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Description of key information

Toxicokinetics data from studies conducted with structurally similar benzyl C12-16 alkyl dimethyl ammonium chloride under in vitro and in vivo condition suggests that coco alkyl trimethyl ammonium chloride has a low bioaccumulation potential and only small fraction is absorbed and distributed over the body. Therefore, a 10% absorption factor was considered for the purpose of chemical safety assessment for both oral as well as dermal routes. Therefore, a 10% absorption factor was considered for the purpose of chemical safety assessment for both oral as well as dermal routes. Experimental toxicokinetics data on C12-C16 ADBAC, show dermal and gastro-intestinal absorption to be limited and rapid excretion of the parent compound via the faeces (over 50%) with only a small amount excreted via the urine. Four major metabolites were identified as oxidation products of the decyl side chains to hydroxy and hydroxyketo derivatives which suggests that this is the only metabolism to have occurred.  All metabolites were more polar and presumed less toxic than the parent compound. To corroborate the experimental findings, a metabolism prediction tool MetaPrint2D-React (metabolic site predictor) (ECETOC TR 116, November 2012) was run to compare the predicted results with the experimental results. The results of the prediction tool showed that the oxidation of the alkyl chain shown in the experimental data matches with the one of the metabolism or transformation reactions suggested by the metaprint2D tool. Similar results were obtained for TMAC using the MetaPrint2D-React (metabolic site predictor). The most frequently reported site for metabolism was at the terminal two carbon positions of the longer alkyl chain. The most common transformation reactions occuring at the terminal two carbon atoms of TMACare hydroxylation, oxidation (including carboxylation, ketonization, unsaturation), dealkylation and demethylation reactions.

Key value for chemical safety assessment

Bioaccumulation potential:
low bioaccumulation potential
Absorption rate - oral (%):
10
Absorption rate - dermal (%):
10
Absorption rate - inhalation (%):
100

Additional information

Metaprint2D-React tool reported that the most frequent reactive sites for all the TMACs (except C16-18 and C18-unsatd. TMAC having an extra metabolism siteat the two adjacent carbons on either side of the unsaturation)and the ADBACs (having an extra metabolism site at the para-position of the benzene ring) occurs at the terminal two carbon positions of the longer alkyl chain.These two reactive sites most likely undergoe different types of Phase-I metabolism transformation reactions (including oxidation, hydroxylation, alkylation, methylation, demethylation, dealkylation) and/or conjugation reactions such as glutathionation. The C16-18 and C18-unsatd. TMAC additionally undergoes reduction, epoxidation, epoxidation/hydroxylation, tautomerization, hydroxylation/ tautomerization, hydration transformation reactions at the site of unsaturation. The para-position of the benzene ring in the ADBACs undergoes hydroxylation, methoxylation and glutathionation transformation reactions.

The most frequently reported site of metabolism in tricetylmethylammonium chloride and lauryltrimethyl ammonium bromide) is also at the terminal two carbon atoms. Like the TMACs, the common transformation reactions occuring at the terminal two carbon atomsinclude hydroxylation, oxidation (including carboxylation, ketonization, unsaturation), dealkylation and/or demethylation reactions.

A guideline compliant toxicokinetic study was conducted with structurally similar substance benzyl C12-16 alkyl dimethyl ammonium chloride. Rats were treated with single and repeated oral doses (50 or 200 mg/kg bw) as well as single dermal dose of 1.5 or 15 mg/kg bw. Following single and/or repeated oral dose, the plasma, blood and organ radioactivity levels were essentially non-quantifiable indicating a low oral bioavailability. The actual fraction of the oral dose absorbed was about 8% (urine and bile fractions); this was eliminated rapidly, essentially within a 48 to 72 h period. Majority of the oral dose was excreted rapidly in the faeces. At the high oral dose-level only, quantifiable levels of radioactivity (2,386 to 23,442 ng-eq/g) were found in some central organs at 8 h post-dosing; otherwise, the vast majority of the dose was confined to the intestines and levels decreased over time. Only about 4% of the oral dose was eliminated in the bile in a 24 h period of which about 30% during the first 3 h. Following single dermal application, the plasma and blood radioactivity levels were non-quantifiable at nearly all time-points. For the 1.5 mg/kg bw group, around 2% and 43% of the dose was eliminated in the urine and faeces, respectively, mostly within a 48 h period, suggesting that the dermal dose was highly absorbed via the skin. However, as the test site was not protected with an Elizabethan collar during the main part of the collection period, this may have been due to the animal licking the test site. This is also supported with the finding that after oral dosing only about 4% was excreted via bile back to intestine, and 4% excreted via urine. If similar routes of excretion are expected for dermal absorbed doses, it would not be possible to find levels of 50% of applied doses in intestine with only 2% excreted via urine. This indicates that about 50% of the dermal applied dose was taken up orally after all, which following the same oral kinetics leads to the 2% excretion in urine as indeed was observed. At 24 h post-dosing, most of the radioactivity was in the "stripped" skin (dermis/epidermis) application site (15.02/8.74% [male/female] and 33.8/24.2% of the dose for the high and low dose groups respectively) and intestines for both dose levels (5.76/8.32% and 5.61/7.79% of the dose for the high and low dose groups respectively), though some radioactivity was in the skin adjacent to the application site and minor traces were in the eyes (both most likely from cross-contamination due to grooming). At 168 h, levels in the application site of the individual animals of the low dose were 5.19 to 9.21% of the radioactive dose, suggesting the skin acted as a drug reservoir. In the stratum corneum of the application site, the levels of radioactivity were of similar magnitude in the different layers at each time-point. For all tissues/organs, the radioactivity levels essentially decreased over time (Appelqvist T, 2006).

