Registration Dossier

Administrative data

Description of key information

Key value for chemical safety assessment

Skin sensitisation

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not sensitising)
Additional information:

Studies in Animals

Skin

Nine reliable adjuvant tests (seven maximization tests according to Magnusson and Kligman, one Draize and one modified Draize test) are reported. Eight of these tests have been performed on Coco AAPB and one on C12 AAPB. None of these studies was performed in full compliance with the current OECD or EU guideline, and information on the purity and impurities of the test materials is available on four studies only. Although the majority of the studies gave no indication of a sensitising potential, the lack of concurrent positive control data, may weaken their reliability. However, the first study selected as a key study on skin sensitisation, has been performed according to OECD Guideline 406 and GLP. As the guideline claims semiannual reliability checks on positive control substances, the missing data on a positive control is probably a deficit in study documentation but not in study conduct. This study (Evonik, 1990) was selected as key study because it is the most recently performed maximisation test available on AAPB. The test AABP in this study was Coco AAPB with 30 % a. i. in minimum and impurities relevant to sensitisation referred to a. i. of in maximum 1.7 % alkylamidopropylamine and 33 ppm DMPA (3-dimethylaminopropylamine). As a second key study (Evonik, 1980), the maximisation test on the test item with the highest amounts of the potentially sensitising impurities alkylamidopropylamine and DMPA was selected. In this study, a Coco AAPB quality with 8.3 % Alkylamidopropylamine and 33 - 50 ppm DMPA based on a. i. has been tested. The results of both key studies as well as further reliable supporting adjuvant tests were all negative. Only in the maximisation study performed by Rantuccio et al.(1983), two out of 20 tested Guinea pigs showed an allergic reaction, whilst the result was ambiguous in four, and clearly negative in 14 animals.Unfortunately, no information on impurities of the test substance, which might have influenced the outcome of the study was provided by the authors of the publication. Furthermore, a second challenge (as recommended in the current OECD TG 406) was not performed that could have helped in the interpretation of the results. Hence, the interpretation of the effects seen in this particular test remains difficult, no firm conclusion about the sensitizing potential of the AAPBs can be drawn from this study. As published results on a further GPMT, and a LLNA are only available as secondary citations, their reliability, relevance and adequacy cannot be judged. It is therefore not possible to draw a firm conclusion about the sensitising potential of the AAPBs from these two studies.

Studies in Humans

The following compilation of studies on human patients and conclusions on photosensitisation and respiratory tract sensitisation is a quotation taken from the OECD SIAR-SIDS Initial Assessment Report on Alkylaminopropyl betaines (remark: Cocamidopropylamine is synonymous to Coco AAPB and amidoamine to alkylaminopropylamine).

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Skin

Patch test results have been reported from several thousands of patients with skin disorders associated with occupational exposure or exposure to cosmetic formulations containing cocamidopropyl betaine.

A complicating factor in most of these studies is the fact that sensitizing impurities and by-products from the manufacturing process, such as amidoamine and 3-dimethylaminopropylamine (DMPA) may have been present in the test formulations, resulting in “false positive” reactions for cocamidopropyl betaine. This is particularly the case for testing performed before the late 90’s when this issue became evident. Furthermore, the patch test reactions to cocamidopropyl betaine (or its impurities) often are irritant in nature, although the morphological picture and crescendo reaction may sometimes suggest a positive allergic reaction (Löffler et al., 2005).

As most of the available reports do not provide information on the purity of the tested material, which appears to have a significant influence on the testing results, they were considered as of limited reliability and are not described in this IUCLID dataset. Only the most relevant and reliable studies are summarized below:

3-Dimethylaminopropylamine and amidoamine have been identified as sensitizing impurities in commercially available cocamidopropyl betaine by several investigators (Pigatto et al., 1995; Angelini et al., 1995, 1996 a, b; Fowler et al., 1997; Hunter and Fowler, 1998; Armstrong et al., 1999; McFadden et al., 2001; Brey and Fowler, 2004; Fowler et al., 2004).

