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Reference
Endpoint:
dermal absorption
Type of information:
other: QSPR
Remarks:
Based on an established human skin model by Potts and Guy (Potts RO and Guy RH (1992). Predicting Skin Permeability. Pharm. Res. 9(5): 663-669)
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
accepted calculation method
Principles of method if other than guideline:
The physicochemical parameters of MW, Log P and saturated aqueous solubility have been used in the evaluation of 56 methacrylate compounds. An output of predicted steady-state flux was calculated using the principles defined in the Potts and Guy prediction model. (Potts RO and Guy RH (1992). Predicting Skin Permeability. Pharm. Res. 9(5): 663- 669)
GLP compliance:
no
Specific details on test material used for the study:
N-[3-(dimethylamino)propyl]-2-methylacrylamide / 5205-93-6 / 226-002-3, pure substance
Species:
other: human skin model
Details on test animals and environmental conditions:
not applicable; in silico modelling
Type of coverage:
other: not applicable; in silico modelling
No. of animals per group:
not applicable; in silico modelling
Absorption in different matrices:
predicted flux 151.3 μg/cm²/h; the relative dermal absorption is high

Based on a molecular weight of 170.25 g/mol and a g Kow of 0.5, the predicted flux of DMAPMA is 0.351 μg/cm²/h; the relative dermal absorption is low.

Conclusions:
The dermal absorption of DMAPMA is predicted to be high; the predicted flux is 0.351 μg/cm²/h.
Executive summary:

The dermal absorption (steady-state flux) of DMAPMA has been estimated by calculation using the principles defined in the Potts and Guy prediction model.

Based on a molecular weight of 170.25 g/mol and a logKow of 0.5, the predicted flux of DMAPMA is 0.351 μg/cm²/h; the relative dermal absorption is low.

Description of key information

Key value for chemical safety assessment

Bioaccumulation potential:
no bioaccumulation potential

Additional information

1.1                     Toxicokinetics (absorption, metabolism, distribution and elimination)

1.1.1               Non-human information

Experimental studies of the toxicokinetics of N-Dimethylaminopropyl methacrylamide are not available.

 

Physico chemical properties of the substance will enable qualitative judgements of the TK behaviour (Guidance on information requirements and chemical safety assessment Chapter R.7.c, R.7.12 Guidance on Toxicokinetics):

 

In general with a log Pow of 0.5 N-Dimethylaminopropyl methacrylamide absorption must be expected. (log Pow values between -1 and 4 are favourable for absorption). With a pKa of 9.2 the substance will be existent predominately in the protonated ionic form. The substance is highly soluble in water, the molecular weight is 170 and it is identified as a skin sensitizer.

 

Absorption

 

GI absorption

Substances with a molecular weight below 500, high water solubility and a log Pow between -1 and 4 are favourable for absorption. As N-Dimethylaminopropyl methacrylamide has ionisable groups in the molecular structure and a pKa of 9.2 the substance will primarily be in the protonated form under the conditions of the gastrointestinal tract. Therefore it does not readily diffuse across biological membranes. Alternatively the substance can be absorbed in the GI tract through aqueous pores or will be carriaged across membranes with the bulk passage of water (small molecules with a molecular weight up to around 200).

 

 

Respiratory absoprtion - Inhalation

The vapour pressure of N-Dimethylaminopropyl methacrylamide is only 0.4 Pa (substances with low volatility have a vapour pressure of less than 0.5 kPa)

As the log Pow of the substance is 0.5 and log Pow values between -1 and 4 are favourable for absorption in the respiratory tract, fractional absorption through the respiratory tract must be predicted. Otherwise the water solubility is very high that the substance will be retained within the mucus and may be transported out of the respiratory tract and will be swallowed.

 

Inhalation is not the favoured route of absorption.

 

Dermal absorption

The dermal absorption (steady-state flux) of DMAPMA has been estimated by calculation using the principles defined in the Potts and Guy prediction model (Heylings 2013). Based on a molecular weight of 170.25 g/mol and a logKow of 0.5, the predicted flux of DMAPMA is 0.351μg/cm²/h; the relative dermal absorption is low.

As N-Dimethylaminopropyl methacrylamide has been identified as a skin sensitizer and shows low, but measurable acute dermal toxicity, uptake to the skin must have occurred.

Some dermal absorption must be expected but it is not estimated to be the favoured route of absorption. All in all GI absorption is the favoured route of absorption but diffusion will be lowered by the reason of the ionized molecule.

Distribution

As the substance is highly soluble in water and ionized under the conditions of blood it will diffuse through aqueous channels and pores. With a log Pow of 0.5 (> 0) the molecule is sufficiently lipophilic to distribute into cells.

Accumulation

Accumulation is not expected as the log Pow is far below 4.

Metabolism

No experimental data are available of the metabolism of N-[3-(Dimethylamino) propyl] methacrylamide. If the substance is absorbed an important pathway for the metabolism in Phase I will be the hydrolysis of the amide into Methacrylic acid and the corresponding amine. While the acid is further metabolised via the valine pathway of the citric acid cycle (ECETOC, 1995, European Union 2002) the diamine may be further oxidised and the nitrogen will be eliminated via urea.

Excretion

As the molecular weight of N-Dimethylaminopropyl methacrylamide is below 300, the substance is little ionized and hydrophilic, the substance itself and its metabolites will be excreted by the kidneys though a small amount may enter the urine directly by passive diffusion and there is the potential for re-absorption into the systemic circulation across the tubular epithelium.

1.1.2               Human information

No human information is available

1.1.3               Summary and discussion of toxicokinetics

Respiratoric and dermal absorption of N-Dimethylaminopropyl methacrylamide are reduced due to hydrophilicity and molecular weight of the substance. GI absporption is the favoured route of absorption but diffusion will be lowered by the reason of the ionized molecule. The molecule is sufficiently lipophilic to distribute into cells. Accumulation is not expected. The substance itself and its metabolites will be excreted by the kidneys.