amides, C18-unsatd., N-[3-(dimethylamine)propyl]

Endpoint summary

Key value for chemical safety assessment

Skin sensitisation

Endpoint conclusion

Endpoint conclusion:

adverse effect observed (sensitising)

Additional information:

A first skin sensitizing studies in Guinea Pigs according to Magnusson and Kligman is available for N-[3-(dimethylamino)propyl]-C18 unsaturated-alkylamide (unsaturated C18). As some interrogations were raised, it was decided to conduct a second study to confirm or not the previous results. As the substance is a surfactant, the Local Lymph Node Assay was inappropriate. In addition, published data reported case of sensitisations in humans with amido amines derivatives.

GPMT CIT 203

The potential of N-[3-(dimethylamino)propyl]-C18 unsaturated-alkylamide (unsaturated C18) to induce delayed contact hypersensitivity was evaluated in guinea pigs according to the maximization method of Magnusson and Kligman and to OECD (No. 406, 17^thJuly 1992) guideline.The study was conducted in compliance with the principles of Good Laboratory Practice Regulations.

Thirty guinea pigs were allocated to two groups: a control group of five males and fives females and a treated group of ten males and ten females.

On day 1, three pairs of interdermal injections were performed in the interscapular region of all animals:

-        Freund’s complete adjuvant (FCA) diluted in 50% (v/v) with 0.9% NaCl (both groups)

-        Test substance at the concentration of 0.1% in corn oil (treated group) or vehicule alone (control group)

-        Test substance at the concentration of 0.1% in a mixture FCA / 0.9% NaCl  (50/50, v/v) (treated group) or vehicle at the concentration of 50% (v/v) in a mixture FCA / 0.9% NaCl (50/50, v/v) (control group).

On day 8, the animals of the treated group received a topical application of the test substance at the concentration of 10% (w/w) in ethanol water (80/20) to the same test site, which was then covered by an occlusive dressing for 48 hours. The animals of the control group received an application of vehicle under the same experimental conditions.

On day 22, all animals of both groups were challenged by a cutaneous application of the test substance at the concentration of 1% (w/w) in acetone to the right flank. The test substance was maintained under an occlusive dressing for 24 hours; The vehicle was applied to the left flank under the same experimental conditions. Skin reactions were evaluated approximately 24 and 48 hours after removal of the dressing. At the end of the study, animals were killed without examination of internal organs. No skin samples were taken from the challenge application sites.

No clinical signs and no deaths were noted during the study. After the challenge application, no cutaneous reactions were observed in the animals of the control group. In the treated group, a discrete erythema was noted at the 24-hour reading in 1/20 animals. No erythema was recorded at the 48-hour reading. Dryness of the skin was observed in 3/20 animals of the treated group and in 1/10 animal of the control group at the 48 -hour reading. Under the experimental conditions and according to the maximization method of Magnusson and Kilgman, the test substance does not induce delayed contact hypersensitivity in guinea pigs.

GPMT CIT 2012

The objective of this study was to evaluate the potential of N-[3-(dimethylamino)propyl]-C18 unsaturated-alkylamide (unsaturated C18) to induce delayed contact hypersensitivity in guinea pigs.This study was conducted in compliance with OECD Guideline No. 406 and the principles of Good Laboratory Practices.

 

Three preliminary tests were performed in order to determine the test item concentrations to be used in the main test.In the main test, one treated group of ten males and ten females received the test item:

.            on day 1 by intradermal injections in the interscapular region at the concentration of 0.10%,

.            on day 8 by topical application to the clipped interscapular region at 10%,

.            on day 22 by topical application to the posterior right flank at 0.5%. The posterior left flank of the animals received the vehicle.

 

Another control group of five males and five females received the vehicles:

.            corn oil on day 1 the interscapular region,

.            ethanol/drinking water treated by reverse osmosis (80/20) on day 8 the interscapular region,

.            acetone on day 22 to the posterior left flank. The posterior right flank received the test item at 0.5%.

 

On day 1, three pairs of intradermal injections were performed in the interscapular region of animals:

.            Freund's Complete Adjuvant (FCA) diluted to 50% (v/v) with 0.9% NaCl,

.            test item in vehicle or vehicle alone,

.            test item in a mixture FCA/0.9% NaCl (50/50, w/w) or vehicle at 50% (w/v) in FCA/0.9% NaCl (50/50, v/v).

 

As in the preliminary tests, the highest well-tolerated concentration was shown to be non‑irritant after topical application, 0.5 mL of sodium lauryl sulfate at 10% (w/w) in vaseline was applied to the induction site on day 7 in order to induce a local irritation. On day 8, a filter paper (approximately 8 cm²) was fully-loaded with the dosage forms, and then applied to the clippedinterscapular region, over the intradermal injection sites. The filter paper was held in place by an occlusive dressing for 48 hours. The control group animalsreceived an application of the vehicle under the same experimental conditions. The presence of local irritation was checked (but not scored).

