor of 2-3 in each direction (as noted for PPD. How this translates into the likelihood of allergy is detailed in the response to subsequent questions.

2. What % of MEPPD vs PPD will it take to induce an allergic reaction?

The EC3 value is a derived measure of allergen potency from a murine local lymph node assay (LLNA) (2). Expressed as a percentage, the smaller the value, the more potent the allergen, with values for known skin contact allergens covering several orders of magnitude (approximately 0.001% to 100%). PPD is the strongest of the hair dye allergens, with an EC3 value about 0.11% (10 determinations; range 0.06% - 0.18%) (2). By comparison, ME-PPD has an EC3 value of 4.3%, approximately 40-fold higher (3). It should be borne in mind that EC3 values are not absolute - they are biological
determinations; typically repeated determinations of a value will vary by around of factor of 2-3 in each direction (as noted for PPD. How this translates into the likelihood of allergy is detailed in the response to subsequent questions.

If these two hair dye actives were used at the same concentration in closely similar products applied to the consumer in an identical manner, a calculation could be attempted. Why attempted? In a permanent hair dye setting, we do not know the minimum concentration of PPD which will be just sufficient to induce allergy; we do know that at currently allowed levels (up to 2% on the scalp), the induction (and elicitation) of allergy occurs. Nevertheless, using a quantitative risk assessment approach, when all other variables are constant, then the difference in % should reflect the difference in potency (as estimated by the EC3 value) (4). Thus, assuming that the dose-response relationship is linear, if ME-PPD is a factor of 40 less potent than PPD, its
use should in theory offer a 40-fold lower risk of the induction of allergy.

It is worth mentioning that the original scientists involved in work on ME-PPD published slightly different figures (remember, this is biology, not chemical constants). So, using the data from reference 3, the ratio of EC3 values would be 4.3% divided by 0.17% - which equates to a factor of 25.

3. What % does MEPPD based formulas decrease the chances of having a severe allergic reaction compared to PPD?

Firstly, it is important to note that I have continued to assume that ME-PPD is used in the
same manner and at the same concentrations as PPD in consumer hair dyes. A number of studies have examined the extent to which ME PPD can elicit a positive patch test reaction in individuals with an existing sensitivity to PPD (e.g. 5, 6). However, a more interesting work from 2016 explored whether such individuals could tolerate the hair dyeing process - thus being a little more reflective of the real life situation (7). 43 PPD positive subjects were enrolled; 5 were screened out in the product pre-test, but 38 continued to use ME-PPD hair dye for several months. 29/38 subjects did so without adverse skin reaction. So, in effect, 2 out of 3 of the original cohort were able to tolerate the use of ME-PPD hair dye. From previous patch test data, I would have expected it might only be half.

The work of Kock et al. also brings out a further interesting point: the allergy alert test with the ME-PPD product (which the manufacturer indicates should always be completed prior to product use), although positive in 5 subjects, was negative in 9 individuals who then went on to develop skin problems. In other words, 9/38 (24%) were false negative, which I would consider an unacceptably high rate. Put another way, the results suggest that almost two-thirds (9/14) of the “at risk” individuals were not identified by the allergy alert test (7).

To address the question of severity is quite challenging. In an individual, the severity of the reaction to one contact allergen does not really predict the severity of the reaction to another allergen. However, what controls this is as much about the extent to which the3 individual has been exposed as it is to their individual allergen susceptibility. Looked at more broadly, I would expect that someone highly allergic to PPD is more likely to react to ME-PPD and also more likely to react more strongly. I judge that this is what can be concluded from published works on ME-PPD cross reaction (4, 5), but of course (further) experimental work on such a topic is unlikely to be ethically acceptable.
As a final comment, it is necessary simply to remark that humans are highly heterogenous. Examination of the clinical literature on allergic contact dermatitis shows that although stronger allergens are generally more common culprits, weaker allergens can and do cause severe allergic responses on an individual basis. This is reflected very clearly in collated diagnostic patch test materials (8).

4. If there is an initial allergy to PPD, what is the likelihood of them being allergic to MEPPD?

Firstly, please check the answer to the question above.

Although ME-PPD has been on the consumer market for a few years, the pool of individuals with a pre-existing allergy to PPD is significant. Several studies have addressed the question of whether PPD positive individuals will cross react to ME-PPD (e.g. 5, 6). Probably 50/50 is my view - some studies suggest a little less, whereas a
small study from Italy had 7/8 cross-reacting, although the skin responses to ME-PPD
were lower than PPD (9). However, the work mentioned above suggests two-thirds may tolerate ME-PPD (7). I think that the absence of evidence that there is a pattern of hair dye allergy emerging that is due to ME-PPD speaks to it being a weaker allergen, and thus there is a lower likelihood of the severe allergic reactions.

5. Is MEPPD a viable alternative for those with a PPD allergy?

With dermatology colleagues, our recommendation was published several years ago in the British Journal of Dermatology: “Advice for patients with hair dye allergy remains stop using permanent hair dyes.” (10). It has to be recognised that the evidence that ME- PPD is less likely to elicit an allergic skin response in those with existing PPD sensitivity does not indicate that it is necessarily a less potent contact allergen.

6. What are the current views on MEPPD?

My perception is that the jury is still out on this question. A very recent review of hair dye allergy failed to mention ME-PPD in its table of the “most frequent hair dye sensitizers” (11). However, this group of authors did comment that ME-PPD was
expected to be less allergenic, but also still noted that it was not necessarily safe for those with existing hair dye allergy.

Final remarks and a consideration of potential claims

It is evident from in vivo toxicology data that ME-PPD appears to be less allergenic than PPD. The extent to which that is the case may have been somewhat exaggerated for commercial reasons. Thus I urge caution in the adoption/interpretation of scientific information directly from publicity material. I have tried only to use the source material of peer-reviewed scientific publications. As has been noted elsewhere (12), the ultimate
“proof” regarding safety in the marketplace comes from the consumer - and that can take
many years to accumulate. That said, as far as I can tell there is no active use of ME-PPD for diagnostic patch testing, suggesting that it has, as yet, to fall under significant degree of suspicion, which would be consistent with the toxicology evidence of markedly reduced allergenic potency.

The consequence of the above is that it is possible to consider whether claims regarding the lower allergenicity of ME-PPD could be supported. I can see that the available data could underpin statements you have suggested, including:

- ME-PPD has substantially reduced skin sensitising properties than PPD.

-  Toxicology data/studies shows that ME-PPD is substantially less allergenic than PPD.

-  ME-PPD is over 95% less likely to induce/cause a new allergic reaction.

With any claim, I think it is important for the company making it to make sure that they
know what the consumer understands from the claim. The third in the list for example must not be seen by someone who is PPD-allergic and is thereby led to believe they are safe. You have separately suggested a footer: While allergic reactions are reduced for those with an initial PPD sensitivity, please consult a doctor before use and perform an AAT. This would be a practical way forward.