2,3-epoxypropyltrimethylammonium chloride

Endpoint summary

Description of key information

Short description of key information on absorption rate: 
Read-across strategy with (3-chloro-2-hydroxypropyl)trimethylammonium chloride.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Absorption rate - dermal (%):

0.685

Additional information

Basic toxicokinetics

Basic physico-chemical characteristics are available, which can be used to estimate toxicokinetic behaviour.

The molecular size of EPTAC is relatively small (MW 151.5 g/mol), which can be a facilitating factor in absorption through membranes. Dermal absorption

through passive diffusion could be expected to be low because the molecule is charged. Data from toxicological tests show that at least some absorption occurs via the gastro-intestinal (GI) tract and skin. Being a small molecule, it is possible that EPTAC pass through G-I tract membranes by passive penetration through aqueous pores at the tight junction. Findings from acute dermal toxicity data indicate that absorption occurs via the dermal route. More importantly, an in vitro skin penetration study is available for CHPTAC, a substance which has a closely related molecular structure. This allows also the assessment of the skin penetration properties of EPTAC. EPTAC can enter lungs as a residue in cationised starch dust. Theoretically, EPTAC could enter lungs also in water solution as aerosol particles. Depending on the particle size various parts of the respiratory system could be affected. The majority of big (> 10 μm) dust particles would probably stay in the nasopharyngeal mucous membranes. There, the residual EPTAC could dissolve in the mucus and be directly absorbed to blood circulation or it could be carried to the pharynx where it might enter the gastrointestinal tract. Smaller (<1 μm) particles could enter the tracheobronchial or alveolar space of the lungs where the substance could be released and enter the blood or be removed by the lymph circulation.

Distribution of EPTAC from vascular space to extracellular or intracellular compartment is probably slow due to the poor membrane passing quality. It may be possible for EPTAC to pass from the vascular space to the extracellular or intracellular compartment via aqueous pores. Entrance into fat is expected to be slow because of the low lipid/water partition coefficient [log Pow = -1.23].

Because EPTAC has a highly electrophilic epoxy group the metabolism is likely to occur mainly in the liver either via hydrolysis by an epoxide hydrolase or phase 2 enzymes, viz. different conjugation reactions such as glutathione S-transferases. These hydrophilic products are normally excreted effectively into urine.

Dermal abosrption

CHPTAC’s percutaneous absorption was examined in this study, which used a 2-14C radiolabelled CHPTAC and viable human and mouse skin membranes (TNO, 2003). The results of this study can serve as a worst case estimate for EPTAC as well. Because EPTAC is slightly more polar and is likely to bind to a higher extend to the stratum corneum due to its reactive epoxide function than CHPTAC, it is therefore likely that in human skin a lower amount is dermally absorbed to lower layers of the skin and systemically available.

Based on the findings in the in vitro skin penetration assay, a maximum penetration rate of 0.685 % was reached in the human skin. Since it is recommended by the TGD that the dose retained is the skin should also be taken in consideration 5 % would then be more appropriate (0.685+ (0.685 x 6.8)). However, this factor does not take into account the amount retained in the stratum corneum. Accounting for the amount retained in the stratum corneum the average absorbed ranged between 0.1-15 %. Taking the highest percentage retained in the stratum corneum would probably be too conservative, due to factors like exfoliation, washing and other processes in which the substance is lost to outside. Moreover, the epidermal uptake is likely to occur slowly because of high water solubility (>800 g/l) and a log P of less than zero. Therefore, an absorption percentage of 6 % will be taken for the risk characterisation.

Discussion on bioaccumulation potential result:

Basic physico-chemical characteristics are available, which can be used to estimate toxicokinetic behaviour. The molecular size of EPTAC is relatively small (MW 151.5 g/mol), which can be a facilitating factor in absorption through membranes. Dermal absorption

through passive diffusion could be expected to be low because the molecule is charged. Data from toxicological tests show that at least some absorption occurs via the gastro-intestinal (GI) tract and skin. Being a small molecule, it is possible that EPTAC pass through G-I tract membranes by passive penetration through aqueous pores at the tight junction. Findings from acute dermal toxicity data indicate that absorption occurs via the dermal route. More importantly, an in vitro skin penetration study is available for 3 -chlorohydroxypropyltrimethylammonium chloride (CAS 3327 -22 -8) (CHPTAC), a substance which has a closely related molecular structure. This allows also the assessment of the skin penetration properties of EPTAC. EPTAC can enter lungs as a residue in cationised starch dust. Theoretically, EPTAC could enter lungs also in water solution as aerosol particles. Depending on the particle size various parts of the respiratory system could be affected. The majority of big (> 10 μm) dust particles would probably stay in the nasopharyngeal mucous membranes. Therefore, the residual EPTAC could dissolve in the mucus and be directly absorbed to blood circulation or it could be carried to the pharynx where it might enter the gastrointestinal tract. Smaller (<1 μm) particles could enter the tracheobronchial or alveolar space of the lungs where the substance could be released and enter the blood or be removed by the lymph circulation.

Distribution of EPTAC from vascular space to extracellular or intracellular compartment is probably slow due to the poor membrane passing quality. It may be possible for EPTAC to pass from the vascular space to the extracellular or intracellular compartment via aqueous pores. Entrance into fat is expected to be slow because of the low lipid/water partition coefficient [log Pow = -1.23].

Because EPTAC has a highly electrophilic epoxy group the metabolism is likely to occur mainly in the liver either via hydrolysis by an epoxide hydrolase or phase 2 enzymes, viz. different conjugation reactions such as glutathione S-transferases. These hydrophilic products are normally excreted effectively into urine.

Discussion on absorption rate:

CHPTAC’s percutaneous absorption was examined in this study, which used a 2-14C radiolabelled CHPTAC and viable human and mouse skin membranes (TNO, 2003). The results of this study can serve as a worst case estimate for EPTAC as well. Because EPTAC is slightly more polar and is likely to bind to a higher extend to the stratum corneum due to its reactive epoxide function than CHPTAC, it is therefore likely that in human skin a lower amount is dermally absorbed to lower layers of the skin and systemically available.

Based on the findings in thein vitroskin penetration assay, a maximum penetration rate of 0.685 % was reached in the human skin. Since it is recommended by the TGD that the dose retained is the skin should also be taken in consideration 5 % would then be more appropriate (0.685+ (0.685 x 6.8)). However, this factor does not take into account the amount retained in the stratum corneum. Accounting for the amount retained in the stratum corneum the average absorbed ranged between 0.1-15 %. Taking the highest percentage retained in the stratum corneum would probably be too conservative, due to factors like exfoliation, washing and other processes in which the substance is lost to outside. Moreover, the epidermal uptake is likely to occur slowly because of high water solubility (>800 g/l) and a log P of less than zero. Therefore, an absorption percentage of 6 % will be taken for the risk characterisation.