 

A guideline study was carried out in Sprague-Dawley rats. 10 animals per sex per group were treated with radiolabelled test substance. The study was conducted in four phases: Experiment 1: single low dose (10 mg/kg); Experiment 2: single high dose (50 mg/kg); Experiment 3: 14-d repeated dietary exposure with non-radiolabelled test substance (100 ppm) and single low dose of radiolabelled (14C) test substance (10 mg/kg), Experiment 4: single intravenous dose (10 mg/kg). Following the single doses or the last dietary dose, urine and faeces were collected for 7 d. Tissues, urine and faeces were collected and analysed for radioactivity and faeces were analysed by TLC, HPLC and MS for metabolites and parent compound.

Following oral administration, radiolabelled test substance was rapidly absorbed, although in very limited amount, consistent with its highly ionic nature. Residual14C in tissues was negligible after administration of radiolabelled test substance by gavage both after single and repeated dosing, indicating low potential for bioaccumulation. After i.v. administration a higher amount of radioactivity (30−35%) was found as residue in the tissues.

About 6−8% of orally administered test substance is excreted in the urine whereas, 87−98% was found in the faeces. Since no data on bile duct-cannulated rats are available, it is not possible to conclude if this radioactivity accounts exclusively for unabsorbed test substance or not. However, the i.v. experiment showed that 20−30% was excreted in the urine and 44-55% in the faeces, suggesting that both the kidney and liver are capable of excreting test substance once adsorbed and that absorption is higher than the % found in the urine after oral administration.

Less than 50% of orally administered test substance is metabolised to side-chain oxidation products. In view of the limited absorption of the test substance, the 4 major metabolites identified may be at least partially formed in the gut of rats, apparently by microflora. No significant difference in metabolism between male and female rats or among the dosing regimens was observed. Repeated dosing did not alter the uptake, distribution or metabolism of test substance, Selim S (1987). Dermal absorption:

A guideline compliantin vitrostudy was conducted to determine the dermal absorption of the test substance. Split-thickness human skin membranes were mounted into flow-through diffusion cells. Receptor fluid was pumped underneath the skin at a flow rate of 1.5 mL/h. The skin surface temperature was maintained at approximately 32°C. A barrier integrity test using tritiated water was performed and any skin sample exhibiting a permeability coefficient (kp) greater than 2.5 x 10-3 cm/h was excluded from subsequent absorption measurements. 

Two test preparations containing [14C]- radiolabelled test substance (i.e., 0.030% and 0.300%), were applied at an application rate of 10 mg/cm2. Absorption was assessed by collecting receptor fluid in hourly intervals from 0-6 h post dose and then in 2-hourly intervals from 6-24 h post dose. At 24 h post dose, the exposure was terminated by washing and drying the skin. The stratum corneum was then removed from the skin by 20 successive tape strips. All samples were analysed by liquid scintillation counting.

 Following topical application of [14C]- radiolabelled test substance in low (0.03%, w/w) and high (0.3%, w/w) concentration test preparations to human skinin vitro, the mean absorbed dose and mean dermal delivery of [14C]- radiolabelled test substance were 0.05% (<0.01 μg equiv./cm2) and 2.22% (0.07 μg equiv./cm2) of the applied dose for the low concentration test preparation, respectively, and 0.03% (0.01 μg equiv./cm2) and 2.16% (0.67 μg equiv./cm2) of the applied dose for the high concentration test preparation, respectively. The stratum corneum acted as a barrier to absorption, with the mean total unabsorbed doses (recovered in skin wash, tissue swabs, pipette tips, cell wash, stratum corneum and unexposed skin) of 96.80 and 94.68% of the applied dose of [14C]- radiolabelled test substance for the low and high concentration test preparations, respectively. The maximum fluxes for the low and high doses were 0.12 ng equiv./cm2/h and 0.74 ng equiv./cm2/h, respectively, at 2 h.