2,3-epoxypropyltrimethylammonium chloride

Dermal absorption

Administrative data

Endpoint:

dermal absorption in vitro / ex vivo

Type of information:

other: EU Risk assessment report

Adequacy of study:

other information

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: see 'Remark'

Remarks:

Although the EU risk assessment report is secondary literature, all data and risk assessment for the human, health and the environment have been evaluated and reviewed by Finland prior to publication. The risk assessment report has been submitted to final approval and published in the Official Journal of the European Union C157/10 dated on 21.06.2008. Thus, it is considered the information reported are reliable with the restrictions that reliability of the data presented has not been assessed again.

Cross-reference

Reason / purpose for cross-reference:

reference to same study

Data source

Reference

Reference Type:

publication

Title:

European Union Risk Assessment 2,3-epoxypropyltrimethylammonium chloride CAS RN 3033-77-0 Einecs No: 221-221-0

Author:

EC

Year:

2008

Bibliographic source:

Risk Assessment. Final approved version. Rapporteur: Finland (FIN). European communities. Printed in Italy. 147pp

Materials and methods

Test material

Test material information

Constituent 1

Reference substance name:

(3-chloro-2-hydroxypropyl)trimethylammonium chloride

EC Number:

222-048-3

EC Name:

(3-chloro-2-hydroxypropyl)trimethylammonium chloride

Cas Number:

3327-22-8

Molecular formula:

C6H15ClNO.Cl

IUPAC Name:

3-chloro-2-hydroxy-N,N,N-trimethylpropan-1-aminium chloride

Radiolabelling:

yes

Administration / exposure

Details on study design:

The tests were conducted using four concentrations: 0.1, 1, 20 and 65% CHPTAC in water. 14C-testosterone was used as the reference compound.
The amount of radioactivity in the receptor fluid and the residual radioactivity remaining in the skin and the stratum corneum 48-h post exposure
were determined. Samples were prepared so that the labelled and non-labelled test substances were mixed to give a concentration of 2.46 MBq of the radiolabel and the above mentioned CHPTAC percentages.
The human skin sample was obtained from a 51-year female after abdominal surgery. The sample was taken to the laboratory within one hour of dissection and directly after that the skin placed in culture. Mouse skin was taken from a 10-week-old male NMRI mouse. Subcutaneous fat was removed and part of the human skin was removed until the thickness was about 0.5 mm. The measured thicknesses were: mouse skin 0.437±0.08 mm, human skin 0.531±0.043 mm. A two-compartment model was used so that the basal membrane was in contact with the receptor fluid and the stratum
corneum was exposed to the air. A glass ring was glued to the skin membranes, which left an internal area of 0.64 cm2 for the test substance, which was applied 10 ul/cm2. The absorption was measured for 48 hours, during which the viability was monitored by the presence of lactate in the
receptor fluid. Receptor fluid samples (500 ul of total 1200 ul) were collected at 1, 2, 4, 6, 8, 20, 24, 28, 44 and 48 hours, except for the 20 % dose.
The controls were sampled for lactate at 4, 8, 20, 28 and 48 hours. After the sampling of receptor fluid, fresh fluid was added to restore the original volume. The cumulative absorption was determined by calculating the sum of sampled radioactivity. Flux constant is defined as DCTx-Ty/(x-y),
where the numerator is the increase in penetrant concentration during the linear portion of the curve and where x refers to the beginning and y to
the end of linear portion of the curve. The permeability coefficient (Kp = flux constant [ug x cm-2x h-1]/applied concentration [ug/cm-3]) was
determined using tritiated water. To determine mass balance, the remaining test substance was removed with cotton swabs and the stratum corneum was isolated by tape stripping at the end of the study. The remaining skin membrane was digested with KOH and the receptor fluid was collected.
Using scintillation counting the total radioactivity was measured in each compartment separately.

Results and discussion

Any other information on results incl. tables

In the viable human skin membranes, the amount of radioactivity in the skin after tape stripping was between 0.5 and 6.8 fold higher than the amount in the receptor fluid. In mouse skin, the amount of radioactivity was 5.3 to 17.6 times lower than the amount of radioactivity in the receptor fluid. The mean recovery of radioactivity was between 91.2 and 102.2 % in mouse and human skin membranes.

Table 7.1.2 a Results of the skin permeation study in mouse skin

Concentration of CHPTAC	65%	20%	1%	0.1 %
Kp-values [cm h-1]	0.026	0.107	0.065	0.151
Flux constants μg cm-2 h-1	18.5	21	0.61	0.15
Relative absorption (% in receptor fluid)	13.9	40.9	22.6	43.6
Mean total abosrption (% of the radioactivity present in the receptor fluid, the receptor compartment wash and the skin (excluding tape strips)	13.0	44.9	29.2	45.0
Mean total abosrption (% of the radioactivity present in the receptor fluid, the receptor compartment wash and the skin (including tape strips)	13.1	45.2	30.8	50.3

Table 7.1.2 b Results of the skin permeation study in human skin

Concentration of CHPTAC	65%	20%	1%	0.1 %
Kp-values [cm h-1]	0.0005*10-3	0.0009*10-3	0.0015*10-3	0.0022*10-3
Flux constants μg cm-2 h-1	0.36	0.18	0.014	0.002
Relative absorption (% in receptor fluid)	0.053	0.148	0.534	0.685
Mean total abosrption (% of the radioactivity present in the receptor fluid, the receptor compartment wash and the skin (excluding tape strips)	0.46	0.46	3.74	5.79
Mean total abosrption (% of the radioactivity present in the receptor fluid, the receptor compartment wash and the skin (including tape strips)	0.8	1.8	15.2	14.2

Applicant's summary and conclusion

Conclusions:

Based on the findings in the in vitro skin penetration assay, a maximum penetration rate of 0.685 % was reached in the human skin.

Executive summary:

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.