Registration Dossier

Administrative data

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.

Key value for chemical safety assessment

Skin sensitisation

Link to relevant study records
Reference
Endpoint:
skin sensitisation: in vivo (non-LLNA)
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Justification for type of information:
REPORTING FORMAT FOR THE ANALOGUE APPROACH
see "General Justification for Read-Across" attached to IUCLID section 13

1. HYPOTHESIS FOR THE ANALOGUE APPROACH
Mutual read across from the AAPBs to one another is justified:

a) Based on the information given in section 1, it can be concluded that all AAPBs mentioned above are similar in structure, since they are manufactured from similar resp. identical precursors under similar conditions and all contain the same functional groups. Thus a common mode of action can be assumed.
b) The content of minor constituents in all products are comparable and differ to an irrelevant amount.
c) The only deviation within this group of substances is a minor variety in their fatty acid moiety, which is not expected to have a relevant impact on intrinsic toxic or ecotoxic activity and environmental fate. Potential minor impact on specific endpoints will be discussed in the specific endpoint sections.

The read-across hypothesis is based on structural similarity of target and source substances. Based on the available experimental data, including key physico-chemical properties and data from toxicokinetic, acute toxicity, irritation, sensitisation, genotoxicity and repeated dose toxicity studies, the read-across strategy is supported by a quite similar toxicological profile of all five substances.
The respective data are summarised in the data matrix; robust study summaries are included in the Technical Dossier in the respective sections.

2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
see "General Justification for Read-Across" attached to IUCLID section 13

3. ANALOGUE APPROACH JUSTIFICATION
see "General Justification for Read-Across" attached to IUCLID section 13

4. DATA MATRIX
see "General Justification for Read-Across" attached to IUCLID section 13
Reason / purpose:
read-across source
Reason / purpose:
read-across source
Reason / purpose:
read-across: supporting information
Reason / purpose:
read-across source
Reason / purpose:
read-across source
Reason / purpose:
read-across source
Reason / purpose:
read-across source
Reason / purpose:
read-across source
Reason / purpose:
read-across source
Reason / purpose:
read-across source
Reason / purpose:
read-across source
Reason / purpose:
read-across source
Reading:
1st reading
Hours after challenge:
24
Group:
test group
Dose level:
10 %
No. with + reactions:
2
Total no. in group:
15
Clinical observations:
erythema score 1 (Slight erythema (barely perceptible))
Remarks on result:
no indication of skin sensitisation
Reading:
2nd reading
Hours after challenge:
48
Group:
test group
Dose level:
10 %
No. with + reactions:
0
Total no. in group:
15
Remarks on result:
no indication of skin sensitisation
Reading:
other: 3rd reading
Hours after challenge:
72
Group:
test group
Dose level:
10 %
No. with + reactions:
0
Total no. in group:
15
Remarks on result:
no indication of skin sensitisation
Interpretation of results:
GHS criteria not met
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not sensitising)
Additional information:

No experimental data on the sensitisation potential of C8-18 AAPB are available. Hoewever, eight reliable adjuvant tests (seven maximization tests according to Magnusson and Kligman, one Draize and one modified Draize test) conducted with the closely related substance C8-18 and C18 unsatd. AAPB are reported. Additionally, a skin sensitisation study comparable to OECD Guideline 406 (Guinea pig maximisation test) is available for C12 AAPB. A justification for read-across is given below.

 

Studies in Animals

Skin sensitisation

None of the 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).

 

(start of quotation)

 

Skin sensitisation

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 % aqueous solution) 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 to both 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.

 

Photosensitisation

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

 

Respiratory tract sensitisation

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

 

(end of quotation)

 

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.

 

Justification for read-across

For details on substance identity and detailed toxicological profiles, please refer also to the general justification for read-across given at the beginning of the CSR and attached as pdf document to IUCLID section 13.

This read-across approach is justified based on structural similarities. All AAPBs contain the same functional groups. Thus a common mode of action can be assumed.

The only deviation within this group of substances is a minor variety in their fatty acid moiety (chain length and degree of unsaturation), which may have an influence on the outcome of skin and eye irritation studies. However,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.

 

a. Structural similarity and functional groups

Alkylamidopropyl betaines (AAPBs) are – with the exception of C12 AAPB - UVCB substances (Substances of Unknown or Variable composition, Complex reaction products or Biological materials), which are defined as reaction products of natural fatty acids or oils with dimethylaminopropylamine and further reaction with sodium monochloroacetate. AAPBs are amphoteric surfactants, which are characterized by both acidic and alkaline properties.

 

Their general structure is:

 

R-C(O)-NH-(CH2)3-(N(CH3)2)+-CH2-C(O)O-

R = fatty acid moiety

 

The fatty acids have a mixed, slightly varying composition with an even numbered chain length from C8 to C18. Unsaturated C18 may be included. Consequently, the AAPBs differ by their carbon chain length distribution and the degree of unsaturation in the fatty acid moiety. However, Lauramidopropyl betaine (C12 fatty acid derivate) is the major ingredient of all AAPBs covered by this justification as listed in table 1 “Substance identities” of the general justification for read-across.

 

The substances under evaluation share structural similarities with common functional groups (quaternary amines, amide bonds and carboxymethyl groups), and fatty acid chains with differences in chain length and degree of saturation.