The induction phase was followed by a 14-day rest period. On day 22, a Finn Chamber filter paper was fully-loaded with the dosage forms. The chamber was held in contact with the skin by an occlusive dressing for 24 hours. The vehicle was applied to the left flank under the same experimental conditions. Cutaneous reactions were evaluated before treatment and 24 and 48 hours after removal of the dressing.

 Each animal was observed once a day for mortality and clinical signs during the treatment and observation periods. Body weight was recorded on day 1 and at the end of each observation period. On completion of the observation period, the animals were sacrificed then discarded without macroscopicpost-mortemexamination. For all animals, skin samples of the challenged application sites were preserved. If no histological examination is requested, the skin samples will be destroyed at the finalization of the study report. No microscopic examination was performed in first instance.

No unscheduled deaths occurred during the main test. No clinical signs indicative of systemic toxicity were observed in any animals. The body weight change of the test item-treated animals was similar to that of controls. In the control group, at the 24- and 48-hour readings, no cutaneous reactions were observed on the left flank (treated with vehicle) and on the right flank (treated with test item) of animals.

In the test item-treated group, at the 24-hour reading, a discrete or moderate erythema was noted at the right flank (treated with test item) of 6/20 animals. This was associated with edema in 1/6 affected animals. Erythema persisted in 5/6 animals at the 48-hour reading as well as edema.

At the 48-hour reading, a discrete or moderate erythema was observed at the right flank (treated with test item) of 9/20 animals.

In addition, dryness of the skin was noted at the right flank (treated with test item) of 4/20 animals. The cutaneous reactions observed on the right flank (test item-treated) of the test item-treated group were of higher incidence and severity than those recorded on the right flank treated (test item-treated) of the control group. Therefore, these findings were considered to be attributed to delayed contact hypersensitivity.

Published data

Several publications reported different cases of contact dermatitis caused by amido amines derivatives used in cosmetic products (see paragraph 7.10.4 sensitisations data (humans)). Different experiments (patch-tests) were performed and seemed to incriminate the substance 3-dimethylaminopropylamine which is the main feedstock of all these products and can be found as impurity afterward or degradation product.

Therefore, taking into account the overall data, it was decided by a conservative approach to classify the test item as moderate skin sensitizer (category 1 and sub-category 1B) and assigned the signal word "warning" and the hazard statement "H317: May cause an allergic skin reaction".

Migrated from Short description of key information:
Two skin sensitizing studies in Guinea Pigs according to Magnusson and Kligman are available. In the first study, the test item does not induce delayed contact hypersensitivity. In the most recent GLP study, the test item induced delayed contact hypersensitivity in 9/20 (45%) guinea pigs . Public literature data reportthat some cases of contact allergy to N-[3-(dimethylamino)propyl]-C18 unsaturated-alkylamide (unsaturated C18) have been observed in humans probably due to the presence as impurity of 3-(dimethylamino)propylamine which is classified skin sensitizer category 1 in anex VI table 3.1 of regulation (EC) No 1272/2008.

Therefore, taking into account the overall data, it was decided to classify the test item as moderate skin sensitizer (category 1 and sub-category 1B) and assigned the signal word "warning" and the hazard statement "H317: May cause an allergic skin reaction".

Justification for selection of skin sensitisation endpoint:
A weight of evidence approach has been performed with two well conducted studies indicating contradictory results and data found in the public literature.

Respiratory sensitisation

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information:

N-[3-(dimethylamino)propyl]-C18 unsaturated-alkylamide (unsaturated C18) is a liquid with a vapour pressure around 1.78 10-7 Pa at 25°C (EPI suite estimation). Also the use of this substance will not result in aerosols, particles or droplets of an inhalable size, so exposure to humans via the inhalatory route will be unlikely to occur.

Migrated from Short description of key information:
N-[3-(dimethylamino)propyl]-C18 unsaturated-alkylamide (unsaturated C18) is a liquid with a vapour pressure around 1.78 10-7 Pa at 25°C (EPI suite estimation). Also the use of this substance will not result in aerosols, particles or droplets of an inhalable size, so exposure to humans via the inhalatory route will be unlikely to occur.

Justification for classification or non-classification

According to the criteria of CLP Regulation, the test item is classified as moderate skin sensitizer (category 1 and sub-category 1B) and assigned the signal word “warning” and the hazard statement “H317: May cause an allergic skin reaction”. According to Directive 67/548/EEC, the test substance should be classified as skin sensitisation and have the risk phrase "R43: may cause sensitisation by skin contact.

There are no concerns for respiratory sensitisation.