N,N-dimethylpyridin-4-amine

Endpoint summary

Description of key information

The substance is considered irritating to the skin, based on a weight of evidence.  Experimental data indicate it causes serious damage to eyes, and it is considered to be corrosive to the respiratory tract.

Key value for chemical safety assessment

Skin irritation / corrosion

Endpoint conclusion

Endpoint conclusion:

adverse effect observed (irritating)

Eye irritation

Endpoint conclusion

Endpoint conclusion:

adverse effect observed (irritating)

Respiratory irritation

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

The data are conflicting concerning the in vivo corrosion of DMAP. The substance is corrosive and lethal on abraded skin of rabbits. However a 4 hour exposure on intact skin of rabbits seems to be tolerated. This behavior seems to be similar in guinea pigs.

DMAP was not irritating to the skin in the U.S. Department of Transportation (DOT) protocol, after 3 min, 60 min and 4 hours occlusive exposure on intact skin rabbit (Fitzgerald, 1991). The classification criteria for DOT “corrosive” clearly state the duration of the exposure and the condition of the skin; the substance does not meet the criteria for classification as a corrosive. As the 4 hour exposure is similar to the exposure conditions of the OECD skin irritation test (OECD 404) except for occlusive rather than semiocclusive patches, it can also be evaluated as non-irritating.

A second irritation study (Fitzgerald, 1992, K1) according to a more aggressive protocol gives positive results. The U.S. Federal Hazardous Substances Act (FHSA) identifies corrosive and irritant substances using a protocol with occlusive exposure of 0.5 g of the test chemical on both intact and abraded skin of rabbits, for a duration of 24 hours. The result for DMAP is definitive corrosion, with necrosis, at all sites in both intact and abraded skin. In addition, the rabbits did not survive the 4-hour application period, supporting the finding that DMAP is toxic (fatal) by the dermal route.

Early study results by industrial scientists add information to the evaluation of DMAP irritation potential. Using a scientifically valid protocol which predates establishment of GLP and guideline methods, a single rabbit was exposed to a 50% aqueous solution of DMAP under occlusive bandage in intact skin for up to 24 hours. However, the integrity of the skin might be challenged, as it is stated that the “entire body is shaved 24 h prior to application”. The one animal was noted as deceased the next day, but without signs of dermal irritation (Dow Chemical Company, 1976, K2).

A study at the Eastman Kodak Company (1981, K2) found that moist DMAP via occlusive exposure to the skin of guinea pigs resulted in moderate edema with necrosis, and, at 14 days from the exposure day, scarring, alopecia and some hemorrhagic bands at the periphery of the exposure site. These dermal symptoms are identified by Regulation EC No. 1272/2008 as evidence of healing after necrosis, and these constitute a designation of Category 1 Corrosive. However, this occurred under occlusion in guinea pigs, not the standard species (rabbit) used for classification purposes. DMAP was evaluated by the study authors as being a strong skin irritant.

In a GLP Buehler sensitization test using Hartley guinea pigs (Fitzgerald, 1992, K1), the induction conditions were occlusive patch testing of solutions (w/v) of DMAP, occlusive testing for 6 hours/day, once per week for 3 weeks. Preliminary screening found moderate to severe irritation at 24-72 hours after application at 100% concentration, and no irritation at 50% concentration. The main test was performed at 50% (w/v). No erythema or edema or other toxicity was observed in the induction or challenge phases of the study, and DMAP was not sensitizing.

The pH of an aqueous DMAP solution is alkaline, and increases with increasing concentration, perhaps due to formation of a nonahydrate. The pH of DMAP (0.1 mg/ml and 100 mg/ml in distilled water, measured at Charles River Laboratories Ltd, UK (CRL)) were found to be 10.23 and 11.89, respectively. This was confirmed by Vertellus Specialties Inc., (readings of 10.09 and 11.42, respectively). The solubility limit of DMAP is 76 mg/ml per Vertellus Specialties Inc., with a measured pH of 11.28. Classification criteria for in vitro pH assessment of corrosion according to the CLP regulation is discussed in ECHA, 2015, Technical guidance on Information requirements, Part B, Endpoint Specific Guidance, R7and in Regulation EC No. 1907/2006, Annex VII, Section 8.1.1, Column 2. If pH is the only criteria used, then an undiluted substance displaying a pH > 11.5 is considered to be corrosive.  This becomes a less critical factor in a weight of evidence approach with in vivo data (ECHA, 2015, R.7.2-2).

The weight of evidence leads to a conclusion that DMAP (dry, not in aqueous solution) is not corrosive to intact skin after 4 hours exposure. When exposure conditions become more extreme (under occlusive patches for more than 4 h) and in concentrated aqueous solutions, DMAP can become corrosive. Facilitating dermal absorption via abrading the skin increases the incidence of lethality of the substance and may have an impact on the incidence of localized corrosion and tissue necrosis.

Experimental data (Dow Chemical Company, 1976, K2) in a study which predates OECD protocols and GLP) indicate DMAP causes serious irreversible damage to the eyes of a single guinea pig. It is considered corrosive to the eyes. 

There are no studies on respiratory irritation of DMAP.

Justification for selection of skin irritation / corrosion endpoint:
weight of evidence from several studies

Justification for selection of eye irritation endpoint:
experimental in vivo data

Effects on skin irritation/corrosion: irritating

Effects on eye irritation: corrosive

Justification for classification or non-classification

The substance is irritating to the skin and is classified as a Category 2 for skin. It is classified as Category 1, corrosive to the eyes, according to Regulation EC No. 1272/2008.