Pigatto et al. (1995) investigated the influence of impurities on patch test results by using cocamidopropyl betaine samples from different manufacturers.In a first study, the authors found that 17 out of 1190 (1.4 %) patients with allergic contact dermatitis were positive to cocamidopropyl betaine (of unknown purity). Subsequently, 15 of these patients were patch tested with cocamidopropyl betaine containing DMPA at concentrations of 200 ppm or below the limit of detection. Whilst all 15 patients showed an allergic reaction to the sample with 200 ppm, only 1 patient reacted to the cocamidopropyl betaine of higher purity. In further tests it was shown that 10 out of 12 patients reacted to DMPA (1 % and 0.1 % aqueous solutions), and 9 out of 13 subjects still reacted to DMPA at 0.05 % (aqueous solution). Two of the 12 patients had irritant reactions to DMPA.

Angelini et al.(1995, 1996a, b) tested 1200 consecutive eczematous patients with a 1 % aqueous solution of cocamidopropyl betaine.Contact allergy was found in 46 subjects (3.8 %), while irritant reactions (i. e., slight erythema only) were observed in 15 cases (1.25 %).30 out of 46 patients with allergic reactions were subsequently tested with the substances used in the synthesis ofcocamidopropyl betaine, together with a sample of cocamidopropyl betaine of a greater purity.In all 30 subjects, positive reactions were obtained to DMPA (1 % aqueous solution), while the cocamidopropyl betaine defined of purer grade, at 0.5 % and 1 %, gave positive reactions in 10 % and 53 % of cases, respectively. According to the study authors, these results suggested that the DMPA present at various levels as an impurity in the commercial product is responsible for cocamidopropyl betaine allergy. Owing to the inconsistency of positive reactions to cocamidopropyl betaine of variable purity, and to the consistency of positive reactions to DMPA, it seems likely that these reactions may also be connected with the presence in the product, defined of purergrade, of unknown amounts of DMPA as impurity.

In product use tests (Fowler et al., 1997; Hunter and Fowler, 1998), amidoamine was shown to be a likely sensitizer in cocamidopropyl betaine formulations. Six out of 9 subjects reacted to amidoamine (0.1 % aqueous solution), none of these individuals reacted to DMPA (0.1 % in petrolatum), and between 1 and 3 subjects reacted to cocamidopropyl betaine (1 % aqueoussolution) of different purity grades.

A significant correlation was found between the amidoamine content and the sensitizing potential of “impure” cocamidopropyl betaine (Armstrong et al., 1999; Foti et al., 2003).

McFadden et al. (2001) tested cocamidopropyl betaine of various purity grades.Partially purified cocamidopropyl betaine, i. e., with less than 0.5 percent of amidoamine, resulted in allergic reactions in 3 out of 4 individuals; these three individuals reacted also towards amidoamine (0.1 %), and 1 subject still reacted to amidoamine at 0.01 %. None out of 6 individuals tested with a 1 %aqueous solution of “pure” cocamidopropyl amine (i. e., with < 0.3 % amidoamine, < 10 ppm DMPA) had an allergic reaction. One out of 6 subjects reacted to DMPA (at 1000 ppm on tapestripped skin and 10000 ppm on normal skin), and three of 6 reacted to DMPA (100 - 10 000 ppm) in 0.2 % sodium lauryl sulfate.

Data was collected during 2001 by the North American Contact Dermatitis Group from consecutive patients presenting for patch testing for diagnosis of presumed allergic contact dermatitis (Fowler et al., 2004; Brey and Fowler, 2004). Of 975 patients tested, 15 were patch-test positive to cocamidopropyl betaine, 25 had positive reactions to amidoamine, and 18 had positive reactions toboth substances.

