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the positive results obtained with hair dye components in bacterial tests for mutagenicity (e.g. the Ames Test), which led to the emphasis on genotoxicity testing in the application of the Directive in relation to cosmetic products ingredients, and to the inclusion of so many genotoxicologists among the experts who were directly involved or consulted. Little attention is paid to cosmetic ingredients per se in the draft chapter. There is a brief discussion on hair dyes, but only to make the point that the in vitro systems used in a study failed to predict the results of the rodent bioassay, so the ‘falsepositive’ results they provided might have led to the unnecessary abandonment of the use of 17 hair dyes. However, given the poor record of predictions based on the rodent bioassay, the in vitro results might have been ‘true-positive’ for humans. As in the case of draft Chapter 1, this draft chapter focuses too much attention on the tests themselves, rather than on the chemicals that need to be considered, how the body is exposed to them, and where and in what circumstances they might reach a TTC. As a result, the statement that, if “an in vivo test is no longer possible, the safety of many potential new cosmetic ingredients will not be able to be substantiated” (line 1103) has no merit and should not influence the application of the 7th Amendment to the Cosmetics Directive. If in vivo testing “is rarely done on cosmetic ingredients because of expense, time, and animal welfare issues” (lines 44 and 92), what problems have arisen as a consequence of this, which now make this a matter of such concern?
Draft Chapter 4: Toxicokinetics The 73-page draft chapter, by Olavi Pelkonen, Sandra Coecke, Sofia Batista Leite, Ulrike Bernauer, Jos Bessems, Esther Brandon, Frederic Bois, Ursula Gundert-Remy, George Loizou, Emanuela Testai and José-Manuel Zaldívar, is very interesting and encouraging, but it is so heavily based on experience with pharmaceuticals that its relevance to the Cosmetics Directive and 2013 is questionable. For example, Table 1 (five pages) on replacement methods for absorption and bioavailability repeatedly states “developed for pharmaceuticals”, “not used for cosmetics” and “suitability for cosmetics should be evaluated”. Then Table 2 and the respective text sections (lines 685 to 857) on replacement methods for distribution are mainly focused on partition between blood and tissues, the blood–brain barrier, the blood–placental barrier and the blood–testis barrier — important issues for pharmaceuticals, but not of primary concern for cosmetic ingredients unless they enter the body in significant amounts which approach the TTC. Figure 2 provides a valuable insight into future human
Comment
risk assessment with no animal assays, but again, it is likely to be more interesting to the pharmaceutical industry than to the cosmetics industry. The same could be said about the sections on plasma protein binding (lines 634 and 658). The sections on models for bioaccessibility (line 505), absorption (line 534) and bioavailability (line 575) are more relevant, and OECD TG 428 (3), on in vitro methods for determining dermal absorption across animal and human skin, is discussed, but the limitations of these methods are emphasised, as they may not provide suitable input for more-conventional physiologicallybased pharmacokinetic (PBPK) models (which, one might say, are more closely-related to oral uptake). Table 3 and the respective text sections (lines 860 to 1099) on metabolism are mainly concerned with the metabolism of pharmaceuticals by the cytochrome p450 system. The situation is best summed up by words from the draft chapter itself (line 1227): “Since only in cases where a cosmetic ingredient is bioavailable following dermal, oral, or inhalation exposure, [will] further tests on systemic and not just local toxicity be necessary, additional efforts are needed to provide reliable alternative methods to assess the bioavailability after oral and inhalation exposure. Several efforts have been undertaken to improve the reliability [of] alternative test methods available [for] assessing absorption via [the] gut and lungs, but still more work would be required.” Surely, however, the key potential route of entry for most cosmetic ingredients is via the skin, and this should have been given more attention in this draft chapter. This criticism is partly countered by the final, short section on “strategic considerations of risk assessment of cosmetic ingredients” (line 1421), and the decision-trees for absorption-based testing (Figure 6) and for (internal) exposure-based testing (Figure 7), which contrast well, at least in terms of relevance, with the schematic representation of a physiologically-based toxicokinetic (PBTK) model for a woman (Figure 3). However, that the authors of the draft chapter are more comfortable with products other than cosmetics re-emerges in the Recommendations section (line 1491), where the need for better models of absorption via the lung and excretion via the kidney is emphasised, and the efficiency of the conventional validation procedure is questioned, and an “expert consensus procedure” is recommended to replace it. However, if these five draft chapters provided by experts for the Commission are anything to go by, that would not be a wise way forward. The validation process need not, and should not, be conventional, but should be scientifically rigorous, adaptable, transparent, and free of bias in support of vested interests.