 

b. Differences

Differences in the sensitising potential of the AAPBs could potentially arise from the following facts:

-Different amounts of different carbon chain lengths (carbon chain length distribution):

Higher amounts of higher chain lengths and corresponding lower amounts of lower chain length could result in a rising average lipophilicity. As fatty acids independently from their chain length 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

- Different amounts of unsaturated fatty ester moieties:

Effects may be expected for e.g. physical state and for some toxicological endpoints, mainly local effects (e.g. irritation). However, as fatty acids independently from their degree of 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

 

Comparison of sensitisation data

 

Endpoints

Source substances

Target substance

 

C8-18 and C18 unsatd. AAPB

C12 AAPB

C8-18 AAPB

Sensitisation,

Animal data

key_GPMT_Skin sensitisation: 61789_40-0_8.3_REWO_1990_OECD 406

key study


OECD TG 406, in vivo, Guinea pig maximisation test, guinea pig

 

33 ppm DMPA

1.7% Alkylamidopropylamine

 

not sensitising

 

Reliability: 2 (reliable with restrictions), GLP

Sup_GPMT_Skin sensitisation: 4292-10-8_8.2.1_8.3_Zschimmer_Schwarz_1986_skin sensitization

 

Supporting study


Similar to OECD TG 406, in vivo, Guinea pig maximisation test, guinea pig

 

No data on DMPA and Alkylamidopropylamine

 

not sensitizing

 

Reliability: 2 (reliable with restrictions), no GLP

No data, read-across

key (highest level of impurities)_Skin sensitisation: 61789-40-0_8.3_THG_1980a

key study

similar to OECD TG 406, in vivo, Guinea pig maximisation test,
 guinea pig

 

33 – 50 ppm DMPA

8.3% Alkylamidopropylamine

 

not sensitising

 

Reliability: 2 (reliable with restrictions), no GLP

Sup_GPMT_Skin sensitisation: 61789-40-0_8.3_THG_1980b

 

supporting study

 

similar to OECD TG 406, in vivo, Guinea pig maximisation test, guinea pig

 

7 ppm DMPA

<0.3% Alkylamidopropylamine

 

not sensitising

 

Reliability: 2 (reliable with restrictions), no GLP

Sup_GPMT_Skin sensitisation: 61789-40-0_8.3_REWO_1987_OECD 406

 

supporting study

 

OECD TG 406, in vivo, Guinea pig maximisation test, guinea pig

 

33 ppm DMPA

Max. 1.7% Alkylamidopropylamine

 

not sensitising

 

Reliability: 2 (reliable with restrictions), GLP

Sup_GPMT_Skin sensitisation: 61789-40-0_8.3_Arimura et al._1998

 

Supporting study

 

Similar to OECD TG 406, in vivo, Guinea pig maximisation test, guinea pig

 

No data on DMPA andAlkylamidopropylamine

 

not sensitising

 

Reliability: 2 (reliable with restrictions), no GLP

Sup_GPMT_Skin sensitisation: 61789-40-0_8.3_Rantuccio et al._ 1983

 

Supporting study

 

Similar to OECD TG 406, in vivo, Guinea pig maximisation test, guinea pig

 

No data on DMPA andAlkylamidopropylamine

 

ambiguous

 

Reliability: 2 (reliable with restrictions), no GLP

Sup_ mod Draize Adjuvans Test_Skin sensitisation: 61789-40-0_8.3_Rantuccio et al._1983

 

supporting study

 

in vivo, modified Draize test, guinea pig

 

no data on DMPA andAlkylamidopropylamine

 

not sensitising

 

Reliability: 2 (reliable with restrictions), no GLP

Sup_Draize Adjuvans Test_Skin sensitisation: 61789-40-0_8.3_Henkel_1976

 

Supporting study


in vivo, Draize adjuvans test, guinea pig

 

no data on DMPA and Alkylamidopropylamine

 

not sensitizing

 

Reliability: 2 (reliable with restrictions), no GLP

Sensitisation, human data

11 supporting studies:

Human, patch test with Coco AAPB

 

DMAPA was found to be responsible for sensitization reactions

 

Reliability: 2 (reliable with restrictions)

No data

No data, read-across

 

The most recently performed maximisation test available on AAPB was selected as one key study. The test item in this study was C8 -18 and C18 unsatd. APB with 30% a.i. and 1.7 % alkylamidopropylamine and 33 ppm DMPA (3-dimethylaminopropylamine) as minor constituents relevant to sensitisation.

As a second key study, the maximisation test on the test item with the highest amounts of the potentially sensitising minor constituents alkylamidopropylamine and DMPA was selected. In this study, a C8 -18 and C18 unsatd. AAPB quality with 8.3% Alkylamidopropylamine and 33 - 50 ppm DMPA has been tested.

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. 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 final conclusion about the sensitizing potential of the AAPBs can be drawn from this study.

Overall, with the exception of one Guinea Pig Maximisation Test with ambiguous results, in all available studies AAPBs were non-sensitisers.

 

Quality of the experimental data of the analogues:

The available data are adequate and sufficiently reliable to justify the read-across approach.

The key studies were conducted according to (or comparable to) OECD Guideline 406 (Guinea pig maximisation test)and are reliable with restrictions (RL2).

Several supporting studies (RL2) are available, which were conducted according to (or comparable to) OECD Guideline 406 (Guinea pig maximisation test) or according to the modified Draize test protocol or the Draize adjuvans test protocol.

The test materials used in the respective studies represent the source substance as described in the hypothesis in terms of substance identity and minor constituents. A study with the test item containing the minor constituent DMPA (3-dimethylaminopropylamine) in concentrations between 33-50 ppm and thus representing the upper level of the specifications, has been selected as one of the key studies.

Overall, the study results are adequate for the purpose of classification and labelling and risk assessment.

 

Conclusion

Based on structural similarities of the target and source substancesas presented above and in more detail in the general justification for read across, it can be concluded that the available data from the source substance C8-18 and C18 unsatd. AAPB are also valid for the target substance C8-18 AAPB.

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.

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.

Respiratory sensitisation

Endpoint conclusion
Endpoint conclusion:
no study 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.