In view of the widespread use of cocamidopropyl betaine in personal cleansing products, only relatively few cases of sensitization have been reported. Most cases alleged to have been sensitized by cocamidopropyl betaine were most probably caused by impurities, such as amidoamine and DMPA that may be present in the formulations.

Because of the similar manufacturing method, the impurity profile with regard to the suspected sensitizers is expected to be the same in all AAPB preparations.

Photosensitization

There is no structural element in alkylamidopropyl betaines present, which could lead to UV absorption and hence photosensitization.

Respiratory Tract

No studies were available on the potential of respiratory tract sensitization.

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Conclusion

Overall, the sensitising potential of the AAPBs is considered to be low. AAPB qualities tested in the past may have, however, contained substantial amounts of impurities meanwhile identified as sensitisers (amidoamine (also named alkylamidopropylamine or Amides, C8-18 even numbered, N-[3-(dimethylamino) propyl]) and/or DMPA (also named 3-aminopropyldimethylamine or 3–dimethylaminopropylamine)), which may explain positive results in human patch tests reported in the literature. However, the production process for AAPBs has been changed since and the level of impurities identified as sensitisers was significantly reduced. Recent AAPB qualities as defined in the submission substance identity (low levels of amidoamine and DMPA) can be expected to be non sensitising based on reliable animal adjuvant tests. These tests have been performed on AAPB qualities with partial even substantially higher amounts of the potentially sensitising impurities amidoamine and DMPA than defined in the submission substance identity. There is no structural element in alylamidopropyl betaines present, which could lead to UV absorption and hence photosensitization.

The sensitising potential of the whole group of AAPBs is assumed to be similar. As fatty acids independently from their chain length and degree on unsaturation are generally considered to be non sensitisers, a variability in the fatty acid moiety is not expected to have any influence on the sensitising activity of the AAPBs. Thus, the use of studies performed on individual members of this group of substances as read-across for the whole group is justified.


Migrated from Short description of key information:
Comprehensive data from animal studies as well as from human data are available. AAPBs are considered to be non sensitising based on the results of reliable animal adjuvant tests. AAPB qualities tested in the past may have, however, contained substantial amounts of impurities meanwhile identified as sensitisers (alkylamidopropylamine and/or 3 -dimethylaminopropylamine), which may explain positive results in human patch tests reported in the literature. However, the production process for AAPBs has been changed since and the level of impurities identified as sensitisers was significantly reduced.

Respiratory sensitisation

Endpoint conclusion
Additional information:
Migrated from Short description of key information:
No data available

Justification for classification or non-classification

Eigth out of nine reliable animal adjuvant tests gave no indication of a sensitising potential of the AAPBs. The ninth study, a Guinea pig maximisation test, gave an ambiguous result. Since this result has been not verified by a second challenge, nor detailed information on the quality of the test item is available, no firm conclusion about the sensitising potential can be drawn from this study. The tested items which gave negative results in animal adjuvant tests included a quality with 8.3 % alkylamidopropylamine and 33 - 50 ppm DMPA based on a.i.. Positive human patch test results have been reported in the literature. AAPB qualities tested in the past may have, however, contained substantially amounts of impurities meanwhile identified as sensitisers (alkylamidopropylamine and/or 3 -dimethylaminopropylamine), which may explain these positive results. However, as the production process for AAPBs has been changed since and the level of impurities identified as sensitisers was significantly reduced. Recent AAPB qualities as defined in the submission substance identity can be expected to be non sensitising based on reliable animal adjuvant tests. These test have been performed on AAPB qualities with partial even substantially higher amounts of the potentially sensitising impurities alkylaminopropylamine and DMPA than defined in the submission substance identity. There is no evidence for a photosensitizing potential.

AAPB qualities as defined in the submission substance identity do not meet the classification criteria regarding sensitisation outlined in regulation (EC) 1272/2008 or the former European directive on classification and labelling 67/548/EEC.